Deutsche Gesellschaft fur Klinische Neurophysiologie und Funktionelle Bildgebunge. V. (DGKN)

Clinical Neurophysiology 116 (2005) e25–e132 www.elsevier.com/locate/clinph

Society Proceedings

Deutsche Gesellschaft fu¨r Klinische Neurophysiologie und Funktionelle Bildgebung e. V. (DGKN) Jena, 15–19 September 2004

The abstracts (1–333) have been published before in Klinische Neurophysiologie by Thieme Verlag (03/September 2004, ISSN 1434-0275). The abstracts submitted in German are left out according to Journal policy. The following abstracts are corrected: 25, 153, 230, 286, 287, 289, 302. The following abstracts are added and placed at the end: 334, 335, 336, 337.

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SPG3: Towards Understanding the Function of the Disease Protein Atlastin 1—Abel A1, Herrmann C2, Auburger G3 (1Frankfurt, 2Bochum, 3Frankfurt) Approximately 10% of all autosomal dominant spastic paraplegia cases are caused by mutations in the large GTPase atlastin 1. Atlastin 1 is a 558 aa transmembrane protein localized to the Golgi apparatus with both the large N-terminal GTPase domain and the short C-terminus being directed towards the cytoplasm. To date 19 missense mutations distributed throughout the protein and one frameshift mutation have been identified, yet the function of atlastin 1 in motoneurons and the disease mechanism are still poorly understood. For this reason we are interested in (1) identifying physiological interactors of atlastin; (2) the influence of different mutations on the enzyme activity and guanine nucleotide affinity of this enzyme. In a Y2H screen with the 63 aa long C-terminal domain we have identified a weak interactor, which is possibly involved in neuronal mRNA processing. Besides a similar expression profile, our confocal microscopy studies in cos-7 cells transfected with HA-tagged atlastin showed partial colocalization of atlastin 1 with this endogeneously expressed interactor in the Golgi apparatus. We also have purified both wildtype and mutated atlastin 1 as GST fusion protein, and will present preliminary data on GTP hydrolysis and binding assays performed in a collaborative effort. doi:10.1016/j.clinph.2005.05.002

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Non-Linear Closed Loop Control and System Identification to Induce Coordinated Finger Movements with Repetitive Peripheral Magnetic Stimulation (RPMS)— Angerer B1, Schro¨der D2, Struppler A3 (1Mu¨nchen, 2 Mu¨nchen, 3Mu¨nchen) The therapeutic effect of the RPMS can be increased by a closed loop control to induce coordinated movements in the forearm and the (index) finger since these movements elicit a quite physiological proprioceptive inflow to the CNS. To induce coordinated movements the main task is to develop a closed loop control for a single movement. In the view of control technology the control loop is non-linear and time varying and cannot be treated with standard (linear) control methods. Hence the capabilities of system identification are used to take non-linear characteristics into account, while the RPMS is applied. Such characteristics are the position and orientation of the stimulation coil, the concomitant muscle fatigue, the spasticity, the remaining voluntary activity and the recovery. The system identification achieves an appropriate model of muscle contractions induced by RPMS by minimizing the difference between the measured contraction and the modeled contraction. The recruitment characteristic and dynamics (results of the system identification) are used to compensate the non-linear recruitment due to RPMS. Together with a proportional (for adequate dynamics) plus integral (to guarantee steady state accuracy due to spasticity and remaining voluntary activity) controller, a closed loop control to induce a single movement is achieved. The PI controller calculates such a stimulation intensity, so that the desired position (of the index finger) is reached. To enhance the closed loop control, the stimulation frequency is also adapted according to the variation of the PI controller output. This leads to a more efficient stimulation and a much more physiological proprioceptive inflow to the CNS. To induce coordinated movements the closed loop control is implemented for each single movement. In combination with desired trajectories (measurement results form healthy subjects) this leads to coordinated movements induced by RPMS. As will be presented, the accuracy of the system identification and therefore the quality of the closed loop control depends highly on the remaining voluntary activity. Hence, it is essential to take the voluntary activity into account. For this purpose an RPMS-artifact suppressing EMG amplifier has to be developed. With EMG and the system identification, the voluntary and the induced activity

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can be distinguished. Hence it is possible to quantify the therapeutic outcome while the RPMS is applied.

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Impedance Measurements and Tissue Characteristics of the Human Brain: Real-Time Impedance Monitoring During Stereotactic Procedures—Axer H1, Gra¨ssel D2, Fitzek S3, Fitzek C4, Jansen RH5, von Keyserlingk Graf D6, Witte OW7 (1Jena; 2Jena; 3Jena; 4Jena; 5Aachen; 6 Aachen; 7Jena) Impedance measurements in intact cerebral structures of human cadaver brains were performed to analyze the potential of this method to verify the position of the needle during a stereotactic intervention. Experiment 1: impedance measurements were performed at 24 selected points in human cadaver brains. The points were labeled using DiI. The texture of the nerve fibers was visualized using confocal laser scanning microscopy, which allowed classification of distinct anatomical regions in the white and gray matter according to their fiber structure. These regions displayed characteristic differences in impedances according to their fiber structure at frequencies between 8000 and 10,000 Hz. The reference frequency used in clinical environments (50,000 Hz) is not useful for distinct localization purposes. Finally, the orientation of the electrode in relation to the tissue is a crucial factor. Experiment 2: using a vector network analyzer, transmission and reflection coefficients were measured from 500 MHz to 18 GHz in four formalin-fixed human brains. The positions of the electrodes were marked, and the tissue was histologically stained to visualize the myelo- and the cytoarchitecture as well as the nerve fiber orientation at the electrodes. The profiles of the transmission coefficients showed characteristic minimum peaks. In order to describe these peaks, a mathematical function was fitted. Parameters derived from digital image processing were used to characterize the myelo- and cytoarchitecure of the tissue at the electrodes. A multiple regression model, with the frequency at the transmission peak minimum as a dependent variable and two tissue characteristics at the two electrodes as independent variables, showed a multiple regression coefficient of 0.765. A neural network model was able to estimate the frequency at the transmission peak minimum from the tissue characteristics at the electrode. Conclusions: The measurements of dielectric properties are well suited to differentiate distinct intracerebral structures. The method could be used for online monitoring of the needle’s position during a stereotactic intervention in neurosurgery.

diseases by means of a high resolution ultrasound system (HDI 5000 and 15–7 MHz-Compact-Linear-Broadband-Scanhead from Advanced Technology Laboratories, Washington, USA). Results: We found only in the three infants with SMA type I the well-known rhythmic and synchronous movements of groups of muscle fibers (fasciculations) as well as a turmoil of arrhythmic and asynchronous twitches of single muscle fibers. Conclusions: By means of high resolution ultrasound it was possible to detect movements of even single muscle fibers. The turmoil of single muscle fibers was very impressive. But we do not think the term fibrillations are right. Fibril is the diminutive form of fiber and myofibrils are the contractile filaments of muscle fibers. That is why we suggest the term fibrations. This term is derived from fiber, because we are not able to see movements of myofibrils but rather of single muscle fibers by the new ultrasound technique. Acknowledgements: We thank the local group of the German Society for Patients with Muscle Diseases (Deutsche Gesellschaft fu¨r Muskelkranke e.V.) in Elmshorn for financial support and we thank the departments for gynecology and pediopathology of Kiel University Hospital for technical support.

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Lateralization of Pupillary Light Reflex Parameters— Ba¨r KJ1, Bo¨ttger MK2, Till S3, Dolicek J4, Sauer H5 (1Jena; 2Jena; 3Jena; 4Jena; 5Jena) The aim of this study was to determine differing reactions of the left and right eyes with regard to pupillary light reflex (PLR) parameters. All together 90 healthy subjects were included. In the first test series, 34 subjects were investigated on both eyes (left eye was tested first, three tests per day and one reliability test). In the second test series, 32 subjects were studied while changing the beginning side. In the last test series, 29 subjects were investigated 12 times each within one hour (beginning side changed/switched/alternated, without spoken advice/instruction). Infrared pupillometry was used to study pupil diameter, latency time, relative amplitude, contraction/dilation velocity, and pupil redilation time. The study demonstrated significant differences of PLR parameters between both eyes. In contrast to the pupil diameter of the left eye the parasympathetically dominated right eye was not influenced by vocal instructions and by changing the beginning side. PLR parameters might indicate functional lateralization of autonomic function in the central nervous system. High sensitivity of the procedure (arousal, time of day) is advantageous for various psychophysiological investigations.

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Detection of Single Muscle Fiber Movements (Fibrations) in SMA Type I by High Resolution Ultrasound— van Baalen A1, Stephani U2 (1Kiel; 2Kiel) Introduction: Movements of a group of muscle fibers innervated by a single motor unit (fasciculations) are detected by clinical inspection, electromyography and ultrasound. Up to now movements of single muscle fibers are realized just by electromyography and can be called fibrillations. We tried to analyze single muscle fibers by a new ultrasound technique and that was when we saw movements of single muscle fibers. Method: We examined three infants with spinal muscular atrophy (SMA) type I and typical deletion in the survival motor neuron (SMN) gene and ten children with other neuromuscular

Loss of Efferent Vagal Activity in Acute Schizophrenia— Ba¨r KJ1, Letzsch A2, Jochum T3, Wagner G4, Greiner W5, Sauer H6 (1Jena; 2Jena; 3Jena; 4Jena; 5Jena; 6Jena) Increased heart rate has been reported in schizophrenia. It is unclear whether this is due to disease-related autonomic nervous system changes or a side effect of antipsychotic medication. Altered cardiac autonomic function might to some extent account for the elevated cardiovascular mortality rate of schizophrenic patients. We assessed heart rate variability (HRV) in 30 acute unmedicated schizophrenic patients and matched controls. Patients were re-investigated 2–4 days after initiation of treatment to assess effects of medication. Our study demonstrates that schizophrenic patients were significantly different in heart rate (increase) and parasympathetic parameters (loss of efferent vagal activity) at rest

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and during deep respiration. No significant effect was found after initiation of neuroleptic therapy. We found a correlation between duration of disease and parasympathetic parameters as well as very low frequency power (VLF) and delusion (SAPS subscale). These data suggest that schizophrenia is accompanied by a loss of vagal efferent activity, probably due to disturbed cortical–subcortical circuits modulating the autonomic nervous system in acute psychosis. The definite mechanisms by which vagal activity might be suppressed in schizophrenia are unknown. Parasympathetic hypoactivity might increase the risk for sudden cardiac death and arrhythmias in this disease. Future studies are warranted to investigate the interaction between cardiac autonomic function and schizophrenia and to identify patients at risk.

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Pain Perception in Depression Depends on the Site of Stimulation—Ba¨r KJ1, Brehm S2, Wagner G3, Jochum T4, Sauer H5 (1Jena; 2Jena; 3Jena; 4Jena; 5Jena) Decreased sensitivity of depressed patients to experimentally induced pain in contrast to prevalent clinical pain complaints characterizes a paradoxical circumstance. The physiological basis of this phenomenon is elusive. Therefore, we applied a testing battery to both arms of subjects, including assessment of heat pain (threshold, tolerance), electrical pain and ischemic muscle pain. We investigated 30 patients suffering from a major depressive disorder and 15 patients with an acute stress disorder and matched controls to both groups. Results of pain testing were comparable in both disorders. While confirming hypalgesia to heat and electrical pain in major depression, we found hyperalgesia to ischemic muscle pain. This suggests that stimuli are processed differentially depending on the site of induction. Furthermore, we again found evidence for a lateralization of pain perception in depression. Further investigations are needed to explain this interesting discrepancy in order to treat pain complaints in depressed patients appropriately.

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Differential Activation of Visual Areas V1 and V5 by Pattern Reversal Stimulation-An MEG Study—Barnikol UB1, Dammers J2, Fieseler T3, Boers F4, Muren A5, Wuttich S6, Mohlberg H7, Hesselmann G8, Amunts K9, Zilles K10, Niedeggen M11, Tass PA12 (1Ju¨lich; 2Ju¨lich; 3 Ju¨lich; 4Ju¨lich; 5Ju¨lich; 6Ju¨lich; 7Ju¨lich; 8Du¨sseldorf; 9 Ju¨lich; 10Ju¨lich; 11Du¨sseldorf; 12Ju¨lich) We have studied the differential activation of visual areas V1 and V5 during early visual information processing in eight healthy subjects in a full-field pattern reversal task (black and white checkerboard). Magnetic fields were registered with a whole-head magnetometer system (Magnes 2500 WH, 4D-Neuroimaging) with 148 SQUIDS and averaged relative to stimulus onset. The underlying current source density was determined by means of the magnetic field tomography [1]. Brain areas displaying stimulus-locked responses were anatomically identified with anatomical probability maps [2]. Our approach revealed that V1 and V5 generate pronounced stimulus-locked responses. The time courses of the V1 and the V5 responses displayed a pattern which was consistent over all subjects: the averaged response in V1 was maximal at 109 ms (standard deviation nZ10 ms), whereas the maximum of the averaged response of V5 appeared at 168 ms after stimulus onset (standard deviation nZ11 ms). Our findings

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contribute to assess the functional role of the different parallel pathways activating V5. References Ioannides AA, Bolton JPR et al. Continuous probabilistic solutions to the biomagnetic inverse problem. Inverse Problems 1999; 6: 523–542. Amunts K, Malikovic A et al. Brodmann’s area 17 and 18 brought into stereotaxic space—Where and how variable? NeuroImage 2000; 11: 66–84.

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Treatment of Neuropathic Pain: Old Concepts and Novel Advances—Baron R1 (1Kiel) The medical management of neuropathic pain consists of five main classes of oral medication (serotonin/norepinephrine reuptake blockers, Na-blocker anticonvulsants, Ca-blocker anticonvulsants, tramadol and opioids) and several categories of topical medications for patients with cutaneous allodynia and hyperalgesia (capsaicin and local anaesthetics). In many cases an early combination of compounds affecting different mechanisms is useful. Antidepressants: the effectiveness of tricyclic antidepressants (TCAs) in neuropathic pain may account for their broad range of pharmacological actions. In a recent controlled trial of venlafaxine hydrochloride, which blocks both serotonin and norepinephrine re-uptake, and imipramine hydrochloride in patients with painful polyneuropathy, both antidepressants demonstrated superior pain relief compared with placebo but did not differ from each other. Anticonvulsants (Ca-channel blockers): for pregabalin, a new anticonvulsant, current controlled clinical trials show efficacy for postherpetic neuralgia (PHN) and diabetic painful neuropathy (DPN). Its mechanism is an action on the a2 d-subunit of neuronal calcium channels, which are involved in the allodynic response in animal models of neuropathic pain. The adverse effects include somnolence and dizziness and mild peripheral edema, especially during the early treatment phase. However, its generally excellent tolerability, safety, and lack of drug interactions and negative impact on cardiac function distinguish pregabalin from most other oral medications used for the treatment of chronic neuropathic pain. An advantage is its superior bioavailability, which makes it easier to use without the need of long titration periods. Anticonvulsants (Na-channel blockers): for lamotrigine there is evidence of efficacy in HIV sensory neuropathy, DPN, and central poststroke pain as well as in a subgroup of patients with incomplete spinal cord lesions. Carbamazepine is very effective in trigeminal neuralgia. However, the strength of evidence is much lower for the benefit of these drugs in other types of neuropathic pain. Long-acting opioids: several recent controlled trials have clearly demonstrated sustained efficacy of opioids in neuropathic pain states. Topical lidocaine: a second topical medication for neuropathic pain are local anaesthetics. Local anaesthetics block voltage-dependent sodium channels.

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Combined EEG and MEG Source Analysis of Interictal Epileptiform Activity in Childhood Epilepsy—Bast T1 (1Heidelberg) Purpose: MEG is used as a non-invasive tool in an increasing number of epilepsy patients in the context of a presurgical evaluation. However, few studies applied simultaneous surface EEG in the determination of potential epileptogenic zones. A

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combination of both methods offers a clear benefit, since MEG only detects activities from neurons with tangential orientation and the EEG signal is dominated by radial sources. Patients: we report on 21 children and adolescents with different forms of cortical lesions (FCD 9, PMG 7, other 5) and partial epilepsy. 6 patients presented with CSWS. Methods: 122-channel whole-head MEG and 32-channel EEG were recorded simultaneously for 25 to 40 min. Using the BESA program, interictal spikes were identified visually and used as templates to search for similar spatio-temporal spike patterns throughout the recording. Detected similar spikes (rO0.85) were averaged, high-pass filtered (5 Hz) to enhance spike onset, and subjected to multiple spatio-temporal source analysis. Source localization was visualized by superposition on T1-weighted MRI and compared to the lesion. Results and Discussion: Intrinsic epileptogenicity in FCD was demonstrated by both EEG and MEG source analysis, since all sources modelling the spike onset were localized within the lesion visible in MRI. There were no marked differences between EEG and MEG regarding onset time and localization observed. On the contrary, EEG spike onset preceded MEG significantly in 1/3 of the spike types in PMG. This was due to radial onset activity in EEG while MEG localized propagated activity, even leading to a wrong lateralization in one case. Discrepancies in MEG and EEG were explained by the lack of deep fissures in PMG. In CSWS, combined EEG and MEG source analysis demonstrated a unilateral onset within the lesional hemisphere followed by propagation to the contralateral hemisphere. Conclusion: EEG and MEG source analysis is a valuable noninvasive tool for analyzing interictal epileptiform activity in symptomatic childhood epilepsy.

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Intrinsic Epileptogenicity in Polymicrogyria: Loss of Deep Cortical Fissures Requires Simultaneous EEG ¨ zkan O2, with MEG Source Analysis—Bast T1, O 3 4 5 Ramantani G , Metzke T , Seitz A , Andre R6, Rating D7, Scherg M8 (1Heidelberg; 2Heidelberg; 3Heidelberg; 4 Heidelberg; 5Heidelberg; 6Heidelberg; 7Heidelberg; 8 Gra¨felfing) Purpose: Multiple source analysis of interictal EEG and MEG spikes was applied to the determination of potential epileptogenic zones in polymicrogyria (PMG). PMG is characterized by a marked loss of deep cortical fissures. Since MEG signals are predominantly generated from tangentially oriented neurons in fissures, an MEG/EEG discrepancy was assumed. Patients: we studied 7 patients (age 7.5 to 19 years) with localization-related epilepsy and unilateral polymicrogyria (PMG) as defined by anatomical MRI. Methods: 122-channel whole-head MEG and 32-channel EEG were recorded simultaneously for 25 to 40 min. Using the BESA program, interictal spikes were identified visually and used as templates to search for similar spatio-temporal spike patterns throughout the recording. Detected similar spikes (rO0.85) were averaged, high-pass filtered (5 Hz) to enhance spike onset, and subjected to multiple spatio-temporal source analysis. Source localization was visualized by superposition on T1-weighted MRI and compared to the lesion. Results: 9 spike types were identified in 7 patients (2 types in 2

patients). Sources modeling the spike onset activity were localized within the visible lesion in 8/9 EEG and 7/9 MEG spike types. MEG spike onset was significantly preceded by EEG in 3 spike types (19 to 28 ms). The radially oriented onset activity was shown by EEG, while MEG localized already propagated activity. This led to a mislocalization of the earliest MEG spike activity to the normal hemisphere in one case, while the preceding radial EEG onset activity was localized within the lesion. Distances between EEG and MEG onset sources varied between 9 to 47 mm in the 8 spike types with concordant lateralization. Conclusion: MEG was blind to the onset of radial interictal spike activity and localized propagated spike activity in several cases due to the lack of deep fissures in PMG. Simultaneous EEG/MEG recordings and multiple source analysis are required to avoid this problem. Intrinsic epileptogenicity in polymicrogyria is suggested by EEG and MEG interictal spike localization.

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Intraoperative Mapping of Vestibular Nerve Subdivisions by Electrical Stimulation—Basta D1, Todt I2, Ernst A3 (1Berlin; 2Berlin; 3Berlin) Vestibular evoked myogenic potentials (VEMPs) are neckmuscle EMGs which are evoked by high-level acoustic stimuli. Recent studies suggest that they are related to saccular hair cell activity and, thus, to inferior vestibular nerve fiber depolarization. The aim of the present study was to investigate if VEMPs, induced by direct electrical stimulation of the human vestibular nerve, are suitable for the intraoperative discrimination between the inferior and superior part of the vestibular nerve. The responses were compared to acoustically evoked VEMPs to evidence the vestibulocollic reflex arch and their saccular origin, respectively. Eight subjects were stimulated at the inferior branch of the vestibular nerve during cerebello-pontine angle surgery. Subdermal needle electrodes were placed in the middle of the sternocleidomastoid muscle (SCM) of both sides. The EMG signals of the SCM were recorded upon bipolar electrical stimulation (0.4–1.0 mA; 0.2 ms duration; 4.7 Hz). All subjects showed normal VEMPs upon acoustic stimulation with a latency (GSD) of 12.8G1.4 ms for P13, and 22.7G2.0 ms for the N23 preoperatively. Upon direct electrical stimulation of the inferior vestibular nerve (IVN), a linear correlation of the response amplitudes of VEMPs and the stimulus was found between 0.4 and 1.0 mA. The mean latency of the positive peak was 9.1G2.2 ms and 13.2G2.3 ms for the negative one. No contralateral SCM response was found. Electrical stimulation of the superior vestibular nerve did not result in any ipsi- or contralateral EMG response of the SCM. The method can be utilized to map VIIIth nerve subdivisions and to intraoperatively monitor IVth nerve integrity in a real-time mode.

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Functional Modulation of Neurotransmitter Receptors using PET Imaging—Bauer A1 (1Ju¨lich) Over the past two decades, there have been significant advances in the ability to study the neurochemistry of the living brain using neuroreceptor radiotracers with PET imaging. The greater availability of radiotracers for neurotransmitter synthesis/metabolism, enzymes, transporters and receptors, as well as neuromodulators and second messengers has enabled the evaluation of hypotheses regarding neurotransmitter function and regulation

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which are generated from basic neuroscience studies, and the investigation of the neurochemical substrates of neurological and psychiatric disorders. Fundamental observations have been made with respect to (1) detecting abnormalities in the availability of neurotransmitter transporter and receptor sites in neurological and psychiatric disorders; (2) evaluating the relationship of these neurochemical measures to symptomatology; and (3) assessing the magnitude of occupancy of the initial target sites of action of psychotropic medication relative to treatment response and drug concentrations. PET provides unique quantitative in vivo information to measure acute fluctuations of synaptic transmitter release and subsequent receptor occupation. These non-invasive studies span the pharmacokinetic/pharmacodynamic evaluation of potential drug candidates, receptor occupancy as an important determinant of efficacy, the pharmacological characterization of potential mechanisms of action, and the biological characterization of disease. PET neuroreceptor imaging combined with pharmacological challenges has been introduced to measure acute fluctuations of synaptic dopamine concentrations in the living human brain. Changes in the in vivo binding of radioligands following manipulation of transmitter levels are generally believed to be driven by binding competition between the radioligand and neurotransmitter. This imaging modality has been very successful in the study of dopamine transmission at D2 receptors. However, the extension of this technique to the study of other neurotransmitter systems has proven difficult. There is recent evidence suggesting that simple binding competition might not be the only phenomenon regulating transmitter-radioligand interactions in vivo. Emerging data indicate that receptor trafficking might also be involved. A better understanding of the mechanisms underlying these interactions should significantly increase our knowledge of neurotransmission and its pathological alterations.

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Hemispheric Asymmetry and Somatotopy of ShortLatency Cutaneomotor Inhibition in Healthy Humans—Ba¨umer T1, Helmich R2, Siebner HR3, Mu¨nchau AM4 ( 1Hamburg; 2Nijmegen; 3Kiel; 4 Hamburg) A conditioning electrical stimulus to a digital nerve can inhibit the motor response in adjacent hand muscles elicited by a supra-motor threshold transcranial magnetic stimulation (TMS) test stimulus to the contralateral primary motor cortex (M1) hand area when given 25 to 50 ms before the TMS pulse. Such sensorimotor inhibition is referred to as short-latency afferent inhibition (SAI). There is good evidence that SAI is mediated through sensory–motor interaction at a cortical level. In righthanded healthy volunteers, we studied inter-hemispheric differences and within-limb somatotopy of SAI in two experiments. In experiment 1, conditioning electrical pulses were applied to the right or left index finger and motor evoked potentials (MEPs) were recorded from relaxed first dorsal interosseus (FDI) and abductor digiti minimi (ADM) muscles ipsilateral to the conditioning stimulus. Conditioning electrical stimulation of the right index finger was more effective in producing SAI in ipsilateral intrinsic hand muscles than stimulation of the left index finger. In experiment 2, electrical stimulation was applied to the right index finger only and MEPs were recorded from ipsilateral FDI, ADM, extensor digitorum communis (EDC) and extensor digiti minimi (EDM) muscles (experiment 2a) or from

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right FDI, ADM and biceps brachii (BB) muscles (experiment 2b). Experiment 2a revealed that the amount of SAI did not differ between right FDI, ADM, EDC and EDM muscles. In contrast, in experiment 2b SAI was also present in right BB muscle but significantly smaller as compared to FDI and ADM muscles. These data demonstrate inter-hemispheric differences in cortical processing of cutaneous input from the hand with stronger SAI in the dominant left hemisphere. In addition, these results show that apart from intrinsic hand muscles adjacent to electrical digital stimulation SAI occurs to the same extent in distant hand and forearm muscles and is also present in proximal arm muscles, albeit less pronounced. This can be taken as evidence that SAI is not a focal and somatotopically specific phenomenon.

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Cerebral Activation Patterns of Tactile, Phasic and Tonic Painful Stimulation in Humans—Baumga¨rtner ¨ zcan M3, Bauermann T4, Treede RD5 U1, Sto¨ter P2, O 1 2 ( Mainz; Mainz; 3Mainz; 4Mainz; 5Mainz) Non-painful and painful stimuli are known to activate neighboring regions or even the same areas like the somatosensory cortices. Other activation areas seem to be predominantly, or exclusively, active when a stimulus is painful. In this fMRI study we compared different cerebral activation patterns evoked by three types of stimulation. 12 healthy subjects underwent a balanced series of (1) non painful tactile stimulation with a 128 mN vs. Frey hair, (2) phasic painful stimulation with a 128 mN pin prick stimulator, and (3) tonic painful stimulation using a thermode (temperature oscillation around the individual heat pain threshold, approx. 47 8C, duration 1 min). fMRI measurements were carried out on a 1.5 T system using a block design and an echo-planar imaging sequence based gradient echo sequence with 23 axial 5 mm slices covering the whole head. Statistical processing was done off-line using spm99 including motion correction and spatial normalization. Coordinates, T-values and the number of activated voxels were compared between the three conditions. The primary somatosensory cortex was activated during all conditions, most pronounced during pin prick stimulation. The posterior parasylvian cortex showed the strongest activation in all conditions, with a separate activation in the anterior parasylvian cortex most pronounced in thermal pain. The strong activation of anterior and posterior insula during heat pain was hardly present in the other two conditions. Activation of anterior cingulate cortex and thalamus was present during heat pain only. These activation patterns suggest that phasic pain is predominantly mediated through the lateral, and tonic pain through the medial pain system. Supported by the Deutsche Forschungsgemeinschaft (Tr236/13–3).

Dystonias—Benecke R1 (1Rostock) Dystonia is described as a motor syndrome characterized by involuntary prolonged muscle contractions causing sustained twisting movements and abnormal postures of affected body parts. The main characteristics of dystonia in surface EMG investigations are cocontractions of antagonistic muscles and

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overflow activities in distant muscles. Voluntary ballistic movements of affected body parts are slowed and the three-burst pattern in agonist and antagonist muscles is prolonged. A number of brainstem and spinal cord reflex investigations demonstrated an abnormal decrease of inhibitory interneuronal activity. The decrease of inhibitory action may contribute to the genesis of dystonia and the disturbance of voluntary movements but cannot be the main cause of dystonia because a decrease of inhibitory action can also be present in unaffected extremities of dystonic patients. Abnormalities of cortical function have been described in functional imaging and neurophysiological studies in patients with various forms of dystonia. Magnetic brain stimulation of the motor cortex revealed changes in motor cortical excitability and activity of intracortical inhibitory interneuronal activity. A decrease in surround inhibition is a modern hypothesis. Most probably, dystonia results from a functional disturbance within the basal ganglia either induced by lesions of basal ganglia or the thalamus including connection between them (secondary dystonias) or by genetically determined abnormalities of proteins with resulting abnormal neuronal activities without degeneration of the affected cells. Overuse dystonia may have a different physiological origin such as exaggerated use-dependent plastic changes within the sensorimotor cortex.

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Contralateral Activation of the Vestibular Cortex in Acute Vestibular Neuritis (FDG-PET Study)—Bense S1, Schlindwein P2, Prange K3, Buchholz HG4, Brandt T5, Bartenstein P6, Dieterich M7 (1Mainz; 2Mainz; 3 Mainz; 4Mainz; 5Mu¨nchen; 6Mainz; 7Mainz) Earlier positron-emission tomography (PET) water activation studies during caloric vestibular stimulation in healthy volunteers showed bilateral increases of the regional cerebral blood flow in several multisensory vestibular areas, e.g., the parieto-insular vestibular cortex in the posterior insula, adjacent temporoparietal areas such as superior temporal gyrus (BA22) and inferior parietal lobule (BA 40), posterolateral thalamus, and anterior cingulate gyrus. This bilateral activation pattern was modulated by two factors: (A) a dominance of the non-dominant hemisphere, (B) a predominant projection to the hemisphere ipsilateral to the stimulation. The aim of this fluorodeoxyglucose (FDG)-PET study was to determine how an acute peripheral vestibular loss right or left caused by vestibular neuritis (VN) influences this cerebral activation pattern. FDG-PET was performed in 16 right-handed patients (11 VN left; 5 VN right) twice: (A) in the acute phase of VN at day 6.5 mean after symptom onset and (B) after clinical recovery due to central compensation 3 months later. For PET scanning, patients were placed supine with the eyes closed without any stimulation. Subtraction analysis (A vs. B; B vs. A) was done with the SPM99b software (P%0.001). In the acute phase patients with vestibular neuritis right and left showed increased rCGM in the posterior insular region contralateral to the affected ear. Further rCGM increases were localized in the paramedian pontomesencephalic brainstem merging into the hippocampus and the thalamus. Within the cerebellum rCGM increases were found in the ipsilateral dentate nucleus and simple lobule as well as the contralateral tonsil. The asymmetry of multisensory vestibular cortex activation could be explained by assuming that the more

dominant ipsilateral ascending projections to the insular cortex are depressed by the lack of the tonic endorgan input due to vestibular neuritis. Alternatively or additionally, the tonus imbalance at the vestibular nuclei level (with a higher resting discharge rate of the unaffected vestibular nuclei complex) could mimic a contralateral vestibular excitation.

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Striatal Hypertrophy: A Mechanism for Preclinical Compensation in Parkin-Associated Parkinsonism?— Binkofski F1, Siebner HR2, Buhmann C3, Pramstaller P4, Hedrich K5, van Eimeren T6, Bu¨chel C7, Klein C8, Gaser C9 (1Lu¨beck; 2Kiel; 3Hamburg; 4Bolzano-Bozen; 5 Lu¨beck; 6Hamburg; 7Hamburg; 8Lu¨beck; 9Jena) 18 F-Fluorodopa (F-DOPA) positron emission tomography (PET) demonstrated a reduction of striatal F-DOPA uptake in asymptomatic carriers of heterozygous Parkin mutations, indicating a latent dopaminergic dysfunction in the basal ganglia. We used voxel-based morphometry of high-resolution structural magnetic resonance images in a comparable group of asymptomatic Parkin mutation carriers to investigate whether this latent dopaminergic dysfunction is associated with structural abnormalities in the motor system. Structural MR data (T1-weighted FLASH 3D MR sequences; TEZ5 ms; TRZ 15 ms; flip angleZ308; isotropic voxel size 1!1!1 mm3) of 13 right handed asymptomatic carriers of heterozygous mutations in the Parkin gene (eight females, mean age: 38.6G5.8 yrs, range: 28–47 yrs) were compared with those of 13 age-matched healthy controls. MR images were preprocessed and analyzed using SPM2 software (FIL, London, UK). We used an optimized protocol for voxel-based morphometry, which involves non-linear spatial normalization to a customized grey matter template. Images were smoothed with a Gaussian kernel 12 mm FWHM. Using a general linear model, voxel-by-voxel t-tests were computed to detect differences in grey matter volume between groups (significance threshold: P!0.01 and P!0.01 for cluster size; Gaussian Random Field theory). All asymptomatic carriers and controls had a normal neurological and neuropsychological examination. Voxel-based morphometry revealed a significant increase in grey matter volume in the left posterior putamen and globus pallidus internus (GPI) [Talairach coordinates: xZK25, yZ0, zZ3; SVC around the striatum PZ0.03, corrected (FDR)]. There was also a subthreshold increase in grey matter volume in the right GPI. The increase in grey matter volume in the posterior striatum showed a close spatial correspondence to the location of dopamine hypometabolism found in the comparable group of asymptomatic carriers in the previous F-DOPA PET study (Hilker et al., 2001). This colocalization may suggest that the increase in grey matter volume might represent a long-term consequence of adaptive plasticity in the basal ganglia. Such an increase in structure might help the motor system to compensate for the preclinical dopaminergic deficit and prevent the manifestation of minor motor symptoms (Brezard et al., 2003). The higher increase in the grey mater density in the left striatum indicates a higher amount of compensation for the dominant right hand.

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Improved Outcome of Microvascular Decompression for Hemifacial Spasm by Advanced Preoperative Imaging and Intraoperative EMG Monitoring of Lateral Spread—Bischoff B1, Naraghi R2, Romsto¨ck J3, Hastreiter P4, Strauss C5, Fahlbusch R6 (1Erlangen; 2 Erlangen; 3 Erlangen; 4 Erlangen; 5Erlangen; 6 Erlangen) Objective: MVD for hemifacial spasm still presents a challenge regarding postoperative outcome. Insufficient improvement in a great proportion of patients undergoing MVD for hemifacial spasm is a limitation for this treatment. The effect of a combination of preoperative imaging and intraoperative monitoring of lateral spread on the outcome is presented. Methods: From 1991 to 2004 a consecutive series of 33 patients with MVD for hemifacial spasm is analyzed retrospectively. Surgical technique consisted of a standard MVD in all cases. In 15 versus 18 cases lateral spread was monitored during surgery. Prior to surgery, depending on the available MRI technique, 17 patients received routine T1- and T2-weighted MRI, 16 received high resolution MRI with 3D-visualization. The immediate postoperative and the long-term outcomes were analyzed depending on the preoperatively and intraoperatively applied imaging and monitoring technique. Results: Patients without intraoperative monitoring had an immediate success rate of 11(18) and 13(18) on long term. 13 out of 15 patients with monitoring of lateral spread had an immediate postoperative relief of spasm. In the long term the success rate was 14(15). Correlated the outcome to the applied technology of imaging and image processing we found only 9(16) immediate relief and 11(16) long-term improvements in the group of patients with routine T1- and T2-weighted MRT and without monitoring of lateral spread. The combination of monitoring of lateral spread and advanced imaging resulted in an immediate relief in 13 out of 14 cases and long-term improvement in 13(14) as well. Conclusions: The positive effect of developing and introducing new technologies on the outcome of MVD for hemifacial spasm is demonstrated. The combination of preoperative advanced imaging technology and intraoperative monitoring of lateral spread can ensure favorable results by guiding the surgeon to the definite site of pathology.

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Headshape Digitization using an Ultrasound 3D Acquisition System—Boers F1, Fieseler T2, Muren A3, Tass PA4, Dammers J5 (1Ju¨lich; 2Ju¨lich; 3Ju¨lich; 4Ju¨lich; 5 Ju¨lich) Localization of neuromagnetic sources requires co-registration in order to map data registered by magnetoencephalography (MEG) onto the corresponding anatomic structure. Coregistration on the other hand often involves head shape digitization, which is usually carried out using a 3D digitization system that has a reference point, which is not fixed at the subjects head. Therefore, the major drawback of such systems is that head motion artefacts during the digitization process cannot be compensated. We instead use the Zebris 3D Motion Analyzer for headshape digitization outside the magnetically shielded room providing a much more comfortable measurement, especially for patients. The foremost advantage, however, is that this system makes use of a 3D ultrasound acquisition device providing three or more reference markers that can be fixed on

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the surface of the subject’s head. Using these reference markers we are able to compensate for any head movements during head shape acquisition. Furthermore, we developed a new 3D localization software to control the Zebris system that is now integrated in our MEG measurement environment (4D-Neuroimaging). With our software we automatically can check the quality of the digitization process, and it may also be used to localize attached head location coils or surface electrodes that are used for the MEG acquisition. Our tests show that the headshape digitization system works reliably and provides an acquisition accuracy of about 1 mm, while it automatically compensates for any head motion artefacts.

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Visualization of symmetric striatopallidodentate calcinosis by using a high-resolution susceptibility-weighted MR sequence—Bo¨ttcher J1, Reichenbach JR2, Sauner D3, Mentzel HJ4, Schmidt P5, Fitzek C6, Kaiser WA7 (1Jena; 2Jena; 3Jena; 4Jena; 5Jena; 6Jena; 7Jena) Purpose: Intracranial calcifications are routinely verified with computed tomography as high-density areas. In the diagnosis of intracerebral calcinosis, conventional MR sequences show inhomogeneous and individually varied signal changes. Furthermore, the quantification of intracerebral calcinosis is often inaccurate and undersized calcifications are usually overlooked. Otherwise MRI frequently proves to be the first diagnostic technique in the case of emergency, especially for the diagnosis of cerebral ischemia. Our study demonstrates the feasibility of high-resolution gradient-echo-phase images for the detection of intracerebral calcinosis and compares the MR visualization of undersized calcifications with CT. Methods: Conventional T1/T2w and FLAIR sequences as well as low-resolution EPI images were acquired on a 1.5 T MRI scanner (Siemens Vision, Erlangen). In addition a high-resolution susceptibility-weighted 3D-gradient-echo sequence with 80 slices of 2 mm thickness, TR/TE/NEX/alphaZ67/40/1/25 and 192!512 matrix with an in-plane resolution of 0.5!1.0 mm2 was used. Magnitude and phase images were reconstructed from the raw data set. Results: Generally T1/T2 and FLAIR sequences reveal in a different manner hypointense and hyperintense lesions in basal ganglia, thalamus and marginally regarding white matter, whereas T2w and FLAIR sequences are notably impaired by associated leukencephalopathy. Especially calcifications in both cerebellar hemispheres and nucleus caudatus are inadequately detected. EPI sequences substantially facilitate the verification of cerebellar and small cortical lesions, but are relevantly affected by spatial distortions. However, application of the new high-resolution, susceptibility-weighted MR sequence allows detailed visualization of intracerebral calcifications equally well as CT. Conclusion: Conventional MRI reveals calcifications as different and inhomogeneous signal changes on a limited scale, which depend on the stage of the disease, differences in calcium metabolism and the compound of these calcifications. Because of a substantial reduction of spatial distortions high-resolution susceptibility-weighted phase images ensure a more sensitive detection of undersized calcified areas in Fahr’s disease without any difference in comparison to computed tomography.

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How to See What you are Looking For in fMRI and PET-or the Crucial Baseline Condition—Brandt T1 (1Mu¨nchen) The conditions of eyes open or eyes closed in complete darkness have served as REST in human brain imaging studies. However, the mere transition from lid closed to lid open could theoretically cause non-trivial differential effects on brain activity without there being any change in external sensory stimulation or behavioral tasks. As a matter of fact, the lid drives the brain to regularly and repeatedly activate different cortical networks. The ocular-motor and attentional systems were activated when the eyes were open; in contrast, the visual, somatosensory, vestibular, and auditory systems were activated when the eyes were closed. These data suggest that there are two different states of mental activity: an ‘interoceptive’ state with the eyes closed which is characterized by imagination and multisensory activity, and an ‘exteroceptive’ state with the eyes open which is characterized by attention and ocularmotor activity [1]. In a subsequent study the impact of the chosen rest condition-eyes open or eyes closed in complete darkness—on the pattern of brain activations during visual stimulation was evaluated in healthy volunteers [2]. This showed that the choice of rest condition is critical for stimulus-induced brain activation pattern. Activity of the ocular-motor system as well as deactivation of sensory cortical areas may go undetected with eyes open as rest condition. References

Marx E, Stephan T, Nolte A, Deutschla¨nder A, Seelos KC, Dieterich M, Brandt Th. Eye closure in darkness animates sensory system. NeuroImage 2003; 19: 924–934. Marx E, Deutschla¨nder A, Stephan T, Dieterich M, Wiesmann M, Brandt Th. Eyes open and eyes closed as rest conditions: impact on brain activation patterns. NeuroImage 2004; 21: 1818–1824.

Imaging Genomics in Psychiatry—Braus DF 1 (1Hamburg) The Human Genom Project opened up unexpected opportunities to explore the genetic basis of individual differences of complex behavioural patterns and to identify factors of vulnerability for neuropsychiatric illnesses and their interaction with environmental variables. At the same time, the development of modern imaging methods offered new opportunities for noninvasive ways of characterising the brain, its microstructure (MRI, DTI), essential aspects of information processing (fMRI), and aspects of metabolism (MRS). On the behavioural level, neuropsychological methods have been developed, which allow improved characterising of cognitive and emotional processes. A combination of these three examination levels now allows to establish relationships between functionally relevant gene polymorphisms (e.g. 5-HTTPR, COMT val-met), emotional and cognitive processes and the neuronal networks and their connectivity as well as brain volume and metabolism. The first studies using this approach are very promising. They established for instance relationships between the function of the hippocampus-amygdala formation and polymorphisms of BDNF and 5-HTTPR, and between COMT and frontal brain functions respectively. It is interesting to note that all these relationships could be found in relatively small collectives, which did not differ on the behavioural level to a noticeable degree. This emphasises the advantage of a direct characterisation of the brain physiology

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by imaging methods when exploring the functional significance of genetic variants in psychiatry.

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Excitation and inhibition during motor cortex stimulation: A combined transcranial brain stimulation and event-related fMRI study—Brocke JH1, Schmidt S2, Irlbacher K3, Kraft A4, Naito A5, Brandt SA6 (1Berlin; 2 Berlin; 3Berlin; 4Berlin; 5Berlin; 6Berlin) What does the BOLD response tell us about excitation and inhibition? Current approaches of fMRI are limited by an ambiguity in correlating BOLD effects with either a predominant inhibitory or excitatory neuronal activity. Transcranial electrical cortex stimulation (TES) was combined with simultaneous fMRI to study the relationship between the activity of inhibitory and excitatory neuronal circuits and the thereby induced BOLD signal changes. In a previous contribution (DGKN 2003) we were able to show that TES will induce similar effects on the motor cortex to TMS if a particular direction of the current flow is applied. Transcallosal inhibition was induced with TES by applying a single stimulus to one cortex. This stimulation lead to an inhibition on the contralateral cortex. We used both single pulse and bilateral stimulation to study the inhibitory effects on resting and activated contralateral cortex and analysed the induced BOLD signal changes. Methodology included event-related fMRI which triggered transcranial stimulation and online recording of the electromyographic responses monitoring the inhibitory influence on discharging corticospinal neurons. Test stimulus and conditioning stimulus had an intensity of 120% of resting motor threshold to evoke a potential of 0.7 mVG0.45 mV. FMRI was performed at 3 Tesla (GE) using an EPI sequence (TRZ3 s, TEZ35 ms, FAZ908, voxel-sizeZ3.75!3.75!3 mm3, slicesZ15). Data was analysed with BrainVoyager 4.9 using ROI based event-related averaging. Results revealed that the test stimulus alone induce a positive BOLD response both in the ipsilateral (0.3 to 0.7% signal change) and contralateral (0.2 to 0.5% signal change) primary motor cortex. Interestingly, contralateral co-activation exactly matched to the previously identified location of the hand area. If a conditioning stimulus preceded the test stimulus then the resulting ipsilateral BOLD signal was significantly reduced compared to the test stimulus alone. Thus, we conclude that both excitatory and inhibitory effects will generally lead to an increased BOLD signal, but that increased inhibitory neuronal activity and reduced corticospinal output results in smaller increases in local signal intensity. Sponsored by the BMBF, Berlin NeuroImaging Centre

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Lamotrigine in Pediatric Epileptology: Long-Term Profile of Cognition and Vigilance in 120 Patients (the L-Child Project)—Brodbeck V1, Mu¨he C2, Armbruster S3, Weber G4, Jansen V5, Fietzek UM6, Heinen F7 ( 1Mu¨nchen; 2Mu¨nchen; 3 Mu¨nchen; 4Duisburg; 5 Mu¨nchen; 6Mu¨nchen; 7Mu¨nchen) Purpose: The aim of this study was to determine the long-term profile of cognition and vigilance under lamotrigine (LTG) monotherapy and add-on therapy over a mean period of 2.5 years. Methods: Retrospective data were acquired through (i) structured interviews with epileptologists and (ii) structured parent

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interviews. Data on LTG dosage, co-medication, seizure frequency, EEG, effects, adverse effects, and epidemiological data were collected and stored in a database. Improvement or worsening of cognition and vigilance were rated on a 5-point scale (1) before any treatment with LTG; (2) during the dose-in phase; (3) during the targeted dosage; and (4) during the individual optimal dosage. Here, we report the epileptologist’s rating. Results: NZ120 therapies (mono NZ20, add-on NZ100) were evaluated. Mean age of patients was 8.7 years, mean duration of treatment 2.5 years. Distribution of epilepsies was: idiopathic epilepsies 16%, symptomatic epilepsies 62%, unclassified epilepsies 22%. Cognition was not altered in 75% of cases, improved in 16% and worsened in 8% cases compared to the time before LTG. Vigilance was rated as unchanged in 80%, improved in 9% and worsened in 2%. Adverse effects were reported in 44%. 2 cases had severe adverse events, one patient experienced toxic hepatic failure, another petechiae. All adverse events were reversible. 26% dropped out before the optimal dosage range could be established. Conclusion: In the epileptologists’ view safe long-term profiles for cognition and vigilance can be observed under LTG therapy. Adverse effects were in almost all cases of mild character and always reversible.

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Volumetry of the Pituitary Gland: An Initial in vitro and in vivo MR Study—Burmeister HP1, Bo¨ttcher J2, Sauner D3, Hahn HK4, Mentzel HJ5, Fitzek C6, Reichenbach JR7, Kaiser WA8 (1Jena; 2Jena; 3Jena; 4 Bremen; 5Jena; 6Jena; 7Jena; 8Jena) Purpose: We have attempted to evaluate the reliability of a new volumetric technique for MR imaging applied on measurements of phantoms with defined volumes and the normal pituitary gland (PG) of healthy individuals. Methods: In nine males without a clinical history of pituitary abnormalities and in a phantom study we performed triplicate MRI measurements before and after repositioning for volumetry of the PG or the phantoms, respectively. Using a standard head coil on a 1.5 T scanner, a tilted sagittal T1w 3D magnetization-prepared rapid gradient-echo sequence was applied with TR/TE/alphaZ 15/5 ms/30, 256!256 matrix, 192 slices, 1 mm thickness and an isovoxel size of 1!1!1 mm3. For interactive segmentation, a semi-automated 3D-watershed transform was applied to the gradient image. Each segmentation took approx. 4 min. Volume was assessed by voxel counting. Results: Mean volume of the nine pituitary glands was 0.62 ml (SD: 0.02 ml) with variation coefficients (VC) between 2.68 and 6.32%, respectively. Furthermore, the intraobserver variability with four repeated volume analyses of an identical MRI measurement ranged from 1.44 to 3.67%. After intravenous administration of contrast medium, the volume calculation showed an overestimation because of reduced demarcation of PG. Reliable and precise results could be ensured up to a slice thickness of 1.8 mm, preferably by coronal scanning. The VC from the phantom volume measurements (0.3, 0.5, 0.9, 1.0 and 1.6 ml) only ranged from 0.49% (SD: 0.006 ml) to 1.98% (0.005 ml). Conclusion: Our initial results demonstrate a high reliability without a significant difference of volumetric measurement for our in vitro and in vivo studies. This method provides a precise volume estimation of PG up to a slice thickness of 1.8 mm and can improve

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the monitoring of PG volume in follow-up-studies after surgical or conservative treatment.

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The Cerebral Oscillatory Network of Writing—An MEG Study—Butz M1, Pollok B2, Gross J3, Dirks M4, Timmermann L5, Schnitzler A6 (1Du¨sseldorf; 2Du¨ssel3 4 5 dorf; Du¨sseldorf; Hamburg; Du¨sseldorf; 6 Du¨sseldorf) Writing is a highly overlearned and complex movement. Functional MRI studies showed the involvement of both cortical and subcortical structures. A characterization of the dynamic interplay between the structures involved in writing is lacking up to now. We studied simultaneously brain activity with magnetoencephalography (MEG) and muscle activity with surface electromyography (EMG) during writing in 11 healthy subjects. Taking the muscle activity as reference we localized brain regions involved in the writing task by using the analysis tool Dynamic Imaging of Coherent Sources (DICS) and characterized the dynamic interplay of these sources. Analysis revealed that writing involves a spatially distributed oscillatory network including the bilateral primary sensorimotor cortex, the ipsilateral cerebellum, the contralateral premotor and posterior parietal cortex and the contralateral thalamus. These cerebral sources are coherent with the muscles primarily at writing frequency (3–7 Hz), whereas the cerebral sources mainly show coherence at around 7–13 Hz. Our results show that writing is based on an extensive motor network. The involved brain regions are coherent at around 10 Hz. Therefore, our study supports the notion of a common motor frequency around 10 Hz.

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Influence of Voluntary Muscle Contraction on the Duration of the Silent Period Evoked by Transcranial Magnetic Stimulation—Chatzikonstantinou A1, Wo¨hrle J 2, Hennerici M 3 ( 1Mannheim; 2Mannheim; 3 Mannheim) Introduction: It is known that the duration of the silent period (SP) following transcranial magnetic stimulation (TMS) can be used as a measure of intracortical inhibition. Thus, the SP is used in the clinical routine and in many studies, e.g., in order to evaluate the prognosis of motor recovery after stroke or for examining the cortical excitability in epilepsy patients. In most studies using TMS, recordings of the SP are performed by asking the subjects to contract their muscles (e.g., the first dorsal interosseous muscle, FDI) with maximal or sub-maximal strength. However, a possible modulation of the SP depending on the grade of voluntary muscle contraction strength has not been sufficiently examined. If present, such a modulation could influence the assessment of the results of TMS examinations. The purpose of our study was to investigate the duration of the SP in the contralateral FDI with different levels of contraction strength. Methods: 6 young healthy subjects (i.e., 12 hemispheres) participated in this study. We used a focal stimulating coil, which was placed over the hand area of the primary motor cortex. After the motor hot spot of the contralateral FDI was identified, the motor threshold (MT) and the maximal voluntary contraction strength (MVC) were determined. TMS was performed with 25%, 50%, 75% and 100% of the MVC, using 120% and 150% of the MT. Contraction strength was controlled and made visible to both

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the subject and the investigator using a hydraulic pinch dynamometer which allowed comfortable pressure application by the finger tips. Results: Using stimuli with an intensity of 120% of the MT, no changes in the duration of the SP became apparent when the subjects contracted their muscles at the different strength levels. The mean SP values for all subjects (in ms, Gstandard deviation) were 110.8 (G36) for 25% MVC, 112.3 (G35) for 50% MVC, 105.6 (G28) for 75% MVC and 109.4 (G32) for 100% MVC. With stimulation using 150% of the MT, the duration of the SP tended to be longer when the force applied from the subjects was higher, but it did not reach significant levels (137.5G39 ms for 25% MVC, 147.3G36 ms for 50% MVC, 146.6G28 ms for 75% MVC and 153.1G42 ms for 100% MVC). Conclusions: The contraction strength does not influence the duration of the SP significantly. This may be explained by modulations of the intracortical inhibition taking place in relation with the changing innervation level of the target muscle.

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Predictive Value of Electrocorticography in Epilepsy Patients with Unilateral Mesial Temporal Sclerosis Undergoing Selective Amygdalohippocampectomy— Chen X1, Sure U2, Haag A3, Knake S4, Fritsch B5, Mu¨ller HH6, Becker R7, Hamer HM8, Rosenow F9 (1Marburg; 2Marburg; 3Marburg; 4Marburg; 5Marburg; 6Marburg; 7Seesen; 8Marburg; 9Marburg) Objective: We have attempted to evaluate the predictive significance of intraoperative electro-corticography (ECoG) in patients with unilateral mesial temporal sclerosis undergoing transsylvian selective amygdalohippocampectomy (sAHE). We presumed that ECoG-spiking restricted to the mesial structures supports the concept of a mesial temporal epileptogenic zone (EZ) whereas spikes recorded from the lateral cortex suggest a more extensive EZ which may not be appropriately treated by an sAHE. Methods: ECoG was recorded before and after resection in 22 patients with medication-resistant epilepsy and mesial temporal sclerosis without other structural lesions diagnosed by MRI and video-EEG monitoring. A standardized sAHE was performed, regardless of the ECoG findings. The follow-up was 12 months (nZ20) or 6 months (nZ2). The ECoG findings recorded from the mesiobasal temporal lobe (MTL) and the lateral temporal lobe (LTL) before and after sAHE were correlated with seizure outcome [Group 1: completely seizure free (Engel class Ia), group 2: not completely seizure free]. The main hypothesis which was tested using Fisher’s exact test was: ‘Patients with pre-resection spikes restricted to the MTL have a higher seizure-free rate than others (with LTL, MTLCLTL or no spikes)’. Results: Fifteen of 22 patients (68%) remained seizure free (Group 1). Of the remaining seven patients (Group 2) four were Engel class Ib or Ic, one was IIa and two were IIIa. Patients with preresection spikes restricted to the MTL (nZ11) more frequently remained seizure free (82%) as compared to the rest of the patients (55%). This difference was not statistically significant (PZ0.361). Two of 4 patients with LTL-spikes and 4 of 7 patients without preresection spikes were in group 1. The frequency of pre-resection spikes was not related to seizure outcomes. No correlation between the seizure outcome and the presence of persistent spikes recorded on postoperative ECoG was found.

Conclusion: Pre-resection ECoG may be helpful in the prediction of seizure outcome in patients undergoing sAHE for mesial temporal lobe epilepsy. Based on the data of this pilot study, a minimum n of 102 is needed to prove a 27% difference in outcome with a power of 80% using a two-sided test with a significance level of 0.05. In order to prove a 20% difference in outcome and assuming a less equal distribution into the ECoGresult groups, 220 patients would be necessary. Therefore, a consecutive prospective study would demand a multi-center design.

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Beyond localization: Strategies to analyze simultaneously acquired EEG and fMRI data in pain research—Christmann C1, Ko¨ppe C2, Braus DF3, Ruf M4, Flor H5 (1Mannheim; 2Mannheim; 3Hamburg; 4 Mannheim; 5Mannheim) Simultaneous measurement of fMRI and EEG promises new insights into the topography and temporal dynamics of cortical processes and a more precise understanding of the relationship between the two measures. Together with a detailed behavioral analysis, this allows for a better elucidation of cortical pain processing. We applied painful stimulation to 6 healthy subjects and acquired fMRI simultaneously to an EEG measurement. After stimulation, all subjects rated different stimulus properties and the individual situation in the scanner. By applying a principal component analysis to the behavioral data, 2 main factors were extracted, the 1st (F1) reflecting the physical properties of the stimulus, the 2nd (F2) the subject’s emotional situation in the scanner. Stimulus correlated BOLD effects were found in the primary and secondary somatosensory areas (SI and SII), the operculum, the insula, the supplementary motor area (SMA), the SMA proper, the cerebellum, and posterior parts of the anterior cingulate gyrus (ACC). In all subjects, neuroelectric source imaging revealed a contralateral source in the ACC and in all but one subject in SI. Sources in SII could be fitted in 3 subjects. While the second order fMRI analysis using F1 as predictor pointed to a cortical network, coarsely comparable to the first order analysis, using F2, the network was restricted to limbic and motor areas. Using dipole strength of the modeled source in SI as predictor, the network was restricted to SI. Over the course of the experiment the evoked BOLD signal change decreased in SI. Within the stimulation block, it decreased in SII from the first to the second third followed by an increase in the last third. In contrast, dipole strength of the ACC source decreased linearly over the experiment. Conclusion: the simultaneous measurement of pain evoked activity by EEG and fMRI results in concordant localizations in sensory and limbic structures. Differential habituation effects for sensory and limbic areas can be shown by fMRI and dipole analysis. The integration of the data reveals a close relationship of the two measures in primary sensory areas. Supported by the Deutsche Forschungsgemeinschaft (Fl 156/25–1)

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Declarative and Procedural Learning in Stroke, Parkinson’s Disease and Sleep Apnea—Clarenbach P1, Horstmann S2, Reinhold N3, Markowitsch H4 (1Bielefeld; 2Bielefeld; 3Bielefeld; 4Bielefeld) Introduction: Both declarative and procedural learning show significant benefits from sleep in healthy people. We were

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interested in challenging this finding in those patients displaying structural damages to cerebral areas important for declarative memory (temporal lesions due to stroke, nZ10) or non-declarative memory (diencephalic lesions due to Parkinson’s disease, nZ10) or chronic hypoxemic damage due to untreated sleep apnea (AHIO25/h, nZ17). The investigations of healthy controls paralleled those of patients. Methods: Daytime learning over 30 min, and 12 h (from 8 a.m. to 8 p.m.) was compared intraindividually to nighttime learning (from 8 p.m. to 8 a.m.) including a spectrum of declarative (Verbal Learning Test, Rey Osterrieth Complex Figure Test, Wechsler Memory Scale) as well as procedural tasks such as the reading of mirror printing as well as full recording of sleep by polysomnography in the nights ‘after learning’ and the nights ‘under learning’. Psychometric Results: Healthy volunteers showed significantly better results after nighttime learning than after daytime learning, which validates the experimental design of this study. All patients showed better learning over night than at day, i.e., their learning benefits from sleep in spite of structural or hypoxemic damage. This benefit, however, is not as great as in healthy volunteers. The sleep benefit in patients with ‘declarative lesions’ was significant for procedural learning only; in patients with nondeclarative lesions it was seen for declarative learning only, but this differential effect is below significance. In patients with untreated sleep apnea investigated until now it is not significantly lower than in controls. Polysomnographic Results: In comparison to the night ‘after learning’ the sleep pattern of the night ‘under learning’ shows no changes in healthy controls, a significant increase of stages 3C4 in stroke patients with lesions of declarative memory, almost significant increases of stage REMS in Parkinsonian patients with deficits of procedural memory. Results of learning in sleep after therapy with nCPAP are underway and will be presented.

Normal Aging: Cognition and the Brain—von Cramon DY1 (1Leipzig) In Paul Baltes words, the Janus head of aging is that we all wish to get old, but at the same time we do not wish to be old. With respect to the demographic development at least in the industrialized countries, we need a clear understanding of the problems involved in normal (sound) aging in addition to what we have learned about pathological aging. There are many social, psychological and neurobiological facets of normal aging, a few of them discussed in this contribution. The problem is looked at from the perspective of cognition (mainly executive functions), morphometry/stereology, and neuroimaging (functional MRI). Normal aging is a structurally heterogeneous brain process. Regional (areal) differences as well as differences in the agesensitivity of cerebral tissue components may or may not provide a plausible structural basis for understanding individually markedly differing profiles of functional (cognitive) deterioration with advancing age. It is stated that the frontal lobes seem to be affected by the process of normal aging both earlier than other brain areas and at a more rapid pace. Because neuroimaging can in principle provide rich empirical evidence on normal aging, functional MRI in elderly persons is briefly discussed with respect to potential age-sensitive changes of the hemodynamic response when making use of the standard BOLD contrast.

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Combined MEG and Cytoarchitectonic Data Imaging— Dammers J1, Barnikol UB2, Wuttich S3, Boers F4, Muren A5, Mohlberg H6, Amunts K7, Zilles K8, Tass PA9 (1Ju¨lich; 2Ju¨lich; 3Ju¨lich; 4Ju¨lich; 5Ju¨lich; 6Ju¨lich; 7 Ju¨lich; 8Ju¨lich; 9Ju¨lich) In most MEG and other functional imaging studies the meaning of an activated cortical area is usually interpreted in relation to the surrounding gyral and sulcal landmarks. In contrast, previous studies showed that such landmarks do not have a fixed relationship to cytoarchitectonic boundaries. Moreover, it is not possible to identify any cortical area from functional imaging or anatomical data alone. In our MEG research group we developed a dedicated software (ROIfinder) to automatically extract strong neural activations from the huge amount of time series of reconstructed current densities for all voxels. First the neuromagnetic activity is estimated by means of the magnetic field tomography (MFT) providing time courses of fully threedimensional cerebral current source density volumes with millisecond time resolution. We then apply the ROIfinder to search for strong neural activity within each whole reconstruction space that fulfils certain spatial and temporal connectivity requirements. However, it remains difficult to unambiguously attribute the underlying neuronal activity to its corresponding neuroanatomical structure. For this reason, the activation patterns are mapped onto MRI scans together with so-called probability maps providing information about the frequency of a given anatomical area being located at a given position in the stereotaxic space of the reference brain. Such maps were derived from cytoarchitectonic analyses of 10 human post-mortem brains that were transferred into the same space. Using a pattern reversal task experiment (black and white checkerboard) we demonstrate the feasibility of automatically extracted neuromagnetic activity that is mapped together with cytoarchitectonic probability maps. With this experiment we combine the necessary information from MEG data analysis, gyral and sulcal landmarks and cytoarchitectonic boundaries to better understand the meaning of neuromagnetic activations.

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Graphical User Interface for Reconstruction and Visualization of High-Resolution SusceptibilityWeighted MR Data—Deistung A1, Rauscher A2, Sedlacik J3, Reichenbach JR4 (1Jena; 2Jena; 3Jena; 4 Jena) Purpose: In recent years, BOLD-MR venography [1] (also named susceptibility-weighted imaging, SWI) has been established for the examination of tumors [2,3] and for studying physiological processes [4]. The creation of BOLD venograms starting from k-space data requires a combination of magnitude and phase information in a rather sophisticated manner. This has not been implemented in MRI scanners yet. Therefore, a platformindependent graphical user interface (GUI) has been developed for the generation and extensive analysis of SWI data. Materials and Methods: High-resolution 3D scans of the human brain of volunteers and patients were acquired with a firstorder flow compensated gradient echo sequence on a 1.5 T wholebody scanner using the headcoil (TRZ67 ms, TEZ40 ms, flip angleZ258, FoVZ256 mm (192 mm (64 mm, matrixZ512 (192 (64). IDL (RSI, Boulder, USA) was used for developing the GUI. The user interface allows a scanner-independent reconstruction of

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MR data beginning from k-space including zero filling, algorithms for reducing phase wraps (homodyne filter or an image-space phase unwrapping algorithm [5]) and the creation of specific phase masks computed from phase images and their multiplication with the corresponding magnitude images. Interactive creation of minimum intensity projections and ROI-based data analysis, e.g., for the comparison of scans acquired under different conditions, are included. Results and Discussion: The software-tool visualizes image data containing phase and magnitude information as well as DICOM data. It enables a very flexible reconstruction of data. The intuitively designed graphical user interface allows physicians and medical technicians to quickly generate venograms and to flexibly set reconstruction and analysis parameters. It can be extended and modified easily according to the user’s needs. Since the software is executed in the IDL-Virtual-Machine, a platform-independent usage without purchase of an IDL license is warranted. Conclusion: This software may help to make the wide range of possible applications of SWI more accessible to a larger number of users. References Reichenbach JR et al. NMR Biomed 2001; 14: 453–467. Haacke EM et al. Image Anal Stereol 2002; 21: 107–113. Barth M et al. Invest Radiol 2003; 38: 409–414. Sedlacik J et al. Eur Radiol 2004;1 4(2, Suppl.2): 298. Xu X et al. IEEE Transactions on Geosciences and Remote Sensing 1999; 37: 124–134.

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Relation between Discharge Rates on Needle Electromyography and Motor Unit Number Estimates in Leg Muscles—Dennebaum M1, Schulte-Mattler WJ2 (1Halle/Saale; 2Regensburg) Discharge rates of motor units on needle EMG depend on the number of motor units available for recruitment. We studied this dependence in extensor digitorum brevis (EDB) and tibialis anterior muscles (TA) in 21 healthy subjects, 24 patients with a neuropathy, and 6 patients with a myopathy. A strong non-linear correlation between the number of motor units and the discharge rate was found (EDB rZ0.79, P!0.001; TA rZ0.80, P!0.001). An increased discharge rate indicated a loss of motor units. The mean value of the maximal discharge rates was 11.5/s in the controls and 18.6/s in the patients with neuropathy in EDB muscles and 11.5/s in the controls, 12.5/s in the patients with neuropathy, and 11.2 in the patients with a myopathy in TA muscles, respectively. Maximal discharge rates also correlated with muscle strength, but did not depend on the gender. The correlation closely resembled the correlation previously found in hypothenar muscles. Thus, increased discharge rates may be used to estimate a loss of motor units in limb muscles.

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How are Mitochondrial Disorders Inherited?— Deschauer M1 (1Halle/Saale) Mitochondrial disorders are complex diseases that are due to defects in genes encoding for the respiratory chain. These genes are located not only in the maternally-inherited mitochondrial genome (mtDNA), but also in the nuclear genome as the majority of proteins that are important for respiratory chain function are encoded by nuclear DNA and subsequently imported into

mitochondria. Thus, in addition to a maternal mode of inheritance, autosomal recessive and dominant traits are apparent while some cases are sporadic. Mitochondrial disorders encompass a wide spectrum of clinical presentations commonly affecting the muscle and nervous systems. One syndrome can be due to different gene defects. For example, a common clinical presentation is progressive external ophthalmoplegia (PEO) that is frequently associated with single, large-scale deletions of mtDNA that are generally sporadic. However, PEO can also be caused by defects in nuclear genes (POLG, C10Orf2, ANT1) that are important in mtDNA maintenance resulting in autosomal inheritance, or by maternally-inherited point mutations of mtDNA such as the 3243AOG mutation that was originally identified in patients with MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes). MERRF syndrome (myoclonic epilepsy with ragged red fibers) is commonly due to the maternally-inherited 8344AOG mutation of mtDNA. The 3243AOG and 8344AOG mutations belong to the group of tRNA mutations that show remarkable phenotypical variability with occurrence of asymptomatic or oligosymptomatic maternal relatives with low levels of mutant DNA (heteroplasmy). Another common mitochondrial disorder is Leber’s hereditary optic neuropathy (LHON) that is also due to point mutations of mtDNA. There are three common mutations (11778GOA, 14484TOC, 3460AOG) that are found in 95% of the LHON patients. Families with LHON also show a maternal mode of inheritance but women are rarely affected, thus an X-chromosomal modifier gene has been postulated. Finally, Leigh syndrome (subacute necrotizing encephalopathy) is a frequent presentation of mitochondrial disease in children that is genotypically heterogeneous. Mutations of mtDNA (e.g., 8993GOT/C, 9176TOC, 13513GOA) result in maternally-inherited Leigh syndrome, while many cases harbor mutations in nuclear genes that are inherited recessively, notably in structural subunits of respiratory chain complex I and assembly proteins required for the biosynthesis of complex IV.

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Asymmetric Hemispheric Activations during 108 Lateral Gaze (fMRI Study)—Deutschla¨nder A1, Stephan T2, Wiesmann M3, Dieterich M4, Brandt T5 (1Mu¨nchen; 2 Mu¨nchen; 3Mu¨nchen; 4Mainz; 5Mu¨nchen) Functional MRI was used to study the differential effects of the direction of gaze on the visual and the ocular motor systems. Fixation of a target straight ahead was compared to fixation of a target 108 to the right and 108 to the left, and to eyes open in complete darkness in thirteen healthy volunteers. BOLD signal increases in fronto-parietal ocular motor and attentional structures were absent during central fixation eyes open and minimal during lateral fixation eyes open, which confirmed the earlier finding that these structures are already activated with open eyes in darkness. During lateral fixation, activations in early visual areas (calcarine sulcus) and deactivations in higher order visual areas (one ventral cluster in the lingual and fusiform gyri and one dorsal cluster in the postero-superior cuneus) were found predominantly in the hemisphere contralateral to the fixation target. Thus, the hypothesis is proposed that even during small gaze shifts into one visual hemifield, visual processing is performed predominantly in the hemisphere contralateral to the direction of gaze in head coordinates. This held true although the visual input, i.e., fixation

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of a single target, was the same in all fixation conditions. A further finding was an activation of the motion-sensitive area MT/V5 despite fixation of a stationary target, which is compatible with the perception of apparent target motion (autokinetic effect).

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Immediate Transcallosal Reorganization of the Somatosensory Cortex following Ipsilateral Anesthesia— Dieckho¨fer A1, Reminghorst U2, Gobbele´ R3, Buchner H4, Waberski TD5 (1Aachen; 2Aachen; 3Aachen; 4 Recklinghausen; 5Aachen) Long-term as well as immediate short-lasting cortical reorganization of the somatosensory cortex following an alteration of the peripheral sensoric input is well established. Sustained attention to the peripheral stimulation modulates the reorganization process. In this study we investigate if a temporary deafferentiation of the contralateral hand results in a different topical arrangement of the somatosensory evoked potentials (SEP) following digit stimulation. SEPs were recorded following electric stimulation of digit D1 and D5 at the left hand before and after anesthesia was applied to D2–D4 at the right hand. Simultaneously to anesthesia the subject was asked to turn his/her attention (i) to the right, (ii) to the left or (iii) to neither hand. Source reconstruction of the N20 component was based on a 96-channel arrangement. Location and 3D-distance of the reconstructed electric sources representing D1 and D5 were compared before and after anesthesia. Before anesthesia we found the expected somatotopic organization of the somatosensory cortex. After anesthesia a significant enlargement of the 3D-distance could be shown for the three different conditions. In particular the cortical representation of the thumb shifted towards the front, along the gyrus postcentralis. A significance of this shift could be demonstrated for the conditions (iii) without spending attention to the stimulation and (ii) when turning attention to the hand being electrically stimulated. The topical reorganization of the somatosensory cortex occurs immediately after interrupting the sensoric input from the hand contralateral to the stimulated side caused by a transcallosal mediated disinhibition. This effect can be modulated by shifting spatial attention.

Pathophysiology of Spasticity—Dietz V1 (1Zu¨rich) Following central motor lesions, two forms of adaption can be observed which lead to improved mobility: (1) the development of spastic muscle tone (for review, see Dietz, 2002), and (2) the activation of spinal locomotor centers induced by specific treadmill training (Dietz et al., 1994; for review, see Dietz and Harkema, 2004). Tension development during spastic gait is different from that during normal gait and appears to be independent of exaggerated monosynaptic stretch reflexes. Exaggerated stretch reflexes are associated with an absence or reduction of functionally essential polysynaptic reflexes. When supraspinal control of spinal reflexes is impaired, the inhibition of monosynaptic reflexes is missing in addition to a reduced facilitation of polysynaptic reflexes. Therefore, overall leg muscle activity becomes reduced and less well modulated in patients with spasticity. Electrophysiological and histological studies have shown that a transformation of motor units takes place following central motor lesions with the consequence that regulation of muscle tone is achieved at a lower level of neuronal organization, which in turn, enables the patient to walk. Based on observations of the locomotor capacity of the spinal cat, 41

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recent studies have indicated that spinal locomotor centers can be activated and trained in patients with complete or incomplete paraplegia when the body is partially unloaded. However, the level of electromyographic activity in the gastrocnemius (the main antigravity muscle during gait) is considerably lower in the patients compared to healthy subjects. During the course of a daily locomotor training program, the amplitude of gastrocnemius electromyographic activity increases significantly during the stance phase, while inappropriate tibialis anterior activation decreases. Patients with incomplete paraplegia benefit from such training programs such that their walking ability on a stationary surface improves. The pathophysiology and functional significance of spastic muscle tone and the effects of treadmill training on the locomotor pattern underlying new attempts to improve the mobility of patients with a central motor lesion are reviewed.

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Screening for Early Stages of Nigrostriatal Alteration (II): Gait Pattern in Healthy Subjects with Increased Echogenicity of the Substantia Nigra—Dillmann U1, Behnke S2, Kra¨mer J3, Krick CM4 (1Homburg/Saar; 2 Homburg/Saar; 3Homburg/Saar; 4Homburg/Saar) Background: The majority of patients with Parkinson’s disease (PD) show an increased echogenicity of the substantia nigra (SN) [1]. In healthy subjects, these abnormalities could be found in 9%. 60% of them had a malfunction of the nigrostriatal system as demonstrated by reduced putaminal 18F-Dopa uptake values [2,3]. These findings have been suggested to represent a risk factor for PD. Objective: We have studied the gait pattern in healthy subjects with increased SN echogenicity. Methods: 31 healthy male subjects were studied. 16 had an increased SN echogenicity (mean age 58G5.4 years, range: 51–67 years), 15 subjects had a normal echogenicity (57G5.6 years; 51– 69 years). UPDRS (part III) was normal in all subjects. Gait was analyzed during walking on a treadmill using two different velocities: (1) the normal gait velocity and (2) the maximal possible gait velocity. The following parameters were measured: the maximal elbow extension, the total range of elbow angle movements, the maximal knee extension, and the total range of knee angle movements of left and right side, respectively; upper body inclination, and stride length and length of arm swing. Results: The combination of parameters which distinguished best between both groups using discriminant analysis (PZ0.0016) were: range of angle movements of knee and elbow of both sides and with both gait velocities, and the gait velocities itself. Stride length, length of arm swing, and maximal angles of knee and elbow could not be proven to be useful for the differentiation between both groups. Conclusion: We could demonstrate that an increased echogenicity of the substantia nigra is associated with an altered gait pattern in healthy subjects. References Becker G, Berg D Mov Disord 2001; 16: 23–32. Berg D, Becker G, Zeiler B et al. Neurology 1999; 53: 1026–1031. Becker G et al. Neurology 1995; 45: 182–184.

This study is dedicated to our former head of the department Prof. G. Becker, who died at the age of 42 years in a sports accident.

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Neural Correlates of Face Processing in Hereditary Prosopagnosia: A Functional MRI Study—Dinkelacker V1, Gru¨ter M2, Klaver P3, Kennerknecht I4, Ruhlmann J5, Elger CE6, Fernandez G7, Weis S8, Gru¨ter T9 (1Bonn; 2Mu¨nster; 3Bonn; 4Mu¨nster; 5Bonn; 6Bonn; 7 Bonn; 8Bonn; 9Bonn) For a long time, congenital prosopagnosia has been described as a low incidence anecdotic entity. Only very recently epidemiologic and genetic studies have indicated that its prevalence may in fact amount to 2% of the population, and an autosomal-dominant inheritance pattern was proposed. In neuropsychological terms, hereditary prosopagnosia is not part of a general visual agnosia but may extend to certain deficits in recognition of other, similarly complex visual stimuli. Here we performed a functional MRI study on a group of 18 hereditary prosopagnosics as compared to 18 matched controls. Neutral and emotional faces as well as houses and visual control stimuli were presented in a blocked design. Our behavioral data show that recognition memory for both faces and houses was significantly reduced in prosopagnosics as compared to controls. This effect was most pronounced for faces with neutral expressions. However, the prosopagnosics showed no memory deficits for faces displaying negative emotions such as anger and fear. In terms of functional imaging, both groups displayed a similar, robust pattern of activation when presented with faces. This comprised the right inferior frontal gyrus, right amygdala, and large inferior temporal regions including the fusiform face area. Preliminary comparative analysis showed increased hemodynamics for controls as compared to prosopagnosics in bilateral inferior temporo-occipital areas. Prosopagnosics, on the other hand, displayed enhanced activation in the left inferior frontal sulcus, left amygdala and bilateral anterior insula, thus indicating language and emotion related compensation for face processing deficits.

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Cerebral Fiber Changes in Patients with Hereditary Spastic Paraparesis Assessed by Diffusion Tensor MRI—Dirks M1, Sach M2, Glauche V3, Ba¨umer T4, Liepert J5, Mu¨nchau AM6, Heimbach B7, Winkler G8, Bu¨chel C9, Weiller C10 (1Hamburg; 2Hamburg; 3Hamburg; 4Hamburg; 5Hamburg; 6Hamburg; 7Hamburg; 8 Hamburg; 9Hamburg; 10Hamburg) Hereditary spastic paraparesis (HSP) comprises a heterogeneous group of congenital diseases with progressive spastic paresis of the legs. Most common are pure forms with autosomal dominant inheritance (HSP4 and HSP3). Pathological findings revealed degeneration and demyelinization of the corticospinal tract increasing from the cervical to the lumbal level of the medulla considering a dying-back axonopathy of these long axons. However, occasional extraspinal involvement like thin corpus callosum, cerebellar atrophy, and cognitive impairment in HSP4 suggests other factors for neural degeneration beside axon length. No alterations of cerebral corticospinal tract fibers have been described so far. Diffusion tensor MRI provides an estimate of the orientation of fiber bundles in the white matter. The directionality of diffusion can be quantified by fractional anisotropy (FA) allowing an estimation of fiber coherence. The aim of this study is the assessment of cerebral fiber changes in patients with pure HSP. We investigated 8 HSP patients

(HSP4/HSP3, autosomal dominant) with spastic paraparesis, hyperreflexia of legs, and positive Babinski sign in comparison to 16 age-matched controls. Diffusion-weighted images were acquired on a 3 Tesla MR system with a STEAM sequence (voxel size 3!3!3 mm3, 24 directions, 4 measurements, whole brain scan). Additionally we obtained a T1-weighted MRI. Images were realigned and spatially normalized. We computed diffusion tensor images on normalized T1 maps and calculated the FA voxel-wise. FA maps of patients were compared in 2 sample t-tests versus healthy controls using standard voxel-based statistics (SPM02). We report areas of significantly reduced FA (P!0.05 corrected, family-wise error) after small volume correction (sphere of 8 mm). In HSP patients the strongest FA decrease was located in the right crus cerebri of the mesencephalon (global maximum, P!0.001, corr.). FA was also decreased in the left posterior limb of the internal capsule (P!0.026, corr.), in the corpus callosum (P!0.008, corr.) and bilaterally in the cerebellum (P!0.004, corr.) and frontal lobe (P!0.004, corr.). The strongest decrease of fiber coherence of the caudal cerebral pyramidal tract fibers is in accordance with the pathological findings increasing to the lumbal level. Additionally, our results suggest an involvement of the corpus callosum, cerebellum and frontal lobe in autosomal dominant pure HSP indicating more extensive fiber degeneration than has been described so far.

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‘The Hierarchy within the Brain’—A fMRI Study of Neuroanatomical Correlation of Semantic Structures of Superordination in Contrast to Synonymy—Dockner TKA1, Krick CM2, Reith W3 (1Kordel; 2Homburg/ Saar; 3Homburg/Saar) This fMRI study looks for anatomical correlations to the semantic structure of super- and subordination. A homogeneous group of eleven students was presented a series of 1000 words during an MRI. A series of 820 nonsense words consisting of random consonants was the baseline. At irregular times in between two sequential meaningful words were shown. The students had to decide whether these two words were in a meaningful order. Three groups of words were shown: words with a concrete vs. abstract content and largest semantic distance, synonyms and terms in relation of hyponymy and superordination. The following linguistic considerations were posed as background: in the context of semantic hierarchy of the vocabulary synonyms are on the identical level while the relation of superordination and hyponymy forms a treelike structure. Concrete vs. abstract terms were selected to design a paradigm in accordance with the oddball-principle. At the recognition of superordinated terms in contrast to the recognition of synonyms a higher activity could be demonstrated bilaterally in BA 10, in left cerebral hemisphere in BA 21, BA 44 and BA 47, and in right cerebral hemisphere in BA 19 and 45. The latter region was the maximally activated one. Thus it was shown that hierarchization of the vocabulary, as derived from theoreticallinguistic reflections, has a neuroanatomic correlation. This result has consequences for psycholinguistic reflections as well as for the research of language acquisition. There are also new aspects considering semantic paraphasia in correlation to destruction of the WERNICKE or the BROCA area.

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Activity in Retinotopic Visual Cortex under Focused Spatial Attention Distinguishes Empty from Distracter Locations—Ebeling D1, Mu¨ller NG2 (1Frankfurt/Main; 2 Frankfurt/Main) Activity in the retinotopic visual cortex is enhanced when the represented visual field region is covertly attended. This observation has been interpreted as a physiological correlate of the spotlight of attention (e.g., Brefczynski and DeYoe, 1999). Moreover, activity in the early visual cortex coding the immediate surround of the attended region is suppressed relatively to passive viewing thereby enhancing the contrast between attended and unattended visual field regions (Mu¨ller and Kleinschmidt, 2004). In this study, we asked whether activity in the retinotopic visual cortex under focused attention is further modulated by the presence or absence of distracting stimuli. More specifically, we aimed to investigate how neural representations of locations neighboring the attended stimulus would be activated depending on their content. Subjects viewed a rapid serial visual presentation (RSVP) of letters at the center of the screen. In two quadrants of the visual field additional clusters of distracting letters were presented permanently, the remaining two quadrants remained empty. A block design was used in which subjects either had to respond to a target stimulus in the RSVP or simply fixated the RSVP without any further task. Distracter locations and empty locations were switched in successive blocks. BOLD responses were recorded with a 3 T Siemens Trio scanner. After retinotopic mapping we assessed the activity in visual cortex representations of locations depending on whether they coded an empty quadrant or one that contained distracter stimuli. Activity of visual areas depended on the allocation of attention and differed between areas coding distracter and empty locations. These data provide a physiological correlate for the behavioral effects of distracting information on visual discrimination performance. References

Brefczynski JA, DeYoe EA. A physiological correlate of the ‘spotlight’ of visual attention. Nat Neurosci 1999; 2: 370–374. Mu¨ller NG, Kleinschmidt A. The attentional ‘spotlight’s’ penumbra: center-surround modulation in striate cortex. Neuroreport 2004; 15: 977–980.

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Is there an Influence of Autonomic Nerves on Sensory Nerves in the Meninges?—Release of CGRP and PGE2 in vitro—Ebersberger A1, Takac H2, Schaible HG3, Richter F4 (1Jena; 2Jena; 3Jena; 4Jena) The perivascular fibers in the dura mater are a putative source of headache. They are either efferent sympathetic or parasympathetic or afferent in the trigeminovascular system. Because the fibers join each other densely, one system might influence the other systems by neurotransmitter or peptide release. It is generally accepted that the trigeminovascular system is activated during headache, e.g., migraine. The release of the vasodilatory neuropeptide CGRP is an indicator for nociceptor activation and neurogenic inflammation, which accompanies the headache. The release of PGE2 supports the inflammatory process. Here we investigated in an in vitro release model of the dura whether transmitters of sympathetic and parasympathetic fibers may influence the release of CGRP and PGE2 from afferent fibers. Rats were decapitated and the skull was divided in halves. The cavities lined with dura were repetitively filled with different sample solutions. The CGRP and PGE2 content

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of the samples was measured with an enzyme immunoassay. Carbachol (10K4 M) neither influenced the basal release of CGRP nor that of PGE2. However, a reduction of the release stimulated by a mixture of inflammatory mediators could be observed suggesting that parasympathetic fibers might influence primary afferents during activation. No significant influences on the release of CGRP were seen with norepinephrine (NE, 10K4 M). In addition, NE had no influence on the stimulated release of PGE2. However, basal release of PGE2 was massively enhanced by NE, an effect which outlasted application. When serotonin was added to NE this effect was reduced by half. The reduction was probably due to 5-HT1D receptors. NE had no influence on the release of CGRP from primary afferent neurons showing that NE does not directly activate or influence afferent fibers. However, the basal level of PGE2 was increased massively by NE, a process probably controlled by 5-HT1D receptors. The balance between 5-HT and NE, both stored in sympathetic fibers, might be a crucial mechanism in the control of PGE2 levels in the meninges.

Physiotherapy in the Spastic Syndrome—Eickhof C1 (1Berlin) The spastic syndrome after a lesion of the CNS is not a primary impairment. Nowadays, it is seen as an adaptive process, which can hinder recovery of function after a paresis as well as create secondary complications. The restructuring of the CNS after a lesion is regulated by lesion-induced plasticity but the activity or non-activity of neuronal pathways seems to contribute to this process. Therefore, to influence the recovery process, therapy in upper motor neuron syndrome should be impairment orientated. The development of so-called ‘positive symptoms’ of the upper motor neuron syndrome needs to be delayed by avoiding stimuli which increase the tonic inputs to the motor neurons. This includes adequate handling by the nursing and therapeutic team, and use of peripheral inhibitory stimuli, in particular from joint receptors to achieve the most functional distribution of tonus between muscle chains and their antagonists. Additionally, secondary changes in muscle and tissue have to be avoided by (active) passive stretching of muscles. At the same time the negative signs of the upper motor neuron syndrome have to be treated. Activity in descending projections for voluntary movements has to be increased to regain the capability to excite motoneurons below threshold and to inhibit motoneurons of the antagonists. For this an analysis of the patient’s motor performance is especially important. Many patients experience their paresis like an external load (a feeling of abnormal heaviness of the plegic limbs). Therefore, they increasingly plan motion, which is used for movements against resistance. Such motor plans include an extraordinary amount of static activity. Mainly cocontraction activity and only little reciprocal inhibition are executed to maintain stability of the body against the putative load. The efficiency of static control pathways can be increased by this, whereas there is little increase in efficiency in the inhibitory pathways. Such a behavior supports the development of muscle hypertonus, while the ability to precisely inhibit this tonus again is not facilitated. Physiotherapy for recovery of central paresis therefore has to include a behavioral therapy. With a systematic repetitive BASIS training, pathways for voluntary movements with a high proportion of reciprocal inhibition can be activated. When a patient can shorten and lengthen his/her muscles again, meaning that sufficient descending

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control of reflex activity has been regained, only then should postural activities be trained.

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The Executive Motor System works Harder when Moving the Non-Preferred Hand—van Eimeren T1, Mu¨nchau AM2, Weiller C3, Siebner HR4 (1Hamburg; 2 Hamburg; 3Hamburg; 4Kiel) Purpose: The aim of the present study was to investigate whether human hand preference has a functional correlate in movement-related neuronal activity. Methods: 12 right-handed and 13 left-handed volunteers performed visually cued choice reaction time tasks during eventrelated 3 Tesla fMRI. The experimental design comprised five conditions, differing in the amount of choice given by spatial cues. Responses were made with the left or right index or middle finger. Subjects were required to choose and execute brisk flexion movements with only one finger in response to the spatial cue. Data were analyzed with SPM2. Results: Using the left hand, right-handed subjects showed significantly (P!0.05, corrected) greater movement-related BOLD increase in the corresponding executive motor areas (right sensory motor cortex, right insula, right putamen, left cerebellum) relative to left-handed participants. Vice versa, using the right hand, the corresponding executive motor system showed greater neuronal activity in left-handed compared with righthanded subjects. This pattern of neuronal activity was similar across all experimental conditions, indicating that the effect was independent of motor selection based on spatial cues. Discussion: Movement-related activity levels in corresponding executive motor areas are higher if motor responses are made with the non-preferred (less trained) hand. We attribute the relative increase in BOLD signal to the additional effort that is required when moving the less skilled hand. Interestingly, this pattern equally applies for both left- and right-handers.

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Integrative Cortical Functions in the Immature Brain— Investigations in Human Newborns using EEG—Eiselt M1, Schwab K2, Putsche P3, Witte H4, Zwiener U5 (1Jena; 2 Jena; 3Jena; 4Jena; 5Jena) The perinatal period in human beings is characterized by rapid developmental changes of the CNS. Results from animal experiments indicate that spontaneous activity may be of essential importance for this development. Insights into the functional organization can be provided by EEG, but up to now only limited information is available. We hypothesize that highly organized functional patterns are generated in newborn brains in spite of their immaturity. We investigated healthy full-term newborns by multichannel EEG during quiet sleep. Part of the EEG is characterized by the recurrent appearance of high voltage periods (burst) and low voltage periods (interburst). Pattern-related analysis of this EEG was performed by calculating instantaneous spectral power, adaptive inter- and intrahemispheric coherence and the coupling between different frequency bands by bicoherence analysis. Burst periods reappeared during discontinuous EEG with a dominant frequency of about 0.1 Hz. During bursts mean spectral power reached a maximum within frequency bands O2.8–14.8 Hz during the first part of this period. Spectral power within the other frequency bands and during interburst periods was distributed

equally. The highest coherence level was observed during burst periods in comparison to interburst periods. Maximal coherence was reached at different moments during bursts—late in the low frequency bands (0.5–1.5 Hz; about 3 s after the burst started) and earlier in higher frequency bands (O2 Hz; about 2 s). The interhemispheric coherence was highest in all frequency bands over the frontal region as compared to the central region during bursts. Mainly in frontal regions phase coupling between high and low frequency components could be described with a temporal dynamic of about 0.1 Hz. It can be shown that during the early period of neurodevelopment, characteristic changes of electric potential occur, functional coupling between hemispheres exists and that the EEG expresses highly organized topographic and temporal patterns. Thus, using pattern-related investigations with high temporal resolution the newborn EEG provides evidence of early integrative cortical functions.

Memory of Traumatic Stress—Elbert T1, Schauer M2, Neuner F3 (1Konstanz; 2Konstanz; 3Konstanz) Extreme stress alters the coding of events in memory and may lead to disorders of the trauma spectrum, such as post-traumatic stress disorder (PTSD). In order to understand the physiological basis and the common thread underlying PTSD, the concept of memory as it is related to trauma must be understood. Autobiographic memory can be divided into cold memories, including knowledge about life-time periods and specific events and hot memories, comprising emotional and sensory memories. Cold memories (On September 18 at 20:30 I was still working in my office) are usually connected with hot sensory memories, (black-masked, dark night, shooting) as well as with cognitive (I can’t do anything), emotional (fear, sadness) and physiological elements (heart racing, fast breathing, sweating). Through this string of hot memories a fear network is built. Physiological changes in the brain and body of the survivor of a life-threatening experience, such as a response of the stress-related messengers (e.g., of the HPA axis) or the functioning and even structure of the medial temporal lobe and connected limbic networks in the brain, have been shown to be affected by traumatic stressors and are linked to the organization of memory. When we drive the organism down the defense cascade, when flight is not possible, fight futile and only a startling freeze is left in our evolutionary repertoire, functioning of the structures in the medial temporal lobe that are the portal for autobiographic memory is altered such that hot and cold memories lose their interconnectivity. Our data from survivors of severe violence and torture demonstrate functional alteration of fronto-temporal regions. In over 100 victims of severe and repeated torture, we observed a 94% prevalence of PTSD. In these patients, generators of abnormal slow waves indicated dysfunctional networks in the frontal lobe. Abnormalities in left fronto-temporal regions were connected with dissociative states. In addition a hyper-responsive fear-network can be demonstrated by rapid visual presentation of emotional material. In torture victims but not in controls, rapid presentation of affective pictorial stimuli activates frontal cortex. We hypothesize that it is this disconnection between hot and cold memories, indicated by abnormal brain waves that leaves those experiencing flashbacks entangled in fear and anxiety. The victim is unable to place the flashback in time and space because the hot memory is not connected to 51

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the autobiographical cold memory. If this connection can be restored, the horror of the memory might be alleviated.

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Changed Acoustic Evoked Neuromagnetic Responses can be Recorded in Schizophrenic Patients with Auditory Hallucinations—Emmerich E1, Richter F2, Steiniger T3, Lemke S4, Rossburg T5, Giebler F6 (1Jena; 2 Jena; 3Jena; 4Jena; 5Jena; 6Jena) There is an indication that central processing in the auditory system is changed in schizophrenics with auditory hallucinations. Otoacoustic emissions generated from cochlear hair cells are a valuable indicator for the functioning of efferent and afferent pathways in the auditory system. They can be recorded easily without strain for the test persons or patients. To test whether auditory information processing is delayed or otherwise changed in schizophrenia, auditory evoked magnetic fields (AEF) were evoked with tone bursts (1 kHz, duration 50 ms, rise time 5 ms, intensity 70 dB SPL; series per 200 single bursts with random interstimulus intervals) in schizophrenic patients with auditory hallucinations (nZ32) and in healthy controls (nZ40). Two recording sessions were performed for each person. Tone bursts were applied via an acoustically tested tube and funnel system to the contralateral ear of the test person. AEF were recorded with the Philips 2!31 channel double Dewar device (spherical sensor plate with a diameter of 140 mm). The cryostat was placed over the temporal cortex contralaterally to the stimulated ear. AEF were evaluated with the CURRY program. For better recognition of the relevant signals, raw data were filtered digitally with a Fourier filter. The patients had suffered for more than 2 years from schizophrenia and were receiving neuroleptic treatment. Most of the patients had no hallucinations during the measurements, only a subgroup of 6 reported on hallucinations during the test. In healthy controls, AEF typically consisted of 4 prominent components, P50m, N100m, P160m, and P200m with latencies resembling the numbering of the components. Significant changes of the AEF, however, were found in schizophrenics: the latency of the AEF component N100m was prolonged and typical components (especially the P160m and P200m) were often missing, although there were no hallucinations during the trials. The data imply that auditory information processing is influenced during auditory hallucinations in schizophrenics. Tests will be repeated in each patient in a hallucination-free period to prove if the changes in AEF persist after ending neuroleptic treatment.

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MR Volumetry and Schizophrenia: What have we learnt in the past 20 years?—Falkai P 1 (1Homburg/Saar) Early brain imaging studies using pneumoencephalography have pointed out as early as in the 1920s and 1950s that there is ventricular enlargement and cortical atrophy in schizophrenia. The introduction of computed tomography in schizophrenia research in 1976 was helpful to support this line of evidence. Since then magnetic resonance imaging has helped considerably to establish schizophrenia as being a brain disorder. Structural brain imaging studies have helped to identify that there is a subtle loss of the whole brain volume in schizophrenia, an enlargement of the ventricular system, especially the lateral ventricles and the third ventricles, and regional loss of brain tissue in frontal but especially temporal lobe

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regions. The temporal lobe changes comprise volume reduction of the hippocampus, amygdala, entorhinal cortex, and superior temporal gyrus. In addition to these cortical findings, a volume reduction of the thalamus and the cerebellum can be replicated in recent studies. Most of these findings are present in an attenuated form in never-treated first relatives of schizophrenic patients. Between this genetic influence there seem to be environmental factors like obstetric complications adding to the extent of structural changes. However, it is clear that some of the changes predate the onset of the illness and are due to subtle remnants of a neurodevelopmental problem. In addition to these changes in the prodromes of schizophrenia, additional volume loss seems to occur. Finally there is some change over time in the course of the illness. Therefore, the structural changes seen in chronic schizophrenia are a mixture of premorbid changes, changes occurring in prodromal schizophrenia, and changes occurring during the course of the illness. Recent studies make clear that treatment in itself, and especially neuroleptic treatment, seems to add to the structural abnormalities. Atypical neuroleptics, for instance, seem to increase the volume of the basal ganglia and the thalamus, while typical neuroleptics seem to reduce the volume of the same structures. In summary, there seems to be a clear-cut pattern of structural abnormalities in schizophrenia. To some extent they are related to positive symptoms (hippocampus) and negative symptoms (cortical abnormalities) and are interesting indicators of disease processes underlying these changes. Functional and genetic studies are needed to elucidate the meaning of these changes on the non-structural level and pointing to their molecular bases.

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Text Comprehension after Brain Injury: An fMRI Study of Inference Processes in Patients with Anterior Temporal or Fronto-Medial Lesions—Ferstl EC1, von Cramon DY2 (1Leipzig; 2Leipzig) Text comprehension requires the continuous integration of utterances with both general world knowledge and the prior discourse context. These inference or coherence building processes have been shown to consistently activate the left fronto-medial cortex and anterior temporal regions bilaterally (Mazoyer et al., 1993; Ferstl and von Cramon, 2001, 2002). However, in behavioral tests, there was evidence for an inferencing deficit after left frontal lesions only, but not after anterior temporal lesions (Ferstl, Guthke and von Cramon, 2002). The goal of the present study was to characterize the network necessary for higher level language processing by describing the changes caused by lesions to one of the key components. We used event-related whole head fMRI at 3 Tesla to directly study cerebral blood flow during an inference task in brain damaged patients. 80 sentence pairs were auditorily presented over head phones. The participants were instructed to judge using a YES/NO response whether there was a pragmatic, content-based connection between the sentences. The brain-injured participants were selected from a pool of former patients of the outpatient clinic for cognitive neurology at the University of Leipzig. For the fMRI analysis participants with more than 25% errors were excluded. Data of 16 patients were included in the analyses: 10 patients with anterior temporal lesions (nZ6 left temporal, nZ4 right temporal), and 6 patients with a likely involvement of the FMC. These latter patients were closed-head injury patients whose anatomic MRI scan showed bifrontal contusions or evidence for microbleeds along the superior frontal

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gyrus. The fMRI data were first analyzed for the whole group. Comparing all language trials to the control task (listening to pseudo-word sentences), we found very similar activation patterns as in the previous studies with healthy control participants. As expected, the FMC group had bilateral involvement of the anterior temporal lobes, whereas for the temporal groups this region was active in the contra-lesional hemisphere only. Furthermore, the patient group showed large regions of activation in the left-sided prefrontal cortex, in particular in the pars triangularis of the inferior frontal gyrus and near the junction of the inferior frontal sulcus and the precentral sulcus. Activation in the fronto-medial wall depended on the patient’s performance level, confirming its role for inference processes.

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The Impact of Context Variables on Error Monitoring—Fiehler K1, Ullsperger M2, von Cramon DY3 (1Leipzig; 2Leipzig; 3Leipzig) When participants make an erroneous response in a choice reaction time task, an error-related negativity (ERN), peaking at about 100 ms after the erroneous response, has been described. Source localization studies suggest that the ERN is generated in the anterior cingulate cortex (ACC). Consistent with these findings, experiments using functional magnetic resonance imaging (fMRI) frequently showed an increased activation for error trials in the ACC and the pre-supplementary motor area (pre-SMA). Affective and motivational factors have been proposed to modulate ERN amplitude and/or latency, i.e., emotional reaction on errors or individual error salience. Furthermore, specific task conditions, e.g., time pressure or instructed error correction, have an impact on the ERN. Few fMRI studies have systematically investigated the effect of different context variables on the brain level. In a series of experiments, we investigated the impact of context variables on error monitoring using event-related potentials (ERPs) and fMRI. The first ERP and fMRI experiment examined motivational effects on error monitoring. In one condition, accuracy was emphasized by associating errors with high financial penalties. In a second condition, speed was emphasized by associating errors with low financial penalties. The second ERP and fMRI experiment investigated error correction. Participants were randomly divided into two groups: one group was instructed to correct errors while the second group was unaware that error corrections were recorded. The results showed a modulation of error-related ERP components by speed-accuracy instruction as well as by error correction. Consistent with the ERP findings, error-related brain regions on the frontomedian wall varied in relation to context variables.

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Synchronization Tomography: Model Calculations of Spatial Resolution and Noise Tolerance; Optimization of Source Localization—Fieseler T1, Dammers J2, Dolan K3, Tass PA4 (1Ju¨lich; 2Ju¨lich; 3Ju¨lich; 4Ju¨lich) Phase synchronization plays an important role both under physiological and pathological conditions. With standard averaging techniques of MEG data, it is difficult to reliably detect cortico-cortical and cortico-muscular phase synchronization processes that are not time-locked to an external stimulus. For this reason, novel synchronization analysis techniques were

developed and directly applied to MEG signals [1]. However, due to the lack of an inverse modeling (i.e., source localization), the spatial resolution of this approach is limited. To detect and localize cerebral phase synchronization, we developed the synchronization tomography [2]. First the cerebral current source density is estimated by means of magnetic field tomography (MFT) [3] for each time step; then the single-run phase synchronization analysis is applied to the current source density in each voxel of the reconstruction space. We model different generators of ongoing rhythmic cerebral activity by current dipoles with time courses of slightly detuned coupled chaotic oscillators subjected to random forces. MEG signals are calculated using these generators for a whole-head MEG system, and subsequently the synchronization tomography is applied to the simulated measurements. We show advantages and limitations of the synchronization tomography. We demonstrate that the measurement noise resistance of the synchronization tomography is much higher compared to MFT alone. Furthermore, we compare different approaches to extend phase synchronization analysis, which was developed for scalar signals, on vector valued signals like the current density. The localization accuracy can be considerably improved using the strongest component of the principal component analysis of the reconstructed current density vector. We applied statistical tests using surrogate analysis [4] to test synchronization tomography for its characteristics concerning non-linearities of sources. In other words, we test whether synchronization tomography removes nonlinearities of sources or introduces non-linearities not present in the sources. References Tass PA et al. Phys Rev. Lett 1998; 22: 3291–3294. Tass PA et al. Phys Rev Lett 2003; 90: 088101. Ioannides AA. Inverse Problems 1990; 6: 523–542. Dolan K, Neiman A. Phys Rev E 2002; 65: 026108.

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Epidemiology and Genetics of Alzheimer Dementia— Finckh U1 (1Hamburg) Alzheimer dementia (AD) affects over 650,000 people in Germany and is the most common form of aging-related dementia. Mutations in the presenilins (PS1, PS2) and amyloid precursor protein (APP) are causative in rare forms of autosomal dominant familial Alzheimer disease (FAD). These findings contributed significantly to the current concept of the pathogenesis of AD. Whereas FAD accounts for !1% of all AD, the vast majority of AD is sporadic, age-related and multifactorial, i.e., late-onset AD (LOAD) due to genetic and non-genetic risk factors contributing etiologically. The genetic association between APOE e4 and (LOAD) was discovered more than a decade ago. Cumulative data of epidemiological, family, twin, linkage, and theoretical studies allow us to conclude that there may exist risk alleles in several genes in order to fully explain the proportion of AD attributable to genetic factors. However, up to now none of the numerous studies involving more than 130 candidate genes revealed convincing evidence for any risk alleles in genes other than APOE. In the published literature there are more than 55 loci with positive association findings. Most of these findings (including those of our group) could not be confirmed. This raises the question of why and how APOE was found and whether there are strategies to be optimized for future association studies on LOAD and

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polymorphic candidate genes. The APOE hypothesis was supported by linkage, existence of intragenic functional polymorphisms, and biochemical data suggesting an interaction between ApoE and beta amyloid peptide. Besides the chromosome 19 region harboring APOE, genome scans and linkage analyses revealed genomic regions suggestive of linkage with AD on chromosomes 1, 5, 9, 10, 12, 21, and X, in addition to several loci with a possible linkage. Furthermore, molecular genetic, biochemical and neurobiological research has revealed several molecular mechanisms involved in the pathogenesis of AD. Based on the data available now, future association studies on AD could focus on candidate genes simultaneously fulfilling several criteria that also were essential for discovering APOE. Supported by DFG, grant FI 704/1-3.

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A New Method to Evaluate Muscle Tone in the Upper Limb—Fincziczki A1, Krause P2, Eggert T3, Straube A4 (1Mu¨nchen; 2Mu¨nchen; 3Mu¨nchen; 4Mu¨nchen) Some neurological diseases can cause changes in muscle tone. These changes can occur after lesions of central motor pathways (spastic syndrome), in Parkinson syndrome (rigidity) and cerebellar hypotonia. Other syndromes with increased muscle tone are less well defined like the muscle stiffness in CRPS. The problem in clinical praxis is that there is only a limited set of evaluation methods mostly using scales, which are highly observer dependent thus limiting the possibility to do inter-rater comparisons. The pendulum test of Wartenberg is a semiautomatic method to evaluate the muscle tone of the lower limb. It is based on an estimate of muscle torque in an unvoluntary periodic movement. Lin modified the test to measure damping and stiffness of the elbow joint (ej). They applied an external sinusodial torque to the limb by a mechanical pendulum to which it was attached. Lin found that the active torques (torques not explained by inertia, gravity torques of the limb and the mechanical apparatus) in the ej could be approximated by damped sinusoial oscillations. They modelled this active torque as a sum of torques proportional to joint angle and velocity (v) [elasticity (e) and damping (d)]. However, the acceleration of a damped sinusoidal oscillation is identical to a weighted sum of joint angle and v. We asked whether the active torque is sufficiently explained by the sum of e and d, or whether a component proportional to acceleration also exists. To address this, we used a similar system with an additional possibility to modify the stable position of the limb by changing the angle between forearm and pendulum. If the model of Lin is sufficient, joint angle phi0 at which no elastic torques occurs should not depend on this change. In a control experiment we tested whether the active torque depends on visual feedback. Aligning the forearm with the pendulum, we observed d-coefficients of 0.1G0.07 N m rad/s and stiffness-coefficients of 4.5G1.0 N m/rad. No elasic torque was estimated at an angle of elbow flection (ef) of j0Z91.3G5.5 deg. When the angle between forearm and pendulum was changed about 10 deg towards smaller ef, phi0 decreased on average by almost the same amount to 80.2G8.7 deg (P!0.01). With smaller ef stiffness-coefficients were slightly smaller (4.0G0.7 N m/rad; P!0.05). This indicates that the active torque might not be sufficiently described by e and d alone. Torques proportional to acceleration may be involved, too.

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Exposure to a Routine MRI Brain Scan at 1.5 T does not affect Subsequent MEG Examinations—Fitzek C1, Haueisen J2, Huonker R3, Reichenbach JR4, Pfleiderer SOR5, Mentzel HJ6, Sauner D7, Brandl U8, Kaiser WA9 (1Jena; 2Jena; 3Jena; 4Jena; 5Jena; 6Jena; 7Jena; 8Jena; 9 Jena) Purpose: We have attempted to investigate whether a routine brain MRI study performed on a clinical whole-body 1.5 T scanner affects a following MEG examination. Material and Methods: Nine healthy volunteers (6 women, mean age 23 years, age range 20–27 years, 3 men, mean age 24 years, age range 23–25 years) underwent one MEG session before and two MEG sessions after MRI of the brain. The first MEG session (MEG1) was finished about 20 min before the MRI scans and the second MEG session (MEG2) was performed within 30 min after the MRI. The final MEG (MEG3) was performed two hours after MEG2. Each MEG session consisted of a measurement of spontaneous brain activity and an examination with stimulation of the median nerve. The MRI scans included standard T1w-, T2wTSE and gradient echo sequences using a clinical 1.5 T scanner. The repeated-measures design was statistically analyzed using ANOVA for Repeated Measures (General Linear Model) both with and without the Greenhouse-Geisser correction. Results: MEG signals were detected and measured without any problems or interference in all volunteers. There was no statistically significant difference between the noise estimation (PZ0.588 corrected; PZ0.665 uncorrected) before and after the MRI scans. All volunteers showed measurable dipole localization of the median nerve stimulation before and after MRI. No measurable differences were observed on the frequency maps of spontaneous brain activity before and after MRI (PO0.290 corrected; p 3 0.295 uncorrected). Conclusion: No measurable influences on MEG signals were detected following MRI examinations of human volunteers. With the present study we were unable to replicate the reported findings indicating a strong interaction of an MRI scan on subsequent MEG measurements.

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Clinical course of isolated brain stem strokes—Fitzek S1, Fitzek C2, Axer H3, Joachimski F4, Marx JJ5, Tho¨mke F6, Urban PP7, Sto¨ter P8, Witte OW9 (1Jena; 2 Jena; 3Jena; 4Jena; 5Mainz; 6Mainz; 7Mainz; 8Mainz; 9 Jena) Introduction: While supratentorial strokes can be classified etiologically into lacunar, territorial, hemodynamic or embolic lesions, brain stem ischemia is often understood as a nosological entity without etiological differentiation. This imposes difficulties in predicting the clinical prognosis of these patients. There is only scarce data on the clinical course of isolated brain stem strokes. Aim: To study the clinical course and prognosis of solitary ischemic brain stem lesions. Methods: Patients with MRI proven acute brain stem ischemia, signs and symptoms were assessed at three time points: 1. acute state (standardized interview and neurologic examination 1–3 days after symptoms onset); 2. early state (standardized interview and neurologic examination 9–11 days after symptoms onset); 3. 5-year follow-up (standardized interview, modified rankin scale). Results: 230 patients admitted for clinically suspected acute brain stem stroke were included in the study. In 103 patients of

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these (45%) an acute and solitary brain stem ischemic lesion could be verified by MRI. The most frequent complaints leading to hospital admission were lurching gait (78%) and vertigo (58%); in 66% ataxia was demonstrable in the neurological examination. These findings were independent of lesion localization. 10 days later most of the signs and symptoms had improved, with the exception of disturbances of sensation of the face/limbs, which remained unchanged in 30%/20% after 10 days. Also ataxia recovered poorly over the first 10 days. In contrast, paralysis showed improvement in 96%, while only in a few cases motor performance deteriorated. After 5 years 50 patients were amenable for follow-up. 40% of these were free of symptoms. 80% had regained functional autonomy (Rankin 0–2). The localization of the ischemic lesion did not influence prognosis. 16% of the patients suffered a further ischemic stroke and 10% had a myocardial infarction. Three patients had succumbed due to consequences of the brain stem stroke—one of these in the acute phase. Conclusion: Our study demonstrates the good clinical prognosis of solitary ischemic brain stem lesion. More data is needed to clarify the clinical course of etiological subgroups of subtentorial stroke.

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GABA Neurons Survive Focal Ischemic Injury—Frahm C1, Haupt C2, Witte OW3 (1Jena; 2Jena; 3Jena) Focal cerebral lesions in the rat brain induced by photothrombosis lead to an impaired inhibitory neurotransmission. A reduced GABA (gamma-aminobutyric acid) mediated inhibition has been revealed by electrophysiological recordings associated with a diminished immunostaining of GABA handling proteins. Changes were found in ipsi- as well as in contralateral brain areas. Inhibition is mediated by interneurons using GABA as neurotransmitter. These cells use GAD (glutamate decarboxylase) to synthesize GABA. To analyze the vulnerability of GABAergic neurons in rats with a lesioned hindlimb area, cells expressing GAD65/67 mRNA were labeled using in situ hybridization. Positive somata were counted 7 and 30 days after focal ischemia in different cortical (hindlimb cortex, frontal cortex, primary and secondary somatosensory cortex) and hippocampal subsectors (pyramidal cell layer, stratum oriens and stratum radiatum/lacunosummoleculare). The lesioned hemispheres were compared with the intact brain sides and with control brains. GABAergic interneurons survived the injury for up to 30 days in all investigated brain regions. Therefore it is unlikely that a loss of GABAergic neurons contributes to the reduced inhibition.

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Functional MRI Activation of Mesial and Anterior Temporal Lobe Structures in TLE—Franke K1, Schacher M2, Mertens M3, Jokeit H4, Witte OW5, Ebner A6, Pohlmann-Eden B7, Wo¨rmann F8 (1Bielefeld; 2 Zu¨rich; 3Bielefeld; 4Zu¨rich; 5Jena; 6Bielefeld; 7Bielefeld; 8Bielefeld) Background: The diagnostic procedure in temporal lobe epilepsy (TLE) and especially presurgical planning requires knowledge about the functional integrity of the areas to be resected. The mesial and anterior temporal lobe (TL) in humans are highly important in emotional, visual and memory processing.

The amygdala itself is involved in the perception of emotional facial expression, particularly for fear. Methods: A new visual paradigm presenting animated fearful faces from movie scenes in alternation with landscape scenes was investigated using functional MRI. As a first step 12 healthy subjects (mean age 35 years, range 23 to 48) were scanned in a 1.5 Tesla MRI (blocked design, coronal EPI, voxel size 3.9!3.9!5 mm3). In ongoing experiments patients with unilateral mesial temporal sclerosis are investigated to look for possible lateralizing effects in anterior TL activation patterns. Imaging analysis is done with SPM99. To test for lateralization of anterior mesial temporal activity we compared the number of significantly activated voxels in the amygdala of both hemispheres. Results: In healthy subjects we found highly significant activation of the left and right amygdala, the anterior and mesial temporal lobe in single subjects as well as in group analysis. There was a mostly bilateral activation pattern of these regions with an averaged 0.93 left-to-right ratio of activated voxels in the amygdala. In contrast first results in 3 patients with right-sided TLE showed a strongly lateralized activation pattern to the left hemisphere with a left-to-right ratio of 2.4 in the amygdala. Conclusions: The new visual paradigm is highly effective to induce bilateral anterior TL activation in humans. In TLE patients with unilateral mesial temporal sclerosis the paradigm seems to effect a pattern that lateralizes the side of the mesial sclerosis and seizure onset. Further measurements will show whether the procedure can be of additional value in the diagnosis of TLE and whether it might improve the definition of eloquent brain areas prior to surgery and have predictive aspects for post surgical outcome (e.g., neuropsychological deficits).

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Mutual Information Function in Respirocardial Coordinations of Healthy Human Neonates in Quiet and Active Sleep—Frasch M1, Zwiener U2, Hoyer D3, Eiselt M4 (1Jena; 2Jena; 3Jena; 4Jena) The complexity of heart rate fluctuations (HRF) is based on several interacting physiological mechanisms operating on different time scales. No prominent time scale for HRF complexity analysis is given a priori. The aim of this work is to discriminate the active and quiet sleep of healthy full-term neonates by quantitatively assessing respirocardial coordination dynamics using the recently introduced complexity parameter mutual information function (MIF). Representing the different time scales of information flow in autonomic nervous system, MIF carries information on a wider scope of complex interdependencies than complexity estimators previously known. Our hypothesis was therefore that MIF discriminates sleep states by comprehensively characterizing complex coordinations of HRF and respiratory movements (RM). RM and ECG-derived HRF of 6 healthy full-term neonates (4G1 days of life) were studied. As standard measures characterizing sleep states linear parameters were calculated (power spectra, coherence, auto- and cross-correlation functions). As non-linear parameters of HRF and RM, auto- and cross-MIF were analyzed. All results were statistically tested for their discriminatory power and non-linearity. Confirming our hypothesis we were able to discriminate active and quiet sleep states

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in all individual cases using one single global time scale parameter of HRF total auto-MIF. We assume that the vagal influence in healthy human neonates mediates mostly complex (linear and non-linear) HRF properties, whereas the sympathetic effect is mainly responsible for linear HRF properties. With the character of the MIF parameters deployed in mind, this finding would explain our success in discriminating the sleep states. Remarkably, HRF complexity was larger in quiet than in active sleep. Complex respirocardial interdependencies cannot be identified completely by the local time scale MIF parameters alone. New information is gained when total MIF values are also considered. This result confirms the relevance of global measures of information flow for a comprehensive discrimination of complex systems. Sleep state-related changes of MIF parameters extend the possibilities of interpreting the underlying physiological processes of complex respirocardial coordination dynamics.

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Audition-Based Higher Cognitive Functions—Friederici A1 (1Leipzig) The mission of the Max Planck Institute for Human Cognitive and Brain Sciences is the description of the neural basis of those abilities that are central to human cognition. These are the ability to use language, to plan and execute complex actions, or to comprehend music. Here we will present parts of our research on human cognition, namely the neural basis of higher audition such as language and music comprehension. Based on converging findings from functional brain imaging (fMRI), EEG and MEG registration in healthy subjects and in patients with focal brain lesions, these processes can be described as follows. Spoken language comprehension requires the coordination of different subprocesses in time. After the initial acoustic analysis the system has to extract segmental information such as phonemes, syntactic elements and lexical-semantic elements as well as suprasegmental information such as accentuation and intonational phrases, i.e., prosody. According to the dynamic dual pathway model of auditory language comprehension, syntactic and semantic information are primarily processed in a left hemispheric temporofrontal pathway including separate circuits for syntactic and semantic information whereas sentence level prosody is processed in a right hemispheric temporo-frontal pathway. The syntactic circuit involves the left superior temporal gyrus, the inferior frontal gyrus (pars opercularis) and the basal ganglia. The semantic circuit also recruits the temporal and inferior frontal areas which, however, are distinct from those subserving syntactic processes. The pathway for the processing of prosody appears to consist of partially homologue areas in the right hemisphere. The observed interaction between syntactic and prosodic information during auditory sentence comprehension is attributed to dynamic interactions between the two hemispheres. This can be demonstrated in patients with lesions in the corpus callosum. Interestingly, aspects of structure (syntax) and meaning (semantics) can also be identified in music. fMRI findings indicate that music processing recruits a neural network quite similar to that of language processing with a slight dominance of the right hemisphere. While I will lay out the dual pathway model and the syntactic processes there in particular, Sonja Kotz will discuss the neural basis of semantic processes, Anja Ischebeck that of prosodic

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processes and Stefan Ko¨lsch the neural implementation of music comprehension.

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Ultrasound Imaging of the Sural Nerve Improves NearNerve Recording—Fu¨rst A1, Draganski B2, Felix S3, Schulte-Mattler WJ4 (1Regensburg; 2Regensburg; 3 Regensburg; 4Regensburg) Introduction: The near-nerve technique is a particularly sensitive method for the detection of demyelination of peripheral nerves. However, the quality of the results critically depends on the position of the recording electrode. Therefore we used B-mode ultrasound to quantitatively study how the properties of sensory nerve action potentials vary with the distance between the needle electrode and the nerve. Subjects and Methods: We examined both legs of 24 healthy people with a standard ultrasound system equipped with a linear 13.5 MHz array. At the beginning of each investigation the sural nerve was located lateral to the gastrocnemius tendon and approximately 15 cm proximal to the ankle. In transversal image planes the nerve was distinguished from vessels by both its speckled appearance and the absence of blood flow. The neurography of the sural nerves was done with the near-nerve technique following standard methods. The distance between the recording needle electrode and the outer diameter of the nerve, as measured by ultrasound, was intentionally varied between 0.1 and 15 mm, and compound action potentials were recorded. Results: Sural nerves could be identified by ultrasound in all subjects. With 2 exceptions, the nerve was located lateral to the posterior tibial vein in a depth of 4 to 10.4 mm. Its circumference varied between 5.3 mm and 12.2 mm. Neither the latency nor the nerve conduction velocity changed significantly with distance to the nerve. The amplitude varied between 4 mV and 70 mV. This variation was largely due to the variation of the distance between the electrode and the nerve, and followed a non-linear inverse relationship (P!0.001). Comments: With ultrasound it is feasible to locate the sural nerve and to position a needle electrode precisely. This should improve both the feasibility and the reliability of the results of near-nerve recordings. Especially, it is possible to control the variation in amplitude that is caused by a variation of the needle-tonerve distance.

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Isolated Local Hypoexcitability to Canalicular Magnetic Stimulation within Three Days after Onset of Facial Nerve Paresis can be due to Borreliosis—Gardill K1, Isenhardt K2, Schneider R3 (1Aschaffenburg; 2 Aschaffenburg; 3Aschaffenburg) Nerve conduction studies of the facial nerve with electric and magnetic stimulation within three days after onset of Bell’s palsy provide information about the differential diagnosis of the etiology, particularly with regard to borreliosis as a specifically treatable cause. Canalicular hypoexcitability is considered as a very specific finding for (idiopathic) Bell’s palsy in the literature. A 38-year-old man presented with a moderate facial palsy of the left side one month after a tick bite on the thigh with erythema, which had been treated with roxithromycine for 10 days. No other neurological abnormalities could be found at admission to

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our hospital. Cranial CT and MRI revealed normal results. Serum antibodies of Borrelia IgM were positive, CSF showed initially the following pathological results: cell count 4275/3 (normal 0–9/3), protein 248.5 mg/dl (15.0–45.0), albumin 2070.0 mg/l (0.0–350.0), elevated IgM and IgA with dominant IgM synthesis. Antibodies of Borrelia (IgM and IgG) were positive with an elevated antibody index that proved intrathecal local antibody synthesis. CSF cytology showed predominant lymphocytes with plasma cells. On the third day after onset of the facial palsy (28/8/2003) electroneurography and magnetic stimulation of both facial nerves were performed for the first time. They were stimulated electrically at the stylomastoid fossa and magnetically within its canalicular portion with 30 and 70% of the maximum output of our device (Magstim 200). The contralateral face-associated motor cortex was also stimulated magnetically. The responses were recorded from the nasalis muscle. The right side showed normal results, but at the left side a canalicular hypoexcitability was found. Similar results were obtained at controls on 1/9 and 9/9/2004. After therapy with ceftriaxone the palsy disappeared within 8 weeks. Our observation shows that isolated canalicular hypoexcitabilty of the facial nerve within three days after onset of Bell’s palsy does not exclude borreliosis reliably. Serum antibody tests and lumbar puncture can provide more specific information in particular cases.

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Cortical Complexity Measured via Regional Surface Shape—Gaser C1, Lu¨ders E2, Toga A3, Thompson P4 (1Jena; 2Magdeburg; 3Los Angeles; 4Los Angeles) Background: Few empirical studies have examined individual differences in the frequency of cortical gyrification/fissuration. Existing approaches only provide complexity measures for the whole brain or for specific lobes or brain hemispheres. Here we present a new regional shape measure to evaluate cortical complexity at each point on the cortical surface. Methods: 3D cortical surface models were created from MRI brain scans of 60 healthy adults (30 M/30 F) in ICBM stereotaxic space. To calculate a local measure of surface convolution, a curvature map was computed on each surface: negative maxima correspond to sulci while positive maxima are associated with gyri. The L2-norm of the computed curvature yielded high values for highly convoluted (folded) areas regardless of whether these areas represent sulci or gyri. We applied a smoothing kernel to locally integrate the L2-norm of the curvature, producing a smooth local measure of the degree of convolution at each cortical surface point. Complexity maps were compared statistically in men and women. Results: Cortical complexity was higher in females than in males. Our recent frequency space analysis of cortical complexity computed global fractal dimension measures for the five different lobes in each hemisphere (Luders et al., Nature Neuroscience, 2004). In contrast, the present method provides detailed measures of cortical convolution at each point of the 3D surface in the same set of data. Interestingly, both approaches revealed higher complexities in females compared to males. Discussion: We could confirm our recent results of the local analysis of cortical complexity. Additionally, our new approach can provide detailed measures of cortex convolution at each point of the surface.

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Gray Matter Volume Loss after Upper Limb Amputation—Gaser C1, Nenadic I2, Weiss T3, Miltner WHR4, Sauer H5 (1Jena; 2Jena; 3Jena; 4Jena; 5Jena) Background: Brain plasticity occurs as a result of sensory and motor adaptation to increased or altered use and leads to reorganization of the respective representations [1]. Plasticity of the adult human brain following deafferentation has only been assessed functionally, revealing functional reorganization of somatosensory and motor cortices [2,3]. Only a few reports exist reporting plasticity of grob brain structure [4]. In this study we explored whether structural brain plasticity occurs after amputation of the upper limb. Methods: We investigated a 33-year-old, right-handed male patient with an amputation of the right forearm following severe trauma. Fifteen weeks after amputation he received a myoelectric prosthesis, which was regularly used. After removing signal uniformities, all scans were registered to the first scan using rigidbody transformation. Remaining local differences were then minimized by applying high-resolution deformations [5] and the local volume changes were calculated using the Jacobian determinant [6]. Results: Significant volume loss was detected in the primary motor cortex (M1), primary somatosensory cortex (S1), and in the superior parietal cortex contralateral to the amputated limb. Further volume loss was seen in the supplementary motor area (SMA), and the ipsilateral primary motor cortex and bilaterally in the cerebellum and the brain stem. Discussion: This case report is the first indication of structural brain plasticity in the adult human brain following limb deafferentation. The data suggest that loss of sensory input and lack of motor output leads not only to a functional reorganization, but may also cause a change of grob brain structure. The regions with volume loss cover most parts of the motor system such as M1, S1, SMA, superior parietal cortex, cerebellum, and brain stem. Thus, short-term changes occur not only in the functional but also in the structural organization of the motor and sensorimotor system. This is in line with current observations of short-term structural changes as a consequence of intensive training [7]. References Black JE et al. PNAS 1990; 87: 5568–5572. Elbert T, Heim S. Nature 2001; 411:139. Weiss T et al. Neuroreport 1998; 9: 213–216. Hamzei F et al. Neuroreport 2001; 12: 957–962. Gaser C et al. Neuroimage 1999; 10: 107–113. Ashburner J et al. Hum Brain Map 2000; 9: 212–225. Draganski B et al. Nature 2004; 427: 311–312.

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Alcohol-Induced Changes of Extra- and Intracranial Volume Flow—Gerum A1, Eicke BM2 (1Mainz; 2Mainz) Clinical and animal trials have shown alcohol-induced peripheral vasodilation with a corresponding decrease in systemic arterial blood pressure. Scintigraphic studies have demonstrated conflicting data about the effects of ethanol on autoregulated cerebrovascular hemodynamics. We tested the extra- and intracranial hemodynamic changes induced by alcohol uptake (appr. 1 g/kg) in 22 healthy volunteers (14 male, 8 female; mean age 23 years) non-invasively by ultrasonic

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techniques. We determined almost simultaneously the extracranial blood flow volume in the common (CCA) (nZ22) and internal (ICA) (nZ11) carotid arteries bilaterally (duplex system) as well as the intracranial blood flow velocities (transcranial Doppler) in the middle cerebral arteries (MCA) (nZ22) before and one hour after alcohol consumption. Mean alcohol concentration one hour after intake was 1.04% (spirometric exhaled air analysis). Flow volume in the CCA increased from 903 ml/min to 1124 ml/min (C24%, P!0.0001), volume flow in the ICA increased only from 481 ml/min to 518 ml/min (C8%, P!0.05). The average MCA peak systolic flow velocity rose by 7.5% from 122 cm/s to 131 cm/s (P! 0.0002). Subtracting ICA volume flow rates from the CCA volume flow rates, we calculated a mean volume flow increase in the external carotid arteries of 46%. These data indicate only a moderate alcohol-induced vasodilation of the intracranial resistance vessels causing a mild hyperperfusion state compared to a massive dilation in the extracranial vascular territory. MCA flow velocity changes correspond closely to the ICA flow volume changes indicating no dilatory or constrictory effect of alcohol on the major basal cerebral arteries.

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Origin and Spread of Periinfarct Depolarization in Rats Detected by ECoG and MEG—Giebler F1, Ringer T2, Ro¨ther J 3, Nowak H4, Eiselt M5 (1Jena; 2Jena; 3 Hamburg; 4Jena; 5Jena) The knowledge about the origin and the spatio-temporal pattern of propagation of spreading depolarization (SD) after focal ischemic brain infarction is limited. Using the information of the simultaneously recorded ECoG and MEG it seems possible to describe the localization of underlying neurophysiological processes. We investigated in 8 rats 32 periinfarct depolarizations by simultaneously recorded ECoG and MEG. The ECoG was recorded by a grid of 4!4 electrodes with a spatial distance of 1.25 mm between adjacent electrodes. The MEG was recorded by a 16-channel Micro-SQUID system built at the Biomagnetic Center (1st order asymmetric gradiometers, 6.7 mm pick-up-coil diameter, 30 mm baselength, covering an area of 3.2!3.2 cm2). Infarction was initiated via occlusion of the right middle cerebral artery. From the ECoG the moment and location of the first detected negative deflection, the sequence of the involvement of cortical regions and the spatial distribution of the amplitude of depolarization were determined. From MEG the temporal pattern of main intracortical current was estimated. The frequency of SD was 5/hr (Z12G6 min). Negative deflection of electric potential could be detected at first over rostro-medial regions. The location of the maximal depolarization amplitude varied intra- and interindividually. In most cases SD waves propagated from rostro-medial to caudal regions. In 26 of 32 electric SD, magnetic field changes were detected. Often (nZ12) long-lasting magnetic field changes started before electric changes. The mean duration of these changes varied considerably (205G163 s). We suppose that the origin of periinfarct depolarization is frequently located in frontal cortical regions and that subcortical depolarization may contribute to the MEG signal.

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Verification of the DTI-Fiber Tracked Tractus Corticospinalis during Neurosurgical Procedures—First Results—Glaser MB1, Welschehold S2, Grunert P3, Perneczky A4, Dellani PR5, Tropine A6, Sto¨ter P7 (1Gau-Bischofsheim; 2Mainz; 3Mainz; 4Mainz; 5 Mainz; 6Mainz; 7Mainz) Object: Our aim was to validate the via DTI constructed pyramidal tract by intraoperative monitoring modalities-only nice images or rendering of a functional sytem? Methods: With help of measurements of the isotropy, white matter tracts could be detected. The pyramidal tract was reconstructed by choosing ROIs within its well known anatomic sites. These results were imported in two neuronavigation systems (either BrainLabw or SonoWandw). During tumor resections the cortical and/or subcortical sites as displayed in the navigation systems were stimulated with an Ojemann cortical stimulator and/or Oxford Medelec Synergy using different patterns. The patient’s postoperative clinical status was examined. Results: In 5 of 11 cases the direct subcortical stimulation of the position of the pyramidal tract displayed in the neuronavigation led to contralateral limb movements and/or electromyographic potential recording. In 4 cases cortical stimulation in the gyrus to which the fiber tracking led was successful. The precentral gyrus was here also identified by phase reversal. In 3 patients there was no motor response in stimulation and no phase reversal detected. The cause was either the large distance to the pyramidal tract or in one case of a recurrent glioma a marked fibrosis in the resection cavity, probably acting as an isolation. Only one patient experienced a postoperative neurological deterioration. Conclusion: The intraoperative electrophysiological findings of the neuronavigation implemented DTI detected pyramidal tract seem to support its correlation with its anatomic sites. In case of confirmation in further investigations, the fiber tracking may be a valuable supplement to neuronavigation and may help to make performance of resections near the motor system safer.

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Functional Dissociation of a Subcortical and a Cortical Component of High-Frequency Oscillations in Human SEPs by Motor Interference—Gobbele´ R1, Waberski TD2, Klostermann F3, Curio G4, Buchner H5 (1Aachen; 2 Aachen; 3Berlin; 4Berlin; 5Recklinghausen) To identify the possibly divergent impact on early and late high-frequency oscillations (HFOs) in human somatosensory evoked potentials (SEPs), we have studied motor interference effects on the HFOs, and the relevance of such effects for the controversy concerning their origins. While the late HFO is thought to be generated in the somatosensory cortex, there is an ongoing discussion whether the early burst is of cortical or subcortical origin. Movements of the index finger were performed in parallel with median nerve SEP recordings. The intracortically generated N20-SEP and the late HFO were attenuated by the motor task, while the brainstem low-frequency P14-SEP and the early HFO remained unaffected. These differing effects are consistent with a generation of the early HFOs by cortical presynaptic activity in terminals of the thalamocortical projection, and confirm a postsynaptic intracortical origin of the late burst subcomponent.

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High-Frequency (600 Hz) SEP Oscillations—Generators and Pathophysiological Aspects—Gobbele´ R1, Buchner H2 (1Aachen; 2Recklinghausen) Human median nerve somatosensory evoked potentials (SEP) contain a low-amplitude (!500 nV) high-frequency (~600 Hz) burst of repetitive wavelets (HFOs) which are superimposed onto the primary cortical response ‘N20’. The following studies in human subjects are aimed to further clarify the cortical and subcortical structures involved in the generation of the HFOs and the (patho)physiological meaning of this somatosensory oscillatory activity. (1) 128-channel SEP recordings were obtained to right median nerve stimulation and ulnar nerve stimulation. Different source evaluation strategies provided converging evidence for a cortical HFO origin, with two different almost orthogonally oriented generators being active in parallel. The cortical HFO source constellation points to a ‘precortical’ source in terminals of thalamocortical fibers and a second intracortical HFO origin. Additionally, generation of the HFOs was localized in subcortical, near thalamic and subthalamic source sites. (2) We tested the hypothesis that HFOs might be more sensitive to temporal dispersion caused by demyelinating lesions in multiple sclerosis (MS) than the N20. HFOs in median nerve SEPs in 50 patients with definite MS and in 30 healthy controls were recorded. Three patterns of SEP alterations were found: (i) abolished HFOs with either normal (11% of stimulated limbs), or delayed N20 (16%); (ii) an attenuation of N20 amplitude with preserved HFOs (13%); and (iii) a mixture of both patterns (21%). The first pattern -normal N20 with abolished HFOs- indicates that the HFOs are a sensitive marker of slight demyelination. The second pattern is suggestive of a mainly axonal lesion type, while the third pattern points to a combined axonal/demyelinating process or a conduction block. Analysis of HFOs allows identification of slight demyelinating processes in MS patients in whom the N20 SEP component remains unaffected. (3) The behavior of HFOs in a cohort of schizophrenic patients in comparison to an age- and sex-matched group of controls was tested. HFOs in the group of patients showed a delayed latency. In the low frequency part of the SEPs an increase in amplitude was found. These results are interpreted as a lack of somatosensory inhibition in the somatosensory pathway, either on a thalamic or a cortical level. HFOs are an interesting tool to explore functionality and pathophysiology of the lemniscal system, especially of dysfunctions in thalamocortical impulse propagation.

slices obtained from one patient suffering from partial seizure with aura, induction of SD elicited ictal-form epileptic activity. In 16 slices obtained from another 6 patients SD did not change the bioelectrical activity. However, initiation of SD after superfusion with gamma-aminobutyric acid (GABAA) receptor antagonist bicuculline (5 microM) for 60 min induced ictal-form epileptic activity in all tested slices. The results indicate that SD may increase the neuronal excitability in human brain tissue and trigger the seizure attacks in some epileptic patients.

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Modulation of Afferent Inhibition in Healthy Subjects—Gorsler A1, Weiller C2, Liepert J3 (1Hamburg; 2 Hamburg; 3Hamburg) Object: To investigate factors that modulate afferent inhibition (AI) in healthy subjects. Methods: AI was evoked by electrical stimuli applied over digit V of the right hand given 15, 25, 35 and 50 ms prior to transcranial magnetic stimulation (TMS) over the left M1. Motor evoked potentials (MEP) of single and double pulse TMS were recorded from the right abductor digiti minimi (ADM) and right abductor pollicis brevis (APB). We first studied the influence of contralateral voluntary preinnervation of the left hand on AI recorded from the right hand. Secondly, we studied effects of electrical stimulation (three times sensory threshold, 12,000 stimuli, frequency of 5 Hz) over right digit V on paired pulse MEP amplitudes and AI. Results: We found that contralateral preinnervation decreases AI in ADM and APB. After 12000 electrical stimuli AI disappeared in the early interstimulus interval (ISI) of 25 ms whereas at 50 ms ISI AI was reduced. The electrical sensory stimulation had no effect on paired pulse and on single pulse MEP amplitudes. Conclusion: First, AI can be modulated by interhemispherical effects. Secondly, after 40 min of high frequency sensory-electrical stimulation we find afferent disinhibition. The absence of changes of paired pulse amplitudes and single pulse MEP amplitudes poststimulation indicates that the sensory intervention did not modify excitability in the motor system. The change in AI suggests that the effect primarily occurs in the somatosensory cortex. An excitability change in S1 probably reduces the inhibitory effect of AI on M1.

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Spreading Depression and Epileptic Activity in Living Human Neocortical Tissues—Gorji A1, Speckmann EJ2 (1Mu¨nster; 2Mu¨nster) The close kinship between spreading depression (SD) and experimental epileptic activity has stimulated extensive investigation into the mutual relationship of these two phenomena. Despite the many studies into the simultaneous occurrence of SD and epileptiform burst discharges in animal neuronal tissues, the interaction of these phenomena in human neuronal tissues is not clear. Therefore, the effect of SD on the bioelectrical activity of human neocortical tissues was tested in neocortical slice preparations from 15 patients who underwent surgery for the treatment of refractory epilepsy. Synchronous rhythmic sharp field potentials appeared spontaneously in 12 slices obtained from 8 patients. SD significantly enhanced the repetition rate and amplitude of these rhythmic potentials in all tested slices. In 4

Alzheimer’s Disease: A Challenge for BAPtists and TAUists—Go¨tz J1 (1Zu¨rich) Alzheimer’s disease (AD) is characterized clinically by a progressive loss of memory and other cognitive functions, resulting in dementia. The cognitive decline is associated with neuron loss and the accumulation in the brain of both extracellular beta-amyloid (Abeta42) containing plaques and intracellular neurofibrillary tangles (NFT). The latter contain hyperphosphorylated tau protein as the major proteinaceous component. Tau pathology is a central neuropathological characteristic of many neurodegenerative disorders that are characterized by dementia. To model tau aggregation and NFT formation in vivo, we generated transgenic mice which express human tau together with mutation P301L which is associated with FTDP-17, an inherited form of dementia with similarities to AD. To test the amyloid cascade hypothesis, that claims a role of beta-amyloid in NFT formation, we stereotaxically injected beta-amyloid into brains of transgenic

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and control mice. Beta-amyloid induced a five-fold increase in NFT in the amygdala of P301L transgenic mice, but not in that of control mice. NFT formation was associated with phosphorylation of tau at S422. Mutagenesis of this epitope in a human tissue culture system abrogated both the Abeta42-mediated reduction in tau solubility and tau filament formation. Amygdala-dependent tasks revealed that P301L mice had anxiety levels not different from wild-types, but their exploratory behavior was significantly increased. Acquisition of a fear response to tone and context as well as taste aversion was comparable to wild-types. However, extinction of a conditioned taste aversion (CTA) was significantly accelerated. To gain insight into pathogenic mechanisms, we used proteomic and transcriptomic approaches. Differentially expressed genes were identified with Affymetrix chips followed by real-time quantitative PCR, in situ hybridization analysis of brain sections, and Northern blots. One of the upregulated genes, glyoxalase I, is part of a cellular detoxification pathway and prevents the formation of advanced glycation end-products (AGEs). We found an accumulation of glyoxalase I protein in tangle-shaped neurons in AD brain. The proteomic approach identified proteins involved in detoxification, mitochondrial function and neurite outgrowth. Together, we aim to identify genes involved in filament formation and neurodegeneration, to dissect patho-cascades and to develop treatment strategies designed to prevent or halt AD and related disorders.

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Effects of Environmental Enrichment on Endogenous Stem Cell Proliferation and Differentiation in the Dentate Gyrus after Focal Brain Ischemia—Grass S1, Wurm F2, Kunze A3, Witte OW4, Redecker C5 (1Jena; 2 Jena; 3Jena; 4Jena; 5Jena) Activity significantly influences endogeneous stem cell proliferation and neurogenesis under physiological conditions, but only little is known about the effects of environmental stimulation on these processes following brain insults like focal ischemic stroke. In the present study, we analyzed the proliferative response and differentiation of progenitor cells in the dentate gyrus after focal cortical infarcts in adult rats. Photothrombotic infarcts (PT) were induced in the forelimb sensorimotor cortex and the proliferation marker bromodeoxyuridine (BrdU, 50 mg/kg per day) was injected intraperitoneally at day 3 to day 7 after the surgery. Controls received a sham surgery. The animals were either housed in standard conditions (ST-Sham, ST-PT) or in an enriched environment (EE-Sham, EE-PT) for 10 or 42 days. BrdU incorporation and differentiation were immunocytochemically analyzed using light and confocal microscopy. After 10 days the number of BrdU-labelled cells was significantly increased in STPT animals compared to ST-Sham controls. EE housing did not enhance the number of BrdU-positive cells in EE-PT animals compared with the ST-PT group and only a slight increase was observed in EE-Sham compared with ST-Sham. However, 42 days after ischemia animals held in the enriched environment (EE-PT) showed a significant postischemic increase in total number of BrdU-labelled cells compared with standard conditions (PT-ST). The present study clearly demonstrates that environmental enrichment after focal stroke increases the survival of newborn cells in the dentate gyrus. Supported by DFG Re 1315/3-1.

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Analysis of EEG and MEG Signals with Matching Pursuit—Gratkowski M1, Haueisen J2 (1Jena; 2Jena) Introduction: A wide spectrum of methods has been used for analysis of biomedical signals. A relatively new and promising approach to signal analysis is matching pursuit (MP). The main advantage of the MP algorithm is its ability to create a concise description of an analyzed signal with a relatively small number of components localized in the time-frequency space with maximal possible, adaptive resolution. We applied MP to real MEG and EEG signals in order to present its possible applications. Methods: MP creates signal approximations based on a linear combination of a small number of vectors (atoms) chosen from a bigger, redundant set (dictionary). The atoms are iteratively chosen in order to best match the signal structure. In the first iteration the best matching atom is subtracted from the signal. This creates a signal residuum. The next step is to find the best matching atom with the residuum. This procedure is repeated until the desired approximation energy level is reached. With a dictionary of Gabor time–frequency atoms (scaled, translated and modulated Gauss functions) MP is an adaptive time–frequency transformation. The Gabor atoms are described by five parameters. These parameters localize the atom in the time–frequency space. We applied MP to real MEG and EEG data. Neuromagnetic fields were recorded over the contralateral somatosensory cortex with a 31-channel biomagnetometer. Constant current 0.2 ms square wave pulses were delivered to the right wrist at a stimulation rate of 4 Hz. The individual sensory and motor thresholds were determined and the stimulation strength was set to a value equal to the sum of sensory and motor thresholds. Simultaneously electric scalp potentials were recorded using 32 electrodes. We analyzed the so-called 600 Hz component and filtered out artefact components. Conclusions: The description of the 600 Hz component obtained using MP was consistent with the one found in a previous study, where a Gabor filter was used for the analysis of the same data. The advantage of MP is that the signals were well described with only 15 components. The parameterization of the signals makes further processing very simple. The possible applications of MP are filtering, i.e., artefact rejection (stimulus artefacts or 50 Hz powerline noise) or separation of the signal components that are of interest (e.g., 600 Hz components) and automatic signal recognition through detection of characteristic signal components or component groups.

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Modulation of Long-Range Neural Synchrony Associated with Changes in Visual Attention—Gross J1, Schmitz F2, Schnitzler I3, Kessler K4, Shapiro K5, Hommel B6, Schnitzler A7 (1Du¨sseldorf; 2Du¨sseldorf; 3 Du¨sseldorf; 4Du¨sseldorf; 5Bangor, Wales; 6Leiden; 7 Du¨sseldorf) A large number of studies have so far tried to uncover the rules governing the attention-driven modulation of bottom-up processes [1] and succeeded in identifying areas for the attentional control of visual processing among which frontal, temporal and parietal areas play a prominent role. Still, little is known about the mechanism by which these areas interact. We used magnetoencephalography to study transient long-range neural communication, by means of phase synchronization among these areas, in a challenging task which induces deficits of temporal visual attention. Two target letters embedded in a stream of 13 distractor letters were visually

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presented to 10 healthy subjects at a rate of seven per second. The targets were separated in time by a single distractor. This condition leads to a dual-task interference in a well-studied behavioral phenomenon known as the ‘attentional blink’ (AB)—the reduced ability to report the second target when an interval of less than 500 ms separates them. A time-frequency representation (TFR) was computed, time-locked to the presentation of behaviorally meaningless distractors and subtracted from the corresponding TFR of correctly detected target letters. The difference TFR reveals an enhancement in the beta-frequency range (around 15 Hz) at a latency of about 400 ms after target presentation. The neural generators giving rise to this TFR signature of target processing were localized in each individual subject using ‘dynamic imaging of coherent sources’ DICS [2]. Spatial normalization and permutation analysis were employed and resulted in the identification of eight significant regions-of-interest across subjects: occipital, frontal left, frontal right, temporal left, temporal right, posterior parietal left, posterior parietal right, cingulum. Mean phase synchronization between specific areas was modulated by the behavioral relevance of the stimuli and the perceptual outcome. Our results demonstrate that distinct spatio-temporal patterns of transient long-range phase synchronization in a frontoparieto-temporal network distinguish the trials in which physically identical stimuli were perceived or not. Thus synchronization/desynchronization appears to be a candidate mechanism for enhancing target processing and may define an important aspect of what we commonly refer to as ‘attention’. References Desimone R, Duncan J. Annu Rev Neurosci 1995; 18: 193–222. Gross J et al. Proc Natl Acad Sci USA 2001; 98: 694–699.

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Oscillatory Communication between Cerebral Areas Associated with Essential Tremor—Gross J1, Schnitzler A2, Mu¨nks C3, Butz M4, Timmermann L5 (1Du¨sseldorf; 2 Du¨sseldorf; 3Du¨sseldorf; 4Du¨sseldorf; 5Du¨sseldorf) With an estimated prevalence of about 5%, essential tremor (ET) is the most frequent movement disorder. Nevertheless, the pathophysiological mechanisms giving rise to this usually bilateral 5–9 Hz action tremor which mostly affects the upper extremities are still largely unknown. There is accumulating evidence that ET is at least partly of central origin. Animal models suggest an involvement of the inferior olive. PET and fMRI studies showed activation in several brain areas including cerebellum, thalamus and primary motor cortex, and an EEG-EMG coherence study demonstrated involvement of the primary sensorimotor cortex. In addition, the effect of deep brain stimulation in the thalamus of patients suffering from essential tremor reduces the action tremor, pointing towards an important involvement of the thalamus in the generation or mediation of tremor. We studied 8 patients with essential tremor by recording simultaneously neural activity with a whole-scalp neuromagnetometer (MEG) and peripheral tremor activity with surface electrodes (EMG). Subjects performed an isometric contraction of the left forearm for a total duration of about four minutes with interleaved rest periods of 30 s. All subjects showed a tremor at a frequency of 5–7 Hz. Tremor frequency and its first harmonic were clearly evident in power spectra of the EMG recordings. We used the localization technique DICS to identify cerebral areas with significant coherence to EMG at tremor frequency and its first harmonic. Coherence is a

correlation measure in the frequency domain, which is normalized between 0 and 1. All subjects showed significant coherence between EMG of the wrist extensor muscle and contralateral primary motor cortex. All but one subject showed significant coherence between EMG and ipsilateral cerebellum. Phase delays between cerebral areas and EMG at the tremor frequency and its first harmonic were computed and indicated the existence of both afferent and efferent components in the coupling. In a further step DICS was used to identify areas of significant cerebro-cerebral coherence. The analysis revealed a network of areas consisting of contralateral primary motor cortex, premotor cortex, thalamus, brainstem and ipsilateral cerebellum, which showed strongest coupling at twice the tremor frequency. Partial coherence analysis excluded the possibility that one central driving oscillator simply entrains oscillations in these areas leading to spurious coherences. These results are consistent with the view that in ET patients a brainstem-cerebello-thalamo-premotor-motor cortical network shows oscillatory interactions which lead to a rhythmic modulation of muscle activity becoming apparent as tremor.

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Cortical and Pyramidal Tract Pathology in ALS Patients as Detected by Voxel-Based Morphometry and Diffusion Tensor Imaging—Grosskreutz J1, Fra¨drich J2, Kaufmann J3, Ribanna H4, Bufler J5, Dengler R6, Heinze HJ7, Peschel T8 (1Hannover; 2Hannover; 3 Magdeburg; 4Hannover; 5Hannover; 6Hannover; 7 Magdeburg; 8Hannover) Objective: We have attempted to detect brain abnormalities in ALS patients by using an unbiased approach with optimized voxelbased morphometry and diffusion tensor imaging in comparison to healthy controls. Background: In ALS patients, the presence of cerebral atrophy on conventional and scientific neuroimaging has been a matter of debate. We therefore applied voxel-based morphometry (VBM) and diffusion-tensor imaging (DTI) as powerful unbiased wholebrain methods to detect subtle regional differences in grey matter volume (GMV) and fractional anisotropy (FA). Methods: 17 ALS patients diagnosed according to the revised El-Escorial criteria and 17 age-matched control subjects were enrolled in this study. The mean revised ALS functional rating scale score (ALSFRS-R, meanGSD) was 40G5. All subjects had a 3D T1-weighted high-resolution anatomical MRI and FA maps derived from 12 bidirectional planes on a 1.5T neuro-optimized GE scanner. Images were analyzed using an optimized protocol in SPM99. Group comparisons of regional grey matter volume (modulated data) were made using ANCOVA with the global mean voxel value as confounding factor. Relationships between significant voxels and the ALSFRS-R were modelled using regression analyses. We also performed a small volume correction (SVC, 10 mm sphere) when a priori hypotheses about regional effects existed. Results: ALS patients showed a relative decrease in GMV in the precentral gyrus bilaterally, inferior parietal lobe and the middle frontal gyrus bilaterally. There was a positive correlation between ALSFRS-R and GMV in the frontal superior gyrus and the inferior parietal lobe. A significant decrease of fractional anisotropy indicating fiber damage was found in the corticospinal tract, along commissural fibers and frontal projections.

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Single subject blinded analysis of FA contrast maps allowed the detection of ALS pathology in 16 out of 17 patients. Conclusion: Using VBM, our results consistently show atrophy in precentral, parietal and frontal regions which is in line with findings of pathology extending from the sensorimotor cortex to frontal areas in ALS. The changes seen in DTI also indicate widespread pathology in the corresponding fiber tracts. Our study supports the view that ALS is a multisystem disorder which is not restricted to the motor system. Longitudinal studies should give new insight into the spatiotemporal characteristics of cerebral abnormalities in ALS.

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Positron Emission Tomography in Psychiatric Research—Gru¨nder G1 (1Aachen) Since the first visualization and quantification of D2 dopamine receptors with positron emission tomography (PET), nuclear imaging technology with PET and single photon emission computed tomography (SPECT) has led to an enormous gain in knowledge about the neurobiology and treatment of psychiatric disorders. With the development of selective high-affinity tracers for a large variety of neurotransmitter receptors and other targets such as enzymes it became possible to study normal and pathological neurochemistry in vivo in the human brain. In neuropsychopharmacology, PET led to a profound understanding of the relationships between dosages and plasma concentrations of psychotropic drugs on the one hand and occupancy of target receptors and related clinical effects and side effects on the other hand. Furthermore, nuclear imaging helped to generate hypotheses regarding the mechanism of action of certain compounds. This presentation will illustrate current approaches in PET research and their clinical applications with applications from research on schizophrenic and addictive disorders, especially alcohol dependence. It will cover a broad range of transmitter systems like dopamine (receptors and metabolism), serotonin, GABA, and opioid, as well as glucose metabolism as studied with fluorodesoxyglucose. The characterization of antipsychotics with PET will exemplify current research strategies in neuropsychopharmacology. PET, like no other method, is suitable to display in vivo the neurobiochemistry of psychiatric disorders and the psychopharmacology that is used to treat those disorders.

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The Influence of Anisotropic Conductivity on the EEG Source Localization Investigated with an FEM Volume Conductor of an Animal Model—Gu¨llmar D1, Reichenbach JR2, Eiselt M3, Haueisen J4 (1Jena; 2Jena; 3 Jena; 4Jena) Purpose: Source localization based on EEG/MEG data is a widely used technique to investigate neuronal activity. It tries to localize focal sources (dipoles) in order to represent the external measured signal (EEG/MEG) solving an inverse problem. Thereby the accuracy of the results depends on the given volume conductor model. Volume conductor modeling using the Finite Element Method (FEM) opens the possibility of taking into account the anisotropic conductivity of, e.g., the white matter tracts. In our study we investigated the influence of this anisotropy on solving the forward and inverse problem using an animal model. Material: Using a T1-weighted MR image, we segmented the head of a rabbit into four different tissue layers (skin, skull, grey

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and white matter). Additionally, we performed diffusion-tensors imaging to obtain the anisotropy of the white matter tissue. The orientation of the diffusion tensors was used to model anisotropic conductivity tensors in the white matter of the rabbit brain employing an adopted anisotropic ratio of 1:10. 650 dipoles in the cortical region in intervals of 1 mm and radial orientation served as sources. Using the anisotropic model we performed EEG simulation to asses EEG potentials at 100 electrodes placed on the rabbit head. With the computed potentials we performed source localization using the same model but with isotropic conductivity tensors. This corresponds to the assumption of a source localization with an isotropic model and realistic measurement data, which include effects of anisotropic conductivity. Results: All dipoles were shifted in their location and changed in their orientation due to the isotropic model with data derived from the anisotropic model. The shift was up to 2 mm with a mean of 0.69 mm. The averaged orientation deviation was 23.7 degrees and the mean magnitude change of the dipole was determined with a value of 24.2 percent. Conclusion: In this study we have shown the influence of conductivity anisotropy on EEG source simulation and localization with the help of an FEM model of a rabbit head. Volume conductor modeling in EEG source localization procedures including anisotropy will improve accuracy of the localization results.

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Ictal Dysprosodia: Documentation by Fourier Spectral Analysis—Gu¨rtler S1, Franke K2, Ebner A3 (1Bielefeld; 2 Jena; 3Bielefeld) Introduction: Dysprosodia in the literal sense is the disturbance of the speech melody which usually transports emotional contents of language. It accompanies sometimes aphasias but appears typically without aphasic symptoms in lesions of the nondominant right hemisphere. Dysprosodia as an ictal phenomenon, however, is reported rarely. Methods: We report on a patient with dysprosodia during ictal speech. Ten seizures were documented by video EEG monitoring. The sound track of the video was then analyzed by Fourier spectral analysis. Results: The 22-year-old woman had suffered from epilepsy since age 13 years, she reported an abdominal aura and psychomotor seizures. As a possible precipitating event there had been febrile seizures at the age of 13 months. MRI showed a rightsided hippocampal sclerosis. Interictal epileptiform discharges had their maximum on the right sphenoidal electrode and, rarely, the right temporal anterior one. We recorded 2 isolated auras without EEG seizure pattern and 8 psychomotor seizures, in all of them we recorded a right temporal EEG seizure pattern. During the psychomotor seizures with mainly oral automatisms the patient remained responsive and could name objects and talk to the EEG assistants, but the speech melody was severely disturbed and sounded unnaturally monotone. The characterization of the dysprosodia by Fourier spectral analysis revealed that the monotone character of the speech was produced by superposition of a ‘wrong’ speech melody and not simply by reducing the pitch range. There was an increasing glissando over an interval of up to a fifth over most of the ictal utterances instead of the falling of the tone in a declarative sentence. In the end of the seizures the normal speech melody gradually reappeared, but the modulation of

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the pitch was diminished. Another feature in this patient was an increase of the pitch level of about a third. Conclusions: Dysprosodia can be a prominent feature of epileptic seizures. We documented this symptom in a classical mesial temporal lobe epilepsy of the non-dominant hemisphere. Dysprosodias may often be unrecognized as they are difficult to describe and prove objectively. Fourier spectral analysis may help in the documentation and description of ictal prosodic changes.

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Cerebral Dysfunctions in Schizophrenia Patients: Characterization of Relevant Factors of Influence— Habel U1 (1Wien) For the valid interpretation of functional neuroimaging results of dysfunctions as well as reorganization processes in schizophrenia patients, several methodological as well as conceptual factors are of relevance. Quality assurance procedures are especially important for multi-center studies but also in general for data acquisition and sequence optimization, especially with respect to investigations of emotional processes focusing on subcortical structures such as the amygdala. Furthermore, existing neuropsychological paradigms have to be evaluated for the neuroimaging environment or/and new neurobehavioral probes have to be developed and standardized, since they constitute the basis for valid results. Gender differences, task characteristics, influence of medication and sample characteristics are further factors of influence that have to be analyzed. Data acquired from different samples of healthy subjects and schizophrenia patients clarify the relevance of these factors for fMRI results. Cognitive and emotional processes, their interaction as well as dysfunctions in schizophrenia have been investigated with fMRI. In an advanced approach we aimed at differentiating trait and state components of these dysfunctions by investigating relatives of patients, firstepisode patients or patients with early-onset psychoses, which point to genetic influences and an early appearance of dysfunctions. Equally, long-term investigations of the illness course and the therapeutic effects of pharmacological as well as psychological interventions on the dysfunctional cerebral networks have been performed. Hypo- and hyperactivations emerged in a subcorticallimbic as well as cortical network in dependence on the task requirements. Results of the longitudinal studies document the therapeutic effects, normally seen on a behavioral level, in the underlying neuronal substrates and demonstrate the specific efficacy of pharmacological and behavioral therapy. They point to the benefit of neuroimaging procedures for clinical as well as basic research.

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Pathological Pulse Wave Latency as a Surrogate of Sympathetic Adrenergic Failure in Patients with Idiopathic and Atypical Parkinson Syndromes—Haegele S1, Vogt T2, Claus D3, Birklein F4 (1Mainz; 2Mainz; 3 Darmstadt; 4Mainz) Autonomic dysfunction is associated with idiopathic Parkinson’s disease (IPS) and atypical Parkinson syndromes (APS) like multiple system atrophy (MSA). One approach to obtain quantitative information about the status of orthostatic hypotension, in which sympathetic adrenergic failure may be predominant, is to measure blood pressure response to active standing up or tilting after supine rest. However, continuous recording of blood

pressure using commercial blood pressure monitors requires special equipment available only in specialized centers. We used the pulse wave latency (PWL) as a surrogate of beat-to-beat blood pressure. The PWL was calculated by the interval between the R wave of the ECG and the blood pressure pulse, which was recorded at the right earlobe by a photoplethysmographic device. It has been shown previously that changes of the PWL are negatively correlated to the changes of intra-arterial blood pressure recording with an almost perfect linear fit. The measurement of heart rate variability (HRV) to assess parasympathetic autonomic function is clinically routine in most autonomic labs. We used the device FANw (Schwarzer, Germany) which allows the recording of PWL and HRV at the same time. In 22 patients with Parkinson syndromes (IPS and APS) and 89 healthy controls we recorded PWL differences and HRV before and after Valsalva maneuver (VM), focusing on phase IV, the blood pressure overshoot. Our patients with Parkinson syndromes showed significantly (PZ 0.002) different results in terms of reduced PWL reduction after VM compared to controls. Concerning HRV only the coefficients of variation during deep respiration (PZ0.004) and at rest (PZ 0.032) were found to be statistically significantly different in patients with Parkinson syndromes as compared to controls. The measurement of PWL reduction after VM seems to detect pathology of the sympathetic adrenergic nervous system in patients with Parkinson syndromes.

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Selected Aspects of the History of Psychiatric Ideas and Institutions in the Past Two Hundred Years—Ha¨fner H1 (1Mannheim) More than any other medical discipline psychiatry has been and still is influenced by great ideas and social change. In the past 200 years psychiatry has experienced two revolutions of its system of care and an inhumane disaster. The French Revolution brought freedom and the right to treatment to the mentally ill locked away like prisoners in mad houses and insane asylums. As neither the causes of mental illnesses were known nor effective treatments available, the asylums soon resumed their old role as providers of custody and treatments that sometimes resembled torture. As a reaction to this situation German psychiatry bore an idealisticeducational movement, which in Kant’s tradition interpreted mental illness as a lost order of mind. Around 1830 C. F. W. Roller developed a theory of isolation, according to which persons suffering from mental illness must be removed from their allegedly pathogenous environment to regain their order of mind in the strictly organized environment of a remote mental hospital. Roller’s idealistic model of the isolated mental hospital spread around the world, thus essentially contributing to the isolation of psychiatry and the dreadful conditions that the mentally ill had to endure for almost a century. Evolutionary theory and genetics were followed by an ideological movement of biologism embraced by the leading classes in many countries. Medicine and care for the disabled were seen as counteracting the evolution of the mankind. The enormous increase in admissions to mental hospitals caused by social and demographic changes at the turn of the 20th century and decreasing fertility of the upper classes were misinterpreted as a degeneration of the population. After 1868 these fears led to more and more radical ideologies of eugenics and selective breeding. As a consequence of this movement Hitler in 1939 breached human rights by ordering the killing of the ‘incurably’ mentally ill. Some

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200,000 individuals fell victim to this policy. After World War II psychiatry had to bear the brunt of this disaster. It was not until the reform process was established-in Germany with a delay of about 15 years-that conditions for the mentally ill started to improve. Substantial improvement in the long history of treatment of mental illness did not occur until psychotropic drugs were discovered in the mid 20th century. Developments from the Expert Commission to the present day will be briefly discussed.

The Neuropsychology of Fear Learning—Hamm A1 (1Greifswald) In the current approach, fear conditioning experiments have been conducted with patients with various brain lesions. Moreover, multiple physiological measures are used trying to disentangle fear acquisition from contingency learning. In the first study, a case of intact fear conditioning to a visual cue is reported in a male patient with complete cortical blindness, suggesting that, at a simple level, fear acquisition does not require a cortical representation of the conditioned stimulus. In a second study, fear conditioning in 28 patients after left and right temporal lobectomy was compared to fear learning in 22 healthy controls. The data show a clear dissociation between conditioned startle potentiation and electrodermal response differentiation. While the latter was intact in half of the patients, startle potentiation could not be detected in patients with acute temporal lobectomy. Finally, data will be reported that suggest differences in learning depending upon whether the learning procedure was either a trace or a delay conditioning paradigm.

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Voxel MR Spectroscopy of Hippocampal Structures in Healthy Adults at 1.5 Tesla—How Stable are the Results?—Hammen T1, Tomandl B2, Neundo¨rfer B3, Stefan H4, Single H5 ( 1Nu¨rnberg; 2Erlangen; 3 Erlangen; 4Erlangen; 5Erlangen) Purpose: Although 1H-MRS is a non-invasive diagnostic tool for measuring metabolite alterations in patients with temporal lobe epilepsy, there are many sources of error, especially with regard to temporomesial structures. In order to meet the requirements of diagnostic tools, we evaluated the inter-subject variability and the test-retest stability of hippocampal single voxel 1H-MRS. Methods: We used an optimized, standardized method of short echo time 1H-MRS to study the hippocampal structures of 30 healthy adults. Spectral analysis and metabolite quantitation of Nacetylaspartate (tNAA), choline (Cho), creatine (Cr), total glutamate plus glutamine (GluCGln) and myo-inosidol (Ins) were carried out using an LC-Model, using water as an internal reference. After 4–6 weeks, 15 subjects were scanned again to determine long-term reproducibility. Results: Mean metabolite quantitation (mean valueGSD) was 6.9G0.38 mM for tNAA, 5.3G0.52 mM for Cr, 1.2G0.15 mM for Cho, 5.0G0.63 mM for Ins and 10.1G1.48 mM for GluC Gln. In terms of absolute quantitation, tNAA showed the smallest coefficient of variation (CV) of 5.6%, followed by Cr (9.8%), Cho (12.2%) and Ins (12.5%). Less stable was GluCGln (15%). Long-term reproducibility was tested by comparing the means of the metabolites of both sessions by paired t-test (tNAA: PZ0.789, TZ-0.273, dfZ14; Cho: PZ0.429, TZ-2.236, dfZ14; Ins: PZ0.734, TZ0.346, dfZ14; GluC

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Gln: PZ0.121, T-1,653, dfZ14; Cr: PZ0,042, TZ-2.236, dfZ 14). Conclusion: Our results show that 1H-MRS of hippocampal structures can be performed in a stable and reproducible way in routine clinical diagnostics.

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Tumors of the Peripheral Nervous System—Hanemann O1 (1Ulm) Tumors of the peripheral nervous system come in different histopathologies. The current WHO classification includes neurofibromas, invasive growing plexiform neurofibromas, schwannomas, cellular schwannomas, perineuromas and malignant peripheral nerve sheath tumors. They are frequent tumors and occur spontaneously as well as hereditary, i.e., as part of hereditary tumor diseases. Neurofibromas, invasive growing plexiform neurofibromas and malignant peripheral nerve sheath tumors are part of neurofibromatosis type 1 (NF1). Schwannomas, and cellular schwannomas are part of neurofibromatosis type 2 (NF2). NF1 and NF2 are prototypic diseases caused by mutation in genes coding for tumor suppressors. They are genetically well defined. These hereditary tumor diseases of the peripheral nervous system are characterized by childhood occurrence of tumors and multiplicity of tumors. In addition other tumors, especially of the central nervous system and non-tumorous pathology are found in these diseases. Until now surgery was the main therapy in these diseases. However, recent research using animal models and human in vitro models is the basis for the hope to find pharmacological molecular targets to treat these diseases. In NF2 many patients in addition suffer from general disease of the peripheral nervous system, presenting as polyneuropathy. In NF1 this is found only in few patients. Examples for tumors of the peripheral nervous system, their clinical presentation, radiological appearance and pathophysiology will be demonstrated.

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Congenital Fibrosis of Extraocular Muscles Type 1 with Progression of Ophthalmoplegia—Hanisch F1, Bau V2, Zierz S3 (1Halle/Saale; 2Halle/Saale; 3Halle/Saale) Recently, different syndromes with congenital, non-progressive, sporadic or familial developmental abnormalities of the cranial nerves and their nuclei were classified as congenital cranial dysinnervation syndromes (CCDD). Duane and Mo¨bius syndromes are well-known examples of CCDD. Another syndrome is the congenital fibrosis of extraocular muscles (CFEOM), which is characterized by a mainly bilateral ophthalmoplegia of the oculomotoric and trochlearic nerves. We present the case of a 60-year-old patient with CFEOM type 1 with autosomal-dominant inheritance and typical phenotype due to the common C2860T mutation in exon 21 of the newly identified KIF21A gene on chromosome 12 encoding a kinesin motor protein responsible for axonal transport. The documented course of our patient, however, clearly showed progression of the bilateral external ophthalmoplegia over the last 23 years. At the age of 37 years he complained about newly occurring blurred vision and diplopia, which implies the capability of binocular vision before. The angle of divergence progressed from 268 at age 37 to 458 at age 50. The poor residual movement on attempted adduction and upgaze had completely disappeared at age 57. Progression of external ophthalmoplegia might be caused by either the consequence of an overuse of

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the reduced number of oculomotoric brain stem alpha-motoneurons or a continuous disease progression due to the kinesin defect. The present case demonstrates the possibility of progression in CFEOM1 and casts doubt on the definition of CFEOM as a strictly non-progressive disorder.

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Vasculitis with Involvement of the Central and Peripheral Nervous System and Anti-Ro Antibodies— Harscher S1, Rummler S2, Oelzner P3, Isenmann S4, Mentzel HJ5, Witte OW6, Terborg C7 (1Jena; 2Jena; 3 Jena; 4Jena; 5Jena; 6Jena; 7Jena) Vasculitis of the nervous system is a rare cause of multifocal neurological symptoms and may involve both the central and peripheral nervous system. Typical symptoms include headache, encephalopathy with cognitive impairment, and psychotic symptoms, epileptic seizures, as well as peripheral neuropathies. Here, we report the case of 71-year-old female who presented with Raynaud syndrome and paresthesia of both feet. Some weeks later, she was admitted to our hospital with a status epilepticus with complex partial seizures. On admission she had mild aphasia and distal paresis of the arms without sensory deficits. MRI of the skull revealed small, multifocal infarctions in several arterial territories. Multiple cerebral artery stenoses were detected by ultrasound and MR angiography. CSF studies were unremarkable. Serological tests for autoimmune disorders detected ENA and Ro antibodies, compatible with systemic lupus erythematodes or Sjo¨gren’s syndrome. A sural nerve biopsy revealed ischemic axonal neuropathy. During administration of i. v. methylprednisolone, symptom progression stopped, but dosages could not be tapered due to severe CNS symptoms (mental decline, disorientation, aphasia, hallucinations). Slow, but sustained clinical improvement was achieved only by combined immunosuppressive treatment with cyclophosphamide, prednisolone, and immunoadsorption over 8 weeks, and was paralleled by a reduction of anti-Ro titers and normalization of cerebral blood flow velocities as detected by repeated transcranial Doppler sonography. Systemic vasculitis may present with multiple neurological and psychiatric symptoms due to an involvement of the central and peripheral nervous system. After exclusion of a systemic infection, immunosuppressive therapy should be started early. In our case, a combination of high-dose methylprednisolone, immunoadsorption with elimination of Ro antibodies, and cyclophosphamide led to the patient’s recovery.

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Astrocytic Connexin 43 mRNA is Upregulated in the Vicinity of the Photothrombotic Lesion in Rat Brain— Haupt C1, Witte OW2, Frahm C3 (1Jena; 2Jena; 3Jena) Intercellular coupling via gap junction channels is vital for astrocytic function. The role of gap junctional communication under ischemic conditions is discussed controversely. In our model of focal cerebral ischemia, we studied the expression of connexin 43, one of the major gap junction proteins in astrocytes. Connexin 43 mRNA is elevated in cells surrounding the lesion site which was shown by RNA/RNA in situ hybridization. The hybridization signal in pericarya around the lesion was much higher than in the remaining brain areas. This upregultion was further investigated by semiquantitative RT-PCR. Biopsies were taken from the lesion site as well as from the corresponding area in the intact hemisphere and

from sham-operated animals. In each analyzed animal (nZ6) with a focal cerebral ischemia the amount of specific PCR product was higher in the sample from the operated site than in the intact. Shamoperated animals (nZ5) showed no variation between sides. Realtime RT-PCR analysis confirmed the results obtained in semiquantitative RT-PCR studies. Our results affirm that gap junctions composed of connexin 43 play a role after ischemia. Whether this upregulation of connexin 43 mRNA after an ischemic insult contributes to neuroprotection or propagation of the cell needs to be determined.

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Model Based Development of Novel Deep Brain Stimulation Techniques—Hauptmann C1 (1Ju¨lich) Pathological synchronization is a hallmark of several neurological diseases like Parkinson’s disease (PD) or essential tremor [Alberts et al., Nature 1969; 221: 670; Nini et al., J Neurophys 1995; 74: 1800]. For example, a pacemaker-like population of neurons, which fires in a synchronized and periodical manner, provokes the Parkinsonian resting tremor [Alberts et al., Nature 1969; 221: 670]. In contrast, an uncorrelated, i.e., desynchronized firing pattern of these neuronal populations is characteristic in healthy subjects [Nini et al., J Neurophys 1995; 74: 1800]. In medically intractable patients, electrical deep brain stimulation (DBS) is administered via depth electrodes chronically implanted in the subthalamic nucleus of the thalamic ventralis intermedius nucleus [Benabid et al., Lancet 1991; 337: 403]. For that purpose, a permanent high-frequency (O100 Hz) periodic pulse train stimulation is used. Up to now the mechanism of high-frequency DBS is not yet sufficiently understood [Benabid et al., Lancet 1991; 337: 403]. We initiated a modelbased development of novel stimulation protocols to find milder and more effective DBS techniques [Tass, Phase Resetting in Medicine and Biology, Springer, 1999; Tass, Biol Cyb 2003; 89: 81]. In a first clinical study performed during electrode implantation, we have shown that the coordinated reset via multiple/several sites can suppress the peripheral tremor, even if the standard high-frequency DBS has no tremor suppressive effect at all [Tass et al., submitted (2004)]. Here we present a technique for the desynchronization of a strongly synchronized target population which we expect to be even more effective and milder. For this, delayed mean field potentials are administered at different sites within a neuronal population to establish a desynchronized state. According to detailed theoretical investigations and simulations, we expect the novel desynchronization technique to be considerably milder, to act in a demandcontrolled way and to be simple in realization. We use a microscopic model of a neuronal population in a relevant target area to show that the method is robust and does not require time consuming calibration. It is suggested that the novel technique is used for deep brain stimulation in patients suffering from Parkinson’s disease, essential tremor or epilepsy.

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Perceptual Decision-Making in the Human Brain— Heekeren H1 (1Berlin) Findings from single-cell recording studies suggest that a comparison of the outputs of different pools of selectively tuned lower-level sensory neurons may be a general mechanism by which higher-level cortical regions compute perceptual decisions. For example, when monkeys must decide whether a noisy field of dots is moving upward or downward, a decision can be formed by

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computing the difference in responses between lower-level neurons sensitive to upward motion and those sensitive to downward motion. I will present fMRI evidence that even for high-level object categories, the comparison of the outputs of different pools of selectively tuned neurons could be a general mechanism by which the human brain computes perceptual decisions. Furthermore I will argue that the posterior dorsolateral prefrontal cortex has general decision-making functions, independent of stimulus and response modalities.

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Physiological Mechanisms of Modulation of Motor Cortex Excitability by 1 Hz Suprathreshold rTMS— Heide G1, Witte OW2, Ziemann U3 (1Jena; 2Jena; 3 Frankfurt) Many studies show consistently that repetitive transcranial magnetic stimulation (rTMS) with a frequency of 1 Hz and an intensity of 115% of the resting motor threshold (RMT) performed for several minutes over the primary motor cortex (M1) leads to a depression of cortical excitability. Furthermore, most of the available studies concur on a facilitation of the non-stimulated contralateral M1. Little, however, is known about the physiological mechanisms underlying these effects. It is currently unclear whether the changes in the stimulated M1 are produced by increased excitability in cortical inhibitory circuits or decreased excitability in facilitatory neuronal circuits, and vice versa in the non-stimulated M1. In 11 healthy volunteers, we stimulated the left M1 for 15 min with 1 Hz rTMS of 115% RMT. Before, immediately after, and 30 min after the rTMS train, we examined short-interval intracortical inhibition (SICI; ISI 2 and 4 ms), intracortical facilitation (ICF; ISI 10 ms), and short-interval cortical facilitation (SICF; ISI 1.5 ms) with an established paired-pulse protocol. Mean unconditioned MEP amplitudes and RMT were measured at the same time points. Two sessions were run at least one week apart, in one session the stimulated M1 was tested, in the other one the non-stimulated M1. Repetitive TMS led to the expected reduction of MEP amplitude in the stimulated M1, which was significant only immediately after the rTMS train. rTMS resulted in an increase in MEP amplitude in the non-stimulated M1, which lasted for at least 30 min. RMT, SICI, ICF and SICF did not show any significant change in either M1, except of a long-lasting increase of SICF in the non-stimulated M1. In conclusion, the MEP increase in the non-stimulated M1 lasted longer than the MEP decrease in the stimulated M1. Only the long-lasting MEP increase was associated with a specific change in intracortical excitability (increase in SICF) compatible with an LTP-like mechanism. In contrast, modulation of motor cortical inhibition did not play a role in explaining the rTMS-induced changes in MEP amplitude.

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Specific Deficits of Saccadic Eye Movements after Sleep Deprivation—Heide W1, Zils E2, Sprenger A3, Gais S4, Born J5 (1Celle; 2Lu¨beck; 3Lu¨beck; 4Lu¨beck; 5Lu¨beck) Sleep deprivation (SD) and reduced vigilance impair not only the performance of cognitive tasks, but also of saccadic eye movements. Previous literature reports reduced peak velocities and prolonged latencies of visually-guided saccades, but the latter remained controversial. To clarify which specific saccadic

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subfunctions reflect reduced vigilance, we investigated the effect of a one-night SD on 3 different types of saccades that are controlled by different cortical networks: (1) visually-guided prosaccades controlled more by the parietal (PEF) than by the frontal eye field (FEF; (2) anti-saccades (performed into the direction opposite to a peripheral target, with respect to the vertical meridian), controlled by FEF, the dorsolateral prefrontal cortex (DLPFC), and the basal ganglia loop; (3) memory-guided saccades (performed to a peripheral target that had been flashed 1 to 30 s before), controlled by the PEF, the FEF, the supplementary eye field (SEF), the DLPFC and the basal ganglia loop. Eye movements were recorded using EOG in 15 healthy adults at 3 different times: in the evening prior to SD (baseline), in the next morning following a one night’s SD (day 1), and 24 h later (day 2), following a night of sufficient sleep. A control group of 15 healthy adults was tested similarly, but without SD. Results showed specific effects of SD only on day 1, that had recovered completely on day 2 and were not found in the control group: (1) reduced peak velocities of all 3 types of saccades, indicating dysfunction of the paramedian pontine reticular formation (PPRF) , which is part of the ascending reticular system involved in sleepwake regulation; (2) prolonged latencies only of memory-guided saccades, but normal metrics, reflecting impaired initiation of voluntary saccades. Due to their long memorization times of up to 30 s they had to be initiated almost like self-paced saccades which are controlled by the SEF. (3) Dysmetria (mainly hypometria) of visually-guided saccades, indicating rather a cerebellar dysfunction, as the essential functions of the PEF (latency of visuallyguided saccades and metrics of memory-guided saccades) and of the FEF (error rate and latency of anti-saccades) were not affected. We conclude that sleep deprivation and reduced vigilance cause dysfunction of specific brain areas, such as the SEF, the cerebellum, and the PPRF, whereas other areas were not affected, particularly the primary frontal and parietal eye fields.

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Pathophysiological Mechanisms in Parkinsonian and Essential Tremor—Hellwig B1 (1Freiburg) The present project deals with the pathophysiological basis of the two most frequent tremor disorders, Parkinsonian and essential tremor. Combined EEG-EMG investigations provided evidence that there is tremor-correlated activity in the sensorimotor cortex in both Parkinson’s disease and essential tremor. This suggests that the sensorimotor cortex is involved in tremor generation, and that the tremor generating mechanisms in both disorders are partly identical (Hellwig et al., Clin Neurophysiol 2000; 111: 806–809; Hellwig et al., Lancet 2001; 357: 519–523). In bilaterally activated essential tremor, tremor-correlated activities in the right and left sensorimotor cortex are not entirely independent of each other. Central oscillators in the right and left brain seem to synchronize in a dynamic way, presumably by interhemispheric coupling via the corpus callosum. This right-left synchronization is associated with increased tremor amplitudes (Hellwig et al., Clin Neurophysiol 2003; 114: 1462–1467). In unilateral Parkinsonian rest tremor, PET studies and morphometrically analyzed MRI studies showed both functional and morphological changes in the ventrolateral thalamus contralateral to the tremor side. The amount of the thalamic changes covaried with tremor amplitudes. The functional changes were located in the nucleus ventrooralis anterior and

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posterior, a thalamic subnucleus receiving input from the basal ganglia. The morphological changes were found in the nucleus ventralis intermedius whose afferences are derived from the cerebellum. The results support the hypothesis that both the basal ganglia and the cerebellum are involved in the generation of Parkinsonian tremor (Kassubek et al., Neurosci Lett 2001: 304: 17–20; Kassubek et al., Neurosci Lett 2002; 323: 29–32). Electromyographic recordings from the wrist extensors and flexors showed that both Parkinsonian and essential tremor are influenced by the position of the hand. This indicates that the activity of the central oscillators in both disorders can be modified by proprioceptive afferences (Lauk et al., Muscle Nerve 2001; 24: 1365–1379). The present results and the studies of other groups provide the basis for pathophysiological models of Parkinsonian and essential tremor. Electrophysiological studies in subcortical structures of the tremor generating networks, for instance, during stereotactic operations, should elucidate the pathophysiological basis of tremor disorders in more detail.

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Pontine Lesions Cause Deficits of Vergence to Step but not to Ramp Targets—Helmchen C1, Rambold H2, Sander T3, Neumann G4 (1Lu¨beck; 2Lu¨beck; 3Lu¨beck; 4 Lu¨beck) The pontine nuclei are part of the cortico-ponto-cerebellar loop of conjugate eye movements, i.e., saccades and smooth pursuit. There is some evidence that the pontine nuclei may also be important in disconjugate eye movements (vergence). As conjugate eye movements, vergence can be separated in vergence to ramp targets (slow vergence) or step targets (fast vergence). It is unknown so far whether pontine nuclei selectively impair slow or fast vergence. To test this hypothesis binocular eye movements were recorded with the scleral search coil system in two patients with median pontine lesions and in 10 healthy controls. As stimuli step targets (7 deg vergence angle), ramp targets (1.5 deg/s vergence velocity), and sinusoidal targets (0.01, 0.15, 0.3 Hz; peak velocity 1.5 deg/s) were used. All targets were presented on a horizontal plane immediately below the eye level in a dark surrounding. Conjugate smooth pursuit and saccades were additionally tested on a tangent screen in 145 cm distance to the eyes. High resolution MRI was performed in all patients. While conjugate saccades were not different from healthy controls, conjugate smooth pursuit eye movements had a reduced gain in horizontal and vertical directions in all patients. In both patients fast but not slow vergence was impaired. The lesion involved the medial pontine nuclei and the rostral tip of the nucleus reticularis pontis (NRTP), but spared the medial longitudinal fascicle (MLF). We conclude that neural control of vergence to step and ramp targets might be anatomically different in the pontine nuclei.

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Improved Helper-Dependent Adenoviral Vectors for High-Level, Neuron-Restricted Gene Transfer into the CNS—Hermening S1, Ku¨gler S2, Ba¨hr M3, Isenmann S4 (1Jena; 2Go¨ttingen; 3Go¨ttingen; 4Jena) Adenoviral vectors (Ad) possess a number of attributes which favour their use for CNS gene delivery, e.g., their ability to infect post-mitotic tissues. However, the widespread distribution of the

cellular receptor for Ad, the Coxsackie/adenovirus receptor (CAR) , allows adenoviral vectors to infect a broad range of cells in the host, thus limiting cell-type specificity for gene transfer in the CNS. Also, the safety issue of these vectors is still a concern. Thus, there is a rationale for the development of Ad vectors capable of enhanced gene transfer specificity and efficacy, yet without evoking an immune response that may lead to reduced transgene expression with time. The use of neuron-specific promoters is a successful means to achieve neuron-restricted expression although gene expression driven by tissue specific promoters is often weak. To boost gene expression, we added the woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) to the expression cassette, which is required for the cytoplasmic accumulation of viral RNAs. High-capacity adenoviral (HC-Ad) vectors are devoid of all viral genes. These vectors feature reduced toxicity, immunogenicity, and increased capacity for foreign DNA. Injection of an adenoviral vector with an EGFP-WPRE cassette under the control of the neuron specific synapsin-promoter (AdSyn-EGFP-WPRE) into the brain of NMRI mice results in an increase of EGFP expression in the neurons. In addition, no signs of inflammation were seen using an HC-Ad vector in the brain, hence allowing for the administration of high vector doses. The combination of these strategies leads to significant improvement in the safety and efficacy of Ad vectors and may have the potential to yield increased therapeutic benefit for therapeutic applications.

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Synchronized Oscillatory Activities of the Human Amygdala and Hippocampus during Emotional Learning in Epileptic Patients—Herpers M1, Huppertz HJ2, Pape HC3, Schulze-Bonhage A4, Zentner J5, Peper M6 (1Freiburg; 2Freiburg; 3Magdeburg; 4Freiburg; 5Freiburg; 6Magdeburg) The interactions of the amygdala with other brain regions during emotional learning have been studied by single cell and local field potential (LFP) recordings in animals. Recently, a synchronization of theta activity in the amygdalohippocampal network has been described as a correlate of conditioned fear. We investigated synchronized oscillatory activities during emotional learning in humans. Deep electrode ERP recordings (LFPs) were obtained from electrode arrays implanted in the human temporal lobe during invasive presurgical monitoring of NZ26 epileptic patients. Contact sites were located within the amygdala, hippocampus, as well as several neocortical sites. We report here on cross correlation data from left (NZ12) and right amygdala and anterior hippocampus (NZ13) contacts to evaluate synchronized activities in the LFP signal during a differential conditioning procedure [a fear face was paired with an aversive acoustic UCS, (CSC) and a neutral face was used as a within-subject control condition (CSK)]. The results indicate that stable ERPs could be obtained, emerging reliably from contacts in right amygdala and anterior hippocampus. A differential response to CSC and CSCalone trials as compared to CSK was found in amygdala and anterior hippocampus LFPs at 450 ms. Event-related synchronizations (ERS) in the theta-band indicated neural coupling of the amygdala and hippocampus as well as temporolateral regions. The findings provide evidence for an involvement of amygdalahippocampus interactions during emotional memory formation in humans. (DFG Pe 499/3-2).

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Pharmacological treatment of spasticity—Hesse S1 (1Berlin) The treatment of spasticity should strictly follow functional considerations in modern neurological rehabilitation. The therapeutic team will develop a multi-lever treatment program for spasticity, with drugs being only one of several options. Oral antispastic medication seems to have lost influence over the last years, at least in stroke rehabilitation. Painful muscle twitches related to spasticity and functionally incapacitating cloni may be an indication, and a close monitoring of the patients at the beginning of the treatment is helpful to detect fatigue and muscle weakness as well known side effects. A new promisising option is gabapentin. Botulinum toxin A and B are first choice in the treatment of focal spasticity. The ‘Rote Liste’ names adult upper limb flexor spasticity and CP-related equinovarus deformity as labelled indications. For stroke patients with upper limb flexor spasticity, several controlled trials showed a muscle tone reduction, ease of personal hygiene and pain reduction in the verum group following the injection of BTX-A. Motor control did not differ between the verum and placebo groups. BTX-B and a highly purified toxin are currently under investigation. A new, old and rather cheap alternative is the neurolytic treatment of focal spasticity with phenol 5%. The EMG-guided local injection of the N. musculocutanaeus or N. tibialis resulted in an immediate muscle tone reduction, effects could last up to 8 months, potential side effects in up to 10% of subjects were a regional dysaesthesia. The intrathecal application of baclofen, long established in the treatment of severe spinal spasticity, has now also been tested in the spasticity management of CP children, and stroke patients. Controlled trials are warranted.

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Decreased Cortical Activity in Impulsivity—Hewig J1, Hagemann D2, Seifert J3, Naumann E4, Bartussek D5 (1Jena; 2Trier; 3Trier; 4Trier; 5Trier) Impulsivity is supposed to be related to several different clinical problems and disorders, such as attention-deficit hyperactivity disorder, conduct disorder, substance abuse, pathological gambling, and certain personality disorders. Several different theories have attempted to reveal the psychophysiology of impulsivity. For example, Gray suggested that a behavioural activation system is the neuroanatomical basis of impulsivity. The personality dimension of impulsivity as proposed by Gray is closely related to extraversion. In a preceding theory Eysenck suggested that extraversion is inversely related to cortical activity and the activity of the ascending reticular activating system. The present study aimed to investigate the relation of trait cortical activity and impulsivity. Fifty-nine participants (29 males and 30 females) defined the sample of the present study, who were assessed at three occasions of measurement each separated by five weeks. At the beginning of each session, the subjects were administered a series of questionnaires, including the Eysenck Impulsivity Questionnaire at one occasion. The EEG was recorded on each occasion during eight 1-min resting baseline periods and 61 electrodes were used to calculate a current source density derivation. General linear models of alpha activity as the dependent variable revealed a main effect of impulsivity on alpha activity across all occasions and electrodes, F(1,57)Z7.92, PZ0.007. The respective correlation between mean alpha activity and impulsivity was rZ0.35. Thus 106

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high impulsive subjects showed an increased alpha activity or decreased cortical activity under rest. The findings may be in line with the suggestion of Eysenck that reduced general cortical activity is related to extraverted personality, in particular impulsivity.

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Enriched Environmental Housing Conditions and Hippocampal Structures of Aged Rats—Hilbig H1, Elsner D2, Merkwitz C3, Dinse HR4 (1Leipzig; 2 Leipzig; 3Leipzig; 4Bochum) Ageing comprises a number of physiological modifications, including structural changes. Hippocampal information processing can deteriorate during normal ageing in the absence of significant neuronal loss. These findings imply that a circuit-specific pattern of variability in the connectional organization of the hippocampus is coupled to individual differences in the cognitive outcome of normal ageing. We addressed the question how enriched environment influences hippocampal structures in aged rats. We used 19 hybrid Fischer 344* Brown Norway rats (FBNF1 rats) of following ages: 3 months (3 animals as controls), 36 months (16 animals divided into 8 animals housed in standard environment and 8 animals housed under enriched living conditions during the last three months of their life) to investigate alterations of glial fibrillary acidic protein (GFAP), extracellular matrix protein as revealed by Wisteria floribunda agglutinin (WFA), neurofilaments (SMI-32 and MAP2), the presynaptic vesicle protein synaptophysin and the calcium-binding protein calretinin. GFAP showed a complementary distribution pattern to WFA binding sites. With progressing age (12–36 months), a strong increase of gliosis occurred, whereas a concomitant, area-specific loss of WFA binding sites was found especially in the CA1 region. The loss of extracellular matrix protein and the reduction of SMI-32 were in part reduced or prevented by housing the animals under enriched environmental conditions between 33 and 36 months of age. Synaptophysin was nearly lost in CA3 in the control rats. Calretinin which labeled the CA2 region exclusively displayed a small reduction only. Taken together we found area-specific both age-related and environment-dependent alterations in the hippocampus of aged rats.

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Low-intensity Paired-Pulse rTMS given to the Primary Motor Cortex at 5 Hz Attenuates Intracortical Excitability—Holler I1, Ilic TV2, Peller M3, Po¨tter M4, Deuschl G5, Siebner HR6 (1Kiel; 2Belgrade; 3Kiel; 4 Kiel; 5Kiel; 6Kiel) Background: Repetitive transcranial magnetic stimulation (rTMS) to the primary motor hand area (M1) at a rate of 5 Hz and intensities at or just below active motor threshold can produce changes in paired-pulse intracortical inhibition (SICI) beyond the time of stimulation (Oliviero et al., Exp Brain Res 2003; 149: 107– 113; Peinemann et al., Neurosci Lett 2000: 296 (Dec): 21–24). Objective: to examine whether paired-pulse rTMS (pp-rTMS) at a frequency of 5 Hz can modify intracortical excitability. Methods: We investigated 10 right-handed healthy subjects. Paired rTMS was applied over the left M1. All participants received either real pp-rTMS (5 Hz, 80% of active motor threshold) or sham pp-rTMS (5 Hz, 3% of maximum stimulator output) on two separate days in a counterbalanced order. The interstimulus

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interval (ISI) between paired stimuli was 2 ms. Using the Kujirai paradigm (Kujirai et al., J Physiol 1993; 471: 501–519), we assessed paired-pulse excitability of the conditioned M1 before and two times after pp-rTMS (1–10 min and 11–20 min after pp-rTMS) . The conditioning effects of rTMS on paired-pulse excitability were assessed by measuring the amplitude of motor evoked potentials (MEPs) of the contralateral first dorsal interosseus muscle. Statistical analysis was performed using an ANOVA for repeated measurements (P!0.05). Results: Real pp-rTMS but not sham pp-rTMS caused a lasting suppression of short-interval intracortical inhibition (SICI) at ISIs of 2 and 4 ms and short-interval intracortical facilitation (SICF) at ISIs of 6, 8, 10 and 12 ms without affecting the amplitude of unconditioned MEPs. The time course of changes in SICI and SICF was different. SICI was already reduced during the first ten minutes after pp-rTMS. SICF was initially unchanged showing a delayed suppression only 10–20 min after pp-rTMS. Conclusion: Low-intensity pp-rTMS of the M1 provides a promising means to suppress intracortical paired-pulse excitability without affecting the excitability of corticospinal output neurons.

Restless Legs Syndrome in Childhood—Hornyak M1 (1Freiburg) Diagnostic criteria of restless legs syndrome were set up in 1995 by the International Restless Legs Syndrome Study Group (IRLSSG). With regard to new scientific knowledge and increasing clinical experience, diagnostic criteria have been revised in a consensus workshop. Participants of the workshop considered as an important topic the development of new diagnostic criteria for special populations: (1) for children and (2) for the cognitively impaired elderly. The common characteristic of both groups is their difficulty to express and formulate adequately subjective symptoms and therefore considerably impeding the diagnosis of restless legs syndrome. A proposal for diagnostic criteria of restless legs syndrome in childhood has been elaborated in 2002 by members of the study groups ‘Movement disorders and sleep’ and ‘Paediatrics’ of the German Sleep Society. The proposal was partially incorporated in the diagnostic criteria for restless legs syndrome in childhood suggested by the IRLSSG. The current diagnostic criteria are recommendations to enhance further research and clinical work and be validated. The presentation gives a synopsis of published studies on restless legs syndrome in childhood, a recapitulation of the proposals for diagnostic criteria and a summary of particulars of the case history in children.

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Carpal Tunnel Syndrome in Patients with Diabetes— zur Horst-Meyer AK1 (1Berlin) The aim of this study was to evaluate the relation of clinical and neurographic data and their possible influence factors on the course of carpal tunnel syndrome (CTS) in patients with diabetes. From a cohort of 230 patients with diabetes, CTS was found in 1/3 of these patients, 52 patients with 82 affected hands were included in our study. Number of examinations varied from 2 to 11 (mean 5) over 1 to 15 years (mean 5,4 years). Outcome variables were: duration of diabetes, type of diabetes, diabetic neuropathy and grade of CTS affection. Measurement were made of sensible and motor nerve conduction velocity of the Nn. medianus, ulnaris, peronaeus, tibialis and suralis. In 51% of the affected hands we found a latent-and in

49% a symptomatic-CTS at study onset. Women were 3-fold more affected than men, 56% of the patients showed diabetic neuropathy. In regard to the neurographic data, in 61% the results decreased, in 22% they increased the course and in 17% the course remained stable. There was a significant difference (P!0.05) between type 1 and type 2 diabetes, i.e., patients with type 1 (C3.09 pts) decreased in our affection scale (0–21) more than type 2 patients (C0.6 pts). Duration of diabetes as covariate showed a significantly better outcome (PZ0.003) for patients with a shorter time of affection. A neuropathy had no severe influence on the course of CTS, in only 1/3 of the patients was there a correlation between the course of CTS and the course of neuropathy. 2/3 of 42 latent courses of CTS turned into a symptomatic one, 1/3 remained clinically latent but with decreasing neurographic values. Due to decreased neurographic and/or clinical results, 26 hands had an operation. Most of these patients suffered from type 2 diabetes with a neuropathy. Postoperatively all patients had an increase in the course of CTS, especially patients without neuropathy. Type 2 patients have a better prognosis in the course of CTS than type 1 and patients with a shorter time of diabetes affection had also a better prognosis. The courses of neuropathy and CTS were not parallel, i.e., neuropathy had no direct influence on the course of CTS. All patients who underwent an operation for CTS improved; especially those without neuropathy. Patients should be neurographically and clinically examined regarding a possible entrapment with a focus on the N. medianus. An operation should not always be the first step in the treatment of CTS.

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Heart Rate Information Flow Specifically Assesses Complex Cardiovascular Communication Alterations due to Multiple Organ Dysfunction Syndrome—Hoyer D1, Zwiener U2, Pompe B3, Friedrich H4, Baranowski R5, Mu¨ller-Werdan U6, Schmidt H7 (1Jena; 2Jena; 3 Greifswald; 4Jena; 5Warsaw; 6Halle; 7Halle) Background: The multiple organ dysfunction syndrome (MODS) as a consecutive failure of several organs has still an unexpected high mortality of more than 50%. Autonomic dysfunction as a feature of an impaired interorgan communication might facilitate the development of MODS (‘uncoupling’ of organs in MODS) and has prognostic implications. This complex interorgan communication is reflected by the information flow of heart rate fluctuations. The present study is aimed at the identification of specific communication deficits based on the time scale of information flow. Methods and Results: 36 MODS patients (28 days lethality: 26 survivors and 10 non-survivors) and 50 controls were assigned to this study and a 24-h ECG was recorded. 24-h, as well as 6-h sequences of the recordings during awakeness and sleep were analyzed and measures of short-term and long-term information flow of the heart rate fluctuations (HRF) according to the heart rate variability (HRV) task force were assessed. Due to MODS we found reduced information flow over the heart beat period, but increased information flow over all longer time scales up to 1000 s. In the HF band filtered heart rate series the information flow was increased during awakeness, but reduced during sleep. The 28 day prognosis based on the information flow parameters of HRF was significantly better than that based of the task force HRV. Conclusions: These results indicate: (1) uncoupling of the sinus node from any modulations, (2) distinguished relevance of the

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vagally mediated communication, and (3) restricted long-time complex communication, reflecting the complete system of autonomic and humoral mechanisms. Consequently, the information flow of the heart beat series over different time scales specifically reflects the altered complex communication and might specify the analysis of ‘uncoupling’ of organs due to MODS. The better prognosis of the patients supports our hypothesis that specific communication measures such as information flow better assesses the complex physiological systems than standard measures in the time and frequency domain.

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Interhemispheric Inhibition Predicts the Magnitude of Mirror Movements in Healthy Subjects—Hu¨bers A1, Ziemann U2 (1Frankfurt; 2Frankfurt) It has been proposed that interhemispheric inhibition mediated through the corpus callosum is important to prevent mirror movements (MM) during intended unimanual finger movements. To test this, we correlated interhemispheric inhibition (IHI) with the magnitude of MM in 12 healthy volunteers (age, 21–40 years). MM were quantified according to an established protocol (Mayston et al. Ann Neurol 1999; 45: 583). Subjects were instructed to perform 50 ballistic index finger abductions with one hand (task hand) at a self-paced rate of about 0.2 Hz whilst maintaining an isometric contraction with the first dorsal interosseus (FDI) muscle of the other hand (mirror hand). EMG in the mirror FDI was rectified, time-locked to EMG burst onset of the task FDI and averaged. MM were quantified as increase of EMG activity relative to pre-burst EMG. Two measurements were obtained. In one, the task hand was the right hand, in the other, it was the left hand. The order was random and counterbalanced. IHI was measured using transcranial magnetic stimulation (TMS, two figure-of-eightshaped coils) according to a previous protocol (Ferbert et al. J Physiol 1992; 453: 525). A conditioning pulse over the motor cortex (M1) of one hemisphere (conditioning hemisphere) preceded the test pulse over the other M1 by 12 ms. The intensity of the conditioning stimulus varied from resting motor threshold (RMT) to 150% RMT in 10% steps (IHI100-IHI150). The intensity of the test pulse was adjusted to produce a test motor evoked potential (MEP) of 1 mV. IHI was expressed by the ratio of the mean conditioned over unconditioned MEP. IHI was tested from the left to right M1 and vice versa in random and counterbalanced order. IHI was correlated with the MM ipsilateral to the conditioning hemisphere. MM amounted to 17.1G9.3%. IHI increased roughly linearly from IHI100 (89.7G23.7%) to IHI 150 (34.8G22.5%). IHI correlated inversely with MM. The correlation was best with IHI140 (PZ0.0031, R2Z0.33). Findings show for the first time that, in healthy subjects, the magnitude of mirror movements can be predicted by the strength of interhemispheric interaction. Quantification of mirror movements may be used as an easy means to study the integrity of interhemispheric interaction in neurological disease, such as patients with multiple sclerosis.

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Comparison of Block vs. Event Design in fMRI of the Somatosensory System—Huonker R1, Sauner D2, Zysset S3, Albermann M4, von Cramon DY5, Witte OW6 (1Jena; 2Jena; 3Leipzig; 4Jena; 5Leipzig; 6Jena) Cortical activation after electrical direct median nerve stimulation either in standard block designs or in an event-related

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design can be found by fMRI. Commonly used stimulation frequencies are in the range from about 100 Hz down to less than one per second. A frequency dependence of the cortical response can be observed. Higher stimulation rates improve the statistical significance of the result, which may be a result of stronger activations. As we know from MEG or EEG studies, higher stimulation rates increase habituation effects yielding a loss of signal change. There were indications of differences in the location and/or weighting of the activated clusters between the block and event designs in our first studies. In this study, different event designs were compared to the standard block design with respect to the localizations of the activated clusters aiming at a robust event design activating most of the somatosensory regions known from MEG and EEG studies. We used an optimized sequence of electrical direct nerve stimulation of the median nerve. In both the event design as well as the standard block design significant activations could be found in the primary and secondary somatosensory areas in area 3b, area 1 and the parietal operculum as well as in the frontoparietal operculum and the medial cortex of the insula. In some subjects activations could be found in PPC, the thalamus and the cingulate cortex. Overall, the random effects model of the group analysis showed 9 activated clusters in the standard block design and 12 clusters in the event-related design. Thus, a robust paradigm for event-related fMRI studies of the somatosensory system could be established. This design is more suitable for studies of cognitive tasks of the somatosensory system.

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Voxel-based 3D-MRI-analysis for the detection of focal cortical dysplasia—Huppertz HJ1 (1Freiburg) Focal cortical dysplasia (FCD), i.e., neuronal derangement due to developmental malformation, is increasingly recognized as an underlying cause of formerly cryptogenic focal epilepsy. However, in subtle cases, its diagnosis by visual evaluation of magnetic resonance images (MRI) remains difficult. Here, we present three novel techniques for postprocessing of 3-dimensional (3D) MRI which may improve lesion detection by enhancing image properties not readily accessible by visual analysis. Following the principles of voxel-based morphometry a T1-weighted MRI volume data set (MPRAGE) is normalized and segmented using algorithms of SPM99 (Statistical Parametric Mapping, Wellcome Department of Imaging Neuroscience, London). Then, the distribution of gray and white matter is analyzed on a voxel-wise basis and compared with a normal database consisting of the MR images of 53 healthy subjects. Based on this analysis, 3-dimensional maps called ‘thickness image’, ‘extension image’, and ‘junction image’, are created which characterize three different features of FCD, i.e., abnormal thickness of the cortical ribbon, abnormal extension of gray matter into the white matter, and blurring of the gray-white matter junction. These methods were applied to the MRI data of 25 epilepsy patients with histologically proven FCD. In each of the new feature maps the locations of the five highest maxima (corresponding to the maximum deviations from the mean of the normal database) were automatically determined and compared with the sites of the lesions in the conventional MR images or—in case of cryptogenic epilepsy— with the resection areas in the post-operative MRI. This approach was able to detect 15/25 lesions in the thickness image and 18/25 lesions in the junction and extension image, respectively. With all feature maps combined, 23 out of 25 dysplastic lesions were

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Fig. 1.

The Processing of Sentence-Level Speech Prosody— Ischebeck AK1 (1Leipzig) Prosody plays an important role in spoken language perception. It assists not only in segmenting the individual words in the often continuous speech signal, but also in segmenting greater chunks of speech consisting of several words, such as phrases and sentences. We have explored two ways by which to investigate the processing of phrase- or sentence-level prosody, that is, first, by studying the processing of phrase boundaries and, second, by comparing normal speech with hummed sentences. Phrase boundaries are a global prosodic characteristic. Within sentences in German, for example, they are often prosodically realized by a rising pitch, a lengthening of the vowel preceding the boundary and a pause before the onset of the next phrase. When a spoken sentence is hummed, all segmental information is lost and only its intonation is preserved. In previous EEG experiments conducted by our group a phrase boundary in an auditorily presented sentence has been observed to cause a positive shift in the event-related averaged signal, which is referred to as the closure-positive shift (CPS). This EEG component seems to be very robust and has also been observed at phrase boundaries in hummed versions of sentences. We will report the results of an fMRI experiment that investigated the neural correlates of the CPS component as observed in EEG at phrase boundaries and that compared the processing of normal speech with the processing of hummed sentences. In this experiment, it has been observed that an additional phrase boundary leads to a greater activation of areas in the right superior temporal gyrus adjacent to the primary and secondary auditory cortices. Normal speech activated areas in the temporal lobe bilaterally as well as areas in the supramarginal gyrus, the inferior frontal gyrus, the thalamus and the cerebellum more strongly than hummed sentences.

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Fig. 2.

detected. Among these cases there were also four patients in whom the dysplastic lesion itself or at least an essential part of it had not been recognized on conventional MR images despite acquisition and assessment in a tertiary epilepsy center. The novel techniques for automated post-processing of MRI presented here facilitate the detection and localization of FCD and increase the sensitivity of MR imaging. Thereby, they provide a valuable additional diagnostic tool in the presurgical evaluation of epilepsy patients and improve the therapeutic options especially in cases of cryptogenic epilepsy (Figs. 1 and 2).

Neuronal Degeneration in the Retina during Ageing and in Neurodegeneration—Isenmann S1 (1Jena) CNS neurons gradually tend to dysfunction and degenerate with increasing age. This process may to some extent be conceived as part of the physiological ageing process, and it does not necessarily lead to relevant functional impairment. Excessive, pathological neuronal degeneration, as occurs in sporadic neurodegenerative diseases such as Alzheimer’s disease, may represent premature ageing and degeneration of neurons in particular brain regions and functional circuits. Alzheimer’s disease is characterized by progressive dysfunction and synaptic as well as neuronal loss of cholinergic neurons in the basal forebrain, cortex, and hippocampus. Deposition of amyloid plaques and the presence of dystrophic neurites are the main histological hallmarks of the disease. The retina is not considered a major site of Alzheimer’s disease pathology. However, there are several hints towards involvement of the visual system in Alzheimer’s disease. Here, we will first discuss the evidence of retinal changes with age. Then, clinical evidence for pathology in the retina and optic pathway in Alzheimer’s disease will be presented. Finally, we will discuss potential retinal pathology in genetic mouse models of Alzheimer’s disease.

Vestibular Control of Posture and Gait—Jahn K1 (1Mu¨nchen) Posture and gait are complex sensorimotor performances based on automated spinal programs which are under control of

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supraspinal centers in the brainstem, cerebellum, and cortex. The vestibular system is important for balance control. The open question-prompted by the observation that patients with vestibular disorders perform better when running then when slow walkingwas whether and how vestibular control was differentially regulated depending on the task performed. To approach this question a number of studies were done using different methods including gait analysis, posturography, 3D eye movement recordings and functional imaging of brain activity in healthy subjects and patients. Measuring gait deviations, patients with acute vestibular syndromes (vestibular neuritis, Wallenberg’s syndrome) showed deviations from their intended path to the side of vestibular deficiency. These patients and healthy subjects during vestibular stimulation performed better (less gait deviation) with increasing locomotion speed. It was concluded that vestibular information was less important for highly automated locomotion like running. This hypothesis was further supported by functional MRI data that showed a deactivation of vestibular cortical areas during locomotion. Another series of experiments demonstrated a close link between ocular motor and vestibulo-spinal function in balance control. Suppression of spontaneous nystagmus in vestibular patients by fixation of a head fixed target which did not provide any information about the visual environment improved balance. These results suggested that eye movements by themselves are involved in postural control. Furthermore, a reduction of nystagmus was observed in patients suffering from acute unilateral vestibular failure during locomotion, which again pointed to an inhibition of vestibular signals. In conclusion, the data clearly show that vestibular control during standing, walking, and running is differentially regulated depending on the requirements of the task performed. Vestibular control becomes more important in slow controlled walking and it is inhibited during automated locomotion like running. The reduction of the redundant information available from different sensory systems during highly automated motor performances is functionally useful as it prevents adverse interactions with the optimized motor pattern. This work was supported by the Deutsche Forschungsgemeinschaft.

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Differential Interaction of BOLD Responses to Simultaneous Finger Stimulation in Subareas of Human Primary Somatosensory Cortex (SI)—Jan R1, Krause T2, Taskin B3, Villringer A4 (1Berlin; 2Berlin; 3Berlin; 4 Berlin) Suppressive interaction of neural activity within the human somatosensory system following simultaneous stimulation of finger pairs has been described in electrophysiological studies (Hsieh et al 1995; Hoechstetter et al. 2001); SI and SII responses to simultaneous stimulation of two fingers appeared to be consistently smaller than the sum of the corresponding separate responses, indicating suppressive interaction between finger representations. In this fMRI study we investigated whether the BOLD responses to simultaneous stimulation of adjacent fingers exhibit a non-linear interference behavior and whether the extent of interference is dependent on subareas of SI. MR imaging was performed on a 1.5 T scanner using a surface coil. Functional images (9 slices, voxel size 2!2!3 mm3) were acquired using a BOLD-sensitive T2*-GE-EPI sequence (TRZ3 s, TEZ60 ms). Electrical stimuli (4 single 200-ms pulses, frequency 4 Hz) of moderate intensities markedly below individual pain thresholds were delivered scan-

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4132#triggered to the right hand (digit 2: 3.9G0.4 mA, digit 3: 3.6G0.3 mA). The experimental paradigm comprised three different stimulation conditions (separate stimulation of digit 2 and digit 3, simultaneous stimulation of digit pair 2 and 3) and null events (84 repetitions each, randomized order, mean interstimulus interval 6 s). Twelve healthy subjects (mean 27 years) participated in the study. Ten out of the twelve subjects exhibited statistically significant activations (P!0.001) in SI due to the two separate stimulation conditions and were further analyzed. Group analysis demonstrated distinct activation foci associated with all three stimulation conditions presumably reflecting the activation of SI subareas 3b, 1 and 2. Within area 3b, the partially overlapping activations exhibited maxima which differed in location, pointing to a somatotopical arrangement of finger representations. In area 1/2 activation maxima shared identical coordinates. T-maps revealed significant interaction in projection to areas 1 and 2. However, as these results might be biased by the height of betas, we performed an independent calculation for all significantly activated voxels in SI. The resulting map revealed that interaction was also prevalent within area 3b. Interaction ratios showed a rostro-caudal increase in interaction from area 3b (26%) to area 1 (32.6%) and area 2 (42.2%). In parallel, the somatotopical arrangement was less clear cut within areas 1 and 2 as compared to area 3b. These results are in agreement with evidence for a rostro-caudal increase in convergence of afferent input and thus in overlap of receptive fields within SI, and concepts suggesting a hierarchical processing from 3b as the primary projection area of somatosensory information (‘SI-proper’) to areas 1 and 2 exhibiting integrative functions.

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Optimized Voxel-Based Group Analysis of Diffusion Tensor Imaging by means of Barycentric Linear Anisotropy—Jarchow S1, Schlo¨sser R2, Nenadic I3, Sinsel E4, Wagner G5, Labadie C6, Krumbein I7, Fitzek C8, Reichenbach JR9, Sauer H10, Ko¨hler S11 (1Jena; 2Jena; 3Jena; 4Jena; 5Jena; 6Jena; 7Jena; 8 Jena; 9Jena; 10Jena; 11Jena) Introduction: Diffusion tensor imaging (DTI) is a non-invasive magnetic resonance method providing a measure of organization of white matter. It has gained increasing popularity to study disorders involving a potential neurodevelopmental origin and disruption of myelination. Employing DTI, altered integrity of the corpus callosum and frontostriatal tracts were reported in schizophrenia. The common quantification of anisotropy for voxel-based group analysis is the fractional anisotropy. This coefficient may be overestimated with low signal-to-noise ratios and may be inappropriate in situations of complex fiber crossing, compartimentalization, exchange of water and in subcortical white matter. To partially circumvent these limitations, the present study aimed at examining the potential of the barycentric representation composed of three complementary anisotropy coefficients describing the following diffusion shapes: linear (e.g. axonal fibers), planar (e.g. crossing structures) and spherical (e.g. purely Gaussian water diffusion). Method: 30 schizophrenic patients (mean age 27.5 years) and 18 healthy volunteers (mean age 28.7 years), matched for age, gender, and education, were measured by DTI on a 1.5T Siemens Magnetom (Vision): double spin-echo EPI (Hunsche 2001), b-value of 900 s/mm2, six independent directions, TE/TRZ100 ms/4000 ms,

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4 repetitions, 0.9375!0.9375 mm2 in-plane resolution, 128!128 zero-filled, 240 mm FOV, 3 mm slice thickness, two acquisitions of 116 s, 38 slices. Diffusion tensor and linear anisotropy processing routines were programmed under MATLAB. Results and Discussion: Linear anisotropy was employed to filter possible crossing structures (planar anisotropy) and compared to fractional anisotropy. At lower signal-to-noise ratios linear anisotropy maps provided better defined boundaries at the edge of white and grey matter. The apparent lesser vulnerability of linear anisotropy to signal-to-noise and its higher specificity to linearly oriented diffusion may provide a more robust basis for voxel-based group analysis of white matter changes near the cortex. This may be particularly important to detect alterations of medium range cortico-cortical connectivity fibers. Support: BMBF IZKF FKZ01ZZ0105, TMWFK B30701-015/016

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Detection and Measurement of Functional Impact of Patent Foramen Ovale in case of Paradoxical Embolism—Jauss M1 (1Gieben) A paradoxical embolism may be the cause of a stroke in case of patent foramen ovale when other potential causes have been excluded. While transesophageal echocardiography (TEE) remains the gold standard, bed-side diagnosis for the neurologist is possible by means of transcranial echocardiography using a contrast agent that does not pass the lung. Previous studies have found the ultrasound test for right-to-left shunt (RLS) being g most sensitive when injection of contrast agent (preferable Echovistw due to higher sensitivity) is performed 5 s before a Valsalva maneuver. Quantification can be obtained by counting of the microbubbles observed at the middle cerebral artery or can follow an arbitrary 4-step categorization scheme according to the count of microbubbles (0, 1–10, 11–50 and ‘shower’ where single microbubbles cannot be discriminated). In case of negative TEE examination, exclusion of non-cardiac RLS (e.g., pulmonary shunts) can be considered, however, reports of paradoxical embolism through non-cardiac RLS are rare. A correlation between functional impact of PFO and size of lesion could not be demonstrated in a study of 87 patients. In a follow-up study of 90 patients, there was no association of functional impact of RLS with recurrence rate, but due to the low recurrence (!1.6%/year) this might be the consequence of lack of power. Decisions about secondary prophylactic treatment should consider morphological issues such as atrial septal aneurysm and anamnestic details such as history of recent cerebrovascular ischemic event and other causes of stroke such as hypertension, since a recent study found patients with hypertension after assumed paradoxical embolism being at increased risk for stroke recurrence. If hypertension in these patients is a concurrent or a supplementing cause of stroke still remains unclear.

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Double Dissociation of Parahippocampal and Amygdalar fMRI Activation in Patients with Mesial Temporal Lobe Epilepsy—Jokeit H1, Schacher M2, Huber D3, Schaumann R4, Grunwald T5, Kra¨mer G6 (1Zu¨rich; 2Zu¨rich; 3Zu¨rich; 4Zu¨rich; 5Zu¨rich; 6Zu¨rich) Functional MRI of limbic mesial temporal lobe structures may help to tailor epilepsy surgery in patients with refractory mesial

temporal lobe epilepsy (MTLE). We have shown earlier that fMRI well lateralizes the side of MTLE by activation of the parahippocampal gyri. In addition, information about the integrity or dysfunction of the amygdala may influence the decision about the anterior extension of the resection. The amygdala is involved in several processes like emotion, memory enhancement, attention modulation and social cognition. Although only in a minority of surgical patients, postoperative deficits in social and emotional cognition and behavior occur. Five male patients (aged 25–45 years) with refractory MTLE (3 left) were investigated. Three patients had hippocampal sclerosis, the others a neoplasia or cavernoma. We measured (i) language-related activity by a verbal fluency task, (ii) parahippocampal activity by Roland’s Home Town Walking Task, and (iii) amygdala activity. Amygdala activation was induced by presentation of scenes from movies showing animated fearful faces. This paradigm was validated in 15 healthy controls showing bilateral amygdala activation (P!0.001). Reproducibility was demonstrated by restudying 6 of the control subjects. All patients had activated left hemisphere regions during a verbal fluency task and demonstrated significant parahippocampal and amygdala activity. In 3 patients contralateral amygdalar and parahippocampal activity was higher compared to ipsilateral activity. In one patient with right-sided MTLE and questionable hippocampal sclerosis, a comparable activity of both amygdala was detected while parahippocampal activity was asymmetrical corresponding to the side of MTLE. In one patient with left-sided MTLE and a paraamygdala neoplasia, only contralateral activity of the amygdala was detected while parahippocampal activity was symmetrical. In 3 out of 5 patients parahippocampal and amygdalar activity were asymmetrical corresponding to the side of MTLE. Two patients demonstrated a double dissociation of amygdala and parahippocampal activation. In patients with MTLE, the use of two simple paradigms allows an individual dissociation of amygdalar and parahippocampal activation within MTL structures. The prognostic value of this information for surgery and counselling of patients has to be evaluated in prospective studies. Studies of limbic mesial temporal lobe structures may help to tailor epilepsy surgery in patients with refractory MTLE.

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Interaction of LTP-Like and LTD-Like Plasticity and Motor Learning in Healthy Human Subjects—Jung P1, Ilic TV2, Ziemann U3 (1Frankfurt; 2Frankfurt; 3 Frankfurt) Motor learning is essential for the acquisition and rehabilitation of motor skills. It is supposed that rapid learning occurs through modification of synaptic strength in which long-term potentiation (LTP) and long-term depression (LTD) form the most important mechanisms. The Bienenstock–Cooper–Munro (BCM) theory states that the threshold for LTP induction increases and for LTD induction decreases if LTP was involved in a preceding learning process. The aim of the present experiments was to verify this prediction of the BCM theory in humans. For motor practice (MP), subjects were instructed to perform 450 fastest possible thumb movements at a rate of 0.5 Hz; the subsequent increase in maximum peak acceleration of the practiced movement was defined as motor learning. Moreover, we induced LTP-like and LTD-like plasticity in the intact human primary motor cortex (M1) by an established paired associative stimulation (PAS) protocol. PAS consisted of 200–225 pairs of electrical stimulation of the right median nerve,

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followed by focal transcranial magnetic stimulation (TMS) of the hand area of the left M1. The interstimulus interval equalled the individual N20 latency of the median nerve somatosensory-evoked cortical potential (PASN20) or was 5 ms less (PASN20-5). PASN20 induced reproducibly an LTP-like long-lasting (O30 min) increase in the amplitude of motor-evoked potentials (MEP) in the prime mover muscle of MP, whereas PASN20-5 induced an LTD-like decrease. As a control condition, a 100 ms interstimulus interval was used in the PAS protocol (PAS100), which had no significant effect on MEP amplitude. Experiment 1 (MP preceding PAS): If MP preceded PASN20, the LTP-like MEP increase produced by PASN20 alone was abolished, even with a trend toward a depression of MEP amplitude. In contrast, if MP preceded PASN20-5, the LTD-like MEP decrease produced by PASN20-5 alone was enhanced. Experiment 2 (PAS preceding MP): PASN20-5 prior to MP resulted in a better learning performance (larger increase in maximum peak acceleration) than PAS100 prior to MP. In contrast, motor learning subsequent to PASN20 did not differ from motor learning following PAS100. These findings support the view that learning in human cortex occurs through LTP-like mechanisms. Moreover, our data maintain the prediction derived from the BCM theory that previous induction of LTD-like plasticity enhances LTPdependent motor learning.

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Magnetic brain oscillations and auditory memory— Kaiser J1 (1Tu¨bingen) Electromagnetic oscillatory activity in the gamma-band range (GBA, about 30–100 Hz) has been proposed as a correlate of cortical network synchronization involved in cognitive processing. Increases in electroencephalographic GBA have been demonstrated during a variety of paradigms including gestalt perception, attention, learning and memory. In magnetoencephalogram topographically focal GBA enhancements have been found in fast frequencies (about 50–90 Hz) during both bottom-up and topdown driven processing of auditory information. Studies on passive auditory mismatch processing have shown that the detection of changes in sound positions was accompanied by increased GBA over posterior temporo-parietal areas. In contrast, deviations in auditory patterns (e.g., syllables or animal vocalizations) induced oscillatory activity over left anterior temporal and inferior frontal cortex. The topography of these findings supported the notion of dual processing streams for pattern versus spatial information (‘what’ and ‘where’ streams, respectively) in the auditory system. During separate delayed matchingto-sample tasks for sound positions and patterns, enhanced GBA was found during the delay phases over posterior parietal and inferior frontal cortex, respectively. In addition, both prefrontal GBA and gamma coherence between putative auditory stream areas and prefrontal cortex were increased during stimulus maintenance in short-term memory. In contrast, an active echoic memory task did not involve prefrontal activations or connectivity increases. This suggests that only the retention of auditory information in short-term memory requires coupling between higher-order sensory areas and putative prefrontal executive networks. In summary, magnetoencephalographic GBA serves as a tool for the investigation of cortical auditory processing at a good spatial and high temporal resolution. Supported by Deutsche Forschungsgemeinschaft (SFB 550/C1).

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Effect of 4-Aminopyridine on Upbeat and Downbeat Nystagmus Elucidates the Mechanism of Downbeat Nystagmus—Kalla R1, Glasauer S2, Strupp M3, Bu¨ttner U4, Brandt T 5 ( 1Mu¨nchen; 2Mu¨nchen; 3 Mu¨nchen; 4Mu¨nchen; 5Mu¨nchen) The effects of the potassium-channel blocker 4-aminopyridine (4-AP) on upbeat nystagmus (UBN) and downbeat nystagmus (DBN) were investigated with the search-coil technique during fixation in different gaze positions and smooth pursuit in two patients before and after ingesting 10 mg 4-AP. DBN of unknown etiology was reduced from K3.9 deg/s to 0.14 deg/s in light, and from K3.8 deg/s to 1.1 deg/s in darkness, thus changing to mild UBN. Impaired downward smooth pursuit was restored (gains: pre 0.42; post 0.68). In the second patient, UBN, possibly due to a small traumatic lesion, was reduced in light from 8.6 deg/s to 2.0 deg/s by 4-AP. Again, impaired upward smooth pursuit was restored (gains: pre 0.38; post 0.86). In contrast to DBN, UBN in darkness was not affected by 4-AP. We propose that 4-AP in both UBN and DBN improved the function of the cerebellar pathways that mediate gaze holding and smooth pursuit by intensifying the excitability of cerebellar Purkinje cells (PCs). Our finding is consistent with the hypothesis (Marti et al., this meeting) that DBN is caused by damage of floccular PCs, which predominantly show downward ondirections. In contrast, UBN may be caused by damage to brainstem structures receiving inhibition from these PCs. In line with this hypothesis, restoring the function of floccular downward PCs by 4-AP cancels DBN even without visual input. In contrast, UBN in darkness is not abolished by 4-AP. However, in light, 4-AP increases the excitability of floccular PCs and thereby helps to mediate smooth pursuit commands that cancel the unwanted downward drift in UBN.

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Neurobiological Correlates of Disturbed Cognitive Functions in Patients with Schizophrenia: A Simultaneous EEG C fMRI Study—Karch S1, Mulert C2, Ja¨ger L3, Teutsch M4, Seifert C5, Propp S6, Pogarell O7, Mo¨ller H8, Hegerl U9 (1Mu¨nchen; 2Mu¨nchen; 3 Mu¨nchen; 4Mu¨nchen; 5Mu¨nchen; 6Mu¨nchen; 7 Mu¨nchen; 8Mu¨nchen; 9Mu¨nchen) Currently, there is evidence demonstrating that schizophrenia is an illness characterized by multiple deficits in fundamental cognitive processes such as attention and memory. The P300 component of the event-related potential is thought to reflect various cognitive processes including the allocation of attentional resources to incoming stimuli. Reduction of the auditory P300 amplitude is constantly found in schizophrenic patients. Besides it could be shown that the P300 amplitude correlated negatively with the severity of thought disorders. Thus, the P300 appears to be a suitable functional parameter of thought disorders in schizophrenic patients. We combined ERP and functional MRI data to examine discrepancies in brain regions involved in information processing as well as in the time course of neural generators of the event-related potential between schizophrenics and normal controls. So far the study comprises six patients with schizophrenia and six age-matched controls with no known history of neurological or psychiatric disorder. The subjects performed an auditive oddball task requiring responses to infrequent tones presented in a series of frequent tones of a different pitch. MR imaging was performed on a 1.5 T Siemens Sonata scanner (EPI

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Fig. 1.

Fig. 2.

sequence; 12 slices; TR/TE: 3000/53 ms). EEG signals were recorded with an amplifier that cannot be saturated by MR activity (61 channels according to the international 10/10 system; Cz reference). The EEG recordings showed the expected positive deflection about 400 ms after the presentation of infrequent stimuli in normal controls and a reduced P300 component in schizophrenics. Besides we could replicate findings of previous P300 studies revealing BOLD activations mainly in frontal, especially anterior cingulate cortex, SMA, insula, inferior and middle frontal gyrus as well as thalamus, temporal and parietal brain structures in healthy subjects (Fig. 1). The functional MRI data of schizophrenic patients showed a reduced BOLD response in a widespread network of cerebral areas involved in task execution (Fig. 2). There was a modest negative correlation between the extent of functional activation in the ACC/SMA region and thought disorders as well as negative symptoms (PANSS) that did not reach significance. Our findings suggest widespread abnormal brain functioning in patients with schizophrenia during information processing.

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Telomere Lagging Strand Synthesis Dysfunction in Cells Lacking WRN Helicase Activity—Karlseder J1, Crabbe L2, Verdun R3, Haggblom C4 (1La Jolla; 2La Jolla; 3La Jolla; 4La Jolla) Werner syndrome is an autosomal recessive disease, and individuals suffering from the syndrome show all signs of premature ageing. Cells from Werner Syndrome patients are characterized by slow growth rates, premature senescence, accelerated telomere shortening rates and genome instability. The syndrome is caused by the loss of the RecQ helicase WRN, but the underlying molecular mechanism is unclear. Here, we report that WRN localizes to telomeres in primary fibroblasts and that cells lacking WRN exhibit telomerase dependent telomere fusions. Werner syndrome cells suffer from the loss of individual telomeres during replication, and only telomeres replicated by lagging strand synthesis are affected. Our data suggest that loss of WRN causes a defect in replicating G rich telomeric DNA, resulting in telomere dysfunction of individual telomeres.

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MRI and Electrophysiological Characterization of Patients Suffering from Pure and Complicated Hereditary Spastic Paraplegia—Kassubek J1, Sperfeld AD2 (1Ulm; 2Ulm) Hereditary spastic paraplegia (HSP) is a phenotypically and genotypically heterogeneous neurodegenerative disease encompassing a group of disorders mainly characterized by spastic paraparesis of the lower limbs. From the clinical point of view, HSP can be classified into complicated and pure forms. The present study contains clinical, magnetic resonance imaging (MRI), and electrophysiological investigations of a total of 33 HSP patients suffering from pure (nZ22) and complicated forms (nZ11), respectively. The MRI standard protocol was performed both for the brain (including a volume-rendering MP-RAGE data set, voxel size 1 mm3) and for the cervical spinal cord (T1- and T2-weighted sequences). Besides visual evaluation of the cerebral MRI and classical thickness measurements of the spinal cord, 3-D MRI of the brains were analysed by the observer-independent technique of voxel-based morphometry (VBM), both in comparison to an age-matched normal data base and in the comparison between complicated and pure forms. With respect to the electrophysiological investigations (e.g., nerve conduction velocities), we present an overview of possible affections of the peripheral nervous system both in pure and complicated forms. It could be demonstrated that clinical presentation and electrophysiological data help to characterize the phenotype of different HSP subtypes. Despite the obvious heterogeneity of complicated HSP, MRI was helpful to elucidate certain patterns of cerebral changes (e.g., of the white matter), and VBM exhibited regional signal alterations (atrophy) of the brain, in particular with respect to morphology of the corpus callosum. In summary, our data showed the different types of involvement of extrapyramidal cerebral and extracerebral structures in a sizeable group of HSP patients and might help to improve the characterization and pathophysiological understanding in this heterogeneous disease.

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Voxel-Based Morphometric Investigations in Basal Ganglia Diseases: Structural Changes and Function— Kassubek J1 (1Ulm) By use of voxel-based morphometry (VBM) as a whole brain-based observer-independent technique to map local signal changes in the brain, it is possible to analyze patterns of structural alterations in neurological disorders at the group level. Investigations are presented in two different basal ganglia diseases, Huntington’s disease (HD) and unilateral tremordominant idiopathic Parkinson’s disease (IPDt). 3-D MRI data of IPDt patients (nZ10) and HD patients (nZ44), respectively, were studied by VBM in comparison to age-matched healthy controls. In IPDt, regional changes of gray matter density were found in thalamic nuclei strictly contralateral to the tremor; in additional functional analyses, these were shown to co-localize with the results of the SPM analysis of metabolic data gained from 18FDG-PET in the same patient sample. In HD patients, the characteristic topography of striatal changes could be mapped (besides less prominent extrastriatal changes) which co-varied with functional scores from UHDRS, but not with

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global atrophy. In a further assessment of correlation with brain function, a covariance analysis with cognitive abilities was performed, resulting in the novel finding of double lesions of cortico-basal ganglia-thalamic-cortical loops in HD. In summary, it could be demonstrated that VBM in conjunction with functional analyses, i.e., bi-modal combined voxel-based mapping including PET or co-variance analysis, respectively, has the potential both to illuminate morphological lesions in vivo and to improve the understanding of their association with functional deficits in extrapyramidal diseases.

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A Systematic Analysis of the Impact of Hemodynamic, Metabolic and Vascular Factors on the BOLD Signal—Kastrup A1 (1Jena) In fMRI studies changes in BOLD signal intensities during task activation are related to multiple physiological parameters such as cerebral blood flow (CBF), cerebral blood volume (CBV), and oxidative metabolism (CMRO2), as well as to the regional microvascular anatomy. The aim of the present studies was to systematically analyze the contribution of these factors to BOLD signal changes during neuronal activation. Assuming similarities between the mechanisms responsible for the coupling of CBF to neuronal activation and the increase of CBF during hypercapnia, a global hypercapnic challenge was used to indirectly investigate the regional sensitivity of the BOLD contrast to neuronal activation, which is mainly influenced by the microvascular system and basal CBV. Moreover, a hypercapnic calibration procedure was employed to determine CMRO2 changes during functional activation. Finally, a combined CBF-sensitized and BOLD fMRI technique was used to obtain activation-induced CBF and BOLD signal changes simultaneously. In the first study BOLD signal changes during hypercapnia were significantly different in various cortical regions. The highest BOLD signal changes were found in those regions with dense capillary networks and large basal CBV values, indirectly suggesting that that these factors will also influence the regional sensitivities of the BOLD responses to neuronal activation. A linear relationship between CBF and BOLD signal intensity changes during bilateral finger tapping with 6 different frequencies (0.5–3 Hz) , as well as significant increases in CMRO2 were found in the second study, supporting the notion that the magnitudes of activation-induced BOLD signal changes are appreciably determined by these two hemodynamic and metabolic factors. In the last study a significantly reduced activation pattern in the primary sensorimotor cortex during finger tapping in a group of old (nZ6; mean age 65 years) compared with a group of young subjects (nZ6; mean age 27 years) could be put down to the fact that age-dependent changes of the cerebral vasculature alter the neuronal-vascular coupling leading to attenuated BOLD responses in spite of similar neuronal activation. The results of these systematic studies clearly demonstrate that activationinduced BOLD signal changes are determined by several physiological parameters. Potential alterations of these variables, especially in patients with neurological disorders, must be considered to acquire valid data.

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Effects of Blinks and Eyelid Closure on the EEG— Kellinghaus C1, Iwasaki M2, Leigh JR3, Alexopoulos A4, Hornig K5, Kumar AN6, Han YH7, Luders HO8 (1Mu¨nster; 2Cleveland; 3Cleveland; 4Cleveland; 5Cleveland; 6Cleveland; 7Cleveland; 8Cleveland) Background: Identification and rejection of eye-related artefacts is important in the interpretation of clinical EEGs. Typical eye-blink artefacts with prominent downward deflection in the most anterior channel and a rapid amplitude fall-off posteriorly are traditionally explained by an upward rotation of the eyeball during lid closure. However, there are no reliable data about the contribution of lid and eyeball movements to the generation of these artefacts. The goal of the present study was to correlate eye and lid movements with EEG potentials using search coils in a magnetic field. Methods: Two healthy male subjects with no known history of neurological disease were studied. Horizontal and vertical eyeball movements and vertical eyelid movements were measured using the magnetic search coil technique. Eighteen scalp EEG electrodes were applied according to the international standard 10–20 system. Signals from the search coils were simultaneously recorded with the EEG machine, and were used to obtain a time correlation between the EEG and search coil signals. Results: A blink was characterized by stereotypical movements consisting of fast descent (8 to 20 degrees for 50 to 80 ms) and slower elevation of the eyelid. During the blinks, eyeballs were slightly rotated downward (1.5 to 3.5 degrees) and inward (0.9 to 3.1 degrees). No upward rotation was seen in either subject. The simultaneous EEG showed typical high-amplitude positive potential bifrontally maximum at electrodes Fp1 and Fp2. As revealed in the wide-band EEG, the time course of the EEG potential corresponded to the lid movement. Forced blinks were characterized by fast descent and slower elevation of the eyelid with a long plateau during the eye closure. The eyeball was rotated upward during the slower phase of the eyelids, although the onset of the eyeball movement was almost the same as that of the eyelids. This corresponds to Bells’ phenomenon. Conclusion: EEG potentials during eye-and-lid movements are mainly determined by the eyelid and not by eye movements. During eye blinks, the eyeballs do not move upward but rather downward and nasalwards. During forced lid closure, the eyes deviate up (Bells’ phenomenon). In both cases typical bifrontal positive EEG potentials occur. Movements of the eyes have only a minor influence on EEG signals.

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Foix–Chavany–Marie Syndrome—Diplegia of the Craniopharyngeal Muscles with Dissociation between Voluntary and Automatic Movements—Kern P1, Faiss JH2 (1Teupitz; 2Teupitz) Introduction: Foix–Chavany–Marie syndrome (FCMS) presents clinically with anarthria, dysphagia and paralysis of the craniopharyngeal muscles with automatic voluntary dissociation. The classical and common form is a bilateral opercular lesion, in most cases associated with strokes. Rare causes are viral encephalitis, neurodegenerative diseases, congenital dysplasias and epilepsy. Case Report: We report the case of a 50-year-old female with two cardioembolic brain infarctions despite an anticoagulation therapy after replacement of the aortic valve in

1987. Three years ago she developed an incomplete bilateral infarction of the posterior cerebral artery territory, one month ago an infarction of the right middle cerebral artery with brachiofacial hemiparesis left and hemineglect to the left side. This time she suddenly became mute. Neurological examination revealed a central facio-pharyngeo-glosso-masticatory diplegia while automatic and emotional movements like laughing, crying, coughing or yawning were still possible without any limitation. Additionally there was an anarthria while listening, comprehension, writing and reading remained intact. MRI showed a new infarction of the thalamic region on the left side. Conclusion: The clinical features of FCMS prove different corticonuclear pathways for voluntary and autonomic motor control of craniopharyngeal muscles. Most common is a bilateral opercular lesion. In this patient we found only on the right side a lesion of the opercular region, on the left side there was a thalamic infarction. This is probably the reason for the almost complete clinical improvement within two months. In general the prognosis described in the literature is very poor.

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The Korean Writing ‘Hangul’ and its Cerebral Organization. An fMRI Study—Kim M1, Krick CM2, Reith W3 (1Homburg; 2Homburg; 3Homburg) This fMRI-study compared cerebral processing of two completely different languages: the lexical writing of German language and the Korean syllable writing. Korean has not developed evolutionary like most other languages, but scientifically. Comparing activities between both writing systems, in Korean we found an increased activation of the phonological loop (BA 45/BA 6, BA 21/BA 22) as well as in BA 7 and BA 40. In German increased activation in the frontal lobe (BA 10) and in the occipital lobe (BA 18) was found. These activations have recently been found to be used by working memory to match visual pattern. As a consequence, we argued that recognition of visual patterns is predominant while reading German words whereas Korean writing is processed more rhythmic-phonologically.

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Vagus Nerve Stimulation—New Insight into the Antinociceptive Effect—Kirchner A1, Birklein F2, Stefan H 3, Neundo¨ rfer B4 (1Erlangen; 2Mainz; 3 Erlangen; 4Erlangen) The antinociceptive effect of vagus nerve stimulation (VNS) is well known from animal studies. Beyond the inhibitory influence that the vagus nerve exerts via its widespread central connections, recently a novel exocrine influence of vagal afferents on nociceptors has been described. Our studies investigate a possible antinociceptive effect of VNS in men and provide insight into the underlying physiological mechanisms. Initially, we investigated pain in 10 patients and 12 controls before and twice after implantation of a vagus nerve stimulator, by using different experimental stimuli including noxious heat, tonic pressure and short impact. Pain was quantified on a visual analogue scale (VAS). VNS significantly reduced increasing pain to trains of five consecutive impact stimuli (wind-up) and pain to tonic pressure (P!0.05, MANOVA). Pain to single impact stimuli and heat pain

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thresholds were unaltered under VNS. The antinociceptive effect was found to be independent of the acute on/off cycles of the VNS. In the following studies we investigated whether VNS would also influence neurogenic inflammation (flare reaction) as a correlate of c-fiber function. Neurogineic inflammation was induced by histamine-iontophoresis and tonic pressure and quantified employing laser-Doppler flowmetry in a group of 11 patients and controls, respectively. Itch and pain, rated on the VAS, were significantly reduced (P!0.05 MANOVA), in contrast the flare reaction to histamine and tonic pressure remained unaltered. Our data indicate that VNS is effective in reducing pain in humans, predominantly in experimental procedures in which pain magnitude is amplified by central processing. In contrast to findings in animal studies, VNS did not influence c-fiber function. We therefore conclude that the antinociceptive effect might rather rely on central inhibition than on alterations of peripheral nociceptors. Our results are promising for a future role of VNS in pain treatment.

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Uni- and Supramodal Categorical Representations— Kleinschmidt A1 (1Frankfurt) The neural routing of information into meaningful categorical representations is an essential prerequisite for multiple cognitive processes. It implies two sequential levels, grouping elements according to given categories and, within categories, identification and discrimination of individual exemples. While localized neural correlates of the former operation have already been identified in many functional neuroimaging studies, there are still few data available that demonstrate coding at the subordinate level of identity representation. Using functional magnetic resonance imaging in healthy human subjects, we addressed these issues for two behaviorally important categories: faces and numerical magnitudes. In the case of faces, we exploited perceptual invariance across spatial scales. From full-range face images we constructed non-overlapping high- or low-pass filtered face images. We then tested where in the brain repetition of individual face identity but with images using different spatial scales would still result in response adaptation. Adaptation is a signature that the neuronal sub-populations within a given brain area that are involved by an individual stimulus process the two versions as identical. In our case, this would mean that they invariantly respond to the identity of a face despite the profound differences between the images conveying this information. We found such functional behavior in fusiform but not occipital face-sensitive areas (Eger et al., NeuroImage 2004; 22: 232–242). The latter only adapted when identical image versions of an individual face were repeated. To study the representation of numerical magnitudes we exploited the fact that across the visual and auditory modality Arabic numerals and number words are always automatically recoded to representations of the corresponding numerical magnitude even when this is not required for the task on hand. Behaviorally, this transpires into the so-called numerical distance effect. If, for example, the task requires subjects to report number 6 as a target and all other numbers shown as non-targets, the reporting of non-targets will be slowed down the closer numerically this non-target is to the target. In other words, it will take longer to report 5 as a non-target than 2. In

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the control categories we used, letters and colors, we found corresponding behavioral distance effects in relation to alphabetic and chromatic distance, respectively. Using an event-related design with randomly interleaved item presentations across all three categories and auditory and visual modalities, we could establish that a cortical region deep in the posterior intraparietal sulcus responds selectively to numbers in a supramodal way (Eger et al. Neuron 2003; 37: 719–725). This finding converges with a body of data from human and non-human primates that have implied this region in the explicit processing of numerical magnitude

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The Extent of Cytokine Induction in Peripheral Nerve Lesions Depends on the Mode of Injury and NMDA Receptor Signaling—Kleinschnitz C1, Brinkhoff J2, Zelenka M3, Sommer C4, Stoll G5 (1Wu¨rzburg; 2 Wu¨rzburg; 3Wu¨rzburg; 4Wu¨rzburg; 5Wu¨rzburg) Background: Nerve injury leads to a degeneration of distal nerve segments, a process named Wallerian degeneration (WD). In the peripheral nervous system (PNS), WD is followed by prompt nerve regeneration facilitated by axonal sprouting from the proximal stumps of injured nerve fibers. Infiltration by inflammatory cells and local induction of chemokines and cytokines play an essential role in this process. Objectives: In the present study we asked whether cytokine gene induction is dependent on the mode of nerve injury and if it involves NMDA signaling. Methods: Interleukin (IL)-1beta, tumor necrosis factor (TNF)alpha, IL-10 and monocyte chemoattractant protein (MCP)-1 induction in the total of 185 mice were assessed in degenerating nerve stumps by quantitative reverse transcriptase polymerase chain reaction and compared between sciatic nerve crush and chronic constriction injury (CCI). Results: Cytokine mRNA levels showed an early and steep increase at day 1 after nerve crush (P!0.001 compared to controls) which was still significant at day 3, and returned to control levels at day 7 and later. CCI led to a similar early gene induction of IL-1beta and TNF-alpha peaking at day 1 which was of a higher magnitude and showed a more sustained time course lasting up to day 28 after surgery. In both lesion paradigms, MCP-1 induction peaked at day 1 (P!0.001 compared to controls), significantly decreased at day 3, and normalized thereafter. The anti-inflammatory cytokine IL-10 showed a different gene expression profile with an early and strong induction at day 1, but maximum levels at the third postoperative day after CCI. In general, transcripts of all cytokines reached 2–5-fold higher levels after CCI, and remained elevated for a longer period of time compared to crush injury. NMDA receptor blockade significantly reduced cytokine expression after CCI on the mRNA and protein level. In dorsal root ganglia, only IL-10 mRNA levels were modified after nerve injury (P!0.05 compared to controls). Conclusion: Our study indicates that the mode of nerve injury influences the extent of cytokine expression, and identifies NMDA-mediated signaling as one mechanism of cytokine induction in peripheral nerves.

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Differential EEG Synchronization at Thalamic, Subthalamic and Cortical Levels during a ChoiceReaction Time Task—Klostermann F1, Ku¨hn AA2, Wahl M3, Marzinzik F4, Pogosyan A5, Kupsch A6, Curio G7, Brown P8 (1Berlin; 2London; 3Berlin; 4 Berlin; 5London; 6Berlin; 7Berlin; 8London) Basal ganglia nuclei are involved in diverse operations, motor and non-motor. Here, we identified EEG changes during a choicereaction time task (CRT) at different brain levels, expressed as event-related synchronizations (ERS) and desynchronizations (ERD). Access to the thalamic ventral intermediate nucleus (VIM) and subthalamic nucleus (STN) was achieved during the externalization of electrode leads for deep brain stimulation (DBS). Recordings were performed in 7 patients with essential tremor and bilateral VIM implants (nZ14), and in 3 patients with STN implants (nZ6) for Parkinson’s disease. EEG was recorded from two bipolar channels per depth-electrode and from 20 scalp positions. Randomized visual Go-signals, 1 s after a pre-cue, were instructive for a button press with either the left or right index finger. The pre-cues followed the reaction to Go-signals by 2 s. Off-line, band-pass filters were set from 8–13 and 14–35 Hz. Referenced to the Go-signal, ERS and ERD were determined bandwise from K1 s to C1.5 s. Baseline-power was determined over 0.7 s before pre-cues. Statistics were calculated with ANOVAs for repeated measurements. In the Alpha-band, a thalamic ERS of 20% was seen 100–250 ms after the pre-cue and Go-signal. Over sensorimotor scalp regions, a similar ERS pattern was seen, but this was followed by an ERD of 30% upon the pre-cue and 60% upon the Go-signal. In the subthalamus, ERS upon the pre-cue was comparable to that at scalp and thalamic levels, but upon the Gosignal it exceeded 100% and persisted through-out the analysis interval. At all levels similar Beta-changes were seen with a small ERD upon the pre-cue, and a pronounced ERD upon the Go-signal. Neither band change was lateralized. The differences between Alpha- and Beta-band and those between thalamic and scalp sites in the Alpha-Band were statistically significant. In the thalamus, pre-cue and Go-signals lead to identical changes in the Alphaband, irrespective of their motor content, and compatible with mechanisms mobilizing event-related arousal. In contrast, at cortical and subthalamic sites, the Alpha-modulation correlated with the instructive value of the presented signal. The ERD in the 14–35 Hz spectrum was similar across recording sites, compatible with the hypothesis of an antikinetic role of distributed neuronal populations, synchronising in the Beta-band. Thus, ERS-ERDpatterns correlate with motor and non-motor brain functions in a site- and band-specific way.

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Enhancement of Hippocampal Neurogenesis following Small Ischemic Cortical Infarcts in the Adult Brain— Kluska MM1, Kempermann G2, Witte OW3, Redecker C4 (1Jena; 2Berlin; 3Jena; 4Jena) Stimulation of cell proliferation and neurogenesis in the adult dentate gyrus (DG) has been observed after focal and global brain ischemia. There is some evidence that this proliferative response is at least in part mediated by NMDA-dependent mechanisms. We here analyzed the effects of cortical infarcts on cell proliferation and differentiation after small cortical infarcts leaving the hippocampal formation intact. Using the photothrombosis model,

focal ischemic infarcts were induced in different cortical areas (sensorimotor forelimb and hindlimb cortex) and proliferating cells were labeled at day 3–14 after infarct induction with bromodeoxyuridine (BrdU, 50 mg/kg, i.p.). 4 and 10 weeks following ischemia, immunocytochemistry was performed with markers. When compared with b antibodies against neuronal (NeuN) and glial (S100 sham-operated controls) both animals with infarcts in the forelimb as well as hindlimb cortex revealed an increase in BrdU-positive cells at 4 weeks after the insult. The ipsilateral DG usually showed more BrdU-positive cells compared with the contralateral side although there was no significant difference. At 10 weeks after ischemia the BrdU-positive cell number was still increased in both groups reaching significance in animals with infarcts in the hindlimb cortex. Confocal laser scanning microscopy revealed an increase in neurogenesis in all groups that was more pronounced 10 weeks after the infarct. Notably, this proliferative response was not influenced by administration of the NMDA receptor antagonist MK-801 during lesion induction. The present study demonstrates that even small cortical infarcts induce an increase in cell proliferation and neurogenesis in the DG. It further indicates that these effects are not mediated by early NMDA-dependent excitatory mechanisms occurring during lesion induction. Supported by DFG Re 1315/3–1.

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Clinical Physiological Investigations to Evaluate the Effects of Repetitive Peripheral Magnetic Stimulation (RPMS)-Experimental Set-Ups—Koch A1, Angerer B2, Struppler A3 (1Mu¨nchen; 2Mu¨nchen; 3Mu¨nchen) RPMS is an innovative approach for the treatment of central paresis, e.g., after a stroke, by inducing muscle contractions. For nerve fiber depolarization, a high time and spatially varying magnetic field impulse is applied. This impulse is repeated with a frequency of 20 Hz. To evaluate the different effects of RPMS, 5000 stimuli with a break of 2 s after every 30 impulses are applied. The concept is based on the activation of a reorganization process in the CNS due to the induced proprioceptive inflow to the CNS. The presented poster shows an overview of the technical approaches and experimental set-ups in order to evaluate the RPMS-dependent effects: (1) Impulse Response: in order to compare the basic effect of magnetic stimulation with the well known electric stimulation, the contraction over time induced by a single stimulation impulse is presented. (2) Index of Spasticity: during a voluntary extension of the index finger, the EMG of the paretic finger extensors and spastic finger flexors as well as the displacement (accelerometer) are registered. This shows a clear decrease of the flexor activity (spasticity) and an increase of the displacement even though the extensor activity is decreased. (3) Video and EMG: to investigate the effect of RPMS concerning goal directed movements a coordinated registration of video data (20 pictures per s) and EMG (6250 samples per s) has been developed and used (4) Cognition: the aim of this experimental setup is to investigate the improvement in body scheme by RPMS. The position sense under static conditions and target movement by non-visual control are registered. The difference between the angle of the elbow joint and the position of a reference point represents the accuracy of the subject’s position sense. (5) Muscle tone: a torque motor is used to elicit a passive movement of the relaxed forearm. To differentiate between viscoelasticity and tonic activity slow movements of 2.5 deg. per s. are applied while the EMG of

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the biceps and the triceps is recorded together with the torque in the elbow joint. The understanding of these effects is the basis for the development of a non-linear adaptive closed loop control (see separate poster), which is used to induce coordinated movements. These movements elicit a near physiological proprioceptive inflow in order to facilitate the reorganization in the CNS.

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The contribution of the left anterior temporal lobe in lexical-semantic processing—Kotz SA1 (1Leipzig) A renewed debate on the role of the left anterior temporal lobe (in particular the anterior superior temporal gyrus, aSTG) in speech perception is based on a diverse functional engagement of this brain region, such as in speech intelligibility (Scott et al., 2000), in lexical-semantic processing (Kotz et al., 2002, 2003a; Scott et al., 2003), in local syntactic processing (Donkers et al., 1994; Kotz et al., 2003b; Meyer et al., 2000; Friederici et al., 2003) as well as in semantic integration (e.g., Stowe et al., 2000). fMRI and ERP lesion experiments on lexical-semantic processing reveal that the aSTG is activated and respectively causing deficits in the case of aSTG lesions. This is shown in fMRI when discriminating between words and pseudowords (Kotz et al., 2002), but is not shown in the case for semantic integration at the word (Kotz et al., 2002) and sentence level (Friederici et al., 2003). Here the posterior STG might play a crucial role. These data are confirmed by lesion data. Patients with left aSTG lesions showed semantic integration at the word and sentence level, even though these processes are temporally delayed. These results indicate that the left anterior temporal lobe may play a role in mapping initial phonetic information to lexical representation during word recognition, but only indirectly in semantic priming and semantic integration (see also McNellis and Blumstein, 2001).

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Zolmitriptan Reduces the Size of the Neurogenic Flare Reaction and the Primary Hyperalgesia after Electrical Stimulation—Kra¨mer H1, Rolke R2, Wehry R3, Birklein F4 (1Mainz; 2Mainz; 3Mainz; 4Mainz) The triptan’s mode of action (migraine medication) is not fully understood. Experimental data suggest a peripheral and a central pathomechanism. The aim of this study was the evaluation of zolmitriptan’s (Z) impact on the peripheral neuropeptide release (neurogenic flare) and the primary and secondary hyperalgesia after electrical stimulation. Moreover, systematic differences between migraine patients and controls were examined. The study was performed in a double-blind, placebo-controlled and cross-over design. Ten migraine patients (8 female, 2 male; age 26.4G1.4 years) and 10 healthy controls (5 female, 5 male; 24.8G0.8 years) were included. Each participant underwent 2 sessions: one 90 min after oral administration of Z and the other 90 min after placebo exposure. Four microdialysis fibers equipped with stainless steel for electrical stimulation were inserted into the right ventral thighs and perfused with NaCl. Electrical current was delivered via a constant-current generator (Digitimer) and stepwise increased to 20 mA. Electrically-induced pain was rated on a visual analogue scale (VAS) every minute. The electricallyinduced axon-reflex flare was measured by a laser Doppler imager. The analysis of the heat pain threshold (TSA 2001) and the mechanical hyperalgesia for pinprick stimuli (Pinprick, intensity 8–512 mN) and dynamic mechanical allodynia (Q-tip,

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cotton wisp, brush) were assessed directly before and after electrical exposure. For statistical analysis an ANCOVA was calculated. Neurogenic flare: Z downsized the area of the neurogenic flare significantly (P!0.002). No influence on the intensity of the flare (laser Doppler flux) could be observed (ns). The pain rating on the VAS was significantly reduced after Z administration (P!0.04). QST: After electrical stimulation a significant heat- and pinprick hyperalgesia was found in the area of primary hyperalgesia (P!0.05). The hyperalgesia to pinprick but not to heat was significantly decreased by Z (P!0.05). QST parameters in the area of secondary hyperalgesia were unaffected by Z (ns). Our results indicate that Z (1) reduces the excitability of primary afferents resulting in a downsizing of the neurogenic flare and (2) induces a reduction of primary hyperalgesia in our pain-model. The secondary hyperalgesia which is normally interpreted as a sensitization of central neuroceptive neurons was unaffected. These data suggest that Z inhibits the release of neuropeptides and the sensitization of primary afferents.

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High-Dimensional Deformation Fields for Longitudinal Intraindividual Volumetry of Cerebral Infarction—Kra¨mer M1, Seitz RJ2, Schormann T3, Witte OW4 (1Du¨sseldorf; 2Du¨sseldorf; 3Du¨sseldorf; 4Jena) The aim of this study is the analysis of 3D morphological changes of human brains after cerebral infarction. The change of brain volume caused by the infarction is measured by highdimensional transformations. These are determined by a multiresolution full multigrid (FMG) movement model [4], resulting in a precise correlation of homologous structures. Thus, volume changes are detected with subvoxel accuracy to determine volume changes between the infarct and remote brain regions without manual interaction. High-dimensional transformations are determined by application of the theory according to Navier–Lamee. Volumes are modelled as an elastic medium. For complex deformations the elastic model is extended to a movement model and the total spatial differences are divided into discrete steps. The gray-value forces driving the movement of each voxel in the source object are determined by minimizing the gray-value difference between source and reference volume. The movement of each voxel is controlled by the data itself and smoothed with respect to noise by the elasticity properties defined by the Lamee parameters for each step. The numerical effort is overcome by a combined multiresolution, full-multigrid method and the correlation of homologous structures improved by application of the ScaleSpace theory. To avoid rotational transformations, coarse and fine alignment is achieved by the extended principle axes theory [2, 3] and by a cross-correlation based procedure using a matrix-norm [1] . The MRI data sets are acquired at different times, enabling the determination of morphological changes over time. The application of the FMG model enables the investigation of morphological brain changes over time. Furthermore, it is possible to detect ischemia-induced spatial distortions and plastic alterations, as the changes of the volume are exactly determined by the deformation fields. The results show that even small infarcts result in morphological changes not only adjacent to the ischemic area but also in remote areas and in some cases the contralateral hemisphere. Supported by the Deutsche Forschungsgemeinschaft (SFB 194 A6, A13, B2).

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References Schormann T, Dabringhaus A, Zilles K. Bioimaging 1993; 1: 19–28. Schormann T, Zilles K. IEEE TMI 1997; 16: 942–947. Schormann T, Zilles K. Human Brain Mapping 1998a; 6: 339–347hf. Schormann T. Method for computing and displaying 2D- and 3D-spatial differences of structures. Int. Patent PCT/EP99/04442 (1998b).

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Voxel-Guided Morphometry (VGM) for Intraindividual Assessment of Delayed Differential Alterations in Human Brain Volume after Cerebral Infarction— Kra¨mer M1, Schormann T2, Hagemann G3, Witte OW4, Seitz RJ5 (1Du¨sseldorf; 2Du¨sseldorf; 3Jena; 4 Jena; 5Du¨sseldorf) In our study, we examined delayed volume alterations in brain areas remote from the lesion proper in 6 stroke patients with an incomplete MCA infarction. MRI scans were carried out 7 days and between 3 and 16 months after stroke onset. Patients were examined by a 3D FLASH MRI scan. The brains from the same patient at two different times were matched to each other using an extended principal axes theory, a cross-correlation based procedure and a fast automated multiresolution full-multigrid movement model [2]. Brains were matched with a 3-step procedure: (i) ePAT and (ii) cross-correlation procedure for linear coarse (i) and fine (ii) alignment and (iii), a non-linear transformation achieving subvoxel accuracy between source and reference brain. This enabled exact reproducibility due to the completely automated procedure and the ability to determine the unique movement to the reference volume using the total gray-value information. The resulting deformation fields could be visualized encoded in gray-values. The investigated brains exhibited a volume reduction in widespread cortical areas even remote from the lesion site and in the underlying white matter. Atrophy was also detected in the ipsilateral thalamus and caudate nucleus that were both not affected by the initial ischemia. These remote atrophic brain areas demonstrate that a secondary long-term atrophy develops after acute cerebral ischemia, probably due to degeneration of white matter projections. The secondary brain atrophy was accompanied by an improvement of the clinical state, marked by an improved European Stroke Scale in the follow-up examination. Obviously, secondary brain atrophy does not necessarily correlate with the clinical outcome. In summary, voxel-guided morphometry demonstrates a widespread and locally differential brain atrophy in brain areas remote from the stroke lesion site. These volume changes do not necessarily correlate with the improvement of clinical outcome. Supported by SFB 194. References

Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 1999; 22:) 391–397. Schormann T, Zilles K. Three-dimensional linear and nonlinear transformations: an integration of light microscopical and MRI data. Hum Brain Mapp 1998; 6: 339–347.

Study Goals and Methods: The interictal, ictal video EEG, MRIs and clinical data from 5 patients with focal epilepsy evaluated for epilepsy surgery were analyzed. Age of onset and at evaluation, localization of the epileptogenic lesion, electrographic focus and surgical outcome were noted. Results: All patients had early onset catastrophic epilepsy, evaluation occurred under age 6 years. Three lesions were frontal, 2 temporal. Histology showed developmental pathology. EEG discharges were multifocal and generalized once with 3 Hz spike waves. Post-surgery all patients became seizure free and the EEG pathology remitted. Conclusion: Propagated epileptiform activity may occur in focal epilepsy in young children as a maturational phenomenon. Surgical resection of the primary epileptic lesion may result in good seizure control. Generalized EEG findings should not be considered a contraindication to surgical treatment in these cases.

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Investigation of Physiological and Pathological Brain Activity using EEG-Correlated fMRI—Krakow K1 (1Frankfurt) Since it has become possible to acquire EEG und fMRI data simultaneously (EEG-correlated fMRI, EEG/fMRI), this technique has been applied mainly to four fields: (1) mapping of fMRI activation associated with interictal epileptiform discharges (IED) in patients with epilepsy, (2) mapping of fMRI activation associated with physiological EEG activity, like alpha rhythm; (3) monitoring vigilance and sleep stages during fMRI experiments; and (4) simultaneous acquisition of fMRI data and evoked potentials. Here, EEG/fMRI studies of IED and alpha- and betarhythm are presented. Several studies have shown that EEGcorrelated fMRI is a practicable method to be applied to patients with epilepsy showing frequent IED on scalp EEG. However, the clinical interpretation of the fMRI maps remains difficult; mainly because EEG/fMRI results have not been systematically validated with a gold standard, which are intracranial recordings and outcome after epilepsy surgery. Currently, EEG-correlated fMRI has to be considered as a research tool providing insights to the pathophysiological processes underlying epileptic disorders and to the effects of epileptiform activity on cognition. It remains unclear if the method will also be used for the routine clinical work-up of epilepsy patients in the future. EEG/fMRI studies of alpha- and beta-rhythm in normal controls have shown that spontaneous fluctuations of the band power during rest are associated with fMRI signal changes, possibly representing alterations of attentionmodulating networks (retrosplenial and fronto-parietal cortices). Similar fMRI activation patterns are found during generalized and focal IED in epileptic patients and might represent an fMRI signature of the cognitive effects of IED.

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Age Dependent Generalized EEG Findings in Pediatric Focal Epilepsy—Krahn-Peper C1, Tuxhorn I2 (1Bielefeld; 2Bielefeld) Background: Generalized features in the clinical semiology and EEG may occur in young children with focal epilepsy as a maturational phenomenon.

Molecular Neurophysiology: Ligand Gated Ion Channels in Neurological Diseases—Krampfl K1 (1Hannover) Ligand gated ion channels mediate fast synaptic neurotransmission. Since this is one of the core features of the nervous system, there is hardly a neurological condition without involvement of synaptic neurotransmission. The development of the patch-clamp technique made it possible to investigate synaptic

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ion channel receptors functionally on the single molecule level as well as within defined neuronal networks. Combined with methods like cell culture, molecular cloning, functional expression, fluorescence microscopy, and ultrafast application techniques, the design of experiments suitable for the investigation of synaptic transmission in neurological disorders was made possible. Examples of our experimental work demonstrate the significance of molecular neurophysiology for the investigation of a broad spectrum of neurological disorders like immunological and neurodegenerative disorders or epilepsies. The direct functional interaction of specific antibodies with nicotinic receptors in myasthenia gravis and Guillain Barre´ syndrome could be studied by defined application of IgG fractions from patients to nicotinic receptors activated by pulse-wise transmitter application. The pivotal role of specific subtypes of glutamate receptor channels for neurodegeneration due to chronic excitotoxicity and CaCC overload of neurons can be demonstrated and in vitro testing of potential neuroprotective drugs becomes feasible. The pathophysiology of familial epilepsies caused by mutations of genes coding for inhibitory ligand gated GABAA receptor channels can be revealed by functional expression experiments that serve as a model of disease for pharmacological screening as well. Thus, molecular neurophysiology enables us to track functional impairment of the nervous system to the single molecule level and can serve in molecular diagnostics.

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Cortical Silent Period in Patients with Complex Regional Pain Syndrome after Conditioning Peripheral Repetitive Magnet Stimulation—Krause P 1, Fo¨rderreuther S2, Straube A3 (1Mu¨nchen; 2Mu¨nchen; 3 Mu¨nchen) In a pilot study, 13 patients suffering from complex regional pain syndrome type I (CRPS I) were stimulated with a peripherally applied repetitive magnetic stimulation (rMS). The goal of this rMS was therapeutic. We used high frequencies and suprathreshold intensities. With the idea of inducing a proprioceptive input to motor cortical areas, we measured the motor evoked potential (MEP), as well as the cortical silent period (CSP) before and after rMS. These data were compared to those from healthy subjects serving as controls. A Magstim 200 was used to induce MEP and CSP over the corresponding motor cortex, while the conditioning rMS was done with a Magstim Rapid applied to the level of affected muscles corresponding to the cervical nerve roots. First the motor threshold (MT) was determined at the ‘motor hot spot’ of each motor cortex, then MEP and CSP (with slight muscle precontraction) were recorded at a defined stimulation intensity. The mean MT was 44% in patients and 40% in healthy subjects. Patients showed in general a significantly smaller MEP amplitude than healthy subjects, independent of the hemisphere and if before or after rMS [F(4,11)Z20.14; P! 0.001]. After application of the conditioning rMS we found a significantly [*F(4,11)Z5.1; PZ0.01] prolonged CSP for the stimulated side only in healthy subjects (52.95 ms before vs. 73.68* ms after; 26.25 ms before vs. 39.3 ms after rMS), but not in patients (51.4 ms/57.75 ms before vs. 56.09/47.86 ms after). A surprising finding was the bilaterally reduced MEP amplitude in patients, but this fits well with former studies showing a bilaterally disturbed motor cortical excitability in

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CRPS patients. The prolongation of CSP only in healthy subjects led us to the assumption that there is a change in afferent input between patients and healthy subjects. This might also be caused by a disturbance in motor cortical excitability as was found with pain syndromes and CRPS I formerly. It possibly indicates a reduced ability of cortical plastic changes within the motor cortex in CRPS patients.

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Effects of Erythropoietin on CNS Neuron Regeneration and Involvement of Signal Transduction Mechanisms in vivo and in vitro—Kretz A1, Happold C2, Marticke J3, Isenmann S4 (1Jena; 2Tu¨bingen; 3Jena; 4 Jena) The cytokine hormone erythropoietin (EPO) promotes differentiation, proliferation, and maintenance of erythroid progenitor cells. Recent investigations have found CNS neurons responsive to local and systemic EPO, and that EPO can prevent physiological neuronal loss, and apoptotic death under pathological CNS conditions. Further, EPO has proved to be neuroprotective in various models of CNS injury, including EAE-related inflammation, kainate toxicity, hypoxic stress, serum deprivation and glutamate excitotoxicity. The impact of EPO on the regeneration of adult neurons is still unclear. Here, we compared outgrowth capacity of adult retinal ganglion cells (RGCs) in the absence and under in vivo EPO treatment immediately after crush lesion of the optic nerve (ON). Alternatively, delayed EPO treatment was administered on cultured RGCs in vitro 10 days after ON injury. Both post-lesional in vivo conditioning, and delayed addition to the culture medium of 10–10,000 IU recombinant EPO (rhEPO) increased numbers and length of neurites regenerating from cultured RGCs in a concentration-dependent manner. As indicated by protein expression analysis, cellular EPO response was mediated by induction of the antiapoptotic Bcl-2 family member Bcl-XL, involving signal transduction by Stat-3 phosphorylation and p42/44 MAPK activation. According to its survival promoting effects observed in vitro, PI3K/Akt phosphorylation was simultaneously up-regulated. Inhibition of the Jak2/Stat3 pathway completely abolished EPO-induced growth promotion. In contrast, inhibition of PI3K reduced intrinsic growth potential, but had only minor effects on EPO-stimulated neuritogenesis. Inhibition of mTOR did not affect intrinsic or stimulated axon growth. In conclusion, we introduce the cytokine EPO as a potent stimulator of survival and regeneration promoting signal cascades in CNS neurons. Such a dual role may imply a therapeutic potential preferential to combined factor treatments and become promising as a future treatment option in cases of CNS degeneration and neurotrauma.

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Screening for Early Stages of Nigrostriatal Alteration (I): MR-T2-Relaxation and TCS in Healthy Subjects with Increased Echogenity of the SN—Krick CM1, Fuss G2, Schro¨der U3, Behnke S4, Dillmann U5, Schreckenberger M 6, Reith W 7, Becker G8 (1Homburg; 2Homburg; 3Homburg; 4Hormburg; 5 Homburg; 6Mainz; 7Homburg; 8Homburg) The diagnosis of idiopathic Parkinson’s disease (IPD) is primarily based on clinical signs and symptoms. Neuroimaging

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like magnetic resonance imaging (MRI) is regarded to reveal no consistent abnormalities and is only applied to differentiate IPD from secondary Parkinson syndromes. Recently, we and others demonstrated that transcranial ultrasound examination (TCS) allows one to detect a signal abnormality of the substantia nigra (SN) in most PD patients. Interestingly, the same echo feature can be found in about 8% to 10% of healthy subjects. This actual study aimed to demonstrate the MR-T2-relaxation to be sensitive regarding changes of SN tissue indicating a nigrostriatal alteration. Seven patients with IPD and 14 healthy controls were included into this study. Patients with IPD were in the early stages of the disease. The healthy subjects were enrolled according to their SN signal intensity on TCS. Seven probands exhibited a distinctly hyperechogenic SN, seven had a normal SN echogenicity. All IPD patients and healthy subjects underwent TCS, 18F-Dopa PET, and MRI examinations. Informed consent according to the Declaration of Helsinki was obtained from all participants. The study was approved by the local Ethic Committee. The healthy subjects with SN hyperechogenicity exhibited shorter SN T 2 -relaxation compared to the healthy participants without this echo feature (Mann–Whitney U-test: PZ0.011). SN T2-relaxion of the IPD patients was once again shorter compared to the controls with SN echogenity (PZ2.2!10K6). However, the IPD patients exhibited slower T2-relaxation of the white matter compared to controls without (PZ0.004) and with (PZ0.038) SN echogenity. T2relaxation of the white matter did not differ between healthy subjects with and without SN hyperechogenicity (PZ0.7). In contrast to this, there was a close correlation of T2-relaxation of the SN with the decrease of striatal 18F-Dopa uptake [Spearman-Rho (R): K0.43; PZ0.007]. Our findings may open new perspectives for screening for early stages of nigrostriatal alteration and IPD. MRI may serve as an instrument assessing the extent of neuronal degeneration of the SN in subjects identified to exhibit risk markers for IPD. One potentially important risk factor may be increased echogenicity of the SN.

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Representation of Person Identity Information in Auditory and Visual Cortex—von Kriegstein K1, Kleinschmidt A2, Giraud AL3 (1Frankfurt; 2Frankfurt; 3Frankfurt) Recent studies have revealed face-responsive visual areas and voice-responsive auditory areas in the human brain. Although these voice and face processing modules are anatomically segregated, voice and face information has been shown to interact on a behavioral level. How is person-specific multimodal information combined? Using functional magnetic resonance imaging, we have shown that recognizing familiar speakers’ voices activates the fusiform face area (FFA) in normal as well as in a developmental prosopagnosic subject. Person recognition models suggest that such a cross-modal effect from auditory to visual association cortices should be accomplished via a supramodal region, i.e., a region that responds to familiar faces and to familiar speakers’ voices. Functional connectivity analyses (PPI), however, revealed that the FFA activation by familiar speakers’ voices results from a direct interaction of voice and face processing modules. These findings will be discussed in the context of current multi-sensory person recognition models.

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Brain Perfusion Imaging in a Case of Cerebral Sinus Thrombosis–Comparison between Ultrasonic and Magnetic Resonance Imaging—Krogias C1, Kahle M2, Eyding J3, Buschleb C4, Schroder A5, Postert T6, Wilkening W 7, Meves S 8 (1 Bochum; 2Bochum; 3 Bochum; 4Bochum; 5Bochum; 6Paderborn; 7Bochum; 8 Bochum) Background: The neurosonological assessment of brain perfusion has been improved recently by more efficient imaging modes like bilateral Phase Inversion Harmonic Imaging (PIHI) enabling the ultrasonic detection of cerebral perfusion deficits in acute ischemic stroke. The aim of this case report is to compare findings from PIHI with findings from perfusion-weighted magnetic resonance imaging (pw-MRI) in order to examine the diagnostic value of PIHI in cerebral venous thrombosis. Methods: A 50-year-old female patient with thrombosis of right-sided transverse sinus, superior sagittal sinus, straight sinus and vein of Galen was examined with bilateral PIHI using a Siemens Sonolinew Elegra system, equipped with a 2.5 MHz phased array transducer. The ultrasound contrast agent was applied following the bolus kinetic approach (2.5 mL SonoVuew followed by 10 mL NaCl). Time-to-peak intensity (TPI), peak intensity (PI) and peak width (PW) were determined from a fitted model function from different regions of interest (ROI), followed by a region-wise and pixel-wise analysis of data. Parameters were compared with findings of established pw-MRI. Results: In region-wise analysis of PIHI a prolonged TPI (39.2 s) in the posterior parietal ROIs compared to the median of TPI of the other examined ROIs (32.3 s) was detectable. The TPI delay was represented in pixel-wise analysis. These findings were comparable to the observed time-to-peak (TTP) delay in pw-MRI. In accordance with previous published data for pw-MRI in cerebral venous thrombosis, increased Mean-Transit-Time (MTT) values were detectable, while the determination of cerebral blood volume (CBV) showed no pathology. Conclusions: For the first time perfusion pathologies in cerebral sinus thrombosis were documented by means of ultrasonic evaluation. Furthermore, it was possible to compare ultrasonic and MRI findings, which demonstrated similar results. In the future, ultrasonic brain perfusion imaging, as an easy available, bedside diagnostic tool might be helpful to diagnose and monitor cerebral venous thrombosis.

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Strategies for the Detection of Focal Lesions in MR Tomograms of the Human Head—Kruggel F1 (1Leipzig) Detecting pathological features in magnetic resonance imaging data sets of the human head is considered a non-trivial segmentation task. Segmentation approaches require prior knowledge about the lesion characteristics (e.g., their expected compartment, size and shape, their signal statistics in relation to the embedding tissue), and thus, are generally targeted for detecting a specific lesion type. We focus on approaches that are targeted to automatically detect (a) large unilateral lesions, (b) small multifocal lesions, and (c) diffuse white matter lesions. While a trained human observer still outperforms automatic approaches for lesion detection and discrimination, estimating the lesion size (in the case of large unilateral or diffuse lesions), count and position (in the case of multifocal lesions) is tedious or even

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impossible. The aim of this work is to provide quantitative descriptors for different lesion types. The three example algorithms discussed here incorporate prior knowledge in fundamentally different ways. These quantitative descriptors are useful measures for the statistical evaluation of a patient’s clinical status.

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Clinical and EEG Findings in Eleven Patients with Insular Epilepsies—Kruse B1, Tuxhorn I2, Schmitt J3, Schulz R4, Wo¨rmann F5, Ebner A6 (1Bielefeld; 2 Bielefeld; 3Bielefeld; 4Bielefeld; 5Bielefeld; 6Bielefeld) Purpose: We have attempted to study auras, seizure semiology, and EEG findings in insular epilepsies. Methods: We reviewed the clinical and EEG data of eleven patients with epileptogenic lesions in the insular region. Ten patients underwent EEG-video intensive monitoring with surface electrodes and three patients subsequently underwent invasive EEG recording with subdural grid electrodes. One outpatient had only a routine EEG taken. Clinical data of two patients were excluded: one patient was too handicapped to report auras reliably. The other patient had an additional large extrainsular lesion making it unclear if seizures arose from the insular or extrainsular cortex. Results: All patients experienced auras: they were epigastric in nature in five, ‘tingling’ in the whole body in four, psychic (fear, mood disturbances) in three, somatosensible (tingling in the contralateral arm) in two, and complex visual in one patient. Two had additional autonomic signs (flush, tachycardia). Seizures were characterized by oral and manual automatisms in seven, hypermotor symptoms in five, and focal tonic seizures of the contralateral arm in two patients. The interictal and ictal epileptiform activity occurred ipsilateral over temporal lateral (three patients), temporal mesial (two patients), frontal, centrotemporal, centroparietal, parietolateral and median regions. Seizure patterns were found over the temporal region in four patients (one with a fast propagation to the frontal region); they were frontal, parietolateral, frontotemporal, or diffuse. One patient had no seizure pattern. Conclusions: Patients with insular epilepsies show a great variety of auras and other seizure symptoms and EEG findings. Seizure semiology and EEG findings can mimic other epilepsies, e.g., temporal or frontal lobe epilepsy.

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Emotionally Arousing Visual Stimuli Modulate Oscillatory alpha Activity Recorded from STN Area in PD Patients—Ku¨hn AA1, Hariz M2, Silberstein P3, Tisch S4, Kupsch A5, Schneider GH6, Limousin P7, Yarrow K8, Brown P9 (1London, 2London, 3London, 4London, 5 Berlin, 6Berlin, 7London, 8London, 9London) High frequency stimulation (HFS) of the subthalamic nucleus (STN) has become a widely accepted therapy to treat motor symptoms in PD patients. In some patients however, stimulation may be accompanied by behavioral and cognitive side effects drawing attention to a possible influence of HFS on associative and limbic circuits within the STN area. To further elucidate the involvement of the human STN region in the processing of emotional information we investigated changes in oscillatory activity within the STN area in response to emotionally arousing visual stimuli. Local field potentials

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(LFP) were recorded through deep brain macroelectrodes (Medtronic, model 3389) from the STN area in 10 PD patients (6 men, 4 women; age 53.2G3.8 years; 19 sides) during a 1 second presentation of emotionally arousing stimuli (selected from the International Affective Picture System). Data were digitally pass-band filtered in the alpha (8–12 Hz) range, squared and responses averaged across pleasant, unpleasant and neutral stimuli. Changes in alpha activity were defined as the percentage decrease (event-related desynchronization-ERD) or increase in band power during the test interval (0.5 s to 3 s post-stimulus) in comparison to the baseline period (2 s before stimulus presentation) for each emotional category. A significant decrease in alpha power was found for all stimulus categories starting at about 0.5 s after stimulus presentation. During the post-stimulus time period from 1–2 s the ERD was significantly larger in trials of pleasant (mean ERD 21.6%G2.8; P!0.001) and unpleasant (mean ERD 15.0%G4.2; PZ0.002) stimuli compared to neutral (mean ERD 4.4%G4.2). The modulation of late alpha activity recorded from the STN area in PD may reflect processing of emotional arousal as it followed both pleasant and unpleasant stimuli. These findings suggest that ‘limbic’ processing occurs in the region of STN and may offer an explanation for why STN-HFS may be complicated by affective disorders in PD patients.

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Proliferation of Distinct Hippocampal Progenitor Cells after Cortical Infarcts in the Adult Brain— Kunze A1, Grass S2, Witte OW3, Yamaguchi M4, Kempermann G5, Redecker C6 (1Jena; 2Jena; 3Jena; 4 Tokio; 5Berlin; 6Jena) Stimulation of cell proliferation and neurogenesis in the adult dentate gyrus has been observed following global and focal brain ischemia even when the hippocampal formation was not directly damaged. We here analyzed the effects of small cortical infarcts on proliferation of subpopulations of nestinexpressing progenitor cells during the first 3 days after ischemia using the photothrombosis model in adult transgenic pNestinGFP-mice. Proliferating cells were labelled by a single i.p. injection of bromodeoxyuridine (BrdU, 50 mg/kg) 2 h after induction of the infarct and further characterized at 6, 24, and 72 h after ischemia using immunocytochemistry and confocal laser scanning microscopy. Compared with sham-operated controls, animals with cortical infarcts showed the following alterations: (i) the number of BrdU-positive cells was significantly elevated after 6 h; (ii) the slowly dividing nestinpositive cells with characteristic astrocytic features (type 1 cells) continuously increased their proliferative activity during the first postischemic days; (iii) the progenitor cells expressing the early neuronal marker doublecortin (type 2b and 3 cells) were only initially stimulated. Notably, the effects were observed in the ipsilateral as well as contralateral dentate gyrus. These findings indicate that focal ischemic infarcts differentially influence the proliferation of distinct subpopulations of progenitor cells during the first hours after the insult. In particular, type 1 cells with only minor proliferative activity under physiological conditions are stimulated by ischemic infarcts. Supported by DFG Re 1315/3–1.

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The Berlin Brain–Computer Interface—Single trial classifications of phantom finger movements of arm amputees—Kunzmann V1, Blankertz B2, Dornhege G3, Krauledat M4, Mu¨ller KR5, Curio G6 (1Berlin; 2 Berlin; 3Berlin; 4Berlin; 5Berlin; 6Berlin) Introduction: The Berlin Brain-Computer interface (BBCI) is based on single-trial classifications of multichannel EEG signals, such as lateralized readiness potentials (LRP), discriminating right vs. left limb movements with accuracies up to 95% in healthy subjects. The current study used 128-channel EEG recordings in patients with traumatic amputations of one arm or hand to compare EEG correlates of real vs. phantom finger/hand movements. Objective: We studied LRPs and event-related desynchronizations (ERDs) associated with phantom movements of amputees over the contralateral primary motor cortex, and analyzed the single-trial classification with the BBCI standard EEG-classifier to clarify if classification rates are as accurate as shown earlier in comparable studies with healthy subjects. Methods: We studied eight patients (1 female, 7 male; 37–74 years) with amputations between 16 and 54 years ago. A digital metronome played alternately two distinct sounds in a steady rhythm, with intersound intervals between 1 and 1.4 s, as chosen by each patient for convenient performance. Concomitant with the higher sound, the patient had to perform either a finger tap on a keyboard using the healthy hand or a phantom movement with a phantom finger/hand. The lower sound called for rest. Results: (1) In 5 of 8 patients we found a typically shaped contralateral LRP associated with the phantom movement. The younger patients, with more recent amputations, tended to show better defined LRP topographies. (2) While real movements were preceded by standard ERDs, phantom finger/hand movements showed a less distinct ERD. (3) The ‘right vs. left’ single-trial classifications performed with the standard BBCI-classifier yielded hit rates between 60–78%. (4) The subgroup with LRPs associated with phantom movements showed hit rates in the single-trial classification not better than the group without lateralization of RP. Conclusions: Patients with traumatic amputations show lateralized RPs associated with phantom limb movements. LRP topographies appeared better defined in cases with more recent amputations. Interestingly, even with no lateralized RP, classifications well above chance level were still possible, but the underlying physiology needs further study. Together, these findings indicate a possibility to exploit lateralized RPs for BCIs in amputees, for example, to control a prosthesis. At present, the hit rates are still too low for such BCI to be useful in the everyday life of amputees.

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Impaired Motor Cortex Plasticity in Patients with ALS—Lang N1, Rizzo V2, Bagnato S3, Quartarone A4 (1Go¨ttingen; 2Messina; 3Messina; 4Messina) Amyotrophic lateral sclerosis (ALS) is characterized by an extensive loss of neurons in the corticospinal motor system. Neurophysiological studies in ALS patients have demonstrated motor system hyperexcitability with increased corticospinal excitability and reduced intracortical inhibition (ICI). We wanted to examine whether the deficient inhibitory control of intracortical circuits in ALS patients is accompanied by impairment of functional reorganization. The capability of the corticospinal system for externally induced, transient plastic changes was tested

using transcranial direct current stimulation (tDCS). Eight patients with ALS and eight age- and sex-matched healthy controls received 7 min of anodal or cathodal tDCS in two sessions. Active and resting motor thresholds, corticospinal excitability using single-pulse MEP and ICI and intracortical facilitation (ICF) using paired-pulse stimulation (interstimulus intervals: 2 and 12 ms) were tested with TMS before and twice after tDCS. As reported previously, ICI was reduced in ALS patients compared to controls. In addition, corticospinal excitability in ALS patients remained unchanged after either type of tDCS, while a polarityspecific effect could be observed in controls with anodal tDCS inducing facilitation and cathodal tDCS leading to inhibition. Motor thresholds, ICI and ICF did not change in response to tDCS in both groups. Our data are compatible with the idea that motorcortical plasticity is impaired in ALS patients.

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Chronic Dose effects of Reboxetine on Motor Skill Acquisition and Cortical Excitability—Lange R1, Weiller C 2, Liepert J 3 (1Hamburg; 2Hamburg; 3 Hamburg) Background: Enhancement of cortical excitability is thought to be potentially beneficial for synaptic plasticity as, e.g., associated with motor skill acquisition. The selective norepinephrine reuptake inhibitor reboxetine (RBX) might therefore be able to facilitate functional recovery after brain lesions. Considering patient administration in the future we studied the effects of a chronic dose regimen on motor skill acquisition and cortical excitability. Methods: The study was randomized, double blind and placebo-controlled. 12 healthy subjects received 4 mg RBX twice a day for 4 full days preceded by 2 mg RBX twice a day for 2 days. Each subject served as its own control. There were at least 16 days between the verum and the placebo session. Measurement of cortical excitability by means of paired pulse transcranial magnetic stimulation (ppTMS) was conducted before and after the motor skill acquisition task for each session. The task was to lift two fingers of the right hand at once while the hand positioned sprawled out on the table. The movements were selfpaced and subjects had to perform as many moves as possible in 60 s. Between 7 blocks of self-paced movements 6 blocks with 60 single trials at a fixed interstimulus interval were presented. Two equally difficult versions of the task using different finger combinations were established in order to avoid carryover effects in performance. The finger movements were recorded with a threedimensional ultrasound movement analysis system (Zebris). Results: All subjects had a substantial gain in performance over the self-paced blocks. Average increase in number of correct moves was 87% (from 27.8 to 51.9). There was no significant difference either between the versions of the task or between placebo vs. verum. Also, there was no significant difference between first and second session, indicating that there was no carryover effect in performance. ppTMS revealed no significant differences in cortical excitability between groups. Conclusion: The newly developed skill acquisition task yields a robust single session gain of performance. As the two versions of the task do not interact, it is suitable to be used in cross-over designs. In contrast to studies using single doses of RBX, motor cortex excitability seems to be unaffected in a chronic dose

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steady-state. This could explain why motor behavior was not modulated by the study medication.

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Developmental Visual Neglect in Infants—LangeKu¨ttner C1 (1London) Infants from 16 to 20 weeks were presented with objects moving across a spatial field of 60 cm. Visual tracking increased between 16 and 18 weeks, reaching increased, while arm lifts (swipes) showed no age change. A neglect of the left visual field in tracking gradually disappeared with the onset of reaching. Similar effects of arm movements towards the neglected side can be found in the successful treatment of adult visual neglect patients. Besides the neurological background, results are evaluated from developmental and comparative perspectives.

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Does TMS help to Better Understand Schizophrenia and Mechanisms of Neuroleptic Treatment?—Langguth B1, Zowe M2, Hajak G3, Eichhammer P4 2 3 (1Regensburg; Regensburg; Regensburg; 4 Regensburg) Transcranial magnetic stimulation (TMS) provides an intriguing in vivo method to investigate motor cortex excitability in men. This offers new insights into the neurophysiological effects of neuroleptic drug treatment. We studied several TMS paradigms in first-episode schizophrenic patients before treatment initiation and under steady-state conditions with different neuroleptic drugs. The patient group demonstrated a significantly lower resting motor threshold as compared with healthy controls, whereas TMS paradigms of cortical silent period, intracortical inhibition and intracortical facilitation failed to show significant differences between patients and controls. This pattern of TMS parameters is similar to that obtained in healthy volunteers investigated under increasing doses of ketamine, a central-acting drug, known to produce psychosis-like effects. In agreement with recent results of functional imaging, our neurophysiological findings suggest that drug-induced and naturally occurring psychosis may share a common pathway, which may base on dysfunctional glutamatergic mechanisms. Neuroleptic treatment was reflected by an increase of cortical silent period and motor thresholds, pointing to a treatment induced improvement of inhibitory functions. These findings demonstrate the potential of TMS to detect excitability changes associated with schizophrenia and with neuroleptic treatment. This method could be further developed as a diagnostic tool or for endophenotypization.

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Brain Areas Activated during Electric Microstates of Mental Imagery versus Abstract Thinking—Lehmann D1, Ko¨nig T2, Henggeler B3, Strik W4, Kochi K5, Koukkou M6, Pascual-Marqui RD7 (1Zu¨rich; 2Zu¨rich/Bern; 3Zu¨rich/Bern; 4Zu¨rich/Bern; 5Zu¨rich/Bern; 6 Zu¨rich/Bern; 7Zu¨rich/Bern) Microstates of EEG and ERP data are time epochs of quasistable map landscapes of momentary potential distribution, lasting !100 ms in duration. In study no. 1, during spontaneous mentation, subjects were prompted to report

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‘what just went through your mind’. Two classes of reports were distinguished, mental (visual) imagery and abstract thought (e.g., ‘house’ vs. ‘theory’). The last EEG microstate before prompting was identified as imagery- or abstract-related. In study no. 2, while reading visually imaginable (‘house’) and abstract (‘theory’) nouns at 1/s, subjects had to repeat the last word if it was followed by a question mark. The ERP microstate 286–354 ms post-stimulus had significantly different potential maps for the two word classes. LORETA tomographic images were computed from the EEG and ERP potential maps. In both studies, maximum activation was for visual imagery right-posterior, for abstract thought left-anterior. Common across subjects for both studies, visual imagery-associated activity was right inferior-temporal in Brodmann areas 20, 36 and 37, for abstract thought left orbito-frontal in Brodmann areas 38 and 47. In both studies, subjects had to remember the last spontaneous mentation or presented word, but did not know that imagery vs. abstract mentation was studied. In sum, the identified brain areas were activated automatically without task to imagine or to formulate, and identical areas were active regardless of whether mentations were triggered by internal, spontaneous events (sudden ideas) or by external, imposed events (word display). The EEG and ERP microstates seem to be valid candidates for ‘atoms of thought’.

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Coherence and Phase Coupling in the Scalp EEG and between LORETA Model Sources, and Microstates as Putative Mechanisms of Temporo-Spatial Functional Organization—Lehmann D1 (1Zu¨rich) What are the brain mechanisms that incorporate the seemingly homogeneous experience of a percept or a thought? Higher brain functions assumedly are generated by sets of neural sub-systems that are distributed in various brain regions and that are temporally coordinated. EEG and ERP measures of coherence or phase coupling aim at such functional temporal connections between regions. However, results obtained from scalp recorded electric data (including recomputations to CSD) are ambiguous concerning source localization because electric sources are oriented, and are not necessarily perpendicular to the head surface. Thus, there is no meaningful functional interpretation of scalp results. On the other hand, time series computed from intracerebral model sources (LORETA cortical areas) permit coherence and phase computations whose results are non-ambiguous, and which may be very different from scalp-obtained results. Whether functional connectivity is executed exclusively by transmission through fibers or to what extent electric field effects directly influence brain cell activity still needs clarification.-An alternative conceptualization assumes that brain activity contributes to a homogeneous experience as long as it occurs within a short, elementary time window. Temporal parsing of global brain electric activity into microstates leads to the identification of such sub-second building blocks in the range of !100 ms. The functional significance of various classes of spontaneous and event-related microstates has been established. The results support the hypothesis that brain work for conscious homogeneous experience might be implemented by these brief temporal packages of a quasi-stable state.

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Tonic Motor Cortex Activation during Finger Movements Analyzed by Simultaneous DC Magnetoencephalography and DC Electroencephalography— Leistner S1, Sander T2, Burghoff M3, Curio G4, Trahms L5, Mackert BM6 (1Berlin; 2Berlin; 3Berlin; 4 Berlin; 5Berlin; 6Berlin) Functional neuroimaging studies showed a linearly stronger motor cortex activation with increasing rates of repetitive finger movements. During very fast movements this correlation is abolished probably because of automation. Methodologically, these studies visualize neuronal activation indirectly via concomitant vascular/metabolic changes. In a complementary approach, DC magnetoencephalography (DC-MEG) as well as DC electroencephalography (DC-EEG) measure slow neuronal activation dynamics directly. Here, simultaneous DC-MEG and DC-EEG were used to characterize cortical neuronal activation during repetitive finger movements. 7 healthy subjects performed self-paced right finger movements. Alternating periods of 30 s fast or slow finger movements, always separated by 30 s rest periods, were performed over 30 min. To prevent automation the subjects bent alternately the second and third finger twice. DC-MEG fields were recorded over the left hemisphere using a modulation-based MEG technique. DC-EEG potentials were registered using a custom-made DC amplifier with 16 electrodes clustered around C3. In 6/7 subjects fast and slow finger movements revealed motorrelated DC-MEG and DC-EEG signals clearly above noise level. Fast finger movements revealed statistically significant stronger magnetic field amplitudes and electric potentials when compared with slow movements: (mean magnetic field strength: 179 fT vs. 155 fT; t-test: P!0.05; mean electric amplitudes: 15 mV vs. 12 mV; t-test: P!0.05). Notably, DC-MEG activity as well as DCEEG activity showed a slow decay after the end of the movement, whereas DC-EEG time curves were somewhat prolonged when compared to the DC-MEG. In conclusion, this study demonstrates that DC-MEG combined with DC-EEG can provide a non-invasive neurophysiological reference for the interpretation of neuroimaging results even in long-lasting, tonic neuronal activation paradigms. In the exemplary simple finger movement paradigm, stronger cortical activation during fast, non-automatized finger movements in comparison to slow movements was demonstrated.

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Methods for Parameter Identification in Oscillatory Networks—Leistritz L1 (1Jena) Directed information transfer in the brain is presumably arranged by coupled oscillators. A suitable model is provided by oscillatory networks. Generally, an oscillatory network is described by a set of coupled oscillators, where each component is given by an ordinary differential equation. Usually, these equations contain unknown parameters like frequency, phase or damping quantities. Furthermore, the network contains parameters describing couplings between the oscillators. A general parameter identification task is the estimation of an optimal parameter set by fitting the network solution to measured data. This results mostly in least squares problems. Least squares problems can be solved by general optimization methods, but it is shown that special techniques were superior to these general approaches. All methods for nonlinear optimization are iterative. From a given starting parameter vector, the methods produce a series of vectors

which converge to a local minimum of a certain objective function. In principle, there are two classes of optimization procedures, the local and the global ones. The local procedures are mostly gradient descent algorithms, and find a local optimum in dependence on starting parameters. In comparison to global ones, they are characterized by a faster convergence. Global search algorithms tend to a reduced dependence of the optimal solution on the starting conditions. In many cases, the resulting optimization problems could be solved easily by a modified Levenberg-Marquardt method. When this method failed, an improvement of the results could be reached by Bock’s multiple shooting method. It attempts to reduce the problems of local convergence in the presence of a vast number of local minima of the objective function. Thereby, the time domain of the network evolution is divided into many intervals, and the parameter identification is performed on each of these intervals with adapted initial values. The disadvantage is that the resulting solution is not necessary continuous, and some effort is required to find an adequate continuous solution. Furthermore, stochastic algorithms like simulated annealing can be useful at least for the determination of suitable starting parameters. The result of a parameter identification is demonstrated on a network model for the description of the spatio-temporal behavior of cortical 600 Hz oscillations within the Brodmann areas 3b and 1 after electrical stimulation of nervus medianus.

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Functional MRI Activation Pattern in Runs of Focal and Generalized Spike Wave Discharges—Lengler U1, Laufs H2, Krakow K3 (1Frankfurt; 2Frankfurt; 3 Frankfurt) Using fMRI correlated with simultaneous and continuous registration of electroencephalography (EEG/fMRI), we analyzed regional changes in blood oxygen level-dependent (BOLD) activity in association with spontaneous focal interictal spikes and generalized spike and waves in two epileptic patients. Patient 1 had newly diagnosed symptomatic focal seizures caused by an astrocytoma WHO Grade II in the right frontal lobe and the right thalamus. Patient 2 suffered from idiopathic generalized epilepsy with frequent absence seizures (GWSD). A 32-channel MRcompatible EEG was recorded continuously inside a 3 T MR scanner. Gradient EEG artefacts were subtracted, image preprocessing and statistical analyses were performed using SPM2. Finally, an event-related model was generated. In patient 1, only runs of spikes showed significant BOLD signal changes, there was no correlation between individual spikes and BOLD signal changes. Brain areas with highest significant (P!0.001 uncorrected) negative correlations were observed in regions adjacent to the brain tumor and in right frontal and temporoparietal regions. On the left side less significant deactivation in the corresponding regions was observed. In patient 2, highly significant (P!0.001 uncorrected) negative correlations were observed bilaterally in frontal, temporo-parietal and retrosplenial areas. These frontal and parietal cortical areas have often been considered to be attention modulation areas. A functional hypothesis of this ‘deactivation’ pattern related to interictal epileptiform discharges (IED) is that runs of IED (but not isolated IED) are associated with a decreased attentional level. Therefore, we conclude that deactivation of frontal and temporo-parietal

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cortices are possibly an fMRI-signature of transient cognitive impairment during prolonged generalized and focal IED.

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Decreased paired-pulse inhibition following induced cortical gliomas in the rat—Liebmann L1, Bru¨hl C2, Redecker C3, Patt S4, Witte OW5 (1Jena; 2Jena; 3Jena; 4 Jena; 5Jena) Epilepsy is a poorly understood phenomenon of many patients with gliomas, meningiomas, and other brain tumor entities. Epileptic seizures are frequently the first symptoms of gliomas. The responsible functional modifications of neuronal activity by neoplastic cells are unknown. However, an imbalance of excitation and inhibition has been observed in the vicinity of the neoplasia. We have established a model that enables different experiments on identical tissue preparations. Inoculation of EGFP-transfected rat C6 glioma cells led to intracortical growing gliomas histologically resembling human gliobastomas. Gliomas showed as a solid tumor and an infiltrative zone (100–200 mM) surrounded by reactive astrocytes. After 7 days and 14 days, respectively, 400 mm thick neocortical coronal brain slices were prepared and the brain excitability was tested with extracellular recording techniques using a paired-pulse stimulus protocol as a measure of excitatory and inhibitory drive. Specifically, we found multiple spikes and a significant reduction of inhibition in the surrounding of the tumoral mass 14 days after glioma cell inoculation. Alterations in the GABAA receptor subunit expression might contribute to this effect. To clarify this we will investigate regional expression of GABAA receptor subunits alpha1, alpha2, alpha3, alpha5, and gamma2 immunohistochemically in a future study.

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Time-Delays during Processing of Sensory-Motor Events within the Cerebro-Cerebellar Network: An fMRI Study—Lienau F1, Erdmann C2, Melchert U3, Nitschke M4 (1Lu¨beck; 2Lu¨beck; 3Lu¨beck; 4Lu¨beck) Introduction: Experiments as well as theoretical models suggest a role of the cerebellum in the control of time-related processes. For the control of movements, models of cerebellar function focus on the prediction of movement sequences based on internal models allowing for faster reaction on new demands. On the other hand, the cerebellum controls ongoing movements online. The aim of this study was to analyze the chronological activation sequence of the cerebro-cerebellar network conducting temporally predictable and non-predictable sensory and motor events. Methods: The measurements were carried out at 1.5 T (Siemens Symphony). 9 probands were asked to execute a visual triggered finger-thumb opposing movement after a preparatory signal either exactly 1 s or after a pseudorandomized time interval of 0.8–1.2 s. A passively performed finger to thumb opposition movement served as complementary sensory stimulus. The execution of the finger-opposition was registered online. SPM2 was used to perform a random effect analysis. Conclusion: The sensory and motor cortico-cerebellar network showed a typical pattern (M1, S1, SMA, premotor-cortex, cerebellar network). After an analysis of the signal intensity time courses in the regions of interest a significant delay of activation (time to maximum) was found in the cerebellar

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regions with respect to the cerebral areas within the network (M1-lobVI and S1-lobVI) for sensory and motor stimulus, respectively. This favors the thesis of cerebellar online correction at least for the lobulus VI. The temporal resolution of the signal of an event-related task seems to be able to give an approximation of the chronological signal-sequence processing of central structures; in this case exemplified for the motorsensory cerebro-cerebellar network.

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Long-Term Active Orthostatic Stress Test (AOST) in Patients with Epilepsy, Syncope, or Psychogenic falls: A Video-EEG Study—Lindenau M1, Malina T2, Stodieck SRG3 (1Hamburg; 2Hamburg; 3Hamburg) Introduction: Many patients are referred to our epilepsy center for the differential diagnosis (DD) of sudden unexplained falls or loss of muscle tone with or without loss of consciousness (SUF). We prospectively evaluated a diagnostic protocol including an active orthostatic stress test in 115 patients. Patients: Evaluation included all consecutive patients referred for DD of SUF between 05/02 and 06/04 in whom syncope was a probable diagnosis. Patients had neurological and cardiological evaluation (incl. normal tilt-table test) without a definite diagnosis. Age was 12 to 88 years with a median of 36 years, 59 were female, 56 male. Methods: Evaluation included a meticulous history of falls, in nearly all cases an observer was interviewed. The AOST was performed in the video-EEG lab following 24–48 h video-EEG with 10/20 scalp EEG C ECG electrodes (Neurofile XP, ITmed). Until 12/03, blood pressure was measured intermittently by an automatic device, since 2004 all 42 patients were evaluated with a noninvasive beat-to-beat blood pressure device (Task Force Monitor, CNSystems). After 15 min lying supine the patients actively stood for 30 min or until a spontaneous fall. Results: In 48 patients (42%) the AOST was classified as abnormal. In 31 patients (27%) a fall (24) or presyncope (7) occurred, comorbid epilepsy was present in 6, cataplexy in 1 of the patients. Of the 24 falls, 15 were classified as neurocardiogenic syncope and 9 as psychogenic (active falling, no changes in blood pressure or pulse). Presyncope was diagnosed when the patient became symptomatic (e.g., dizziness) and a significant change in blood pressure or heart rate occurred. Diffuse high amplitude theta or delta EEG activity was seen in 13/15 patients with neurocardiogenic syncope, 3/7 patients with presyncope, and 0/9 patients with psychogenic falls. In 17 other cases (15%) postural orthostatic tachycardia occurred. Discussion: The AOST is of great diagnostic value in selected patients during video-EEG. It is preferable to tilt-table test because of the more physiological situation, the high rate of psychogenic falls, and abnormal results in patients with previous normal tilt-table tests. The video can be shown to compare the documented fall with other falls. Conclusions: EEG is helpful in discriminating psychogenic falls from syncope with generalized EEG-slowing. Continuous measurement of blood pressure is necessary, since changes may be too short to be detected by intermittent measurements.

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Information Processing and Synchronization in the Thalamo-Reticular System by Beta Phase Coding in a Model of Neural Oscillators—Liske B1, Stevens A2, Schwarz J3 (1Tu¨bingen; 2Tu¨bingen; 3Heidenheim) Information in the brain is suggested to be coded by either the firing rate or the relative timing of neuronal activity. Temporal coding is particularly relevant to brain structures with strong oscillatory behavior, such as the thalamo-cortical system or the hippocampus. The thalamus has a key position in information processing in the brain: first, it is the major gateway for sensory information to the cortex. Second, thalamocortical pathways are reciprocated by massive feedback connections from the cortex back to the thalamus. Thalamic relay neurons are coupled to cortical neurons, as well as to the inhibitory neurons of the reticular nucleus of the thalamus and the resulting reciprocal interactions generate synchronous oscillatory patterns in the thalamo-cortical system depending on input frequencies, phase deviations, and delay time. In the present work we have studied a simple neural network model of the thalamo-reticular system based on the Wilson–Cowan model of neuronal oscillatory behavior and show how different input patterns result in several spatio-temporal patterns of synchronous activity. A main finding of the numerical simulations is that the network connectivity and the intrinsic oscillatory properties result in distinct characteristic, collective spatiotemporal behavior within the network. By varying the connectivity schemes comparable with lesioned or damaged brain regions, our results are in good agreement with experimental results. For example, it could be seen that the sensory input and the cortical feedback are essential for an information processing in the thalamo-reticular system. Suppressing the sensory input results in temporal oscillatory activity in the beta and gamma range and a strong spatial dependence of the network dynamics. References Borisyuk, RM, Hoppensteadt FC. Oscillatory models of the hippocampus: a study of spatio-temporal patterns of neural activity. Biol. Cybern. 1999; 81: 359–371. Contreras D0, Steriade M. Synchronization of low-frequency rhythms in corticothalamic networks. Neuroscience 1997; 76: 11–24. Jones EG. The thalamic matrix and thalamocortical synchrony. Trends Neurosci 2001; 24: 595–601. Schwarz J, Bra¨uer K, Dangelmayr G, Stevens A. (2000) Lowdimensional dynamics and bifurcations in oscillator networks via bi-orthogonal spectral decomposition. J Phys A: Math Gen 2000; 33: 3555–3566.

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The Influence of Preceding Movements on Motor Cortical Activity in Finger-Tapping—Losch F1, Blankertz B2, Mu¨ller KR3, Curio G4 (1Berlin; 2Berlin; 3 Berlin; 4Berlin) Introduction: Brain-computer interfaces (BCI) enable the control of external devices via EEG signals, possibly substituting the brain’s normal output pathways in paralysed patients. One key problem is the still limited information transfer. This could be improved by increasing the rate of BCI commands; however, a faster command rate might be restricted eventually by the refractory

behavior of EEG features commonly used in non-invasive BCI b paradigms, such as event-related desynchronizations (ERD) of pericentral m rhythms or lateralized readiness potentials (LRP). Objective: We conducted a study in healthy subjects addressing (a) the stability of ERD and LRP for increasing rates of self-paced typewriting finger movements and (b) the possible ERD/LRP dependence on ipsi- vs. contralaterally preceding hand movements. Methods: 8 healthy subjects performed self-paced typewriting (randomized left vs. right index finger tapping on a computer keyboard) in blocks with 30, 60 or 120 keystrokes per minute. Using 64-channel EEG recordings, we compared -ERD depending on the preceding, intraindividually averaged LRP and m movements. Results: Grand averages over 8 subjects showed for all parameters (LRP, -ERD) and tap rates activation profiles which differed significantly between m ipsilaterally vs. contralaterally preceding finger movements: greater negativation (LRP) or, respectively, desynchronization (ERD), prior to EMG onset was found in case of contralaterally preceding taps compared to ipsilateral movements. Remarkably, the post-movement m/b event-related synchronization (ERS) was stronger after repetitive ipsilateral movements. Conclusions: These findings demonstrate that motor-related EEG features depend on preceding finger movements in a typical BCI setting with self-paced finger movements. Importantly, these EEG features can be distinguished from each other so that classifiers could be trained for single-trial classifications in BCI applications.

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Influence of Deep Brain Stimulation on the Autonomic Nervous System in Patients Suffering from Parkinson’s Disease—Ludwig J1, Guballa C2, Remien P3, Wasner G4, Binder A5, Pohle S6, Schattschneider J7, Herzog J8, Volkmann J9, Deuschl G10, Baron R11 (1Kiel; 2Kiel; 3Kiel; 4Kiel; 5Kiel; 6Kiel; 7Kiel; 8Kiel; 9 Kiel; 10Kiel; 11Kiel) Introduction: Deep brain stimulation of the subthalamic nucleus (STN) is one of the most effective options of therapy in Parkinson’s disease. On the other hand dysfunctions of the autonomic nervous system are very common in Parkinson’s disease. How STN stimulation influences the autonomic nervous system, and therefore autonomic disorders, is not known yet. The aim of this study is to examine the coherences between autonomic dysfunctions and deep brain stimulation. Methods: So far 5 patients suffering from Parkinson’s disease being treated with bilateral STN stimulation were examined. For this purpose blood pressure and heart rate during rest were taken and a heart rate variability test was performed. For investigations of the functions of sympathetic cutaneous vasoconstrictor neurons, a laser-Doppler was used for measuring vasoconstriction after deep inspiration. All examinations were randomized and performed on oral medication during ‘On’ as well as ‘Off’ states of the stimulator. Results: There was a trend to higher systolic and diastolic blood pressure in the supine position and an increased vasoconstriction due to increased activation of sympathetic cutaneous vasoconstrictor neurons during STN stimulation. Blood pressure during rest and heart rate variability were not influenced by deep brain stimulation. Conclusions: The results suggest an influence of STN stimulation on the sympathetic nervous system whereas tests

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examining mainly parasympathetic innervation have not been influenced. Further studies are needed to prove these preliminary data. Supported by the Deutsche Forschungsgemeinschaft (DFG Ba 1921/1–3).

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Neurovascular Coupling Non-Invasively Characterized by Simultaneous DC-Magnetoencephalography and Time-Resolved Near-Infrared Spectroscopy— Mackert BM1, Leistner S2, Sander T3, Liebert A4, Wabnitz H5, Burghoff M6, Macdonald R7, Trahms L8, Curio G9 (1Berlin; 2Berlin; 3Berlin; 4Berlin; 5Berlin; 6 Berlin; 7Berlin; 8Berlin; 9Berlin) Functional brain imaging methods map neuronal activations indirectly through the accompanying neurovascular response. However, awareness is increasing that the link between neuronal and vascular task-related responses is all but a simple linear transform. Recently, we have shown that in a technically complementary approach neurovascular coupling can be analyzed non-invasively in the human brain in principle by simultaneous DC-magnetoencephalography (DC-MEG with brain-to-sensor modulation) and near-infrared spectroscopy (NIRS). As an extension to the first non-selective NIRS and DC-MEG recordings, we demonstrate here that time-resolved multichannel NIRS in combination with DC-MEG permits us to analyze neurovascular coupling in the human cortex. Simultaneously, DCMEG signals and time-resolved multichannel NIRS at three wavelengths (687 nm, 803 nm, 826 nm) allowing for depthselective analysis of absorption changes were recorded over the left primary motor cortex hand area in healthy subjects during finger movements of the right hand (30 s followed by 30 s rest; nZ25 periods). DC fields and NIRS parameters (deoxy-Hb and oxy-Hb) followed closely the motor task cycles revealing statistically significant differences between periods of finger movements and rest. Analysis of variance of distributions of photon times of flight demonstrated changes of hemoglobin concentration originating from a deeper compartment of the head, i.e., the cortex. Notably, the leading slope of the DC-MEG response was found to be steeper and correspondingly the 50% level of its maximum was reached about 1 s to 3 s earlier compared to the NIRS responses. These results indicate that the vascular response, analyzed here in a simple motor task, is slower compared to the neuronal activation. Taken together, this dual approach provides a new opportunity to analyse non-invasively the ‘hemodynamic inverse problem’ which refers to the challenge of making valid and precise estimates of underlying cortical neuronal activity from measured hemodynamic responses, e.g., in NIRS and fMRI.

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Functional Imaging in Complex-Regional Pain Syndromes—Maiho¨fner C1, Handwerker HO2, Birklein F3, Neundo¨rfer B4 (1Erlangen; 2Erlangen; 3Mainz; 4 Erlangen) Complex-regional pain syndromes (CRPS) are distressing neuropathic pain syndromes, mainly resulting from injury at the extremities. The clinical triad comprises sensory, motor and autonomic disturbances. Pain and hyperalgesia are hallmarks of this syndrome. Patterns of sensory and motor symptoms may indicate that the pathophysiology of CRPS is not only limited to the

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affected limb, but also includes changes in the central nervous system (CNS). Therefore, we employed functional imaging techniques in CRPS patients in order to explore potential CNS changes in more detail. In a first study we investigated the somatotopic organization within the primary somatosensory cortex (S1) in acute forms of CRPS by means of magnetoencephalography (MEG). We found a significant shrinkage of the corresponding cortical hand field contralateral to the CRPS affected side. The hand position was switched to a more lateral and inferior position towards the lip. Predictors for these plastic changes were overall pain and the extension of mechanical hyperalgesia. In a second MEG follow-up study (at least one year of follow-up) we could demonstrate that cortical reorganization reversed following successful treatment of CRPS. The recovery from neuropathic pain symptoms predicted recovery from cortical reorganization. Therefore, we could demonstrate a link between central nociceptive sensitization and cortical plasticity. In a third study we used functional magnetic resonance imaging (fMRI) in order to delineate the neuronal matrix of touch-evoked pain (i.e., dynamic-mechanical allodynia) in CRPS. Our results suggest the recruitment of a complex brain network underlying allodynia in CRPS. The most important cortical areas identified within this network were secondary somatosensory cortices, insula, prefrontal cortices, parietal cortices and the cingulate cortex. In summary, the presented studies provide further evidence for an involvement of the CNS in the pathophysiology of CRPS. Supported by the German Research Network ‘Neuropathic Pain Syndromes’ of the German Federal Ministry of Education and Research (BMBF).

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Influence of a mutation of the calcium ATPase 2 (SERCA 2) gene in patients with Darier’s disease on the central and peripheral nervous system—Marziniak M1, Hasselmann D2, Tilgen W3, Sommer C4, Dillmann U5 ( 1Homburg/Saar; 2Homburg/Saar; 3 Homburg/Saar; 4Wu¨rzburg; 5Homburg/Saar) Objective: To investigate neurological manifestations in patients with Darier’s disease. Introduction: Darier’s disease is an autosomal dominant skin disorder characterized by warty papules and plaques in the seborrheic area (central trunk, flexures, scalp, and forehead), palmoplantar pits, and nail abnormalities. ATP2A2, which encodes the sarcoplasmic reticulum calcium ATPase 2 (SERCA2) pump, has been identified as the defective gene in Darier’s disease. SERCA2 belongs to a family of P-type membrane bound ATPase, which pumps calcium from the cytoplasm into reservoirs in the endoplasmic reticulum. Up to now neurological manifestations of the disease have not been described. Methods: 6 patients with Darier’s disease were seen by a neurologist. AEP, nystagmography, EMG of the quadriceps muscle, and electroneurography of the lower limb were performed. Additionally isometric contractions of the adductor pollicis muscle were recorded after supramaximal ulnar nerve stimulation. The compound muscle action potential (CMAP) was recorded by surface electrodes. Results: In 5/6 patients the electrophysiological investigations including the electromyography were normal. One patient who was affected most heavily by Darier’s disease showed a generalized muscular atrophy and myopathy in the EMG. The muscle contraction test was pathological in all patients. The contraction

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time and the half relaxation time (1/2 RT) were prolonged. In 5/6 patients the twitch potentiation after 2 Hz stimulation was not detectable. Discussion: We could show for the first time that patients’ with Darier’s disease had a pathological muscle contraction. No pathological changes of the central nervous system were detectable. These muscle alterations correspond very well with the known mutation in the SERCA2 gene, coding for a calcium ATPase 2, and suggest a relevant physiological influence of the mutation for the muscle physiology.

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Deficits in Executive Control Function in Parkinson’s Disease with Dementia Compared to Alzheimer’s Disease and Parkinson’s Disease without Dementia— Marzinzik F1, Hermann A2, Klostermann F3 (1Berlin; 2 Berlin; 3Berlin) Objective: Besides motor deficits, patients with Parkinson’s disease can suffer from cognitive and attentional decline, particularly from a lack of executive control functions. This specific problem was analyzed in view of the motor and cognitive symptomatology occurring in this condition. Method: Target detection, response inhibition and response switching were tested in outpatients with Parkinson’s disease with dementia (PDD, nZ9), Parkinson’s disease without dementia (PD, nZ13), Alzheimer’s disease (AD, nZ3) and controls (CO, nZ9), using a visual Go/NoGo paradigm. PDD and AD were matched for level of Mini-Mental State Examination. Participants were instructed either to perform or to inhibit a button press with the right or left index finger due to a Go- (green rectangle) or NoGoCue (red rectangle). At intervals of 2 s these stimuli were preceded by Warning Cues (arrow), indicative for the side of the putative motor response. In the non-switch condition the arrow was presented only to one side. In the switch condition the upcoming arrow indicated either to the right or left side. Results: In the non-switch condition, patients with PDD had a lower detection rate for targets (Go-trials) than patients with AD, PD and CO. In the switch condition, patients with PDD and AD had a comparably low detection rate for the Go-trials, whereas PD patients performed as CO. Further, response inhibition (NoGotrials) was more deficient in patients with PDD than in patients with AD, PD and CO, irrespective of the condition. Throughout all tasks, patients with PD had a similar performance as CO, independently of their motor score in the Unified Parkinson’s Disease Rating Scale. Conclusions: For patients with PDD, specific deficits of (i) target detection in the non-switch condition and (ii) general response inhibition were identified, as compared to patients with AD. On the other hand, target detection in the switch condition was similarly impaired in PDD and AD patients. Interestingly, no specific deficit of PD patients was unmasked by the tests used, if compared to controls. We conclude that PDD is a specific condition of dementia, which can be differentiated from AD by adequate tests on executive control functions. As executive dysfunction in Parkinson’s disease seems to affect as an inhibitory as excitatory control, putative pathophysiological parallels to the motor deficits, impairing as movement initiation and cessation, should be addressed in future studies.

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Improvement of Kinaesthetic Deficits by Subthalamic Nucleus Stimulation in Parkinson’s Disease—Maschke M1, Tuite PJ2, Pickett K3, Wa¨chter T4, Konczak J5 (1Essen; 2Minneapolis; 3Minneapolis; 4Minneapolis; 5 Minneapolis) Recent studies have revealed that patients with Parkinson’s disease (PD) exhibit kinaesthesic deficits. For example, they have higher perceptual thresholds in detecting passive elbow movements. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor deficits in PD, but its effect on kinaesthesia is unknown. We have now examined how STN DBS affects the perception of limb position. 9 PD patients with bilateral chronic STN DBS and 7 controls were tested. The subject’s forearm was moved passively (w0.5 deg/s) while resting on a splint. A torque motor was mechanically connected to the splint, moving it at a constant speed causing either forearm flexion or extension. For each condition (ON or OFF stimulation), 40 flexion and 40 extension movements were recorded with elbow joint angular displacements of 0.28, 0.68, 18 up to 88. To account for order effects, a subset of the PD patients (nZ5) was tested in the ONstimulation state first, while the remaining patients were first examined during the OFF-stimulation state (nZ4). A 18 displacement was detected in 78% of the trials and a 28 displacement in over 91% of the trials by the control subjects. In contrast, PD patients were clearly impaired in the correct detection of movement direction. During ON-stimulation they showed correct responses in 74% for 28 displacements. Deficits worsened when the DBS device was OFF with PD patients correctly detecting 28 displacements in only 60% of the trials. Thresholds for 75% correct responses were 0.98 for controls, 2.58 for PD patients when stimulation was OFF and 2.08 when stimulation was ON. We conclude that STN DBS may improve kinaesthesic deficits in PD, but does not lead to a full recovery of proprioceptive function. (Work supported by a grant from the DFG (MA 2209/3–1.)

CNS and plasticity: sleep, juggling and pain—May A1 (1Hamburg) In neuroscience, next to ‘functional imaging’ some innovative new imaging techniques based on structural attributes have begun to be established and their potential recognized. Using the high spatial resolution of three-dimensional structural MRI-datasets, transformed into a common stereotactic space, morphometric techniques such as voxel-based (VBM) and deformation based analysis (VBM) are designed to seek significant regional differences by applying voxel-wise statistics in the context of Gaussian random fields. VBM is fully automated, unbiased, and has been cross-validated with region-of-interest measurements and functional data in a number of studies. VBM demonstrated in the past two years, that it is observer-independently capable of revealing subtle changes in grey matter volume/density by averaging across subjects. This technique establishes a ‘lesion’ in the brain that can not be detected by conventional MRI and may allow extremely subtle anatomical traits to be imaged and localised pointing the way to future neuropathological examination. In ‘idiopathic’ syndromes VBM has proven to be a powerful method to detect regional differences in cerebral structures in a variety of diseases like narcolepsy and restless legs syndrome, cluster headache and migraine, parkinsonian tremor, Huntington duisease and schizophrenia to name a few. Particularly for cluster headache

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it is remarkable, that findings in functional imaging and VBM have been directly translated into a successful therapeutical approach, i.e. deep brain stimualtion of the hypothalamus. Additionally, recent data regarding learning point towards the fundamental capability of the adult human cortex to adapt and change structurally in response to changes in the enviroment. This competence on a physiological level is crucial in our understanding of specific findings in so called idiopathic diseases. However, it is still one of the most interesting questions, whether those structural changes are primary or secondary to the syndrome. Only if we understand what exactly happens on a macroscopic and microscopic level, will we be in a position to use and translate our knowledge regarding plasticity into new treatment options. This will be extremely interesting with respect to progressive diseases such as dementia and chronic pain.

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Memory for Emotional Content and Context: Insights from Event-Related Potential (ERP) Studies—Mecklinger A1, Johansson M2 (1 Saarbru¨cken; 2 Saarbru¨cken) A large number of studies has highlighted the modulatory role of emotion on memory. While studies of free recall have consistently revealed an emotion-induced memory enhancement, studies of recognition memory have produced mixed results in this respect. A series of ERP memory studies using either faces with emotional affects or emotional objects and scenes as stimulus materials will be presented. It will be shown how emotional valence and arousal modulate recollection and familiarity, the two subprocesses for recognition memory, as well as other cognitive processes, i.e., decision behavior. A second series of studies will focus on source memory for emotional events. These studies revealed that emotionally arousing events reduce source memory for some but not all features of a study context. A potential electrophysiological correlate for this emotional modulation of contextual memory will be discussed.

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Quantified Analysis of Wrist and Trunk Movements Differentiates between Hypermotor and Automotor Seizures—Meier A1, Cunha J2, Mauerer C3, Vollmar C4, Feddersen B5, Noachtar S6 (1Mu¨nchen; 2Aveiro; 3 Mu¨nchen; 4Mu¨nchen; 5 St Martin d’He` res; 6 Mu¨nchen) We have attempted to evaluate the movement characteristics of hypermotor and automotor seizures based on an observerindependent objective method. We included EEG and video recorded automotor (nZ10) and hypermotor seizures (nZ10) of 17 patients considered for resective epilepsy surgery, in whom the camera position was perpendicular to the trunk facing the camera in an upright position and wrist and trunk movements were continuously visible on the video recordings. The movements were quantified from the videos by analyzing all video frames during the entire seizure (25/s). Seizure duration, movement angular speed, movement extent and predominant frequencies (power spectral analysis) of the movements were analyzed (Wilcoxon rank sum test). Maximum speed (median 902 pixel/s vs. 223 pixel/s, P!0.001) and extent (median

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45597 pixel2 vs. 2304 pixel2, P!0.001.) of the wrist movements were significantly faster and greater in hypermotor seizures than in automotor seizures. The extent of trunk movement was significantly greater in hypermotor seizures (median 4458.5 pixel2) than in automotor seizures (median 412.5 pixel2) (P!0.001). The analysis of wrist movement extent separated all automotor from hypermotor seizures. The analysis of maximum angular speed of the wrist movement showed that only one automotor seizure (585 pixel/s) was above the lowest maximum angular speed of wrist movements of hypermotor seizures (553 pixel/s). The predominant repetition rate of the automatisms in automotor seizures was ca. 1/s, whereas no predominant frequency of movements was observed in the hypermotor seizures. The duration of the automotor seizures (median 81G41 s) was longer than that of the hypermotor seizures (69G54 s) (P!0.04). The quantitative analysis of wrist and trunk movements provides objective measures for the differentiation of hypermotor and automotor seizures. This information is helpful for the classification of seizure types in patients considered for resective epilepsy surgery.

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BOLD-MR Angiography as a Diagnostic Tool for Asymptomatic Cavernomas in Children—Mentzel HJ1, Fitzek C2, Bo¨ttcher J3, Brandl U4, Reichenbach JR5, Kaiser WA6 (1Jena; 2Jena; 3Jena; 4Jena; 5Jena; 6 Jena) Purpose: The purpose of this study was to evaluate the diagnostic potential of a high resolution MR venography technique in a child with asymptomatic cerebral cavernomas. The blood oxygen level dependent (BOLD) venography method is based on susceptibility-induced phase contrast and is sensitive not only to the oxygen content of intravascular blood but also to breakdown products such as hemosiderin, due to increased signal dephasing. Methods and Materials: We studied a 12-month-old asymptomatic girl with a history of familiar multiple cavernomas. Imaging was performed on a 1.5 T MR unit (Siemens, Vision plus) using a standard head coil. Conventional MRI consisted of T1- and T2weighted SE sequences, FLAIR and susceptibility sensitive EPI sequences (slice thickness 6 mm). 2D TOF-MR angiography was performed. A high-resolution 3D highly T2*-weighted gradient echo sequence with first-order flow compensation, and radiofrequency spoiling was created for BOLD-venography (TR 45– 67 ms, TE 25–40 ms, flip angle 608, 32–64 partitions, FOV 240– 270 mm, 512 matrix, bandwidth 78 Hz/pixel). Magnitude and phase images were reconstructed. Results: Using standard spin echo sequences and the susceptibility EPI sequence only three cavernoma-suspicious lesions could be detected. Seven cavernous angiomas could be detected with high-resolution BOLD venography. Highly detailed information about the veins was obtained. Discussion: Cavernous angiomas may bleed and cause neurological deficits or seizures. Using BOLD venographic imaging, cavernomas can be evaluated at a spatially high resolution. The assignment between anatomical and vascular structures may be of importance for the evaluation of cavernomas and their risk of possible bleeding.

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Migration of Cortical Spreading Depression (CSD) in Adult Rats can be Inhibited by Norepinephrine, Clonidine, Yohimbine, and Propranolol—Mikulik O1, Richter F 2, Ebersberger A 3, Schaible HG4 (1Jena; 2Jena; 3Jena; 4Jena) Spreading depression is thought to be a neuronal mechanism that expands the penumbra zone after focal brain ischemia. Furthermore, cortical spreading depression (CSD) is assumed to be a neuronal mechanism underlying migraine aura. Interestingly, the sizes of the penumbra after both focal ischemia and migraine are significantly influenced by adrenergic agonists and antagonists. In human migraine beta-adrenoreceptor blockers are efficiently used for prophylaxis. The particular action of these adrenergic drugs is unknown, but vascular effects are often discussed. Alternatively, it is conceivable that adrenergic compounds act on the neuronal events that are involved in the pathophysiology during ischemia and migraine. Indeed, propranolol efficiently blocked SD in a retinal preparation where no vessels were present. To study whether adrenergic agonists or antagonists influence CSD, we applied different drugs topically to an area of the exposed cortex of anaesthetized adult rats (sodium thiopental, 100 mg/kg, i.p.) and observed the migration of CSD-related DC potential deflections with glass microelectrodes at cortical depths of 800 and 1200 mm in front of and behind the treated area. The adrenergic agonists norepinephrine (1 mM) and clonidine (0.56 mM) blocked reversibly the migration of CSD. The beta-blocker propranolol (250 mM to 1 mM) dose-dependently diminished migration velocity or even blocked migration of CSD. The alpha2-antagonist yohimbine (1.75 mM) showed a similar effect as norepinephrine, probably via its affinity to inhibitory 5-HT1A receptors. None of the substances in the concentrations used had an influence on regional cerebral blood flow or on systemic arterial blood pressure. The results show that alpha2-agonists, and beta-adrenoceptor antagonists can inhibit the migration of CSD. Thus, the interference of these compounds with CSD may contribute to their beneficial effect. The effect of beta-receptor antagonists in human migraine needs further exploration, because only a subgroup of migraine patients suffers from migraine with aura and because CSD does not directly activate the trigeminal nociceptive system. Supported by IZKF Jena (IZKF B378-10102).

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Investigation of Blood-Flow Changes During Cognitive Task Activation using CASL—Mildner T1, Zysset S2, Trampel R3, Driesel W4, Mo¨ller HE5 (1Leipzig; 2 Leipzig; 3Leipzig; 4Leipzig; 5Leipzig) Functional perfusion imaging (p-fMRI) was applied for the first time to a cognitive paradigm that produces activations in a number of brain regions. An adapted single-trial version of the color-word Stroop interference task was used as a paradigm. This experiment is known to produce robust activations in the lateral prefrontal, the fronto-median, and parietal cortices. Perfusion contrast was created by continuous arterial spin labeling (CASL) of the blood in the left common carotid artery, and was applied for all repetitions of the functional run in a quasi-continuous fashion, i.e., it was interrupted only during image acquisition. For imaging, a spin-echo (SE) echo planar imaging (EPI) sequence with a 64!36 acquisition matrix was used. A short echo time of TEZ13 ms was employed in order

to suppress blood oxygen level dependent (BOLD) signals. For comparison, BOLD contrast was detected using conventional gradient-echo (GE) or SE-EPI. Positive activations in BOLD imaging appear in p-fMRI as negative signal changes corresponding to an enhanced transport of inverted water spins into the region of interest (i.e., increased cerebral blood flow [CBF]). Negative BOLD responses (areas of deactivation) appear as positive signal changes in p-fMRI indicating areas with decreased CBF. p-fMRI was capable of reproducing most of the GE-BOLD-fMRI activations and deactivations as signal changes of opposite sign. The localization of the local maxima of p-fMRI agreed reasonably with SE-BOLD-fMRI and GEBOLD-fMRI. Significant shifts between the covered areas of each contrast were also detected. In certain areas, p-fMRI yielded a low sensitivity compared to BOLD-fMRI. The quantification of CBF changes during cognitive task activation is demonstrated for several well-separated cortical areas. The observation of a decreased CBF during the Stroop task in the parietomedian cortex confirms previous PET results which showed decreases of CBF in well-separated cortical regions related to a decrease in neuronal activity.

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Effect of Endotoxin on the Peripheral Nerve Leading to Critical Illness Polyneuropathy—Mohammadi B1 (1Hannover) Introduction: Critical illness polyneuropathy (CIP) is a mixed motor and sensory axonal polyneuropathy which complicates sepsis or hypotension and occurs with the development of multiple organ failure. CIP is a relatively common problem in intensive care units. It has a frequency of 33% to 100% depending on the criteria used for the diagnosis and the type of patients. Patients who survive recover within weeks, in case of mild CIP, or within months, in case of severe CIP. In this study we investigated electrophysiological, microbiological and inflammatory parameters to evaluate factors possibly associated with the pathogenesis of CIP in patients with severe sepsis or septic shock. Methods: This prospective study was performed in the interdisciplinary intensive care unit (ICU) of the Medical School of Hannover, Germany. Twenty patients with severe sepsis or septic shock were enrolled into the study as early as possible after admission to ICU. Electrophysiological tests were performed at different days (1, 7 and 14 day) after diagnosis of sepsis. In parallel, to investigate the development of CIP the plasma concentration of different endotoxins, as well as activation of inflammatory and coagulation cascades were determined. Results: The median age of patients was 51.5 (range 19–74) years, and total median Acute Physiology And Chronic Health Evaluation II (APACHE II) score was 19 (range 0–32). Total median Sequential Organ Failure Assessment (SOFA) score was 10.55 (range 1–17). The mortality during this study was 25%. The main electrophysiological finding of the study was a reduction of the amplitude of the compound muscle action potentials (CMAP) at all three nerves studied. The values of other parameters (sensible nerve action potential, nerve conduction velocity and distal latencies) were mostly normal. Interestingly, there was a significant correlation between the axonal damage of motor nerves and the serum concentration of endotoxin.

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Discussion: This study shows the onset of CMAP reduction as an early sign for beginning of CIP. The correlation between CMAP and endotoxin points to a direct effect of endotoxin on the peripheral nerve. Thus, inhibition of the biological effects of endotoxin might be an effective therapy of CIP in vivo.

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Brain State-Dependence of Coherent Oscillatory Activity along the Cortico-Striatal Axis of the Rat— Moll CKE1 (1Hamburg) Anatomically and physiologically, the cerebral cortex is tightly linked to the striatum, which is the head-end of corticobasal ganglia circuits. However, the nature of cortico-striatal interactions is poorly understood. To assess the coupling between neuronal assemblies in the cerebral cortex and the striatum, we recorded single unit activity (SUA) and local field potentials (LFP) in healthy, halothane-anesthetized rats. To this end, we employed a bihemispherical multi-site approach with eight microelectrodes in the striatum together with simultaneous recordings of electro-corticographic activity (EcoG). EcoG served as the primary indicator of brain state. During halothane anesthesia, cortical field potentials are generally dominated by oscillatory activity in the delta range (2–5 Hz). The fine structure of these delta oscillations revealed an alternating pattern of two different activation states. Phases with a more irregular highamplitude slow wave activity (‘high-delta’) were interrupted by episodes dominated by regular, clockwork-like delta oscillations with low amplitudes (‘low-delta’). In addition to the spectral peak representing the slow wave activity, both cortical and striatal LFPs displayed a spectral peak in the upper gammafrequency (range 45–75 Hz). These high-frequency oscillations consistently showed a frequency shift coinciding at the transition from high-delta to low-delta episodes. Spontaneous activity in the cortex and striatum was significantly coherent in the delta range during high-delta episodes, encompassing both hemispheres. Cortico-striatal coherence in the delta frequency range was significantly lower during epochs of low d. Interestingly, beta-band coherence (15–30 Hz) between cortex and striatum was low, while coherence in the upper gamma band was significantly increased, irrespective of the prevailing cortical activation state. We found that during high-delta episodes, striatal single unit activity is synchronized even interhemispherically and shows a strong oscillatory modulation in the delta frequency range. In contrast to this, striatal spiking is desynchronized and tonic during low-delta epochs. Taken together, our results suggest that the cortex exerts a powerful influence on neuronal activity in the striatum. We propose that dynamic coupling and de-coupling of cortical and striatal neuronal assemblies is an important mechanism in the functional organization along the cortico-striatal axis.

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Motivated Attention in Emotional Picture Processing is Reflected by Activity Modulation in Cortical Attention Networks—Moratti S1, Keil A2, Stolarova M3 (1Konstanz; 2Konstanz; 3Konstanz) In the present study, we presented subjects with high (pleasant and unpleasant) and low (neutral) arousing emotional

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pictures in a steady-state visual evoked field paradigm while recording the magnetoencephalogram. Applying a minimum norm estimation (MNE) technique we determined the origin and the strength of the evoked neuromagnetic field. In addition to magnetocortical data, we examined subjective ratings, heart rate change and viewing time to obtain a multi-variate database of emotional experience related to the activation of affective stimulus representation. As evidenced by the MNE, pictures rated as high arousing elicited a greater activity in fronto-parietal cortical networks than low arousing pictures, with a right hemispheric predominance. This effect was also observed in occipito-temporal regions but to a lesser extent. Longer viewing times for high arousing pictures and sustained heart rate deceleration for high arousing unpleasant pictures indicated that these stimuli were of high motivational relevance compared to neutral pictures. Taken together, we argue that activity in higher order fronto-parietal cortical attention networks is modulated by emotional arousal. In turn, this attention network influences activity in the systems performing stimulus processing.

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Use-Dependent Plasticity in Patients with Multiple Sclerosis—Morgen K1, Kadom N2, Sawaki L3, Tessitore A4, Ohayon J5, McFarland H6, Frank J7, Martin R8, Cohen L9 ( 1Gieben; 2Bethesda; 3Bethesda; 4 Bethesda; 5Bethesda; 6Bethesda; 7Bethesda; 8 Bethesda; 9Bethesda) Background: In patients with multiple sclerosis (MS), cumulative tissue injury develops in the central nervous system. Axonal damage is known to occur early on in the disease. Cortical reorganization has been observed in MS patients during the performance of motor and cognitive tasks and may prevent functional deficits. A better understanding of cerebral plasticity could help optimize therapeutic options. Methods: In the current study, we analyzed the effects of training a simple motor task on cortical organization. Functional MRI activation patterns of patients with relapsing-remitting MS and of healthy control subjects were evaluated before and after a thirty-minute training period with a random effects analysis (SPM99). Kinematic properties of the trained movement as well as a control movement were controlled with an accelerometer; potential mirror movements were detected with an EMG attached to the passive hand. Results: Performance of the thumb movements before, during and after the training phase was comparable in both groups; mirror movements were not observed. Before the training, MS patients showed a more pronounced activation of the contralateral dorsal premotor cortex (PMd) than healthy controls. After the training, patients did not exhibit a task-specific reduction of activation in the contralateral somatosensory cortex (S1), motor cortex (M1) and parietal association cortex (BA 40). Conclusions: These findings indicate that patients recruit the contralateral PMd more than healthy subjects in order to perform a simple untrained motor task. The absence of a task-specific reduction of activation in S1, M1 and BA 40 suggests a reduced capacity among MS patients to optimize neuronal recruitment with training.

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On the history of depth microelectrode recordings during functional stereotaxy—Mu¨ller D1, Moll CKE2, Engel AK3, Struppler A4 (1Hamburg; 2Hamburg; 3 Hamburg; 4Mu¨nchen) The first recordings of subcortical potentials of man fall into the pre-stereotactic era of movement disorder surgery. In the early 1940 s, Meyers inserted manually an electrode through a craniotomy into the striatum of Parkinsonian patients under direct inspection, but found no correlation between his electrocaudatograms on the one hand and the clinically estimated degree of Parkinsonian symptoms on the other. However, Meyers’ demonstration of the potential benefits of basal ganglia surgery together with the high mortality rates of these ‘open’ procedures led Spiegel to introduce the less invasive stereotactic method to the human brain in 1947. Functional exploration of subcortical structures by means of macroelectrode techniques complemented conventional electrical stimulation and was soon routinely performed by many other stereotaxic research groups all over the world. Nevertheless, the results of macroelectrode recordings were heterogeneous and somewhat disappointing, since the relatively crude EEG-like signals did not allow for a differentiation of the various structures. The introduction of microelectrode recordings into functional stereotaxy by Madame Albe-Fessard and her collaborators in the early 1960s was therefore welcomed enthusiastically by the stereotactic community because the finer recording probes provided the first recordings of multiple unit spike activities, enabling a reliable differentiation and delineation of various human thalamic nuclei. An enormous amount of electrophysiological investigations were carried out until the introduction of levodopa for the treatment of Parkinsonian patients in 1967 and resulted in a detailed anatomophysiological description of the human thalamus and pallidum. Thereafter, interest in functional stereotaxy waned and the accompanying neurophysiological investigations were only sporadically continued, until the introduction of new imaging techniques and the implementation of deep brain stimulation as a substitute for ablative surgery led to a resurrection of functional stereotactic surgery in the late 1980s. Besides giving a survey of the historical development of this exciting field of applied neurophysiology, the present report highlights both practical and methodological challenges of intraoperative microphysiology in the context of non-invasive imaging techniques and an increased impact of observations from animal studies.

Gait Training with a Driven Gait Orthosis–Comparison between Lokomat and Treadmill Therapy— Mu¨ller F1, Husemann B2, Heller S3, Krewer C4, Quintern J5, Koenig E6 (1Bad Aibling; 2Bad Aibling; 3 Bad Aibling; 4Bad Aibling; 5Bad Aibling; 6Bad Aibling) Rehabilitation approaches for impairments in motor function of neurologically impaired patients like stroke victims rely heavily on physiotherapy. After the introduction of treadmill training for paraplegia, there has grown a body of experience in the use of treadmill training for hemiplegia as well. Since exercising with stroke patients or paraplegic patients on the treadmill is a very demanding task for therapists, new robotic devices have been developed to assist and even increase the effect of training sessions. We report our experience and results of first recordings with the Lokomat, a PC-controlled and driven orthosis, developed to enable

completely paralyzed patients to walk on a treadmill without the physical help of therapists. The patients are supported with a suspension of the body weight by a harness, when walking in a driven gait orthosis, with actuators at hip and knee joints of either side inducing cyclic gait patterns. During treadmill training periodic excitation of muscular and cutaneous receptors is supposed to stimulate neural circuits in the spinal cord to facilitate or even induce cyclic gait patterns as put forward by the concept of central pattern generators. We measured EMG activity in 4 muscles of each leg during walking on a regular treadmill as well as on a treadmill with assistance of the Lokomat. Subjects were healthy controls and 9 hemiplegic stroke patients. Our results support the hypothesis that the use of an extrinsically given cyclic leg movement will induce typical muscular walking patterns, however reduced on the paralyzed side. Faster velocities would lead to higher EMG amplitudes. Treadmill training without the Lokomat induced less pronounced muscular patterns. Gait symmetry can almost perfectly be induced by Lokomat training. In addition, patients were able to use faster velocities on the Lokomat compared to the regular treadmill, leading to a higher number of repetitive gait cycles. Since the exercise is less strenuous for patients and therapists, the duration of training can be increased producing still augmented exercise. Our data show that Lokomat training is a highly effective gait exercise for severely disabled hemiplegic patients. First results indicate that it is at least as effective as typical physiotherapeutic gait training.

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High Frequency Oscillations as Neuronal Substrate of Priming and Learning—Mu¨ller M 1, Gruber T2 (1Leipzig; 2Leipzig) Contemporary research in cognitive neuroscience suggests that induced high frequency synchronized neuronal activity in the gamma band range (O25 Hz) is the neuronal mechanism of the formation of so-called Hebbian cell assemblies (networks). By means of learning paradigms, we were able to investigate the formation of cortical networks and their re-activation during memory retrieval. We demonstrated that synchronized neuronal activity acts as an important neuronal substrate of various mnemonic phenomena, e.g., repetition priming and information maintenance.

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Neuronal Dynamics of Selective Information Processing in the Human Brain as Exemplified in the Visual Cortex—Mu¨ller M1 (1Leipzig) It is commonly accepted that stimulus processing is performed in a neuronal network, comprising several cortical and possibly subcortical areas. In a series of experiments, we investigated the role of synchronized neuronal activity in selective visual stimulus processing. In the first studies, we investigated the hypothesis that synchronized neuronal activity might serve as mechanism for preferred processing of an attended stimulus. In a second series, we drove cortical networks, related to visual stimulus processing, with an external pacemaker to study basic principles of visual attention. In particular, we were interested in cortical principles of sustained attention. We were able to show that the allocation of attention may be governed by different principles under conditions of sustained

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attention for continuously presented stimuli as opposed to transiently presented stimuli with long inter-stimulus intervals.

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New Insights into Visuospatial Attention: The Spotlight Metaphor meets fMRI—Mu¨ller NG1 (1Frankfurt) Covert spatial orienting enhances perceptual capabilities in the part of the visual field one attends. This classical observation was made by Michael Posner and colleagues a quarter of a century ago and made them coin the classical metaphor of a ‘spotlight’ of attention. Beyond intuitive appeal, the virtue of any powerful metaphor comes from its simplicity, and the single spotlight metaphor has inspired a vast amount of psychological research centered on the question of how spatial attention modulates perceptual performance. While confirming Posner’s basic observation the models emerging from these subsequent studies have produced several variations on the theme and raised the following questions: does the spotlight have a zoom lens, can there be multiple separate spotlights, and is the spotlight’s tuning enhanced by an inhibitory surround? And finally going beyond mere spatial mechanisms: do the objects scattered across the visual field affect the spotlight’s shape? Functional neuroimaging has permitted us to submit the various hypotheses surrounding the spotlight model to testing at the level of the associated neural activity changes. Our studies are based on the general finding that covert attending enhances activity in the retinotopic visual cortex that represents the selected visual field region. In a first study, we could demonstrate that the number of activated visual subareas increased when subjects had to monitor a larger visual field region. At the same time, the level of activity in a given area decreased compared to conditions in which attention could be narrowly focused and this level correlated with discrimination performance. We took these results as evidence for a zoom lens function implemented in the spotlight metaphor. In another study, by asking subjects to attend to a spatially defined part of an object we found that activity in the retinotopic visual cortex was modulated with respect to whether a subarea coded a location on the attended object or not. Moreover, during search when the relevant information had not turned up at the cued location, preferably those areas became activated that coded locations occupied by the already attended object. In yet another study, we demonstrated that the attentional focus encompasses an inhibitory surround where activity in the respective early visual cortex representations is suppressed relative to passive viewing. Together, these studies show that the spotlight metaphor is now well supported not only at the behavioral but also the neural level. The studies illustrate how spatial attention is optimized and can flexibly adapt to the ecological needs imposed both by the real visual world and the sensory mechanisms on which we rely to perceive it.

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Are Pain Reports as well as Autonomic and Motor Reflex Responses Changed in Parallel while Ageing?— Mylius V1, Kunz M2, Schepelmann K3, Lautenbacher S4 (1Marburg; 2Marburg; 3Marburg; 4Marburg) Most studies of experimentally induced pain revealed an increase of pain threshold and a decrease of tolerance threshold in

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the elderly. Physiological indicators have not yet been studied and compared with the verbal reports very often. Therefore, we intended to find out whether the assumed changes in the pain report are similar to the nociceptive evoked autonomic and reflex responses. Forty healthy young persons (age: 24.2G3.2 years) were compared to forty healthy elderly persons (age: 70.7G5.0 years). At first, the nociceptive flexion reflex (NFR) threshold was assessed by applying electrical suralis stimulation and employing a staircase method for threshold determination. Thereafter, ten consecutive supra-threshold reflex recordings (5 mA above reflex threshold) were averaged and the reflex parameters were calculated (latency, amplitude and reflex area). At the same time evoked heart rate responses (area of the heart rate increase in 3 time intervals, 0–3 s, 3–6 s and 6–9 s) and the sympathetic skin response (SSR, latency and amplitude) were assessed. Following each stimulation, the pain report was measured with a 6 step categorical scale (no pain, slight pain, moderate pain, intense pain, very intense pain and unbearable pain). The verbal pain report at different stimulation levels and the nociceptive flexion reflex threshold were found not to differ significantly between age groups. Significant decreases of the reflex area (P!0.05), the SSR amplitude (P!0.001) and the heart rate area within each time interval (P!0.05) were found in the group of the elderly compared to the group of the young (Student’s t-test). The group differences of SSR latency, NFR latency and amplitude were not significant. The present study revealed a decrease in suprathreshold nociceptive evoked autonomic and motor reflex responses in the elderly, while the pain report and the nociceptive flexion reflex threshold remained unchanged. Accordingly, an age-related dissociation of the different reaction systems can be seen, suggesting that the underlying ageing mechanisms in these systems differ. One can conclude that the elderly feel the same ‘pain’, but are limited in their defensive reactions.

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Retinal Vessel Analysis for the Morphological and Functional Examination of a Central Microcirculation Area-A New Clinical Method—Nagel E1, Vilser W2, Riemer T3 (1Rudolstadt; 2Ilmenau; 3Jena) Purpose: Changes of retinal blood vessels have been known in a number of vascular systemic diseases for a long time. The examination by a ophthalmoscope performed usually in hypertensive patients gives hitherto a subjective assessment of the morphological condition according to a qualitative scale. Method: The retinal vessel analysis is based on measured vessel diameters and their local and temporal changes. The static vessel analysis (SVA) examines quantitative vessel parameters in one single image of the fundus, i.e., the arterio-venous ratio. Signs of retinopathy were evaluated additionally in the image. The dynamic vessel analysis (DVA) observes automatically and online changes of the vessel diameters in a sequences of images (25/s). By means of standardized external influences (i.e., flicker light), the regulatory function of the arteries and veins can be measured. Results: The correlation of parameters of the SVA and vascular risks (i.e., stroke) was proved in epidemiological studies [1]. SVA using new automated routines possibly enables a more precise monitoring of individual vessel changes. In DVA retinal arteries and veins showed different responses to flicker light. A reduced arterial response to flicker light was shown by DVA in

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hypertensive patients [2]. The flicker reaction of neighbouring arterial segments of 20 mm vessel length can be different. Conclusions: DVA is a functional non-invasive examination technique for arteries and veins of a central microcirculation area. The combination with morphologic-descriptive and well evaluated parameters of SVA seems to be useful. The significance of the results for the prognosis of vascular risks (i.e., stroke) and for the control of the time course of hypertensive organ damage should be evaluated in controlled studies. References Wong TY, Klein R, Couper DJ et al. Retinal microvascular abnormalities and incident stroke: the Atherosclerosis Risk in Communities Study. Lancet 2001; 358:1134–1140. Nagel E, Vilser W, Lanzl I. Age, blood pressure and vessel diameter as factors influencing the arterial retinal flicker response. Invest Ophthalmol Vis Sci. 2004 45: 1486–1492.

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Event-Related Potentials (ERPs)–An Up-to-Date Technique in Cognitive Neurosciences—Nager W1 (1Hannover) Non-invasively recorded ERPs provide a superb temporal resolution that goes far beyond other up-to-date techniques such as fMRI, PET or TMS. Beyond that, in the auditory modality, the ERP technique offers the unique opportunity to differentiate between attentive behavioral processing and preattentive stimulus detection such as during intraoperative sedation. The current report summarizes a series of cognitive studies that, on the one hand, emphasize time-dependent cognitive functioning in the auditory domain and on the other hand, provide an insight into cognitive functioning where other techniques fail due to logistical reasons [i.e., in cochlear implant (CI) users or during anesthesia]. A first line of evidence comes from studies in awake healthy subjects. It was shown that even a 300 ms interaural stimulus delay causes a preattentive cortical ERP that indicates automatic discriminative auditory processing. Moreover, there was evidence for a fast preattentive auditory discrimination within the first stimuli of a complex auditory sequence. In contrast, electrophysiological indicators of attentive stimulus selection processes were delayed by several seconds, thus indicating a dynamic function for attentiondependent auditory processing, whereas preattentive discrimination resembles a preset-like function. Several studies were conducted during anesthesia. It became clear that cortical preattentive auditory discrimination still operates during sevofluran sedation. Beyond that, meaningful auditory novel events (i.e., dog barks) led to a cortical ERP that has formerly been linked to an attentive orienting reaction in awake subjects. Thus, we obtained evidence for a more detailed intraoperative auditory perception than was previously assumed. There is a strong need for objective evaluation in postimplant rehabilitation for CI users, but magnetic interference contraindicates fMRI or TMS. ERPs indicated that CI users preattentively monitor even weak stimulus changes that fail to activate attentively guided selection responses. However, preliminary results indicate that CI users differ from normal controls by means of amplified occipital scalp activation in an auditory discrimination task, thus pointing to a recruitment of the visual cortex for distinctive processing in the auditory modality.

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Cortical Representations of Auditory Phantom Perception (Tinnitus)—Najib A1, Plewnia C2, Reimold M3, Plontke S4, Brehm B5, Gerloff C6 (1Tu¨bingen; 2 Tu¨bingen; 3 Tu¨bingen; 4Tu¨bingen; 5Tu¨bingen; 6 Tu¨bingen) Tinnitus has originally been seen as a disturbance of the peripheral auditory system. In view of the fact that tinnitus can persist even after surgical transection of the cochlear nerve, the hypothesis evolved that it could be a phenomenon similar to phantom pain and a consequence of maladaptive neuronal plasticity (cf. Jastreboff Neurosci Res 1990: 8: 221). The terms ‘centralization of tinnitus’ or ‘central tinnitus’ have been used to differentiate chronic subjective tinnitus from acute or objective forms. In the present study we sought to identify cortical representations of chronic subjective tinnitus. Regional cerebral blood flow associated with tinnitus perception was measured with H15 2 O positron emission tomography (PET). Two conditions were statistically compared, a baseline condition when patients had their typical tinnitus sensation and a condition in which tinnitus was suppressed by an intravenous bolus injection of 1.5 mg/kg lidocaine. The patients (nZ9) had a total of four scans on two separate days. The data were processed with statistical parametric mapping (SPM99). Significance of increased rCBF during tinnitus perception was tested in a fixed effects analysis (multi-subjects, conditions and covariates) and random effects analysis (one sample t-test based on the individual contrast images). Increased rCBF was consistently found in left secondary auditory areas (BA 42, 22), the region of the angular gyrus (BA 39), and in right prefrontal areas (BA 9, 11). These results identify a neocortical network involving prefrontal and secondary auditory areas, which could underlie the perception of tinnitus. Ongoing experiments in our laboratory are geared at the question whether neurostimulation of this tinnitusrelated neural network can alleviate symptoms in patients suffering from chronic subjective tinnitus.

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Reevaluation of Patients with Clinically Probable Parkinson’s Disease but Normal DAT Scan—Neukirch D1, Sabolek M2, Storch A3 (1Ulm; 2Ulm; 3Dresden) In recent years about 200 patients with clinical probable Parkinson’s disease treated at our outpatient unit were examined with DAT scan. As reported by other authors, about 10% of these examinations showed not a Parkinsonian, but a normal pattern. We clinically reevaluated 15 patients out of this subgroup about two years after the first examination. Our task was to find out what kind of disease developed out of the syndrome primarily estimated as Parkinson’s disease. We performed a complete neurological examination, UPDRS together with video recording and evaluation by an independent neurologist, L-Dopa test, Hoehn and Yahr Scale, Schwab and England activities of daily living-scale, MontgomeryAsperg Demention Scale, PDQ39 and Nu¨rnberger Self Evaluation Scale. We hope to be able to provide an aid for the evaluation of patients with clinically probable Parkinson’s disease who do not profit by dopaminergic treatment and show a normal pattern in the DAT scan. 196 Autonomic Neuropathies—Neundo¨rfer B1 (1Erlangen) The autonomic nervous system is involved in the most types of polyneuropathies but in some forms the autonomic dysfunctions may prevail. These are the acute pandysautonimia, the diabetic

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polyneuropathy, the acute Guillain–Barre´ syndrome, the amyloid polyneuropathy, the acute intermittent porphyria and the hereditary sensory autonomic neuropathy (HSAN). The clinical symptoms and signs are caused by dysfunctions of autonomic nerve fibers which accompany the somatic nerves as well by lesions of the visceral autonomic nerves. The following findings can be observed: pupillary disorders, trophic disorders with ulcers, oedema and osteoarthropathy, hypo/anhidrosis, vasomotor disorders, cardio vascular dysfunstions with resting tachycardia, and decrease of heart rate variability, lack of reflectory hyperventilation, gastrointestinal disorders with diarrhoe or constipation, disorders of emptying the bladder and erectile dysfunction. Sequelae of afferent autonomic denervation abscence of pain in coronary ischiaemia abscence of perception and vegetative response to hyperglycaemia, faecal incontinence, lack of sensation for the filling of the bladder and abscence of labour pains. The therapy depends on the cause of the polyneuropathy. Sometimes symptomatic treatment is possible.

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Transcranial Sonography (TCS) of Brain Parenchyma in Corticobasal Degeneration—Niehaus L1, Gruber D2, Hertel R3, Ebersbach G4, Eckert M5, Kupsch A6 (1Magdeburg; 2Berlin; 3Magdeburg; 4Beelitz; 5Magdeburg; 6Berlin) Introduction: TCS of brain parenchyma has recently been demonstrated to be able to detect characteristic ultrasound features in various movement disorders. Aim of the study was to evaluate the echo pattern of parenchymal structures in patients with corticobasal degeneration (CBD). Methods: TCS was performed in 8 patients (mean age 67G8 years) who met the clinical diagnostic criteria for CBD (Litvan et al., 1997) and 20 age-matched non-parkinsonian controls using a standardized protocol. The signal intensity (echogenicity) of the substantia nigra (SN) and the thalamus was assessed bilaterally and the width of the third ventricle was measured. Results: In CBD, the echogenic signals of the SN were more extended contralateral (21G4 mm2) than ipsilateral (17G5 mm2) to the more affected body side. The area of SN echogenicity was significantly increased in patients with CBD compared to healthy controls (SN area: 19G5 vs. 9G7 mm2; P!0.01). The echo pattern of the thalami and the width of the ventricle did not differ between patients and controls. Conclusion: These preliminary data suggest that the brain parenchyma sonography in CBD is characterized by an asymmetric hyperechogenicity of the SN. The abnormal echo pattern in the SN region might reflect some degree of nigrostriatal injury in CBD.

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Pharmacological Consolidation of Motor Cortical Neuroplasticity in Humans—Nitsche MA1, Grundey J2, Jaussi W3, Liebetanz D4, Lang N5, Tergau F6, Paulus W7 (1Go¨ttingen; 2Go¨ttingen; 3Go¨ttingen; 4 Go¨ttingen; 5Go¨ttingen; 6Go¨ttingen; 7Go¨ttingen) Introduction: Amphetamine, a catecholaminergic re-uptake blocker, and D-cycloserine, a partial NMDA receptor-agonist, are able to improve neuroplastic mechanisms in humans. However, so far not much is known about the underlying physiological mechanisms. Here we study the impact of amphetamine and D-cycloserine on NMDA receptor-dependent excitability

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modifications in the human motor cortex elicited by weak transcranial direct-current stimulation (tDCS). Methods: tDCS protocols which elicit long-lasting motor cortical excitability modifications were applied under premedication with 20 mg amfetaminil (AMP), 100 mg D-cycloserine (CYC) or placebo medication. For the excitability-enhancing anodal tDCS a premedication of 20 mg AMP and 150 mg dextromethorphan, an NMDA receptor-antagonist, was administered in a control experiment. Motor cortex excitability was monitored by single pulse transcranial magnetic stimulation. Results: AMP and CYC significantly enhanced and prolonged increases in anodal, tDCS-elicited, long-lasting motor cortical excitability. Under AMP and CYC premedication, anodal tDCS resulted in an enhancement of excitability which lasted until the morning after tDCS, compared to about 1 h in the placebo condition. The additional administration of the NMDA receptorantagonist dextrometorphan blocked any enhancement of tDCSdriven excitability under AMP. Conclusions: In this study, low-dosage AMP as well as CYC administration consolidated tDCS-induced neuroplastic effects, but did not initiate them. This result may enable researchers to optimize neuroplastic processes in the human brain on the rational basis of purpose-designed pharmacological interventions.

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Differential Functional Predominance of the Frontal and Parietal Areas during Performance of Isolated or Combined Eye and Hand Reaching Movements— Nitschke M1, Ludwig K2, Vassilev G3, Erdmann C4, Ko¨mpf D5, Heide W6, Binkofski F7 (1Lu¨beck; 2Lu¨beck; 3 Lu¨beck; 4Lu¨beck; 5Lu¨beck; 6Lu¨beck; 7Lu¨beck) Introduction: Reaching movements are combined of different subcomponents consisting of information regarding the position in space or the effector of the movement itself. Separate cortical areas seem to exert a differential influence. Whereas premotor and prefrontal areas are hypothesized to code for the motor effector, the parietal areas code for position in space. We compared the fMRI activations during combined eye-hand reaching movement with respect to the quality of information given before the execution of the task. Methods: We investigated 14 volunteers at 3 T (EPI-Sequences, whole brain). Each task consisted of the performance of saccades or reaching movements towards a target presented on a screen in front of the scanner. The target, a computer-generated laser point, was presented in horizontal positions at 108 left and right in the visual field. The event-related experimental paradigm consisted of performance of isolated or combined fixation of the laser point and reaching movements towards the target with their right hand after a cue 1500 ms before preparing the movement by presenting information about either the position (left or right), or the effector (eye, hand, combined) or both (full information). Saccade performance was controlled with an MR-compatible infrared-oculography (Cambridge Research Systems) during the scan. Activation was determined by individual and group analysis using SPM 2. Results: Isolated eye movements activated the saccade related areas (i.e., frontal and supplementary eye field, intraparietal sulcus) and reaching movements related areas including the motor cortex, the supplementary motor area, prefrontal and parietal cortex. Information about the effector before movement execution resulted in a relative increase in premotor and

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prefrontal activation, information about the position in space in parietal areas. Analysis of saccade measurements demonstrated good compliance and correct performance of the volunteers during the scan and resulted in exclusion of faulty performance before data processing. Conclusion: Apart from the activation of the saccade and hand movement related networks during isolated or combined reaching, we could demonstrate a differential predominance of the premotor, prefrontal and parietal areas with respect to the different subcomponents during reaching movements in space.

The Role of Seizure Evolution for the Localizaion of the Epileptogenic Zone—Noachtar S1 (1Mu¨nchen) Epileptic seizures frequently evolve from one seizure type to another. There are typical seizure sequences, which point to different epilepsy syndromes. For example, generalized myoclonic seizures not infrequently occur in cluster, particularly if precipitated by sleep deprivation and evolve into a generalized tonic-clonic seizure. Another example is abdominal aura, which is followed by an automotor seizure. This sequence is frequently, although not exclusively, seen in patients with temporal epilepsy. The version of the eyes and the head during epileptic seizures was reported to have a lateralizing significance. However, this has been debated by other investigators. We could recently show that the sequence of the head movement during the seizure evolution is crucial for the lateralization of the seizure onset zone. In summary, the analysis of seizure sequences provides valuable information about the epileptogenic zones and epilepsy syndromes.

tangential N1/P2 activity was partly more pronounced in the (K) TRP condition while there were some trends for an increase of the overall resulting intensity dependence as opposed to the control (C) TRP condition. There were no significant differences for latencies between the study conditions. Conclusions: Contrary to the hypothesis, our results of a homogeneous female population provide some minor arguments for the hypothesis of an influence of serotonin on the N1/P2 intensity dependence in spite of a strong depletion situation. A low serotonergic neurotransmission may contribute to the intensity effect in AEP only to a lesser extent while interactions with other neurotransmitters of the CNS will have to be considered.

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Effects of Acute Tryptophan Depletion on the Loudness Intensity Dependence in a Healthy Female Population—Norra C1, Buchner H2, Bro¨cheler A3, Becker S4, Kawohl W5, Vreemann S6 (1Aachen; 2 Aachen; 3Aachen; 4Aachen; 5Aachen; 6Aachen) Objectives: Animal and human studies suggest an inverse influence of the serotonergic system on the intensity dependence of early event-related potentials for the primary acoustic cortex, namely the N1/P2 component. Meanwhile, procedures by tryptophan depletion tests (TDT) represent an established human challenge tool for a temporary reduction of tryptophan levels and central nervous serotonin. Methods: 16 healthy females volunteered twice to ingest a highly concentrated amino acid mixture with (C) TRP or without (K) TRP in a double-blind cross-over study design: in relation to the individual basic value plasma tryptophan levels decreased extensively to 18.69% (G5.32) in the (K) TRP condition. Sinus tones of 1000 Hz of different intensity levels (60–90 dB) were presented binaurally. A 32-multichannel EEG was recorded continuously. Following the averaging procedures we performed dipole source analysis [BESA] applying a model of a tangential and radial dipole per hemisphere. Results: Within their groups, all subjects showed increasing N1/P2 amplitudes of the relevant tangential dipole in series of higher stimulus intensity with significant differences of the individual change rates (P!0.001–0.05). Augmentation of

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Pattern of Neural Activity in Ventromedial Prefrontal Cortex Predicts High- and Low-Risk Behavior in Healthy Subjects—Northoff G1, Grimm S2, Bo¨cker H3, Schmidt C4, Bermpohl F5, Heinzel A6, Hell D7, Bo¨siger P8 (1Magdeburg; 2Zu¨rich; 3Zu¨rich; 4Zu¨rich; 5Boston; 6 Boston; 7Zu¨rich; 8Zu¨rich) We are confronted with high- and low-risk decisions in our everyday life. Damasio argues in his somatic marker theory that not only cognitive components but also affective components are crucial in decision making. Since emotional judgment requires an interplay between emotional and cognitive function, it might be considered a key component in decision making. Although the ventromedial prefrontal cortex (VMPFC) has been demonstrated to be crucial in decision making, determination of highand low-risk decisions via emotional judgment and underlying VMPFC function has not been demonstrated yet. We therefore investigated neural activity in VMPFC during emotional judgment and related it to performance in decision making. In this study, we investigated using fMRI the neural correlates of emotional judgment in healthy subjects. We incorporated a judgment expectancy period in our paradigm to shift the accent from the emotional component (Zemotional reactions and experience) to the cognitive component (Zjudgment) within emotional judgment. We then tested whether the BOLD effect of emotional judgment and expectancy could be related to highand low-risk decisions as measured by the Iowa Gambling Task (IGT). For this purpose we correlated IGT performance with fMRI results during emotional judgement without and with expectancy. Our main findings included: (1) expectancy reverses the signal type in the VMPFC during emotional judgment from signal increases to signal decreases; (2) global IGT performance correlates significantly with signal changes in VMPFC, namely with signal increases and decreases during emotional judgment without and with expectancy, respectively; (3) predominant highand low-risk IGT performers differ significantly in VMPFC activity during emotional judgment without and with expectancy. Our results demonstrate that emotional judgment induces signal changes in VMPFC which, in turn, determine whether high-or low-risk decisions are made. In conclusion, our findings provide evidence for emotional judgment and thus the affective component being a key component in decision making. This complements the theory of somatic marker as suggested by Damasio by revealing the neural correlates of the affective component in decision making.

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Quantification of Ipsilateral and Contralateral Head Movements during Seizures in Patients with Temporal Lobe Epilepsy—O’Dwyer R1, Cunha J2, Vollmar C3, Mauerer C4, Ebner A5, Feddersen B6, Noachtar S7 (1Mu¨nchen; 2Aveiro; 3Mu¨nchen; 4Mu¨nchen; 5Bielefeld; 6St Martin d’He`res; 7Mu¨nchen) We have attempted to evaluate quantitatively the lateralizing significance of ipsilateral and contralateral head movements during seizures in patients with temporal lobe epilepsy. We included only EEG and video recorded seizures of patients with temporal lobe epilepsy, for whom the camera position was perpendicular to the head facing the camera in an upright position and bilateral head movements were recorded. Head turning in a reaction to outside stimuli was excluded. A total of 12 seizures in 10 patients, in whom both contralateral and ipsilateral head movements were recorded with high quality video were investigated. Nine patients have unilateral temporal lobe epilepsy. One patient has bilateral temporal lobe epilepsy with ictal EEGs of the two seizures showing independent seizure onset from either side. Ipsi- and contralateral head versions were defined according to the side of ictal EEG seizure patterns. Head movements were quantified for speed analysis on the videos by selecting the movement of the nose in relation to a defined point on the trunk (25/s) in the inner 908 angle facing the camera. The analysis of the duration was independent of the camera angle. The angle, the duration, and the angular speed of the ipsilateral and contralateral head movements were computed. Inter- and intrasubject analysis was performed (Mann–Whitney test). The positive predicting value was 100% for both the ipsi- and contralateral head movement with regards to the ictal EEG pattern. Ipsiversion always preceded contraversion. The duration of the contralateral head version was significantly longer than that of the ipsiversion (7.4G3.2 s vs. 4.6G2.9 s, P!0.036). The angular speed of the contralateral head version was similar to the ipsilateral version (11.5G7.8 vs. 11.1G8.6 deg/s). Ictal head versions have a high lateralizing significance in temporal lobe epilepsy. The quantitative analysis of ipsilateral and contralateral head versions shows that the duration of head version and the occurrence in the seizure evolution is important for the correct lateralization.

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Cortical Control of Smooth Pursuit Eye Movements: Sensory and Motor Components. An fMRI study— Ohlendorf S1, Speck O2, Rutschmann R3, Haller S4, Kimmig H5 (1Freiburg; 2Freiburg; 3Regensburg; 4 Basel; 5Lu¨beck) Smooth pursuit eye movements (SP) serve to keep a moving object in our fovea, the place of highest visual acuity. For this purpose, the SP system must detect the object moving across our retina (sensory input), process its velocity, and prepare a motor command signal being sent to the eye muscles (motor output), which enables the eyes to follow the object. The purpose of this study is to identify which cortical regions process the sensory input information, which process the motor output signals, and which are related to both processes (possibly sensorimotor transformation sites). For this purpose we measured cortical activation related to pure visual (sensory), pure oculomotor, and combined visuo-oculomotor stimulation. A central fixation dot

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and a second dot, 48 below the center dot, were presented in darkness. Subjects always fixated the center dot. Moving the lower dot sinusoidally in the horizontal plane yielded a visual (sensory) stimulation. Moving both dots while subjects pursued the upper dot yielded oculomotor (but almost no sensory) stimulation. Moving only the upper dot while subjects tracked this dot yielded oculomotor plus sensory stimulation. Eye movements were measured with an infrared light technique (MR-Eyetracker), cortical activation with a 3 T Siemens Trio scanner. Twelve healthy subjects participated in this study. SP gain was close to one, indicating that subjects followed the moving dot accurately. Analysis of saccadic eye movements showed that small saccades occurred during both fixation (rest) periods and pursuit (stimulation) periods, such that these saccades do not add to the cortical activation investigated here. Cortical activation was found in areas V5/V5A, precuneus, intraparietal sulcus, SEF, FEF, cingulate gyrus. Visual stimulation activated mainly occipito-parietal regions V5/V5A, precuneus and the intraparietal sulcus, while oculomotor stimulation activated predominantly the frontal regions FEF and SEF and the cingulate gyrus. This was confirmed by the combined visuo-oculomotor stimulation, which activated all these regions. Parts of V5/V5A and the intraparietal sulcus seem to be involved in both sensory and motor processing. Our data show that the occipito-parietal regions are processing the sensory input signals of pursuit eye movements, while the FEF and SEF are related to the motor output signal. Parts of V5/V5A and the intraparietal sulcus are possible sites for sensorimotor transformation

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Transcranial DC Stimulation and Corticospinal Transmission—Oliviero A1, Lang N 2 (1Toledo; 2 Go¨ttingen) Transcranial DC stimulation (tDCS) is a non-invasive technique for the induction of long-lasting changes in neuronal excitability. tDCS of the human motor cortex leads to polarityspecific changes in corticospinal excitability: anodal tDCS facilitates TMS-evoked MEP while cathodal tDCS inhibits them. Here we report on an experiment on tDCS and corticospinal transmission in a patient with electrodes implanted in the high cervical epidural space for the relief of pain. TMSevoked descending volleys and MEP from the right FDI were recorded before and after 5 min of anodal tDCS of the left motor cortex. MEP amplitudes after tDCS were facilitated for about 5 min before they returned to baseline level. Cervical recordings before tDCS revealed that at 110% RMT PA magnetic stimulation evoked three negative waves and the first had a latency of 3.8 ms. This was 1.2 ms longer than the earliest volley evoked by LM magnetic stimulation. Since the earliest volley elicited by LM stimulation is probably a D-wave we have termed this volley as the I1 wave. After tDCS, the I1 wave was unchanged regarding amplitude and latency. However, for the period of tDCS-induced MEP-facilitation an increase in number and amplitude of the later I waves was recorded. This observation supports the theory that tDCS-induced modulation of MEP arises from changes in excitatory circuits in the human motor cortex.

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Perioperative Fluctuations of Lamotrigine Serum Levels: One Risk Factor for Early Postoperative Seizures after Epilepsy Surgery?—Paul F1, Fritz G2, Lehmann TN 3, Meencke HJ 4 (1Berlin; 2Berlin; 3 Berlin; 4Berlin) Purpose: Insufficient serum levels of antiepileptic drugs are an important risk factor for postoperative seizures. Several possible influencing factors might contribute to a postoperative decrease of serum levels such as anesthetics and postoperative co-medication including steroids, analgetics and drugs for ulcer prophylaxis. Methods: We studied medical records and anesthesia protocols of 20 patients on lamotrigine during epilepsy surgery and evaluated perioperative fluctuations of lamotrigine serum levels. All patients had standardized so-called TIVA (total intravenous anesthesia) without barbiturates, only three patients had additional isoflurane. Results: 16 out of 20 patients had a relevant postoperative decrease of serum levels of more than 20% (mean 47.5%). Six patients had one or more postoperative seizures, in two cases serum levels on the day on which seizures occurred were documented and showed a correlation with the lowest postoperative serum level. The nadir of serum levels was in more than 50% of the patients not in the early postoperative period (POD one and two) but later (between POD 5 and 13). Conclusion: Our retrospective analysis shows a relevant postoperative decrease of lamotrigine serum levels in the majority of our patients. This might be a relevant and evitable co-factor for early postoperative seizures. We hypothesize an influence not only of anesthetics but also of postoperative medication, which included in the majority of our patients dexamethasone and ranitidine or a proton pump inhibitor. As a consequence from our data, we recommend frequent postoperative analysis of serum levels, a temporary perioperative dose augmentation should be considered to avoid a relevant postoperative decrease of serum levels with the risk of early postoperative seizures.

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Memory and Covariation Estimation Processes in Panic Disorder Patients—Pauli P1, Dengler W2, Wiedemann G3 ( 1Wu¨rzburg; 2Freundenstadt; 3 Frankfurt/Main) Panic patients are characterized by episodes of intense anxiety accompanied by bodily symptoms like palpitations, breathlessness, sweating, etc. Distorted or biased cognitive processes related to bodily symptoms are assumed to play a major role for the development and maintenance of these panic attacks. In a series of studies, our group has examined biased memory and covariation processes in panic patients compared to healthy participants. Behavioral as well as event-related brain potentials (ERPs) were registered. A memory bias in favor of body-related stimuli was verified for explicit but not for implicit memory processes. An enhanced late positive potential triggered by body-related stimuli during encoding seems to be the basis for this memory bias. Regarding covariation estimates, panic patients seem to selectively overestimate the association between panic-associated stimuli and aversive consequences. This overestimation is reflected in an enhanced contingent negative variation (CNV) in the interval between panic-associated stimulus and aversive consequence. The relevance of these results for theories of panic disorder and for effective treatments will be discussed.

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In vivo Detection of the Neuropathological Hallmarks in Different Parkinsonian Syndromes by Voxel-Based Magnetization Transfer Imaging—Peschel T1, Kaufmann J2, Bodammer N3, Dengler R4, Heinze HJ5, Eckert T6 (1Hannover; 2Magdeburg; 3Magdeburg; 4 Hannover; 5Magdeburg; 6Magdeburg) Objective: To determine whether a whole brain voxel-by-voxel analysis of magnetization transfer imaging (MTI) using statistical parametric mapping (SPM) detects the known neuropathological changes in idiopathic Parkinson’s disease (IPD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) in comparison to healthy controls. Background: Although much is known about the neuropathology of IPD, MSA and PSP from histological studies, the assessment of these changes in vivo remains difficult. MTI is an MRI technique, which is more sensitive to neuropathological changes than conventional MRI and provides a quantitative measure of macrostructural integrity in vivo. It has previously been shown by our group to reveal changes, which match the underlying pathological features of the different Parkinsonian disorders using an ROI approach (Eckert et al., 2004). By the use of SPM it is now possible to study the whole brain in an exploratory fashion without having to make a priori assumptions about the structures to be investigated. Methods: We investigated 15 IPD, 12 MSA, 10 PSP patients and 20 age-matched controls by means of voxel-based MTI (VBMTI) which was performed on a 1.5 T neuro-optimized GE-scanner. After calculation of the Magnetization Transfer Ratio (MTR), images were pre-processed and analyzed using a new approach adopted from voxel-based morphometry, which included an optimized normalization procedure, automated removal from skull and CSF as well as smoothing. ANCOVA with total brain volume as confounding factor was performed to differentiate regional effects between the groups (P!0.05, corrected for multiple comparisons for the entire brain volume). Results: In comparison with controls, VBMTI revealed a significantly decreased MTR in IPD patients within the substantia nigra (SN) bilaterally. In MSA patients decreased MTRs were detected in the dorsolateral putamen, the SN and along the border of claustrum and putamen. PSP patients exhibited reduced MTR in the globus pallidus, the SN as well as the thalamus on both sides. Increases in MTR were not detected in any patient group compared to controls (Fig. 1). Conclusions: Magnetization transfer imaging as analyzed by statistical parametric mapping was sensitive in visualizing the neuropathological hallmarks of the different Parkinsonian disorders in vivo. It may assist in early diagnosis and individually discriminate between IPD, MSA and PSP patients.

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MR Morphometry by Means of Deformation Field Analysis—Pieperhoff P1, Amunts K2, Hoemke L3, Mohlberg H4, Habel U5 , Klein M 6, Shah JN7, Schneider F8, Zilles K9 (1Ju¨lich; 2Ju¨lich; 3Ju¨lich; 4 Ju¨lich; 5Aachen; 6Aachen; 7Ju¨lich; 8Aachen; 9Ju¨lich) Brain morphometry techniques which are based on structural MR tomography enable one to examine the anatomy of human brains in vivo. These techniques can also be used to search for structural characteristics being related to mental or neurological diseases. Such characteristics may help to understand the

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Fig. 1.

mechanisms of these diseases, and may be relevant for their therapy or diagnosis. Considering that the resolution of routine MR techniques for in vivo scans of the whole brain is limited to approximately 1 mm, MR morphometry usually examines the macroscopic structure of human brains. We have employed a new technique, which is based on the registration of the MR datasets of individual brains (sources) to a target brain: the registration algorithm aims to map anatomically corresponding regions of the source brains and the target brain onto each other. The registration process consists of a global, affine transformation and a following local, elastic warping. The latter defines, for each source dataset, a deformation field: this is a three-dimensional vector field, which assigns to each voxel of the target brain a deformation vector, pointing to the corresponding position in the source data set. Thus, the deformation fields relate the anatomical structure of the source brains to the target brain. From these deformation fields, we have derived voxel-wise maps of the local volume changes. The maps of different subjects are overlaid with each other, thus enabling a voxel-wise statistical analysis of local structural differences. In a next step, we compared the locations of structural differences with maps of cytoarchitectonical areas, which were obtained by microscopic analysis of post-mortem brains. As the position of cytoarchitectonical areas relative to macroscopic landmarks is not fixed, these areas are represented by probabilistic maps. The probabilistic maps had been warped to the same target brain, which was used for the morphometric analysis. We have applied this technique for a comparison of the MR datasets of 12 schizophrenia patients, 12 unaffected siblings, and 24 matched normal control subjects. Main regions of differences between patients and controls were the amygdala (left), insula (left), Heschl’s gyrus (left), gyrus parietalis inferior (left, right), and gyrus frontalis medius (left, right). Supported by the Deutsche Forschungsgemeinschaft (Schn362/13-1,-2) and by the National Institute of Health (MH52176–10).

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Behavioural Treatment Reduces Pain Parallel to Restoration of Cortical Reorganization and Tactile Discrimination in Complex Regional Pain Syndrome—Pleger B1, Tegenthoff M2, Ragert P3, Foerster AF4, Dinse HR5, Schwenkreis P6, Nicolas V7, Maier C8 (1Bochum; 2Bochum; 3Bochum; 4Bochum; 5 Bochum; 6Bochum; 7Bochum; 8Bochum) Patients with complex regional pain syndrome (CRPS) and intractable pain showed a shrinkage of cortical maps on primary (SI) and secondary somatosensory cortex (SII) contralateral to the affected limb. This was paralleled by an impairment of the 2-point discrimination thresholds. Behavioural treatment over 1 to 6 months consisting of graded sensorimotor retuning led to a persistent decrease in pain intensity, which was accompanied by a restoration of the impaired tactile discrimination and a regain of cortical map size in contralateral SI and SII. This suggests that in CRPS the reversal of tactile impairment and cortical reorganization is associated with a decrease in pain.

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Spatial and Temporal Characteristics of Pain Processing in the Human Brain—Ploner M1, Schnitzler A2 (1Duesseldorf; 2Duesseldorf) Contrary to the traditional view that the cerebral cortex is not involved in pain perception, an extensive cortical network associated with pain processing has been revealed during the past decades. This network essentially includes the primary (S1) and secondary somatosensory cortices (S2) and the anterior cingulate cortex (ACC). In a series of studies we investigated the spatial and temporal characteristics of pain processing within these cortical areas by using magnetoencephalography and selective nociceptive cutaneous laser stimulation. Time courses of activations show that within this cortical network the processing of pain is organized in a predominantly parallel mode. This parallel

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organizational mode of pain processing is distinct from the elaborated and mainly serial organization of tactile processing and may allow for fast and effective reactions to harmful stimuli. Stimulus-response functions of activations suggest that the different cortical areas differentially contribute to the multidimensional experience of pain. S1 is mainly involved in discriminative aspects of pain while S2 seems to have an important role in cognitive aspects of pain perception and the ACC has been shown to be closely related to pain affect. Furthermore, extending the analysis of pain processing to very late activations revealed different contributions of these areas to first and second pain sensation. First pain appears to be particularly related to activation of S1 whereas second pain is closely related to ACC activation. Both sensations were associated with S2 activation. These findings may reflect the different biological functions of first and second pain. First pain signals threat and provides sensory information for an immediate withdrawal whereas second pain may attract longerlasting attention and initiate behavior to limit injury and optimize recovery. The analysis of interactions between processing of touch and pain show that pain facilitates processing of touch in S1 and S2, which may represent a physiological correlate of the attentionattracting property of pain. Taken together, these findings contribute to the fundamental understanding of pain processing in the human brain and may provide the basis for understanding and optimizing pain therapy.

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The Oscillatory Network of Simple Bimanual Repetitive Movements—Pollok B1, Suedmeyer M2, Gross J3, Schnitzler A4 (1Du¨sseldorf; 2Du¨sseldorf; 3Du¨sseldorf; 4 Du¨sseldorf) A characteristic of bimanual coordination is the strong and spontaneous tendency to favor spatially and temporally symmetric movements. This observation gave rise to the assumption that timing mechanisms controlling each hand independently might be integrated during bimanual temporal coordination. Although a specific role of the cerebellum for this integration process has been suggested, its neural foundations are still poorly understood. Since there is growing evidence that synchronization of oscillatory neural activity might be a fundamental mechanism of information coding in the brain, the aim of the present study was to determine the oscillatory network underlying a simple auditorily paced bimanual synchronization task and to characterize the interplay between underlying brain structures. Seven right-handed subjects synchronized left and right index finger-taps to a regular auditory pacing signal. We recorded continuous neuromagnetic activity using a 122-channel whole-head neuromagnetometer and surface EMGs of the first dorsal interosseus (FDI) of both hands. Data demonstrate that an oscillatory network coupling at 8–12 Hz subserves task execution. The constituents are bilateral primary sensorimotor and premotor areas, posterior-parietal and primary auditory cortex, thalamus and lateral portions of the cerebellum. Coupling occurred within and on different cortical and subcortical levels between both hemispheres. Coupling between primary sensorimotor and premotor areas was observed directly and indirectly via the thalamus. Coupling directions suggest that information was integrated within the left premotor cortex corroborating a specific role of the left PMC for motor control in right-handers. Most importantly, our data indicate strong coupling between both cerebellar hemispheres substantiating the hypothesis

that cerebellar signals might be integrated during temporal bimanual coordination.

215 Inflammatory Myopathies—Pongratz D1 (1Mu¨nchen) Inflammatory myopathies represent a small but important group of acquired muscular disorders. The most important forms of immunogenic inflammatory myopathies are dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM). A hallmark of all types of immunogenic inflammatory myopathies is infiltration (B-cells, CD4C and CD8CT cells and macrophages) in muscle tissue. In DM, inflammatory infiltrates with B-cells and CD4CT cells are found predominantly in perivascular and perifascicular regions, producing the picture of a myositis of the perifascicular type. There are striking lesions of the small intramuscular vessels with CD5b9 complement deposits and tubulovesicular inclusions seen on electron microscopy. In PM infiltrates are predominantly endomysial, producing the picture of a diffuse myositis. Immunhistologically, cytotoxic CD8C lymphocytes are the predominant cells that invade non-necrotic muscle fibers. IBM is characterized by endomysial infiltrations with CD8C lymphocytes. In addition, rimmed vacuoles with eosinophilic cytoplasmatic inclusions can be found. On electron microscopy filamentous inclusions in the cytoplasm and nuclei are pathognomonic. First-line treatment strategies of DM and PM are corticosteroids and Immunosuppressives. High-dose Immunoglobulins are only necessary in relatively seldom cases in which the first-line drugs are not successful or severe side effects are prominent. In inclusion body myositis the only therapeutic possibility is the administration of immunoglobulins. Newer studies on drugs against cytokines, such as TNF-alpha inhibitors are underway.

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Visualizing the Dynamics of Structural Brain Change—Preul C1, Tittgemeyer M2, von Cramon DY3 (1Leipzig; 2Leipzig; 3Leipzig) Introduction: A morphometric assessment of the dynamics of structural brain change relies on a precise and informative visualization. Time-series examinations with magnetic resonance imaging (MRI) allow the assessment and monitoring of changes in intra-individual brain structures that are altered by pathological processes or surgical intervention. Three examples resemble structural alterations in the context of selected diseases: (1) Ventricular adjustment after surgical relief of elevated intracranial pressure in internal hydrocephalus corresponds to highly dynamic changes. (2) Intraoperative brain shift of the subthalamic nucleus as the target structure for deep brain stimulation in the treatment of Parkinson’s disease demands a high precision in monitoring. (3) Long-term changes such as structural degeneration in Alzheimer’s disease necessitate a subtle follow-up. Methods: The evaluation of the structural change follows a multi- step approach: upon reorientation to the bi-commissural plane, images are processed for grey-scale normalization and intensity inhomogeneities. Rigid registration is applied to align the images followed by a fuzzy means algorithm to segment tissue types. A region-growing algorithm was adapted to the assessment of ventricular volume. Cortical surfaces are generated as smooth triangular meshes. Non-rigid registration is employed to monitor residual differences between the images, which reflect

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morphological changes. The resulting vector field is 1:1 superimposed to the MR image to allow a direct measurement of structural change. Results and Conclusion: The capability of the deformationbased analysis to visualize tissue changes of high (hydrocephalus) and low temporal (Alzheimer’s disease) dynamics will be illustrated in detail as well as subtle changes due to brain shift in the deep nuclei. The deformation-based analysis is a valuable tool in the interpretation of MR images. Such an analysis is applicable to any disease or condition where a careful observation of tissue changes is of particular importance for a reliable monitoring of the course of a disease or the success of a neurosurgical intervention.

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Sensorimotor Integration in Basal Ganglia Disorders: New Findings on Impaired Kinaesthesia in Focal Dystonia and Parkinson’s Disease—Putzki N1, Stude P2, Graf K3, Maschke M4 (1Essen; 2Essen; 3Essen; 4 Essen) The term ‘movement disorders’ is often used to subsume conditions resulting from basal ganglia pathology and refers to the predominating motor symptoms. However, clinically unapparent sensory deficits were also found in these disorders. Recent neurophysiological, neuroimaging and animal studies have revealed that sensory processing is impaired in Huntington’s disease, Parkinson’s disease and focal dystonia. This raised the interesting question to what extent impaired sensorimotor integration contributes to the clinical symptoms in these disorders. We analyzed kinaesthesia, the conscious perception of limb position, in a passive movement task (repeated extension and flexion of the index finger between 0.28 and 48 in 45 trials of random order) and compared results of patients with idiopathic focal dystonia (blepharospasm nZ3, torticollis nZ6) and patients with idiopathic PD (nZ8) to an age-matched group of healthy controls (nZ5). Patients and controls were without cognitive decline and did not show sensory deficits in routine clinical examination. PD patients detected the correct direction of a 0.28 displacement of the index finger in only 59% of the trials compared to 82% in healthy controls. Patients with focal dystonia also revealed a kinaesthetic deficit given that they responded correctly in only 76% of trials in the same task. The overall differences for detecting the correct direction of index finger movements between patient groups and controls were statistically significant (b2, PZ0.001 for PD group, PZ0.002 for dystonia group). Calculated thresholds for 75% correct responses were 0.38 in PD patients, 0.28 in dystonia patients and 0.18 in control subjects. Additionally, we analyzed the ability to judge the extent of a passive movement of the index finger by asking the patients to compare two consecutive passive movements. PD patients appeared to be more impaired than dystonia patients and both groups were different from the control group. Our findings in PD patients confirm results of previous studies that revealed kinaesthetic deficits in PD. Furthermore, the results of the present study suggest that a kinaesthetic impairment is also prevalent in focal dystonia. Together with previous findings the present results indicate that a deficit in processing multimodal sensory information might contribute to motor deficits in distinct basal ganglia disorders. Our results show the potential role of the basal ganglia as a sensory analyzer.

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Impaired Tactile Performance in Patients with Hand Immobilization—Ragert P1, Pleger B2, Voelker B3, Maier C4, Schwenkreis P5, Foerster AF6, Nicolas V7, Tegenthoff M8, Dinse HR9 (1Bochum; 2Bochum; 3 Bochum; 4Bochum; 5Bochum; 6Bochum; 7Bochum; 8 Bochum; 9Bochum) Recent studies have provided evidence that training, differential use and alterations in behavior cause plastic reorganizational changes in the human central nervous system. However, no report addressed the issue of how immobilization and thereby sensorimotor restriction caused tactile behavioral changes besides the previously described neural changes in the human motor system. To investigate the implication of a several-week immobilization induced by wearing a cast due to bone fractures of the hand, we tested spatial 2-point discrimination abilities of the healthy and immobilized hand during immobilization. To study the reversibility of the observed behavioral effects, subjects were additionally tested 2 weeks after removal of the cast. Here we found that, in spite of large variations in age and duration of immobilization, the thresholds measured for the index finger of the affected hand were significantly higher than the thresholds of the intact hand, indicating impaired discrimination abilities on the affected hand. Based on these findings, we then asked whether enforced disuse of the affected hand accompanied by restricted tactile acuity in cast patients is closely related to the duration of wearing a cast. We therefore correlated side-to-side differences between both IF with the individual duration of immobilization revealing a strong positive correlation. Accordingly, little impairment of discrimination abilities was associated with short-term immobilization. On the other hand, those subjects with long-term immobilization also had the highest discrimination thresholds and therefore the highest restriction of their affected hand. Retesting of discrimination behavior 2 weeks after removal of the cast indicated the reversibility of the observed effects. We conclude that enforced disuse over several weeks impairs discrimination abilities, whereby the impairment was reversible within 2 weeks. Moreover, functional MRI was performed in cast patients to test not only behavioral but also cortical changes within primary somatosensory cortex (SI) due to several weeks of immobilization.

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Detection of Interictal Epileptiform Activity during Spontaneous Sleep: An MEG-EEG Comparison— Ramantani G1, Boor R2, Paetau R3, Rating D4, Bast T5 (1Heidelberg; 2Raisdorf; 3Heidelberg; 4Heidelberg; 5 Heidelberg) Introduction: Simultaneous interictal EEG and MEG sleep recordings were compared as to their sensitivity in the visual detection of focal epileptiform activity. Because MEG is indifferent to radial activity, i.e., sleep changes, a higher ratio of epileptic discharges (ED) unique to MEG compared to EEG was presumed in the case of overlapping sleep changes. Patients: we studied 14 children and adolescents aged 3.5–17 years with localizationrelated epilepsy. Methods: The 122-channel whole-head MEGs and 33-channel EEGs were recorded simultaneously for 20–40 min, most of them in segments of 5–20 min. Segments of artefacts or bilateral polyspikes (O2 ED/200 ms) were excluded from the evaluation. The EEG and MEG data were separated and a blinded independent

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review of the 28 data segments was performed by 4 raters for the presence oEf D. EEG and MEG data were matched and ED identified by 3 reviewers were classified in three categories: (1) EEGZMEG (3 raters each), (2) EEG OMEG (difference of 3 raters) and (3) MEGOEEG (dto). The presence of simultaneous sleep changes (spindles, vertex waves, K-complexes, slow wave sleep) was visually determined for every single ED segment (G 500 ms). Results: Out of 4704 detected ED, 1387 spikes fulfilled the above criteria; 689 spikes unique to MEG (54% within EEG sleep changes) and 136 spikes unique to EEG (21% sleep changes). 562 spikes were identified by 3 raters in both EEG and MEG (42% sleep changes). The presence of vertex waves alone led to a significantly higher number of spikes unique to MEG. Conclusion: A higher number of spikes was detected by MEG compared to EEG. Beside various factors such as focus localization and source orientation, overlapping sleep changes contribute to the differences observed.

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Application of Exogeneous Gaseous Agents in Patients with Brain Tumors using High-Resolution Susceptibility-Weighted Imaging—Rauscher A1, Sedlacik J2, Fitzek C3, Hochstetter A4, Kalff R5, Kaiser WA6, Reichenbach JR7 (1Jena; 2Jena; 3Jena; 4Jena; 5Jena; 6 Jena; 7Jena) Introduction: Blood oxygenation level dependency (BOLD) magnetic resonance contrast has been used for functional and anatomic investigations. The oxygenation level of venous blood can be modulated by exogeneous agents, such as carbogen and oxygen. The aim of this study was to employ a high resolution BOLD method to investigate the response of brain tumors to these breathing gases. Methods: Data of six patients [four with glioblastoma multiforme (all grade IV), one with an astrocytoma (grade II), and one with a cerebral metastasis; all histologically confirmed] were acquired using a susceptibility-weighted 3D gradient echo, first order velocity compensated sequence, on a 1.5 T MR Siemens Magnetom scanner (TE/TR/alphaZ 40 ms/67 ms/258,FOVZ256!192!64, matrixZ512!192!64) . The scan was repeated up to three times while the patients were breathing oxygen, carbogen and/or air. Informed consent was obtained from all individuals. The protocol was approved by the local ethics committee. Susceptibility-weighted images (SWI) of the spatially realigned data were computed by multiplication of the magnitude images with phase masks computed from the same scans. Minimum intensity projections (mIPs) were calculated for visualization of small venous vessels. The relative signal changes between the three breathing situations were evaluated over 3D ROIs of typically 0.5 cm3 (i.e., 15!15!10 voxels) in different tumor ROIs. Maps of relative signal changes were computed. Results: An ROI-based evaluation of the signal intensities in the tumors revealed a signal decrease during carbogen breathing compared to oxygen inhalation in 3 cases. The glioblastomas displayed the highest response but also the highest heterogeneity (signal changes from K7% to C28%). The astrocytoma and the cerebral metastasis showed a negative response in all ROIs ranging from K9.3% (edema) to K2.0% (central areas) for the

astrocytoma and K8% to K16% for the cerebral metastasis. Edemas or areas of high tumor vascularity were clearly identified on maps of oxygen/carbogen response. Discussion: The method proved its potential to non-invasively probe the human brain response in patients with brain tumors to exogeneous contrast agents and at the same time to visualize venous vascularity at very high spatial resolution. Systematic studies on different tumor types may allow for a better classification of brain tumors or areas of abnormal blood supply.

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Activity-Induced Changes in GABAA Receptor Subunit Expression in the Senescent Rat Brain—Redecker C1, Stangl M2, Schroeter M3, Jander S4, Witte OW5, Dinse HR6 (1Jena; 2Jena; 3Du¨sseldorf; 4Du¨sseldorf; 5 Jena; 6Bochum) Ageing and senescence are commonly associated with a characteristic decline in cognitive and sensorimotor performance that can be decelerated by physical and mental activity. Experimental investigations in aged rats demonstrated that this sensorimotor decline coincides with a reduction in receptive field size and sensory stimulation thresholds which could be both reversed by activating housing conditions in an enriched environment. We here analyzed the effects of environmental enrichment on regional expression of GABAA receptor subunits in the very old brain. At the age of 33 months standard housed rats were transferred to an enriched environment for three months (EE) whereas controls were kept in standard cages further on (ST). At 36 months all rats were transcardially perfused and brains were processed for immunohistochemistry with antibodies against five major GABAA receptor subunits (a1, a2, a3, a5, and g2). Regional expression of receptor subunits was semi-quantitatively evaluated using optical density measurements. Using this approach a significant increase in expression of subunits a3 and a5 was observed in EE animals compared with ST-housed controls. This increase was most prominent for subunit a3 and was restricted to the primary and secondary somatosensory cortex as well as to the forelimb and hindlimb representation cortex. Subunits a1, a2, and g2 did not reveal any significant change in regional distribution. EE-induced alterations in subunit expression were not observed in the hippocampal formation. In a further series of experiments mRNA expression of these subunits was analyzed by rt-PCR. This study demonstrates a significant activity-induced plasticity of cortical GABAA receptors in the very old brain. The upregulation of subunits a3 and a5 which both are abundantly expressed in the cortex during early life might indicate a recapitulation of a juvenile expression pattern. These changes probably contribute to the sensorimotor plasticity found in very old rats following environmental enrichment

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Experimental Assessment of the b-Matrix using a Reference Phantom in Diffusion Tensor Imaging— Reichenbach JR1, Gu¨llmar D2, Haueisen J3 (1Jena; 2 Jena; 3Jena) Purpose: Diffusion tensor imaging (DTI) has opened new possibilities to investigate the brain. It is, however, very important to know the exact diffusion weighting (spatial orientations and strengths) which is summarized in the so-called b-matrix. The

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coefficients of the b-matrix are usually calculated by using a simple equation, which only takes into account the diffusion gradients and their spatial orientation. In this study we have determined the b-matrix analytically taking into account all gradients (including the imaging gradients). This leads to a system of equations with three unknown parameters (mean diffusion weighting strength, cross-term contribution of the gradients oriented in readout and slice selection direction, respectively) which requires at least three measurements in different directions to determine these unknowns. Since DTI is always acquired with at least six diffusion-weighted measurements in different directions, one is able to asses the full b-matrix experimentally, provided that the gradient scheme of the sequence and the diffusion coefficient of an isotropic phantom (e.g., water) is known. Materials: All measurements were performed using a 1.5 T whole-body MR-Scanner (Siemens Vision, Erlangen, Germany). The diffusion coefficient of the phantom was determined by using a cross-term free diffusion acquisition method. To determine the full b-matrix we acquired a full diffusion tensor scan (six different diffusion-weighted directions) and derived the correction factors and the mean diffusion strength by solving the corresponding system of equations. Results: As expected the individual elements of the experimentally determined b-matrix were different from the elements obtained by using the simplified b-value calculation Depending on the actual b-value (100–1000 s/mm2) deviations of up to 30% (for low b-values) were observed for some of the elements. The experimentally determined b-matrix was in very good agreement with the fully analytically calculated b-matrix. Discussion: The presented experimental approach provides a simple way to assess the b-matrix in very good correlation to the analytically calculated b-matrix. For this approach only knowledge of the gradient scheme, the protocol parameter (field of view, matrix size and slice thickness) and the diffusion coefficient of the phantom is required. However, the accuracy of this method critically depends on the accuracy of the numerical value of the diffusion coefficient.

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Effect of Amantadine on Human Motor Cortex Excitability as Measured by TMS—Reis J1, John D2, Mu¨ller HH3, Hamer HM4, Oertel WH5, Rosenow F6 (1Marburg; 2Marburg; 3Marburg; 4Marburg; 5Marburg; 6Marburg) Introduction: Amantadine has been frequently used for therapy of Parkinson’s disease and influenza. The exact mechanism of action remains unclear. In vitro data suggest its main mechanism of action is NMDA receptor antagonism leading to a reduction of intracortical excitation. Aims: The aim of this study was to investigate the acute effect of amantadine on human motor cortex excitability in healthy subjects by transcranial magnetic stimulation (TMS) to reflect its mechanism of action and to get information on other ways of cortical modulation in vivo. Methods: In a placebo-controlled double blind crossover study the effect of a single oral dose of 50 mg and 100 mg amantadine on motor cortex excitability of 14 healthy subjects was measured by TMS. Used paradigms were motor thresholds, MEP amplitude and recruitment curves, silent period, and-by

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double pulse TMS-intracortical inhibition ICI (interstimulus interval 2 and 3 ms), facilitation ICF (interstimulus interval 10 and 15 ms) and late inhibition at 150 ms interstimulus interval prior to and 90 min after oral drug ingestion. A peripheral effect was measured by F-waves and M-latency. For statistical analysis the Wilcoxon sign rank test with Bonferroni adjustment was performed. Results: 90 min. after intake of 100 mg amantadine a significant decrease of ICF was measured. Furthermore, late inhibition at 150 ms increased significantly. A trend towards an increased ICI at interstimulus interval of 3 ms was also detected. Other parameters remained unchanged. Amantadine did not lead to changes of peripheral excitability. Conclusions: The in vivo TMS data support the action as an NMDA receptor antagonist reflected by a decrease of ICF. Possibly GABAergic effects may also play a role in presynaptic modulation of glutamatergic excitability, which can be assumed by the increased ICI and increased late inhibition.

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Spreading Depression (SD) Waves in the Brainstem of Immature Rats Propagate Independently of Glutamatergic Synaptic Transmission—Richter F1, Lehmenkuhler A2, Schaible HG3 (1Jena; 2Du¨sseldorf; 3Jena) Spreading depression (SD) is thought to occur mainly in the cerebral cortex but barely or not at all in other parts of the CNS. Specifically it was believed that the brainstem is not able to generate SDs. Recently, we confirmed that the brainstem of the adult rat does not show SDs but, interestingly, SDs could be elicited in the brainstem of rats younger than 13 days, when excitability was enhanced by replacing extracellular chloride ions with sodium acetate or by transient periods of asphyxia or hypoxia (2 min breathing 6% O2 in N2). Sustained spreading depressions in the brainstem stopped breathing (Richter et al. J Neurophysiol 2003; 90: 2163–2170). In the present experiments we further studied the mechanism of propagation of SD in the immature brainstem. SDs elicited by KCl were recorded in 11-day-old rat pups (anesthetized with urethane, 1.5 g/kg body weight i.p.) with glass microelectrodes in a region close to the trigeminal nucleus at depths of 1600, 1200, and 800 mm. We tested whether the elicitation and/or propagation of KCl-induced SD can be inhibited in the immature brainstem either by a blockade of voltage-gated calcium channels (VGCCs) that are involved in glutamate release (P/Q-type by omega-agatoxin IVA, 10-6 M; N-type by omegaconotoxin GVIA, 10K6 M; L- and T-type by flunarizine, 1– 2 mg/kg body weight) or by a blockade of NMDA receptors by ketamine (doses of 2 to 100 mg/kg body weight). Application of agatoxin for 60 min to the brainstem surface did not influence SD. Blockade of N-type VGCCs by conotoxin did not influence SD but disturbed the normal breathing rhythm when it was applied for 30–40 min. Flunarizine (1–2 mg/kg body weight) either injected intraperitoneally or applied onto the brainstem surface did not influence elicitability of SD, SD amplitudes or SD migration velocity in the brainstem within a period of up to 2 h. SD amplitudes amounted to 12 mV and were accompanied by increases in [KC]e up to 40 mM before and after flunarizine. Specific doses of the NMDA receptor blocker ketamine (! 10 mg/kg body weight) did not influence the SD in the cortex and in the brainstem. Higher doses of ketamine inhibited breathing. AMPA elicited SDs in the cortex, but was barely able to elicit SDs

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in the brainstem. These findings suggest that SDs in the immature brainstem do not propagate via glutamatergic synaptic transmission. Rather potassium ions seem to mediate both initiation and propagation of SD. Supported by IZKF Jena (IZKF B378-10102).

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Visual Connectivity in Cases with Unilateral Focal Cortical Dysplasia or Hemispherectomy in fMRI— Riedel E1, Marx E2, Stephan T3, Deutschla¨nder A4, Bruening R 5, Brandt T6 ( 1Mu¨nchen; 2Jena; 3 Mu¨nchen; 4Mu¨nchen; 5Mu¨nchen; 6Mu¨nchen) Structural and functional changes caused by malformations of cortical development or early cortical lesions are poorly understood. Earlier brain activation studies showed that plastic reorganization and recruitment of additional cortical areas may be responsible for residual sensorimotor function. We describe two patients (one with unilateral focal cortical dysplasia, the other with right hemispherectomy), both of whom had preserved but significantly diminished object motion perception within the contralateral hemifield. FMRI during hemifield motion stimulation revealed two different types of plastic reorganization of the visual system. Imaging was done using a Siemens 1.5 Tesla MRI scanner and echo-planar imaging sequences during hemifield visual motion stimulation. Data processing was done using SPM99 and MATLAP scripts. In the patient with unilateral hemispherectomy, activations in the motion-sensitive areas MT/V5 for the right and left hemifields were both atypically located in the right hemisphere in distinct and separate locations. This finding supports the view that residual visual motion perception in the hemianopic field is mediated by the unaffected ipsilateral hemisphere. In the patient with right-sided focal cortical dysplasia, the motion-sensitive areas MT/V5 in the same hemisphere appeared to be dislocated. They were displaced anteriorly, superiorly, and medially as well as separated into two distinct activation clusters. Temporo-occipital areas that best correspond to the areas MT/V5 were bilaterally activated during left and right hemifield motion stimulation, indicating preserved transcallosal visuo-visual interaction. Thus, motion perception is obviously mediated by cortical structures that are dislocated in the same hemisphere in the hemispherectomized patient and in the opposite unaffected hemisphere in the patient with focal cortical dysplasia. FMRI with visual hemifield motion stimulation appears to be a suitable tool for identifying the location of motion-sensitive cortical areas and their transcallosal connectivity.

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Prevention of Alzheimer’s Associated Ab-Aggregation by Rationally Designed Non-Peptidic b-Sheet Ligands—Riesner D1, Rzepecki P2, Nagel-Steger L3, Feuerstein S4, Linne U5, Molt O6, Zadmard R7, Aschermann K8, Wehner M9, Schrader T10 (1Du¨sseldorf; 2Marburg; 3Du¨sseldorf; 4Du¨sseldorf; 5Du¨sseldorf; 6Du¨sseldorf; 7Du¨sseldorf; 8Du¨sseldorf; 9 Du¨sseldorf; 10Du¨sseldorf) A new concept is introduced for the rational design of b-sheet ligands, which prevent protein aggregation: oligomeric acylated aminopyrazoles with a DAD hydrogen bond pattern complementary to that of a b-sheet efficiently block the solvent-exposed b-sheet portions in Ab(1–40) and thereby prevent the formation of insoluble protein aggregates. Density gradient centrifugation

revealed that, in the initial phase, the size of the Ab aggregates was efficiently kept between the trimeric and 15meric states, whereas after 5 days an additional high molecular weight fraction appeared. With fluorescence correlation spectroscopy (FCS) exactly those two out of nine similar aminopyrazole ligands were identified as efficient aggregation retardents whose minimum energy conformations showed a perfect complementarity to a b-sheet. The concentration dependence of the inhibitory effect of the most favorable ligand allowed an estimation of the dissociation constant to be well below 10K5 M. Finally, electrospray ionization mass spectrometry (ESI-MS) was used to determine the aggregation kinetics of A b (1–40) in the absence and in the presence of inhibitors. From the comparable decrease in A b monomer concentration, we conclude that the b-sheet ligands do not prevent the initial oligomerization of monomeric A b, but rather block further aggregation of spontaneously formed small oligomers. Together with the results from density gradient centrifugation and FCS, it is now possible to restrict the approximate size of soluble A b aggregates formed in the presence of both inhibitors to 3- to 15mers.

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Clinical Relevance of Microembolus Detection—Ringelstein EB1 (1Mu¨nster) One domain of neurovascular ultrasound not competing with any other diagnostic technique is the evaluation of microemboli in the large basal cerebral arteries, commonly the medial cerebral artery (MCA). Microembolic signals (MES) can represent both corpuscular microemboli (cholesterol crystals, fibrin thrombi, platelet thrombi, necrotic debris from plaques, lipid droplets, calcified particles etc.) or, alternatively, gaseous emboli like artificially inserted air, microcavitation at mechanical heart valves, diagnostic compounds containing gaseous microbubbles and spontaneous gaseous bubbles during compression sickness. The clinical setting as such often allows one to differentiate already between gaseous and corpuscular microemboli. Additionally, we have various biophysical and ultrasound techniques to differentiate MES. Microcavitation has been shown to be clinically irrelevant, whereas massive gaseous embolism to the brain during cardiovascular surgery has turned out to be prognostically poor and should be prevented by better cardiovascular techniques. Clinically most relevant are corpuscular microemboli of thrombotic material, particularly in embolizing arteriosclerotic plaques of the internal carotid artery. In symptomatic, as well as asymptomatic carotid stenosis, ipsilaterally occurring MES in the MCA are prognostically relevant and might influence the indication for carotid endarterectomy. Findings of the recent CARESS trial demonstrate the potential of MES detection as a surrogate parameter for impeding stroke.

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Spontaneous EEG Rhythms and their fMRI Correlates—Ritter P1, Moosmann M2, Villringer A 3 (1Berlin; 2Berlin; 3Berlin) A major limitation of the routinely used clinical EEG lies in the ambiguous assignment of measured brain potentials to anatomic structures. By means of simultaneous EEG-fMRI the non-invasive imaging of structural correlates of EEG rhythms has become feasible, thus improving the interpretability of EEG findings. During MRI acquisition, however, large artifacts are induced in

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the EEG signal, making the physiological EEG unrecognizable. We employed a mathematical algorithm for artifact removal and validated this algorithm by means of visual evoked potentials (VEPs) recorded during and between MRI acquisition periods. We also showed the feasibility of MR imaging of physiological background rhythms like Alpha rhythm, functionally connected with the visual system, and sensorimotor Mu-rhythm. The MRI blood oxygenation level-dependent (BOLD) signal was negatively correlated with posterior Alpha rhythm in occipital areas, indicating deactivation in a metabolic sense. This result was confirmed by near infrared spectroscopy (NIRS), an optical method for monitoring local changes in deoxygenated hemoglobin concentration. Positive correlations between BOLD signal and Alpha activity in the thalamus indicate its generator role for this rhythm. For the 10- and 20-Hz components of the central Murhythm we identified different cortical and subcortical representations. MR correlates of pathological EEG rhythms were investigated in patients with hepatic encephalography. Inevitable changes of vigilance during EEG-fMRI measurements, affecting EEG as well as BOLD signal, make simultaneous monitoring of vigilance necessary. A methodological approach is in progress with first results available.

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Quantitative Sensory Testing in Patients with Bell’s Palsy—Rolke R1, Schalber C2, Magerl W3, Birklein F4, Dieterich M5, Treede RD6, Urban PP7 (1Mainz, 2 Mainz, 3Mainz, 4Mainz, 5Mainz, 6Mainz, 7Mainz) Aim of the Study: Patients with facial palsy often report sensory symptoms over the paretic part of the face. To test for the presence of sensory disturbances we applied a battery of sensory tests according to the Quantitative Sensory Testing (QST) protocol of the German Research Network on Neuropathic Pain (GRNP) over ipsi- and contralateral parts of the face. Methods: Sixteen patients with idiopathic facial palsy and 32 controls were studied. All patients were investigated within 3 days after onset of symptoms. Seven tests were performed determining 13 variables over ipsi- and contralateral cheeks and forehead including thermal (cold and warm perception threshold, thermal sensory limen, paradoxical heat sensations, cold pain and heat pain thresholds) and mechanical stimuli (von Frey filaments, pinprick stimuli, vibration threshold using a tuning fork, and pressure pain thresholds using a handheld algometer). Results: Heat pain threshold was lowered by 1.38C over the ipsilateral face (PZ0.036; ANOVA; LSD post hoc-test) without a significant cheek-forehead difference. All other pain thresholds were not reduced (PO0.16). Additionally, thermal and mechanical perception thresholds tended to be increased over the affected side of the face. However, this effect was only significant for cold perception threshold (PZ0.02; ANOVA; LSD post hoc-test), again with no cheek-forehead difference. These findings were not related to the presence of dysaesthesia (6 out of 16 patients). Conclusion: Our finding of heat pain hyperalgesia in patients with facial palsy is consistent with peripheral rather than central sensitization of nociceptive neurons, probably due to a trigeminal affection. This result also contributes to the old concept of polyneuritis cranialis rather than mononeuritis facialis in patients with idiopathic facial palsy (Adour et al. Arch Otolaryngol 1976; 102: 262–264). Supported by GRNP (BMBF grant 01EM0107) and MAIFOR (University of Mainz).

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What determines the amplitude decrease of eventrelated potentials by repeated auditory stimulation?— Rosburg T1, Trautner P2, Haueisen J3, Boutros NN4, Sauer H5, Elger CE6, Kurthen M7 (1Bonn; 2Bonn; 3 Jena; 4New Haven; 5Jena; 6Bonn; 7Bonn) Repetition of auditory stimuli results in a suppression of eventrelated potentials (ERPs) if it occurs within a time window of approximately 0.4 s to 15 s. Depending on the kind of the experiment and the view of the experimenter, this process might be termed sensory gating, habituation, adaptation or refractoriness. The different denomination already indicates that the functional (and anatomical) foundation of this response decrease is yet poorly understood. One paradigm for the investigation of these foundations is the application of stimuli trains, interspersed with longer intervals of silence. The event-related activity is then calculated for each stimulus position of the train separately. In intracranial recordings a decrease of the N100 amplitude was obtained only from the 1st to 2nd stimulus of a train. In that experiment stimulus material and interstimulus interval were comparable to sensory gating experiments. Similar as the N100, the P50 decrease was completed after the 2nd stimulus of the train. Both findings are not in line with the assumption of a habituation process and indicate that no additional information would be obtained in sensory gating experiments if trains instead of pairs of stimuli would be applied. An induced high frequency activity (80– 160 Hz) occurred in a latency range 80–350 ms. Analyses of single trials revealed that the activity consisted of 30–70 ms bursts of activity rather than an ongoing activation and the number of bursts as well as their amplitudes decreased by stimulus repetition. In line with the intracranial recordings, in a magnetoencephalography experiment a significant decrease of the auditory evoked field component N100m was observed only from 1st to the 2nd stimulus of a train. In the context of an ongoing and varying stimulation, stimulus repetition had no significant effect on the N100m, but elicited a mismatch negativity (MMN), which is usually evoked by discernible deviations from a repetitive auditory stimulation. Besides a short-term decrease (from one stimulus to another), cortical responses decrease continuously in course of an experiment, as shown for the N100m and, even more dramatically, for the neuromagnetic MMN. In conclusion, the investigation of various aspects of a response decrease by repeated stimulation elucidates very basic brain functions. The observation of alterations of these functions in neuropsychiatric disorders might provide useful information about pathological brain processes.

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Synchronization of Neural Oscillators: Data Analysis and Control—Rosenblum M1, Pikovsky A2 (1Potsdam; 2 Potsdam) Two applications of the synchronization theory in neuroscience will be considered. First, the synchronization approach to multivariate data analysis will be discussed, with an emphasis on the analysis of brain activity. In particular; the following three tasks will be considered: quantification of a weak interaction of different oscillatory sources, analysis of directionality of interaction, and estimation of delay in coupling. The synchronization approach will be compared with the standard coherence technique. Next, the control of collective synchrony in a population of neuronal oscillators will be discussed from the viewpoint of a possible application to suppression of the Parkinsonian activity by

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means of deep brain stimulation. The method is based on the timedelayed feedback via the local field potential (mean field). The method is illustrated by numerical simulation of the dynamics of globally or randomly coupled neuronal oscillators. It will be shown that efficient suppression is possible for large domains of control parameters (delay and amplification in the feedback loop). It is important that, as soon as the undesired synchrony is suppressed, the intervention into the neuronal population becomes very small (it is then determined by the noise level in the desynchronized population). This means that the suggested control scheme is noninvasive. A theory based on the consideration of the synchronization transition as a Hopf bifurcation will be presented and compared with the numeric case. Several practically important problems will be discussed: the influence of the measurement noise, imperfect measurement, finite-size effects, etc.

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Mutual Information and Assesment of Dynamic Cerebral Autoregulation—Roth M1, Reinhard M2, Hetzel A3, Timmer J4 (1Freiburg; 2Freiburg; 3Freiburg; 4Freiburg) The assessment of dynamic cerebral autoregulation (DCA) and cerebral hemodynamics is a central task in patients suffering from cerebrovascular diseases or from stroke. We present an investigation of the DCA assessment on the basis of mutual information (MI) analysis in patients suffering from severe unilateral carotid stenosis and a control group of healthy volunteers. Besides the evaluation of the MI approach a comparison with various other approaches and validated DCA parameters is presented. We find significant differences between the healthy volunteers and the patients suffering from stenosis in the new approaches and the validated DCA parameters. Moreover side-to-side differences ipsi- and contralateral to the stenosis are found. Finally, the concordance of the various approaches for DCA assessment is discussed.

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Fear and Depression as Side Effect of Deep Brain Stimulation of the Subthalmic Nucleus in Parkinson’s Disease—Sabolek M1, Uttner I2, Seitz K3, Storch A4 (1Ulm; 2Ulm; 3Gu¨nzburg; 4Dresden) For the treatment of advanced Parkinson’s disease deep brain stimulation in the Nc. subthalamicus has gained more and more importance in recent years. Usually this technique is considered as safe and short of psychiatric side effects, except for sometimes seen changes in frontal executive functions and transient postoperative depression. We report a 58-year-old patient with a 14 year history of Idiopathic Parkinson’s disease. Due to severe L-Dopa-Induced dyskinesias and motor fluctuations the patient was deep brain stimulated in the Nc. subthalamicus. During intraoperative macrostimulation the patient developed sudden severe existential anxiety together with vegetative dysregulation for no obvious reason. After ending the test stimulation the anxiety vanished within a few seconds. This phenomenon was reproducible in another test stimulation. Using the next apical lead resulted in good symptom control considering IPD with no obvious side effects at first sight. During the next half-year the patient developed a fixed passiveness, loss of interest, apathy and loss of humor very unusual for him considering the preoperative state. The symptoms extended

the sometimes seen mild transient postoperative dysthymia considering severity as well as duration of symptoms. Treatment with SSRI’s led to no improvement of mental situation. A reprogramming of the neurostimulator, now using an even further apical lead resulted in a sudden and complete vanishing of the depressive symptoms within a few minutes. The now used lead still provides good symptom control, but without side effects with regard to mood.

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Functional Connectivity between Cortex and Motor Nuclei of the Basal Ganglia across the Human Sleep– Wake Cycle—Salih F 1, Grosse P2 , Sharott A 3, Khatami R4, Trottenberg T5, Schneider GH6, Kupsch A7, Brown P8 (1Berlin; 2Berlin; 3Berlin; 4Berlin; 5 Berlin; 6Berlin; 7Berlin; 8Berlin) Functional imaging has shown a basal ganglia involvement in the activity changes across the human sleep–wake cycle. Here we used frequency analysis to explore whether motor nuclei of the basal ganglia (Globus pallidus internus [GPi], subthalamic nucleus [STN]) are functionally connected to the motor or the visual cortex in wakefulness, NREM2, NREM3/4 and REM sleep. To this end, we examined patients undergoing deep-brain stimulation for Parkinson’s disease (PD; nZ5) or dystonia (nZ5). We simultaneously recorded local field potentials either from GPi or STN using a bipolar montage as well as scalp EEG (F3/4-C3/4, Pz-O1/2). Frequency analysis of scalp EEG between motor and visual cortex in GPi patients confirmed previous studies in healthy subjects during sleep (Achermann and Borbe´ly, 1998), whereas in STN patients additional peaks were present in the delta-/theta-frequency range. In the coherence spectra strong peaks can be shown at 12–16 Hz between GPI and both motor and visual cortex in NREM2, corresponding to the sleep spindle frequency range. Further, a distinct peak could be identified in the higher alpharange (10–12 Hz). In contrast, in NREM3/4 the 12–16 Hzcoherence peak was not present while the 10–12 Hz-peak remained. For NREM2 and NREM3/4 the 10–12 Hz peak disappeared after partialization of the surface EEG with GPi as the predictor. The directed transfer function (dtf) revealed that the peak at 12–16 Hz is predominantly propagated from the visual cortex to GPi and motor cortex in NREM2 and NREM3/4. The dtf for GPi to motor and visual cortex showed a distinct peak in the higher alpha-range (10–12 Hz) in NREM2, while in NREM3/4 distinct peaks at 10–12 Hz were present between GPi and motor cortex as well as from motor to visual cortex. Principally, the same coherence patterns were also present in STN patients, however at a much lower level and less homogeneously than in GPi patients. There was no significant coherence in REM between STN or GPi and cortex. We can show functional connectivity between motor nuclei of the basal ganglia and both the motor and the visual cortex in NREM sleep in the frequency range of sleep spindles. The motor system seems to be additionally synchronized with a peak in the higher alpha-range (10–12 Hz), propagated through the GPi to the cortex. Most likely, the synchronization at 10– 12 Hz can be regarded as a specific signature of the motor system in NREM sleep, which parallels the overall synchronization at 12–16 Hz.

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Oscillatory Activity during the Processing of Musically Induced Emotions—Sammler D1, [3] rigutsch M2, Koelsch S3 (1Leipzig; 2Leipzig; 3Leipzig) The purpose of the present experiment was to investigate neuroelectric oscillatory activity during the processing of emotions. Drawing on studies showing that (a) music is capable of inducing strong emotions in listeners (Krumhansl, 1997) and (b) dissonance is associated with unpleasant experiences while consonance is perceived as pleasant (Blood et al., 1999), a newly developed experimental paradigm (Koelsch et al., 2004) was applied. Listeners were presented with excerpts (1 min length each) of joyful (consonant) dance tunes of the past 4 centuries and electronically manipulated unpleasant (dissonant) counterparts. Participants were instructed to listen with closed eyes, tap the metre and rate how (un) pleasant they felt after each musical piece. Additionally, the experiment comprised 6 silence periods as baseline condition and the measurement of an ECG during the whole experimental session. An FFT (fast Fourier transform) was performed on EEG data and frequency bands were adjusted individually according to the methods of Doppelmayr et al. (1999). Instantaneous heart rate was calculated. Behavioral data and the typical triphasic pattern of heart rate (Bradley et al., 1999) indicate that the applied experimental paradigm induced pleasant and unpleasant emotions in listeners. Pleasant musical pieces evoked an increase of midfrontal theta power towards the end of the excerpts, whereas theta power remained constant during unpleasant pieces (Fig. 1). The comparison of both music conditions (consonant/dissonant) with rest revealed correlates of (a) attention-related processes (namely an overall power increase in the delta range during the listening to music) and (b) motor activity related to the tapping with the right index finger (left central power decrease in the alpha and beta range during tapping). In conclusion, our results show that the applied experimental paradigm using consonant/dissonant music and the analysis of neuroelectic oscillatory activity are suitable methods in the investigation of emotions. The findings suggest that power changes in midfrontal theta rhythm might relate to

general emotional processes such as emotional self-regulation or decision-making. Fig. 1, Theta power during the first and the second 22 s of pleasant and unpleasant musical excerpts (compared to rest).

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Primary Motor Cortex Involvement in a Handedness Recognition Task-Evidence from Transcranial Magnetic Stimulation—Sauner D1, Siebner HR2, Bestmann S3, Rothwell J4 (1Jena; 2Kiel; 3London; 4London) Motor imagery and motor execution share common neural substrates. While the primary motor cortex is crucial for motor execution, its contribution to motor imagery is still debated. We applied transcranial magnetic stimulation (TMS) to the primary motor hand area (M1-HAND) during a hand recognition task to assess the involvement of M1-HAND in motor imagery of body parts. A schematic picture of the back or palm of a human hand was presented at various stimulus orientations. Subjects were required to indicate whether they thought it was a right or a left hand by pressing a button with their right or left toe as fast as possible. Single-pulse TMS at 120% of resting motor threshold was given to left M1-HAND 0, 200, 400, 600, 800 or 1000 ms after onset of stimulus presentation. Reaction times (RTs) and error rates were measured as was the size of the motor-evoked potential (MEPs) evoked by the TMS pulse in the relaxed right first dorsal interosseous (FDI) muscle. Mean RTs and error rates increased with angle of rotation depending on the actual biomechanical constraints of the hand. TMS had no effect on reaction times or error rates regardless of the relative timing of stimulation. However, the size of the MEPs that it evoked in the right hand was modulated during the reaction. Stimuli that depicted the left hand caused MEP amplitudes to decrease 300– 100 ms prior to the response, whereas stimuli indicating the right hand caused MEP amplitudes to increase immediately before the response. These effects were the same for pictures of backs and palms and independent of the angle of rotation. The failure of TMS to affect task performance suggests that M1-HAND is not critically involved in motor imagery of body parts. However, the fact that the amplitude of evoked MEPs varied according to the laterality of the stimulus is compatible with a secondary effect of the task on motor excitability.

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Intraindividual Long-Term Stability of BOLD Response within the Mesial Temporal Lobe (MTL)— Schacher M1, Kra¨mer G2, Huber D3, Jokeit H4 (1Zu¨rich; 2Zu¨rich; 3Zu¨rich; 4Zu¨rich) Functional MRI allows one to study pharmacological treatment effects (Leslie and James, 2000). Long-acting drugs, such as antiepileptic drugs, require measurement designs, which are stable over time. Therefore, we investigated the long-term within-subject stability of the BOLD response across several sessions. Six healthy volunteers (five males, one female, aged 24– 31 years) were examined six times with a modified version of the Roland hometown walking task (Jokeit et al., 2001): Four measurements were performed at four different days within an interval of 1–4 weeks (between-day measurements). On the first and the last day, one additional scan was carried out (within-day measurements). Intraindividual reproducibility was evaluated on a

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global basis including (1) extent of activation based on number of significant activated voxels in MTL and (2) magnitude of activation based on mean of percent BOLD signal change in anatomical VOI (within parahippocampal gyrus). On a voxel-byvoxel basis (1) the relative amount of overlapping volume (Rij overlap) between two activation maps and (2) the correlation of t-values within MTL were evaluated. Concerning between-day measurements the intensity of activation (mean percent BOLD and correlated t-values) and localization of activation (Rij overlap) were stable in four out of six subjects in at least 3 out of 4 measurements. Localization of activation was dispersed over time, resulting in a linear decrease of overlapping volumes. The lowest stability was observed in number of activated voxels: only three subjects revealed ‘stable’ frequencies (less than 25% deviation) in 3 out of 4 measurements. Frequency of activated voxels decreased linearly over 4 baseline measurements. Stability of between-day measurements was comparable to within-day measurements. The instability within subjects was not related to behavioural changes. The long-term stability of the BOLDresponse in MTL was intraindividually variable. In order to investigate pharmacological effects within MTL, experimental designs with more than one measurement per condition are required. In addition, a sufficient number of baseline measurements should be performed to exclude instable subjects. (Supported by Novartis, Switzerland)

Fig. 1.

was observed with SE-iDQC, functional maps were reproducibly obtained with GRE-iDQC (Fig. 1). These maps showed less activated pixels compared to routine BOLD experiments, however, the averaged functional signal change was O10% (GRE-iDQC) as compared to only 2% in the BOLD experiments. The optimized sequences provide a basis for future experimental investigations into the origin of the functional iDQC contrast.

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Functional MRI Based on Intermolecular DoubleQuantum Coherences (iDQC) at 3 Tesla—Scha¨fer A1, Mo¨ller HE2 (1Leipzig; 2Leipzig) Contrast generated by intermolecular double-quantum coherences (iDQC) is a novel approach to fMRI, which is qualitatively and quantitatively different from the standard blood oxygen level dependent (BOLD) contrast. Specifically, it was suggested that the sensitivity of iDQC to local susceptibility gradients can be adjusted on a mesoscopic scale (between 10 mm and 1 mm) externally by the experimenter. A drawback of iDQC experiments, however, is their inherently poor signal-to-noise ratio leading to substantial signal fluctuations in previous pilot studies. In the current work, parameters of modified CRAZED sequences were carefully optimized to achieve high signal stability in iDQC experiments at 3 T with the standard birdcage headcoil. Initial phantom experiments were utilized to verify that the detected signal was due to iDQC by recording its angular dependence. A four-step phase-cycling scheme was used to filter out specific multiplequantum coherences. Contributions from unwanted coherence pathways at the center of the k-space were of the noise level. In in vivo experiments (series of 60 repetitions) in healthy volunteers a systematic variation of the repetition time (TR) yielded sufficient signal stability (as compared to ordinary EPI time series) if a relatively long TR 3 5 s was used. A two-step phase cycling scheme was used in these experiments. A reason for the suboptimal signal stability at shorter TRs are contributions from additional stimulated echoes, which are not suppressed by the crusher gradients after image acquisition. fMRI studies were performed in 6 subjects with a simple visual paradigm (blocked design). In all subjects, both gradient-recalled echo (GRE) and spin-echo type iDQC sequences were recorded. Additional GRE or SE BOLD measurements were also performed. While no functional contrast

Direct or Indirect? Graphical Models for Neural Oscillators—Schelter B1, Winterhalder M2, Timmer J3 (1Freiburg; 2Freiburg; 3Freiburg) Up to now, time series analysis techniques like synchronization analysis or coherence analysis are mostly applied to bivariate data sets. If more than two signals are available, investigations based on pairwise combinations are still the most favored procedure. However, multivariate data contain more information than those inferable from multiple bivariate examinations. Direct as well as indirect influences may lead to significant inter-relations between signals. A methodology that is able to distinguish between spurious and non-spurious influences will yield deeper insights into underlying physiology. Furthermore, in many cases, detections of causal influences are hardly possible by, for example, coherence analysis. Graphical models are a rather general concept to graphically visualize multivariate systems. Graphical models applying partial coherence are a methodology to decide whether significantly coherent signals are directly linked or not. In multivariate data spurious links could thus be detected. Abilities as well as limitations will be discussed on the basis of neural oscillators. Recent extensions for graphical models in application to partial directed coherence allowing us to determine causal dependencies will be presented. In specific cases time lags can be estimated through this procedure.

Functional Genetics of Spastin—Schickel J1, Beetz C2, Marx M3, Meixner A4, Bastmeier M5, Deufel T6 (1Jena; 2Jena; 3Jena; 4Jena; 5Jena; 6Jena) Mutations in the human spastin gene (SPG4) cause the most prevalent form of autosomal dominant hereditary spastic paraplegia (HSP), a neurodegenerative disorder characterized by progressive weakness and spasticity of the lower limbs. Human spastin is ubiquitously expressed and encodes a member of the

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AAA (ATPases associated with various cellular activities) protein family which is characterized by a conserved domain with ATPase activity. In a previous study, using polyclonal antibodies against the N-terminal spastin sequence, we have shown that the native protein is localized in both the perinuclear cytoplasm and the nucleus. Furthermore, using a reporter system based on four inframe fused copies of green fluorescent protein we demonstrated that spastin carries two nuclear localization sequences both independently functional in mediating nuclear entry. We suggest a dual function for the spastin protein: one involving it in cytoplasmic trafficking and another, still unknown function in the nucleus. The precise localization of spastin may be a regulated process involving import into the nucleus as well as export back into the cytoplasm. Supporting this notion, we have identified two potential nuclear export sequences (NES) within the spastin amino acid sequence. Our present study was aimed at characterizing domains in the N-terminal part of spastin that impede nuclear entry of transiently expressed spastin in cultured cells. Using appropriate deletion constructs with a GFP reporter, we were able to identify a short sequence motif of approximately 25 amino acids in size to be responsible to retard spastin in the cytoplasm of the cell. Ongoing experiments are aimed at investigating whether functionality of NES or rather abolition of tubulin binding and sequestration of spastin in the cytosol is the mechanism underlying this observation. Spastin is widespread among different organisms and highly conserved between species. Thus, animal models provide an excellent tool for functional and localization studies. Studies focus on the distribution of spastin in different stages of mouse brain development as well as the identification and knockdown of zebrafish spastin and its consequences for early development.

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Novel Deep Brain Stimulation Techniques based on Stochastic Phase Resetting Principles—Schiek M1, Silex C2, Tass PA3, Barnikol UB4, Hauptmann C5, Freund HJ6, Sturm V7 (1Ju¨lich; 2Ju¨lich; 3Ju¨lich; 4 Ju¨lich; 5Ju¨lich; 6Ju¨lich; 7Ko¨ln) Synchronization of neuronal activity appears to be the hallmark of several neurological diseases like Parkinson’s disease and essential tremor. In patients who do not respond to medication, permanent electrical high-frequency (O100 Hz) deep brain stimulation (DBS) turned out to be the therapeutic gold standard. This standard DBS basically mimics the effect of tissue lesioning. However, its mechanism is still not sufficiently understood. For this reason, we have investigated stimulation-induced dynamics in mathematical models of relevant target areas. We have developed novel stimulation techniques using methods from statistical physics, especially from the field of stochastic phase resetting. The standard DBS seems to block the neuronal firing, in particular neuronal populations. In contrast, our novel DBS techniques work on demand and desynchronize the pathologically synchronized activity. In this way the neuronal firing is maintained and modulated in a way that comes closer to the physiological mode. In this poster we explain how our novel DBS techniques have been optimized by means of real-time model simulations. Furthermore, we show our first successful results obtained in intraoperative test stimulations during deep electrode implantation. We expect our novel, model-based and physiologically oriented DBS techniques to be milder and more effective compared to the standard high-frequency DBS.

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Cerebral Correlates of the Activation of the Cardiovascular Autonomic Nervous System—An FDG-PET Study—Schlindwein P1, Birklein F2, Dieterich M3, Buchholz HG4, Bartenstein P5 (1Mainz; 2Mainz; 3 Mainz; 4Mainz; 5Mainz) Background: Visual self-motion perception is induced by large-field visual motion stimulation (circular vection, CV). The stationary observer perceives the surroundings as being stable and himself as being moved. This stimulus provides profound activation, in particular, of the sympathetic nervous system (arousal reaction) Our fluorodeoxyglucose (FDG)-PET study focused on those brain areas that are involved in the processing of autonomic changes during CV. Correlation analyses were performed between metabolic effects and autonomic parameters during visual motion stimulation. Methods: FDG-PET (Siemens, Germany) was performed in 14 healthy subjects (8 male, 7 female; mean age 29.5 years) during CV induced by a computer-animated coherent dot pattern moving clockwise, or a random dot pattern of the same size. Correlation analyses with different parameters for autonomic cardiovascular control (blood pressure, heart rate variability, blood pressure and plasma catecholamines) were performed with the SPM99b software (threshold for significant activation was set at P! 0.001, uncorrected). Results: Significant positive correlations were found between the high frequency spectrum of heart rate variability and activations in the anterior cingulate gyrus (BA 6) and nucleus caudatus.. Low frequency heart rate variability correlates either with activations in the anterior cingulate and the amygdala bilaterally. Deactivation in the caudate nucleus significantly correlated to frequency changes of heart rate and levels of plasma catecholamines. Conclusion: Our study showed that arousal reaction activates and deactivates a network of ‘autonomic’ brain areas. Obviously the limbic cortex and the basal ganglia are the most important to control cardiovascular function.

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Time Courses of Cortical Vestibular Responses to Caloric Stimulation (fMRI)—Schlindwein P1, Bauermann T2, Bense S3, Brandt T4, Sto¨ter P5, Dieterich M6 (1Mainz; 2Mainz; 3Mainz; 4Mu¨nchen; 5 Mainz; 6 Mainz) The multisensory vestibular cortical circuit on the basis of monkey experiments as well as human functional brain imaging studies includes the posterior insula, central sulcus, superior temporal gyrus, and inferior parietal lobule with the intraparietal sulcus. The aim of this fMRI study was to determine whether one can differentiate the time course of activation of different vestibular and ocular motor areas. Ocular motor areas were considered since vestibular stimulation induces not only the perception of being rotated or tilted but also an ocular motor response, e.g. a vestibular nystagmus. The effects of caloric vestibular stimulation (right ear irrigation with 16 8C water for 30 s, 4 runs) on cortical activation were studied in 9 right-handed healthy volunteers. The protocol included 372 volumes, each consisting of 40 slices of a T2*-weighted EPI sequence in alternating blocks of ten images at rest (eyes open in the dark), ten during caloric stimulation, and 60 images after caloric irrigation. Statistical analysis was done with SPM2 (P!

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0.001, uncorrected). Horizontal nystagmus was recorded by the MR-Eyetrack System while the subjects kept their eyes open in a completely darkened room. Caloric irrigation induced a direction-specific sensation of rotation and nystagmus away from the stimulated ear. Significant activations were found in a cortical network within both hemispheres but predominantly in the right. This network included the superior frontal gyrus/sulcus, the precentral gyrus, the superior temporal gyrus, the inferior and superior parietal lobule with the supramarginal gyrus, the precuneus, as well as the posterior and anterior insula. Analysis of voxel intensity over time showed that activation within the PIVC began immediately after the start of irrigation and reached its maximum about 16 s later on the ipsilateral right hemisphere but 32 s later on the contralateral left side (mean values of single subject analysis). Activation peaks of the areas in the superior temporal gyrus occurred about 33 s after the irrigation onset on the right and after 45 s on the left hemisphere. This is the first demonstration by means of fMRI that monaural vestibular stimulation causes bilateral vestibular cortex activation with different latencies. Activation peaks in the insular-temporal cortex seem to occur earlier within the right hemisphere during irrigation of the right ear in right-handers than in the left hemisphere.

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Pharmacological Modulation of Cognitive Functions: Studies with fMRI—Schlo¨sser R1 (1Jena) There is ample evidence that normal cognitive and emotional information processing is functionally dependent on the concerted activity of different interacting neurotransmitter systems. In a series of studies, we employed acute pharmacological challenge paradigms and subchronic pharmacological interventions in order to elucidate GABAergic and dopaminergic effects on functional brain imaging patterns subserving short-term working memory, learning processes and prediction uncertainty. An acute lorazepam challenge was associated with decreased cortical and subcortical activity during a 2-back working memory task. For alcoholdependent patients, a blunted dopaminergic cerebellar response could be observed suggesting altered cerebellar GABAergic setpoints. On the other hand, fMRI activation during a prediction uncertainty task was found to be pronounced in the DLPFC after a dopaminergic methylphenidate challenge. Additionally, atypical antipsychotic drugs with a potential to enhance dopaminergic functions were associated with altered information processing not only in the PFC but also in an entire cortical-subcortical cerebellar circuitry in schizophrenic patients. Taken together, these findings indicate the regulatory capacity of both GABAergic and dopaminergic mechanisms and the existence of propagated effects involving changes in effective connectivity between segregated brain areas. Functional MRI appears to be a suitable tool to monitor the restoration of normal activation patterns during psychopharmacological interventions.

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Age-Dependent Alterations of Functional Inhibition in a Rat Model of Cortical Lesions—Schmidt S1, Divanach A2, Bru¨hl C3, Witte OW4 (1Jena; 2Jena; 3 Jena; 4Jena) Cortical lesions in the rat brain induce changes in neuronal activity like reduced functional inhibition. Here we investigated

post-lesional effects of a focal lesion on cortical field-potentials in young, middle-aged and old rats. Focal cortical lesions were induced at the border of parietal and occipital areas by injection of the photosensitive dye rose bengal and illumination of the skull. The surgery was performed on 3-, 12- and 24-month-old rats. Cortical field potentials were recorded 7 days after lesion induction on coronal brain slices using the paired pulse protocol. A bipolar stimulation electrode was placed in layer VI and field potentials recorded in layer II/III. GABA-ergic paired-pulse inhibition was investigated through the application of double pulses of 50 ms duration with 20 ms inter-stimulus intervals. In young rats with a photothrombotic lesion the ratio of the second versus the first response was significantly increased over wide regions of the neocortex, both in the ipsilateral and contralateral hemispheres. This pattern of alterations between sham-operated and lesioned animals was not observed in older rats. Furthermore, we found significant age-dependent alteration in the functional inhibition of the parietal cortex. These results suggest that neocortical infarcts induce different changes in inhibition, depending on the animal age. This supports the hypothesis of differential plasticity and functional reorganization in juvenile versus aging brains.

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Effect of Oligodendroglial Microdomain Components on NGF Signaling—Schmitz M1, Klopfleisch S2, Kloeppner S3, Althaus HH4 (1Go¨ttingen; 2Go¨ttingen; 3 Go¨ttingen; 4Go¨ttingen) Recent results indicate that the integrity of the myelin sheath is compromised with age [1], and that myelin destruction could be a precipitating event in age-related disorders [2]. Furthermore, oligodendrocytes (OL), which furnish the CNS myelin, do not support remyelination in older animals to the same extent as in younger animals. An increased process formation reflects an OL response to NGF, however, differentially depending on age of the donor [3]. We were interested to know as to whether NGF signaling is modulated by microdomain components such as caveolin and cholesterol, which might undergo age-related changes. Immunocytochemistry of cultured pig OL revealed the co-expression of caveolin1 and the 140 kDa NGF receptor TrkA. Caveolin-containing microdomains were isolated via previously published buoyant density centrifugation methods (GTriton X-100) and by using MACS technology. Western blotting showed a co-labeling of the caveolar protein, flotillin-1, in addition to TrkA, which is enriched in the Triton X-100 insoluble fraction, p75 NTR, and p21 Ras. Preliminary results indicate that oligodendroglial caveolin and cholesterol are up-regulated from 8 DIV to 16 DIV, a period of extensive oligodendroglial process regeneration. Cells exposed to PEG-cholesterol increased their process formation; PEG-cholesterol plus NGF accelerated the NGF response; under both conditions, an in-gel-kinase assay demonstrated an increased MAPK activity, a step of the downstream TrkA signaling. On the other hand, exposure to cyclodextrin (1.2 mM), which disrupts caveolar microdomains by removing cholesterol from the plasma membrane, resulted in a less effective NGF response. The results at present indicate that NGF signaling is modulated by cholesterol; the effect of caveolin-1 siRNA is under investigation.

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References Peters A et al. J Comp Neurol 2000; 419: 364–376. Bartzokis G. Neurobiol of Aging 2004; 25: 5–18. Althaus HH et al. MRT 2001; 52: 689–699.

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Long-Term Brain Atrophy after Focal Ischemic Stroke: A Longitudinal Study Applying Deformation-Based Morphometry—Schnaudigel S1, Ugur T2, Kruggel F3, Mentzel HJ4, Fitzek C5, Witte OW6, Hagemann G7 (1Jena; 2Jena; 3Leipzig; 4Jena; 5Jena; 6 Jena; 7Jena) Introduction: Cerebral ischemia leading to brain infarction results in an area of focal damage. Results from clinical, electrophysiological and neuroimaging studies clearly suggest remote effects ipsi- and contralaterally which are believed to play a role in the dynamic mechanisms of cerebral reorganization and functional recovery. Remote structural alterations have also been detected in terms of, e.g., ventricular enlargement, accelerated global atrophy after large ischemic stroke, cerebellar diaschisis and with recent quantitative MRI studies. This pilot MR study addresses volume alterations after focal cerebral ischemia with a focus on perilesional and also remote ipsi- and contralateral changes in brain volume and cortical thickness. Methods: 14 patients suffering from acute ischemia in the middle cerebral artery territory with small lacunar infarctions were included in the study. 3D T1-weighted MRI scans (Siemens Symphony, 1.5 Tesla) were obtained in the acute stage and at 6 and 12 months follow-up. In addition to neuroimaging, all patients were neurologically assessed and scored on three outcome measures (NIHSS, Rankin Scale and Barthel Index). Image analysis was carried out with the Brain Image Analysis tool (BRIAN, MPI Leipzig) with subvoxel accuracy using linear and non-linear registration methods and subsequent visualization of changes. Results: Direct perilesional but no remote ipsilateral changes were seen in 8 patients with microvascular hemispheric lesions. Contralesional volume changes in a distinct, presumably homologous area, were detected only in a patient suffering from a larger ischemia. Neurological deficits improved in all patients, the majority reported only minor handicaps in daily activities. Conclusion: The present study shows that small infarcts are associated with brain volume changes mainly in the vicinity of the infarct. The detection of remote volume changes seems to be associated with the size of the lesion. These remote effects are particularly pronounced in the ipsilateral hemisphere, but can also be detected contralateral to the lesion. The lack of callosal changes suggests a mechanism which is not bound to fiber degeneration. Although neurological impairment was found to improve in all patients, it may be helpful to further elucidate the mechanisms behind this remote cortical atrophy. The understanding of these processes may help to further improve outcome and to prevent long-term sequelae after stroke.

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FMRI activation patterns in adult patients with Attention-deficit Hyperactivity disorder (ADHD)— Schneider M1, Krick CM2, Retz W3, Hengesch G4, Reith W5, Ro¨sler M6 (1Homburg; 2Homburg; 3Homburg; 4Homburg; 5Homburg; 6Homburg) With a prevalence of 3 to 5% ADHD is the most common disorder of child and adolescent psychiatry. The clinical signs are attention deficits, impulsiveness and hyperactivity and start at the age of 6. ADHD persists in about 20–30% into adulthood. This disorder has a strong genetical link. The rates of concordance (0.7–0.9) in twin studies give strong evidence for this hypothesis. Different candidate genes have been found in molecular genetic association studies and genome studies that differentially modulate monoaminergic transmitter systems (Retz et al. 2002, 2003, 2004; Ogdie et al. 2003). Based on empirical data, methylphenidate is supposed to positively influence the imbalance of dopaminergic and noradrenergic transmission in different brain regions (Volkow et al. 1998). Focus points of interests for investigations are especially the frontal brain regions and the striatum as well as the brainstem/cerebellar regions. In this study, adult patients with ADHD according to the ICD-10 criteria were investigated by functional magnetic resonance tomography. Using an event-related design a continuous performance test with a Go/NoGo-paradigm was used. Thus motor executive function and inhibitory mechanisms could be analyzed. Patients (nZ19) and controls (nZ17) did not significantly differ in age or gender distribution. Correlation analysis of fMRI activation data with the ADHD self-rating subscores for the attention category showed a diminution of activation at both sides of the gyrus frontalis sup., right gyrus frontalis med., both sides of the nucleus caudatus, left lobulus parietalis sup. and right side of lob. par. inf. as well as at the left gyr. supramarginalis the higher the pathological scores were (condition: ‘NoGo’: motor inhibition; SPM 99). These data support the hypothesis that in ADHD there are distinct regions with less activity compared to controls in the striatum as well as frontal and parietal lobes. These brain regions are known to be involved in motor execution, planning and attention.

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Adult-Onset Primary Limb Dystonia: Clinical Description of a Rare Entity—Schneider S1, Edwards MJ2, Quinn NP3, Bhatia KP4 (1London; 2London; 3 London; 4London) Objective: In this study we report on 5 patients with adult-onset primary lower limb dystonia. Background: Adult onset primary dystonia generally affects the cranio-cervical region and remains focal. Lower limb onset usually occurs in the childhood form of idiopathic dystonia and is uncommon in primary adult onset dystonia. Methods: The charts of patients with the diagnosis of primary dystonia seen at a movement disorder clinic were reviewed. Results: Clinical details of five patients with adult-onset lower limb dystonia are summarized below. Average age of onset was 51.6 years (3 F, 2 M). Family history of dystonia was negative in all cases. None noticed diurnal fluctuation. Four patients showed dystonic movements when walking, including one presenting with an actioninduced dystonia when walking downstairs. One patient (5) had a dystonic foot posture even at rest. Investigations included DYT 1, copper, acanthocytes, CT or MRI of brain and spine, myelogram, electrophysiology, CSF, and other studies of secondary dystonia

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were all normal. Except for case 3, patients were unresponsive to treatment normally prescribed in dystonia including anticholinergics, levodopa, tetrabenazine, pimozide, and which were tried. Case 1: 56-year-old woman with a 3-year progressive history of involuntary jerky spasms of foot and leg. Exam showed an inverted gait with dorsiflexion of the foot and internal rotation of the leg. There were no other abnormal neurological signs. Case 2: A 54year-old man with a 3-year progressive history of abnormal posturing of the foot. Exam showed inverted foot, plantar flexion and fanning of toes when walking. Case 3: A 42-year-old woman with a 2-year history of involuntary movements of the lower limb. Exam showed dystonic twisting of the leg. She had benefit from combined treatment of tetrabenazine, pimozide, and benzhexol. Case 4: A 52-year-old man with a 10-year history of an isolated action dystonia of the leg when walking downstairs. Exam showed flicking outwards of the leg with dystonia posturing. Case 5: A 72year-old lady with a progressive 3-year history of inversion of ankle and foot. Exam showed dystonia with inverted foot and a striatal toe. Conclusion: The diagnosis of primary adult-onset limb dystonia was made as none of the patients had any other abnormal signs even on prolonged follow-up (mean 7.2 years). We conclude that there is a rare form of adult-onset primary dystonia with onset in the legs and no further spread.

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Neural Reorganization versus Functional Compensation following Brain Lesions—Schoenfeld A1, Hopf M2, Vielhaber S3, Heinze HJ4 (1Magdeburg; 2Magdeburg; 3Magdeburg; 4Magdeburg) Lesions of brain tissue cause important damage that is usually reflected in the loss of function. In some cases there is at least some recovery of the lost function, raising the question about the responsible underlying neural mechanisms. Combined neuroimaging (electroencephalography, magnetencephalography and functional magnetic resonance imaging) was used to study the neural mechanisms of preserved visual functions after posterior cerebral artery (PCA) stroke and of degraded motor function in amyotrophic lateral sclerosis (ALS). In the first case functional magnetic resonance imaging showed that motion stimuli presented to the hemianopic field of a patient produced activation in several extrastriate areas of the lesioned hemisphere. Magnetencephalographic recordings indicated that evoked activity occurred earlier in the higher-tier area V5 than in lower-tier areas suggesting that preserved vision for motion is mediated by subcortical pathways that bypass the primary visual cortex and that require neural reorganization in area V5. In ALS fMRI was employed to test the hypothesis that the limited resources in the motor cortex of the patients require the recruitment of additional motor-related areas resulting in a different pattern of hemodynamic activity compared to controls. Patients and controls executed a motor task that indeed elicited different patterns of hemodynamic activations in patients compared to controls. Importantly, the task was more difficult for patients than for controls. At equal difficulty the elicited hemodynamic patterns of the controls matched well those of the ALS patients, suggesting that the previously observed differences in hemodynamic activity between patients and controls were mainly caused by differences in difficulty. These results point out that ALS patients use the same resources as controls, arguing for the idea that functional compensation in ALS relies on existent resources and less on the development of new pathways or synapses as a consequence of the lesion.

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Intraoperative fMRI for Monitoring the Effect of Deep Brain Stimulation in Four Patients with Intractable Obsessive–Compulsive Disorder—Schormann M1, Lee SH2, Lenartz D3, Hesselmann V4, Daumann J5, Koulousakis A6, Wilkening M7, Sturm V8, Lackner K9, Klosterkoetter J10 (1Ko¨ln; 2Ko¨ln; 3Ko¨ln; 4Ko¨ln; 5Ko¨ln; 6 Ko¨ln; 7Ko¨ln; 8Ko¨ln; 9Ko¨ln; 10Ko¨ln) Purpose: To investigate the effects of low and high frequency deep brain stimulation (DBS) of the right nucleus accumbens (ACC) and right internal capsule in four patients with intractable obsessive compulsive disorder (OCD) using functional magnetic resonance imaging (fMRI) under intraoperative conditions. Method and Materials: MRI was used to control the stereotactically guided implantation of an electrode for DBS of the right ACC in four patients with intractable obsessive compulsive disorder (OCD). After inserting the electrode, the patients were transferred to the MRI unit. fMRI scans were performed under alternating stimulation conditions using a ‘blockdesign’. Stimulation parameters were varied according to stimulation frequency (high/120 Hz vs. low/4 Hz), voltage (4 V vs. 8 V) and location (nucleus accumbens vs. internal capsule). Results: Notably, we observed a high magnitude of variation across patients: under high frequency stimulation, the first patient showed activations in the right striatum (globus pallidus, caudate nucleus, claustrum), the right orbitofrontal cortex (Brodmann area 9, 10) and the fusiform gyrus (Brodmann area 19). Under lowfrequency stimulation, activation was visualized in the right lateral striatum. The second patient showed a strong left frontal cortical and anterior cingular activation under low frequency stimulation and a deactivation under high frequency stimulation in the same cortical areas. The third patient demonstrated activation under high frequency/high voltage stimulation of the internal capsule in the medial occipital cortex and the left inferior frontal lobe. In the fourth patient, high frequency stimulation led to strong activations with emphasis on bilateral limbic, thalamic and right dorso- and ventrolateral prefrontal cortical structures. Conclusions: Our preliminary findings show the feasibility to perform fMRI under intraoperative conditions. Intraoperative fMRI may provide additional information about the early mechanism of action of DBS of the right nucleus accumbens. Considering the heterogeneity of the results in a small patient population (nZ4), further analysis on a broader empirical basis seems advisable and is currently under investigation.

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Associative Motor Cortex Plasticity is Reduced on the Non-Affected Side in Focal Hand Dystonia—Schramm A1, Weise D2, Reiners K3, Naumann M4, Classen J5 (1Wu¨rzburg; 2Wu¨rzburg; 3Wu¨rzburg; 4Wu¨rzburg; 5 Wu¨rzburg) Maladaptive plasticity has been implicated in the pathophysiology of focal dystonia. In support of this, we have recently shown that associative motor cortical plasticity induced by an external stimulation protocol is greatly enhanced and its somatotopic organization lost on the affected side in patients with writer’s cramp (WC). However, it remains unknown whether these abnormalities are related to the dystonic phenotype or to an underlying pathogenetic disposition. We therefore studied the non-affected side in nine WC patients. In addition, the non-dominant hand of nine healthy control

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subjects was examined. Data were compared with previously obtained results on the contralateral (affected or dominant) side. Paired associative stimulation (PAS) consisted in repetitive electrical stimulation (0.1 Hz, 180 pulses) of the left median nerve paired with transcranial magnetic stimulation (TMS, interstimulus interval 21.5 ms) over the hot-spot for the abductor pollicis brevis muscle (APB) on the right hemisphere. Changes in excitability of the motor cortex were monitored by recording motor evoked potentials (MEP) of the APB and abductor digiti minimi muscle (ADM) for up to 85 min after intervention. In healthy controls, PAS targeting the nondominant hemisphere led to an increase of cortical excitability (APB C6.6Gs.e.m. 5.6%, ADM C21.5G9.6%) comparable to that found previously on the dominant side (APB C12.3G s.e.m. 8.7%, ADM C4.6G2.9 s.e.m.%). However, because MEP size increased similarly in APB and ADM muscles, the somatotopical specificity of the excitability change, as found on the dominant side, was lost. Surprisingly, PAS did not induce any increase in cortical excitability on the non-affected side in WC patients (APB K0.8Gs.e.m. 9.1%, ADM C0.5G 9.7 s.e.m.%). These findings suggest that in healthy subjects the somatopical specificity of PAS-induced plasticity may be related to skilful hand-usage. Furthermore, development of focal dystonia in WC patients is unlikely to be causally related to loss of somatotopy alone. By contrast.

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Characteristics of Sensory Trick Maneuvers in Idiopathic Oromandibular Jaw Opening Dystonia— Schramm A1, Classen J2, Reiners K3, Naumann M4 (1Wu¨rzburg; 2Wu¨rzburg; 3Wu¨rzburg; 4Wu¨rzburg) Objective: We have attempted to evaluate the efficacy of different sensory trick manoeuvres in oromandibular dystonia (OMD). Background: Jaw opening OMD is a form of focal dystonia involving lower facial, labial, lingual as well as pterygoid and submental muscles resulting in unvoluntary muscle spasms especially during speaking. As in other forms of dystonia, symptoms may be alleviated by several sensory trick manoeuvres (e.g., biting on a toothpick) although hitherto only little is known about the underlying pathophysiological mechanisms. Methods: In this study we systematically examined a homogeneous group of seven patients with idiopathic jaw opening dystonia performing a standardized counting task with and without the use of a small wooden stick serving as a sensory trick. The following conditions were tested while counting: (1) no use of the stick, (2) stick placed in the mouth between teeth and cheek, (3) slight biting on the stick, and (4) voluntary jaw closure without use of the stick. For further analysis we assessed the following parameters: self-rating using a visual analogue scale, quality of speech using audio recordings for blinded evaluation and surface electromyographic (EMG) recordings from the temporal, perioral, and submental regions. Results: Self-assessment showed a significant reduction of symptoms for both conditions using the stick, while biting on it was most effective (K48%, P!0.015). Analysis of EMG data showed a significant reduction of perioral EMG activity during condition 2 (- 28%, P!0.05) whereas biting on the stick (condition 3) had a significant effect mainly on submental muscles (K21%, P!0.01). Although voluntary jaw closure (condition 4) did neither improve

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speech nor self-assessment, it significantly reduced EMG activity of submental muscles to a similar degree as biting on the stick (K23%, P!0.015). Speech showed no significant changes although there was a trend for condition 3 (biting on the stick, K15.1%, PZ0.114). Conclusions: Sensory tricks in jaw opening OMD are an effective and valuable tool to reduce dystonic muscle activity. Besides primary sensory stimulation of the oral region, slight voluntary jaw closure (with or without the use of a stick) decreases dystonic muscle activity indicating that muscle spindle afferents may play a role in the action of sensory trick manouevers. These findings may have therapeutic implications to be used in specific speech training programs for OMD patients. Supported by Dystonia Foundation, USA.

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Involvement of Selective Attention in Somatosensory Extinction and its Relation to Conscious Stimulus Perception: Evidence from Event-Related Potentials (ERPs)—Schubert R1, Blankenburg F2, Lemm S3, Curio G4, Villringer A5 (1Berlin; 2Berlin; 3Berlin; 4 Berlin; 5Berlin) Conscious perception of a weak somatosensory ‘target’ stimulus can be suppressed in a significant number of trials by a rapidly succeeding higher-intensity ‘mask’ stimulus applied to the contralateral finger at an ISI of 50–100 ms. A recent fMRI analysis of such somatosensory backward-masking (Blankenburg et al. NeuroImage 2003; 19: 1432) revealed comparable activations for perceived and extinguished targets in the contralateral primary somatosensory cortex. When the target was consciously perceived, there was additional bilateral BOLD activity in the inferior parietal cortices and frontal insulae. In the present study, we used highdensity electroencephalography (EEG) (nZ12) in a backwardmasking paradigm analogous to the previous fMRI study in order to investigate correlates of selective attention and conscious perception in the somatosensory system. We hypothesized that stimulating both index fingers with an ISI of adequate duration to elicit potentials in contralateral S1 following the first stimulus is not sufficient to create perceptual awareness. In addition, components correlated with selective attention between 100 and 500 ms over posterior parietal and frontal areas should be modulated by the level of perception. Electrical current pulses were applied to both index fingers with asymmetrical intensities (left target!right mask) at an ISI of 70 ms (left before right stimulus). Subjects indicated perception of stimuli by pressing a button with their right foot. Subsequent ERP analysis revealed that early components (P45, N80) peaking over the contralateral S1 did not differ significantly between levels of perception. Significant differences arose from amplitudes correlated with selective attention (P100, N140, N200) and stimulus evaluation (P300) on contralateral parietal, central and bilateral frontal electrode positions between perceived/extinguished targets. In congruence with our fMRI results, these data support the notion that early activation of modality-specific areas is a necessary but not sufficient condition for conscious perception of somatosensory stimuli. Rather, attentional engagement recruiting the parietal and frontal regions appears to be essential for conscious stimulus perception.

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Motor Areas Serve Attention: Functional Magnetic Resonance Imaging on Memory-Driven versus Stimulus-Driven Sequencing—Schubotz RI1, von Cramon DY2 (1Leipzig; 2Leipzig) Serial prediction of perceptual events engages the premotor cortex (PM) in the absence of motor requirements, supporting attentional functions in this area. The present fMRI study used a modified serial prediction task (SPT) to investigate whether mesial and lateral portions of PM may support different sub-functions of this task. According to the canonical view on motor functions, mesial PM (pre-supplementary motor area, preSMA) serves internally driven processes rather than externally driven ones, whereas the opposite is true for the lateral PM. Capitalizing on this dichotomy, the present study introduced a parametric fMRI design that aimed to force internally driven aspects, and hence preSMA engagement, in serial prediction. 16 young healthy volunteers participated in the study. Imaging was performed at 3 T on a Bruker Medspec 30/100 system. Slices were positioned parallel ACPC, with 22 slices (4/1 mm) covering the whole brain. Results revealed that both lateral PM and SMA were activated by the SPT paradigm, as expected. Moreover, we found the internally driven processes to draw on anterior portions of both mesial and lateral premotor areas extending into prefrontal cortex. However, activation in SMA exposed the best fit to the manipulation forcing internally driven sequencing. The present results confirm a functional dichotomy between SMA and PM even in the attentional (non-motor) domain.

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Repetitive Transcranial Magnetic Stimulation (rTMS) over Dorsal Premotor Areas Interferes with Visuospatial Attention—Schubotz RI1, Tewes A2, Wolfensteller U3, von Cramon DY4 (1Leipzig; 2Leipzig; 3 Leipzig; 4Leipzig) The present study used repetitive transcranial magnetic stimulation (rTMS) to investigate interference of the dorsal premotor cortex (PMd) during a spatial serial prediction task (SPT). Using a 3!2 design, rTMS was applied either targeting the right or left PMd, or a sham position in the vicinity of the occipital pole (factor SITE), and either during the early sequence encoding phase or during the late sequence deviant monitoring phase (factor TIME). Estimated stimulation sites over the target areas were determined individually using anatomical MRI scans. Performance was assessed by difference of error scores between the SPT and a neutral baseline task. Performance was found to be impaired in early-right vs. early-left, and in late-left vs. early-left stimulation. Our findings confirm that rTMS over PMd can cause behavioral impairments in an SPT. Moreover, the specific affects suggest different functional roles of right and left PMd in encoding and deviant monitoring in perceptual sequences.

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Intrauterine Cerebral Processing of External Vibroacoustic Stimuli—Schwab M1, Menz C2, Bludau T3, Gerhardt KJ4, Abrams RM5 (1Jena; 2Jena; 3Jena; 4 Gainesville; 5Gainesville) The human and the sheep fetus, the animal model of human pregnancy, respond to external stimuli such as vibrations or noises with behavior state changes from 0.8 gestation onwards. It is not clear yet (1) if the behavior state changes that

represent a ‘subcortical’ arousal are accompanied by a ‘cortical’ arousal as a condition of conscious perception of the stimuli; (2) to what extent the perception of the stimuli depends on the behavior state and the quality of the stimulus; and (3) if the proprioceptive system is important for perception of the vibratory component of the signal. Via Cesarean section, sheep fetuses were chronically instrumented at 0.8 gestation with ECoG (electrocorticogram) electrodes as well as EOG, EMG and EKG electrodes to define fetal behavior states. After a recovery period of five days, stimuli were presented from the abdominal wall of the ewe during periods of NREM and REM sleep. We tested pure vibratory (30 min) and acoustic (5 h) stimuli as well as dynamic amplitude and frequency modulated and two static vibroacoustic stimuli (VAS) produced by an electronic artificial larynx (EAL) and a laboratory shaker. ECoG changes were analyzed using linear (power spectral analysis) and non-linear methods. For non-linear analysis we used an algorithm based on the Wolf algorithm (calculation of the leading Lyapunov exponent) which calculates a point prediction error (PE) regarding the course of the time series in the phase space. The vibratory and acoustic stimuli did not induce a cortical arousal. The VAS produced an arousal with similar effectiveness during NREM and REM sleep. The dynamic stimulus induced 100%, the EAL 70% and the laboratory shaker 40–50% responses. The PE showed a high predictability in NREM and a low predictability of the ECoG in REM sleep. Although the power spectrum differed between VAS in NREM (decrease of delta activity) and REM sleep (beta activation), the PE showed that the cortical activation pattern did not depend on the sleep state and the stimulus. Processes of cortical activation and deactivation during spontaneous sleep state changes and VAS were similar in their time courses. Cochlear ablation prevented from arousal, suggesting that stimuli were detected through the auditory rather than the proprioceptive system. The results show that external VAS induce a cortical arousal during the last trimester depending on the stimulus. The time course of cortical activation within 32 s suggests an arousal via the ascending activating reticular system rather than via specific fiber systems.

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Intrauterine Development of Sleep States—Schwab M1, Schwab K2, Kott M3, Szeto HH4 (1Jena; 2Jena; 3 Jena; 4New York) The fetal sheep is an important model of human pregnancy. The time-course of brain development is similar to the human situation. We aimed to investigate functional brain maturation in regard to the development of sleep states by examination of developmental changes of the electrocorticogram (ECoG) in utero. We recorded the ECoG of five chronically instrumented fetal sheep continuously between 105 and 139 days gestation (dGA, term 150 dGA). Three to five artifact-free 10 min ECoG-epochs from NREM and REM sleep, respectively, were analyzed every third day using linear (power spectral analysis) and non-linear methods because the ECoG is a highly complex signal that does not fit the criteria of ‘linearity’. For non-linear analysis we used an algorithm based on the Wolf algorithm (calculation of the leading Lyapunov exponent) which calculates a point prediction error (PE) regarding the course of the time series in the phase space. A high PE typically for REM sleep stands for a low predictibility or causality and vice versa. The

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sheep fetus developed distinct sleep states from approximately 115–120 dGA conventionally defined by ECoG, EOG and EMG measures alternating between REM and NREM sleep. This age corresponds to the first occurrence of fetal behavior states at 28 to 30 weeks of gestation in human pregnancy. We did not find phases of wakefulness. At 106 dGA, ECoG showed predominantly premature REM sleep patterns defined by a relatively high PE but already there were phases with a lower PE suggesting the occurrence of a premature NREM sleep. These phases reveal the occurrence of coordinated thalamocortical rhythms on a regular base. The PE decreased continuously in that state over the investigated period suggesting maturation of the ECoG synchronization mediating thalamic pacemaker circuits. Development of complex neuronal interactions reflected by a PE increase during premature REM sleep could not be proven before 124 dGA, i.e., after emergence of distinct sleep states between 115 and 120 dGA. We conclude taht maturation of thalamic pacemaker circuits leads to the occurrence of organized sleep states and precedes maturation of complex cortical neuronal interactions. PE changes after transition to cyclic electrocortical activity reflect continued functional brain development during REM and NREM sleep.

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Pain-Related Motor Cortex Disinhibition in Patients with Neuralgia after Peripheral Nerve Lesion—A Transcranial Magnetic Stimulation (TMS) Study— Schwenkreis P1, Scherens A2, Pleger B3, Maier C4, Tegenthoff M5 ( 1Bochum; 2Bochum; 3 Bochum; 4 Bochum; 5Bochum) Different studies have suggested a relationship between chronic pain and reorganization in the human sensorimotor cortex, e.g., in patients with limb amputation or complex regional pain syndrome (CRPS). Cortical reorganization might be based on changes of synaptic efficacy requiring a reduction of GABAergic inhibition and an activation of NMDA receptors and, therefore, be linked to changes of cortical excitability. Such cortical excitability changes might be reflected by changes of intracortical inhibition (ICI) and facilitation (ICF) as assessed by paired pulse TMS. The aim of the present study was to assess such possible changes of ICI and ICF in patients with neuralgia after incomplete peripheral nerve lesion, and its relationship to the intensity of neuropathic pain. In 19 patients with neuralgia after incomplete unilateral lesion of the median or ulnar nerve, ICI and ICF were assessed by paired pulse TMS according to the paradigm described by Kujirai et al. (1993). Recordings were taken from the abductor pollicis brevis and the abductor digiti minimi muscles of both hands. Results from the muscle supplied by the lesioned nerve were considered separately from results from the muscle supplied by the unlesioned nerve of the affected hand. Both were compared to results from the corresponding muscles of the unaffected hand. There was a significantly reduced ICI (i.e., higher relative amplitudes) in the hemisphere contralateral to the nerve lesion as revealed by recordings from the muscle supplied by the lesioned nerve (mean relative amplitude 85.1G78.7% vs. 44.1G28.5%; P!0.05) and by recordings from the muscle supplied by the unlesioned nerve (mean relative amplitude 57.9G35.4% vs. 37.1G16.8%; P!0.05). ICF did not differ significantly between the two hemispheres. The amount of disinhibition correlated positively with the pain intensity as

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assessed by a numeric rating scale (rZ0.577, P!0.05). We conclude that in patients with neuralgia after incomplete peripheral nerve lesion there exists a unilateral disinhibition of the corresponding motor cortex, which is related to pain intensity. This finding suggests a relationship between cortical excitability changes, cortical reorganization and chronic neuropathic pain in these patients. The results contrast with the bilateral motor cortex disinhibition in CRPS patients. This points to important pathophysiological differences between CRPS and neuralgia, and might have a future diagnostic and therapeutic impact.

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Modulation of Susceptibility-Weighted Contrast in Volunteers by Using Caffeine—Sedlacik J1, Rauscher A2, Deistung A3, Reichenbach JR4 (1Jena; 2Jena; 3 Jena; 4Jena) Purpose: Changes in cerebral blood flow can be induced by exogenous agents, such as carbogen or caffeine. One consequence of these physiological challenges is a change of the oxygenation level of the venous blood, which influences the BOLD signal or the SWI contrast. The aim of this work was to investigate the influence of caffeine on the contrast observed with high-resolution susceptibility-weighted imaging (SWI) in volunteers. Materials and Methods: High resolution T2*-weighted images were acquired in four volunteers on a 1.5 T system using a velocity compensated 3D gradient echo imaging sequence. Sequence parameters were: TR/TE/FAZ 67 ms/50 ms/258, in-plane resolutionZ0.5!0.75 mm2, slice thicknessZ1.8 mm, scan time 13 min. A native scan was performed first, then the subjects drank two cups of coffee (equivalent to 300 mg caffeine) through a plastic tube directly in the scanner without changing position. The 3D scan was then repeated 4 times to cover a period of nearly one hour after drinking coffee. Phase and magnitude images were reconstructed from the raw data. The phase images were unwrapped using homodyne filtering. The phase and magnitude images were combined to produce susceptibility-weighted images (SWI). The SWI and magnitude images were spatially realigned and maps of relative signal changes between the different scans were computed. Results and Discussion: Maps of relative signal change clearly visualized the caffeine-induced response of venous vessels. Larger veins, such as the thalamostriate vein or the internal cerebral veins, showed a distinct signal decrease of up to 20%. Signal intensities in gray and white matter, however, changed only marginally during the post-caffeine scans. These signal changes have to be compared with the results obtained during breathing of carbogen where signal increases and decreases of 8% and K5% in gray and white matter, respectively, were observed. The signal in larger veins increased by even more than 300%. Conclusion: BOLD imaging is able to visualize the cerebral vascular response to caffeine. Signal changes induced by caffeine were distinctly weaker compared to changes observed with carbogen. However, further studies are required to investigate the signal response and to optimize the applied dose. One advantage of caffeine is that it is better tolerated compared to the inhalation of carbogen.

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Presurgical Multimodal Imaging in Patients with Cerebral Tumors—Seitz RJ1, Nickel J2, Sabel M3, Kleiser R4, Joergens S5, Tellmann L6, Neeb H7, Stoecker T8, Shah JN9, Pauleit D10, Stoffels G11, Langen KJ12, Indefrey P13, Stummer W14, Herzog H15 (1Du¨sseldorf; 2Du¨sseldorf; 3Du¨sseldorf; 4Du¨sseldorf; 5Du¨sseldorf; 6Ju¨lich; 7Ju¨lich; 8Ju¨lich; 9Ju¨lich; 10 Ju¨lich; 11Ju¨lich; 12Ju¨lich; 13Nijmegen; 14Du¨sseldorf; 15Ju¨lich) We introduce a concept for presurgical localization of speech and motor function, which we apply to patients with brain tumors located near eloquent cortex regions. By using standard hard- and software which enables the coregistration of brain structure, amino acid uptake and brain function into one stereotactic dataset, a refined planning of tumor surgery is feasible. The cortical localization for finger-tapping and syntactic speech processing with fMRI (block design, TR time 4000 ms, FOV 200 mm, 30 slices a` 4 mm each frame, gap 0.4 mm) is based on two recently validated paradigms. PET imaging is done using the amino acid-tracer fluoroethyltyrosine (FET) which shows an uptake in vital brain tumor tissue. The structural dataset is a 3D high-resolution MRI of each patient consisting of 160 sagitttally acquired slices in a 256!256 matrix, allowing us to compute isotropic voxels with a size of 1!1!1 mm. So far, 11 patients (9 males, 2 females, age 40G12 years) have been studied. Thereof 7 patients with a left-hemispheric fronto-temporal tumor were studied with speech activation and FET-PET. To highlight our approach, we describe the case of a 33-year-old right-handed woman with a left-hemispheric astrocytoma WHO II who presented with an acute speech arrest followed by a generalized tonic-clonic-seizure. The clinical-neurological findings disclosed a latent hemiparesis on the right side. During the neuropsychological testing the patient achieved throughout normal percent ranks in all applied tests [Rivermead Behavioural Memory Test (RBMT immediate recall 48.5%, delayed recall 63.6%), Wechsler digit-span (forward 95%, backward 26%), Wechsler block-span (forward 43%, backward 19%), verbal fluency (category ‘forenames’ 85%), ‘Token Test’ from the AAT faultless]. The structural MR imaging showed a hypointense lesion in the frontocentral junction of the left hemisphere involving the left frontal operculum showing a focal uptake of FET in the dorsal part of the tumor. FMRI revealed an anterior displacement of the frontal speech area and a posterior displacement of the presumed posterior speech area. In addition, there were abnormal activations in a mirror-like fashion in the right cerebral hemisphere.

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The Somatosensory Hand Representation is Shrunken in Thalidomide-Induced Dysmelia—Seitz RJ 1, Stoeckel MC2, Pollok B3, Joergens S4, Witte OW5, Schnitzler A6 (1Du¨sseldorf; 2Du¨sseldorf; 3Du¨sseldorf; 4 Du¨sseldorf; 5Jena; 6Du¨sseldorf) It is well established that functional representations in the cerebral cortex expand due to excessive use]. Little is known, however, about the reverse. In this study we investigated the relationship between congenitally missing fingers and the size of the

somatosensory hand representation in thalidomide embryopathy. Twenty-one subjects participated in our study, ten with normal, and eleven with malformed upper extremities due to intrauterine exposure to thalidomide. The number of developed fingers varied between two and four in the dysmelic subjects. Fingers were missing systematically from radial (D1 first finger to be missing) to ulnar (D5 last finger to remain). The somatosensory hand representation was studied using electrical stimulation of the most distant fingers of each hand in combination with MEG and fMRI. The localization of the finger representations was based on equivalent current dipoles (ECD) with localization in SI (MEG) and significant (P!0.001) activation peaks on the lateral surface of the postcentral gyrus (fMRI). To estimate the size of the somatosensory hand area and the effect of the malformation disorder, Euclidian distances between the representations of the most distant fingers and correlations between the size of the hand representation and the number of fingers were calculated. Both methods showed an agreement with similar results: the mean size of the hand area was significantly smaller in the dysmelic subjects (5.67 and 8.6 mm, respectively) as compared to controls (11.26 and 20.4 mm). There was a significant rank correlation (P!0.05) between the number of developed fingers and the Euclidian distance between the cortical representations of the most distant fingers (rsZ0.62 and 0.69). Both methods showed a somatotopic arrangement of cortical finger representations. In the dysmelic subjects, however, the representation of the ulnar finger was shifted towards the thumb representation of the controls. Our data show an effect of congenitally missing fingers on the size of the sensory hand area. In contrast, when fingers were experimentally amputated or webbed, the size of the sensory hand area appeared unchanged. We suggest that our findings reflect the negative counterpart of lifelong use-dependent plasticity related to dysmeliainduced impairment in hand use.

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Long-Term Effects of Sequential Small Cortical Infarcts on Brain Volume and Cognitive Function— Shanina E1, Redecker C2, Reinecke S3, Schallert T4, Witte OW5 (1Jena; 2Jena; 3Jena; 4Austin, Texas; 5 Jena) Multiple ischemic brain lesions are commonly associated with progressive cognitive impairment leading to some types of vascular dementia in the elderly. Only little is known about the underlying pathophysiological mechanisms. We here analyzed the effects of single and multiple small cortical infarcts on brain volume and cognitive function using the photothrombosis model in rats. Different experimental groups received single small infarcts in the forelimb somatosensory cortex (SL) or two sequential infarcts either immediately (DL0), 2 days (DL2), 7 d (DL7), or 10 days (DL10) after the first infarct in the same area of the contralateral hemisphere. Compared to the animals with unilateral lesions (SL), brain volumetry performed 1 month after the second lesion revealed a global reduction in brain volume of 2.2–8.0% (excluding the lesioned area) in all groups with sequential infarcts. In a further study sham-operated as well as SL and DL2 animals were tested in a Morris water maze 2 months after the lesions. While SL animals showed no cognitive impairment in acquisition and probe trial tests compared with controls, DL2 animals revealed a slight but significant memory deficit, although there was no difference in swim speed between these groups. The present findings

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demonstrate a general loss of brain volume associated with cognitive deficits following sequential cortical infarcts, probably providing an animal model for the investigation of degenerative processes leading to vascular dementia.

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Novel Modulating Deep Brain Stimulation Techniques based on Real-Time Model in the Loop Concepts— Silex C1, Tass PA2, Schiek M3, Hermes N4, Rongen H5, Barnikol UB6, Hauptmann C7, Freund HJ8, Sturm V9 (1Ju¨lich; 2Ju¨lich; 3Ju¨lich; 4Ju¨lich; 5Ju¨lich; 6Ju¨lich; 7 Ju¨lich; 8Ju¨lich; 9Ko¨ln) To improve deep brain stimulation (DBS), we have studied stimulation-induced dynamics in target areas for DBS in mathematical models. We have implemented these neuronal networks on special fast digital hardware. Our real-time models enable us to simulate stimulation-induced processes in patients under real-time conditions. Our approach makes it possible to evaluate and optimize software and hardware realizing our novel demand-controlled DBS techniques (so-called model in the loop concept). The models and the control algorithms have been coded with the graphical programming language SIMULINK by Mathworks which enables a modification of the model dynamics and the control concepts in a fast and transparent way and thus facilitates and improves the interdisciplinary research in the field of neuromodulation. The goal of our approach is the design of novel stimulation protocols which specifically modulate the affected neuronal dynamics.

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Neurofunctional Correlates and Pharmagological Modulation of Cognitive Inhibition in Major Depression: A Study with erfMRI—Sinsel E1, Schlo¨sser R2, Wagner G3, Ko¨hler S4, Labadie C5, Mentzel HJ6, Sauer H7 (1Jena; 2Jena; 3Jena; 4Jena; 5Jena; 6 Jena; 7Jena) Introduction: Neurofunctional studies provided evidence that a dysfunctional fronto-cingulate circuit might be related to deficits of cognitive control in major depression. Altered prefrontal and ACC blood flow associated with cognitive deficits in the depressive state were described (George et al. 1997; Okada et al. 2003). Moreover, altered activation of the anterior cingulate cortex (ACC) has been reported to have a predictive power for antidepressant treatment response (Mayberg, 2003). Aside from influencing depressive mood, antidepressants appear to have a differential effect on cognitive functions. However, treatmentrelated effects of different antidepressant drugs on cognitive brain activation patterns have not been examined in more detail yet. Therefore, the present study aimed to investigate patterns of cognitive brain activation in patients with depression during the course of a 6-weeks antidepressant treatment regimen. Methods: Fifteen patients (mean ageZ39.6 years) with a major depressive episode (MDE) according to DSM IV were examined with fMRI drug-free and after 6 weeks of treatment with either Citalopram or Reboxetin. Fifteen age-, gender- and education-matched healthy controls were included as the comparison group. The subjects were investigated with event-related functional MRI while performing a cognitive control task (Stroop-Color-Word-Task). Results and Conclusion: Although there were no significant differences in performance between groups, the depressed

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subjects demonstrated reduced cognitive activation in the ACC. This regional difference could no longer be observed after remission. The patients showed also increased activation in the right prefrontal and parietal cortex compared to their baseline measurements. These results indicate a central function of the ACC for remission. A normalization of ACC activity might be accompanied by a more efficient implementation of cognitive control. Supported by the German BMBF FKZ01ZZ0105, TMWFK B30701-015/-016, IZKF grants.

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Orthostatic Tremor during Modification of Stance— Spiegel J1, Fuss G2, Becker G 3, Dillmann U4 (1Homburg/Saar; 2Homburg/Saar; 3Homburg/Saar; 4 Homburg/Saar) Introduction: The primary orthostatic tremor (OT) is a fast tremor occurring only in the standing position. We have now studied whether OT is influenced by modification of the condition ‘stance’. Patients and Methods: We investigated 7 patients with primary OT (age 46–77 years, median 68 years). All patients revealed a 14–18/s tremor in the muscles of both legs during standing. The tremor activity was analyzed under different conditions: 1) Relief of the body weight to 75%, 50%, 25% and 0% (complete relief of the body weight, the patient’s feet still touched the bottom) by vertical elevation of the patient. 2) Relief by a tilting table with the positions 908 (upright stance), 808, 458 and 08 (horizontal position, the feet still touched the base). OT was measured with surface EMG (4 traces) from the muscles of both legs. Results: In all patients, there was a clear OT activity during all conditions, even at complete relief of the body weight or, respectively, in the horizontal position with the tilting table. The tremor frequencies at the different conditions were not significantly different (ANOVA, PO0.05). Conclusion: Modifications of the condition ‘stance’ as tested in this study were not sufficient to suppress OT generation. Our data suggest that the body weight plays a less important role in OT generation.

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Effect of 3,4-Diaminopyridine on the Gravity Dependence of Ocular Drift in Downbeat Nystagmus— Sprenger A1, Zils E2, Sander T3, Rambold H4, Ko¨mpf D5, Straumann D6, Helmchen C7 (1Lu¨beck; 2 Lu¨beck; 3Lu¨beck; 4Lu¨beck; 5 Lu¨beck; 6Zu¨rich; 7 Lu¨beck) Background: The pathomechanism of downbeat nystagmus (DBN) remains controversial but each mechanism has to account for (i) its gaze evoked vertical centripetal drift which increases with vertical gaze eccentricity, and (ii) the vertical bias component of the upward slow phase velocity on gaze straight ahead. The vertical velocity bias has a gravity-dependent component which leads to maximal drift velocity when patients lie in a prone position and minimal in a supine position. Recently, the potassium channel blocker 3,4-diaminopyridine (3,4-DAP) has been shown to be effective in DBN of patients with the head upright. Purpose: To investigate the effect of 3,4-diaminopyridine on gaze- and gravity-dependent mechanisms of DBN.

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Material and Methods: Eye movements were recorded in one patient with idiopathic DBN with the video-based EYELINK II system. Fixation targets were head-fixed LEDs, which were presented in front of the patient at a fixed distance (60 cm) in gaze straight ahead and C100 up and down. Horizontal targets were presented at 400. The pitch head position was monitored and adjusted by an inclinometer. Results: There was a strong gravity-dependent velocity bias component which was maximal in the prone position and turned into upbeat nystagmus (UBN) in the supine position on gaze straight ahead. Following 3,4-DAP ingestion, the slow phase velocity of DBN was hardly affected in gaze straight ahead or lateral gaze but was strongly reduced in the head tilted forward position, i.e., in the prone position by O50%, whereas upbeat nystagmus in the supine position was not affected. Conclusions: This effect cannot simply be explained by a shift of the velocity bias in a downward direction but rather implicates that 3,4-DAP may particularly influence the gravity-dependent component of DBN which may be the leading clinical feature in DBN.

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Associative Motor Cortical Plasticity is Modulated by the Activation History of Motor Cortex—Stefan K1, Wycislo M2, Leussink V3, Schramm A4, Naumann M5, Reiners K6, Classen J7 (1Wu¨rzburg; 2Wu¨rzburg; 3 Wu¨rzburg; 4Wu¨rzburg; 5Wu¨rzburg; 6Wu¨rzburg; 7 Wu¨rzburg) Pairing median nerve stimulation repetitively with transcranial magnetic stimulation over the contralateral motor cortex (paired associative stimulation, PAS) may increase, or decrease, human motor cortical excitability at interstimulus intervals of 25 ms (PAS25), or 10 ms (PAS10). The properties of this plasticity resemble associative long-term potentiation (LTP) and long-term depression (LTD) as established in vitro. We employed these protocols to examine possible physiological correlates of motor memory formation. Subjects performed brisk isometric abductions with their right thumb at a defined force window adjusted to their individual maximum force in a series of 10 training sessions consisting of 50 contractions each. The percentage increase of successful attempts was taken as a measure of motor learning. Motor cortex excitability changes induced by PAS25 and PAS10 were evaluated before and after motor training on day 1 and day 2 in two different groups A (NZ11) and B (NZ11). At baseline LTP-like plasticity and LTD-like plasticity were similar in both groups (% change of MEP amplitude; group A: PAS10: K22.1G 3.5 mean, s.e.m.; PAS25:C41.1G9.6, group B: PAS10: K23.8G 3.9; PAS25:C43.4G7.9). Similarly, training-induced percentage successful attempts (A: 14.6G3.2; B: 19.3G4.4%) did not differ between both groups. Immediately after training (day 3), the capacity of the motor cortex to undergo LTP-like plasticity in response to PAS25 was abolished (group A,% change: K9.1G6.2; different from baseline, PZ0.001). When retested several days after motor training (day 4), PAS25-induced plasticity recovered to baseline levels. PAS10-induced plasticity remained unchanged by prior training. In a separate experiment evidence was obtained for continued improvement of motor performance at a time when PAS25 was ineffective in inducing LTP-like plasticity. PAS25induced plasticity was restored when the induction protocol was applied immediately after motor learning and subsequent

depotentiation of the previously enhanced synapses by induction of PAS10-induced plasticity (before C30.2G3.0%, after C79.5G 16.2%) Immediately after training, normal PAS25-induced plasticity was observed in the untrained motor cortex (before C29.8G6.3%, after C46.6G17.6). These results are consistent with a concept of temporary (heterosynaptic) suppression of associative LTP by mechanisms involved in motor memory formation. Supported by Hertie foundation, Germany.

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Spatiotemporal Analysis of Visuospatial Attention and Modulation by Repetitive Transcranial Magnetic Stimulation (rTMS)—Stegelmeyer U1, Rache K2, Meister IG3, Gobbele R4, Buchner H5, Waberski TD6 (1Aachen; 2Aachen; 3Aachen; 4Aachen; 5Recklinghausen; 6Aachen) Introduction: Previous studies showed that repetitive TMS produces temporary virtual lesions. If performed over the right posterior parietal cortex (PPC) visuospatial tasks are impaired due to the effect of the stimulation [1]. The aim of the present study was to deconvolute the temporal dynamics of the neural processes involved in line bisection judgement tasks and their dependency on the function of the PPC. Materials and Methods: We studied twelve right-handed healthy subjects. The performance on a computerized visuo-spatial line-bisection judgement task was examined before and after the application of rTMS over the right and left PPC at P3 and P4 locations. We used a Magstim magnetic stimulator with a figure-of eight coil. Each stimulus train consists of 900 stimuli delivered with a frequency of 1 Hz. Visual stimuli consisted of black vertically centered lines presented for 450 ms with an interstimulus interval of 1050 ms. Continuous EEG was recorded with a 64channel system. Spatiotemporal analysis was performed within the temporal coupled current density approach within a standardized head model. Results: Six regions were identified to contribute significant source activity related to the line bisection judgement task. Right middle occipital gyrus (BA 18), bilateral inferior occipital gyrus (BA 19), right superior PPC (BA 7), right inferior PPC (BA 40) and right superior temporal cortex (BA 41). Differences in the time course of the source activation depending on the side of stimulation were evaluated. After left side stimulation there was an increase of source acitivty within the right superior and inferior PPC compared to a reduction of source activity within the PPC after right side stimulation in the time range of the N1. Noteworthy, after right side stimulation there was an increase of activity at the right-sided temporal source. Conclusion: The present study demonstrates the effects of virtual lesions to the PPC on the processing of visuospatial perception on a source-activation level. The increased activation of the right PPC after left side stimulation might reflect transcortical disinhibition [2]. In addition the results suggest that inhibition of the right PPC induces an activation of the right temporal cortex, supporting the hypothesis of an alternative visuospatial processing. References Fierro B et al. Neuroreport 2000; 14: 1519–1521. Di Lazzaro V et al. Experimental Brain Research 1999; 124: 520–524.

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Constructive Brain Processes in Motion Perception— Sterzer P1 (1Frankfurt) Bistable perceptions allow the dissociation of perceptionfrom stimulus-related neural processes. We investigated the neural mechanisms underlying bistable apparent motion (AM) perception using functional magnetic resonance imaging (fMRI) . In a first set of experiments, we asked how perceptual reversals during bistable AM are coded in extrastriate visual areas. We assessed event-related activations associated with perceptual reversals during continuous presentation of two different ambiguous AM stimuli, the ‘spinning wheel illusion’ and the ‘dynamic dot quartet’ (see Figs. 1 and 2). Contrasting with previous studies that used bistable paradigms involving objects or faces, we detected no reversal-related activations in ventral extrastriate regions, but instead in the human motion complex (hMTC/V5) with both ambiguous AM stimuli used. This suggests an attribute-specific coding of perceptual reversals in extrastriate visual cortex. In the spinning wheel illusion but not in the dynamic dot quartet, we observed additional reversalrelated activations in the ‘kinetic occipital’ area, which has been implicated in the processing of kinetic contours. Since the spinning wheel stimulus, in contrast to the dynamic dot quartet, evokes the impression of a moving object contour in front of a stationary background, the different response patterns indicate a fine-tuning of reversal-related activations to stimulus features. In a second set of experiments, we were interested in the neural correlates of ‘correspondence’, which refers to the question of how the visual system determines which object in one frame corresponds to which object in the next in ambiguous AM displays. To investigate the influence of intrinsic object properties on the path of AM, we used dynamic dot quartets with differences in color or luminance serving as correspondence cues. We observed a suppression of neural activity in the calcarine cortex (V1) whenever perceived AM paths violated color and luminance cues. In contrast, when AM paths matched the correspondence cues, V1 activity was the same as during perception of uncued displays. This finding might reflect regulatory mechanisms that flexibly gate early visual feature processing in accord with an overruling perceptual decision. Taken together, our findings indicate that reversal-related activation patterns in bistable visual perception are not only attribute-specific but depend on stimulus characteristics in a

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Fig. 1.

Fig. 2.

finely tuned way suitable to encode perceptual content in the absence of sensory input changes. Moreover, perceptual decisions seem to be associated with adjustments of activity levels at early visual processing stages.

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Influence of Selective Norepinephrine Reuptake Inhibition on Motor Function Recovery after Focal Cortical Brain Infarction—Storch P1, Knieling M2, Metz GA3, Witte OW4 (1Jena; 2Jena; 3Lethbridge; 4 Jena) Earlier studies suggested that the neurotransmitter norepinephrine (NE) plays a major role in motor function recovery. Stimulation of central norepinephrine was postulated to enhance cortical excitability. This, in turn, is thought to influence functional recovery after focal cortical infarction. Reboxetine is a selective norepinephrine (NE) reuptake inhibitor and a clinically efficacious antidepressant drug. Thus, Reboxetine might facilitate functional recovery and cortical reorganization after ischemic stroke, and it might potentiate the benefit of other neurorehabilitation strategies. The objective of this study was to investigate whether Reboxetine promotes motor function recovery after focal cortical brain infarction in adult rats housed in an enriched environment. Twenty-four adult male Wistar rats were pre-trained in a skilled reaching task to grasp and retrieve food pellets. They then received a unilateral focal ischemic lesion of the sensorimotor cortex induced by photothrombosis. After the infarction the animals were assigned to one of the following treatments: standard housing condition/no reboxetine; enriched environment/no reboxetine; enriched environment/reboxetine (15 mg/kg i.p. once daily up to four weeks after lesion). The animals were tested daily in the reaching task (20 food pellets/day) until asymptotic levels in motor performance were reached. The endpoint measures at day 28 after lesion revealed improved reaching success in animals treated with Reboxetine as compared to non-treated animals suggesting that Reboxetine promotes improvement of skilled motor function. Further analysis of reaching movement performance and processing of histological data is currently being performed. The findings of this study bear implications to improve rehabilitation strategies in stroke patients in combination with other rehabilitative therapy.

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Support contributed by The Center for Interdisciplinary Medical Research of Germany (IZKF).

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Attentional Modulation of Brain Responses to PhobiaRelevant Stimuli: An Event-Related fMRI Study— Straube T1, Miltner WHR2, Mentzel HJ3 (1Jena; 2 Jena; 3Jena) Using event-related functional magnetic resonance imaging (fMRI), brain activation to phobia-related pictures (P, spiders) and neutral pictures (N, mushrooms) was measured in spider phobic subjects and healthy controls under two task conditions. In the direct task, subjects were asked to identify the object (spider or mushroom) depicted in the background of the pictures. In the highly demanding indirect task subjects had to match geometric figures in the foreground of the pictures. In controls, there was no increased brain activation to P vs. N under any task condition. In contrast, phobics showed greater responses to P vs. N in the amygdala regardless of task, while the insula and anterior cingulate gyrus (ACC) were more strongly activated only during the direct task. The pronounced amygdalar activation during the demanding indirect task suggests an important role of the amygdala for the rather automatic processing of phobogenic threats. In contrast, activation of areas such as the insula and ACC requires focused attention and evaluation related to the threatening stimuli. Therefore, our findings propose specific neural correlates for the detection vs. the detailed processing of phobia-relevant threats.

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Repetitive Peripheral Magnetic Stimulation (RPMS) for Rehabilitation of Central Paresis—Clinical Experimental Investigations and Technical Approach— Struppler A1, Angerer B2 (1Mu¨nchen; 2Mu¨nchen) Concept of Repetitive Peripheral Magnetic Stimulation (RPMS) is based on the activation of a reorganization process in the CNS (neuromodulation) by induction of a proprioceptive inflow to the CNS, which corresponds physiologically to the lost inflow during active movements. For the induction of this inflow, we use RPMS which depolarizes thick myelinated nerve fibers of the terminal sensorimotor branches. In contrast to fES, the magnetic field penetrates to deeper regions of the muscle, whereas the current caused by the electrical field will take the way of lowest resistance, thus being fairly limited spatially on the surface. Various components of an improvement due to RPMS are clinically and experimentally investigated: (1) Spasticity independent of the level of origin can always be suppressed by RPMS. In a clinical experimental investigation with spastic paresis of finger and hand extensors a dramatic decrease of spasticity together with an increase of voluntary movement could be demonstrated. (2) In a PET study of eight patients it was shown that, due to RPMS, areas of the fronto-parietal circuits which are involved in goal-directed controlled movements, are activated. (3) In disturbed goal-directed motor performances such as reaching and grasping, the regularity of the performed trajectory could be improved. (4) In patients with local tactile extinction (neglect), RPMS reduces the recognition error of different local tactile stimuli. Also the spatial cognition (position sense) can be improved by means of RPMS. We may assume that these various and long-lasting effects on the spinal and

cortical levels are based on neuromodulation which is caused by muscle mechanoreceptor afferents. The development of a nonlinear adaptive closed-loop control to induce coordinated finger movements by RPMS is the overall target in order to increase the therapeutic outcome. For this purpose our physiological findings from RPMS form the basis to realize the dominant and time-variant components (i.e., recruitment, spasticity, muscle fatigue and rehabilitation progress). These components have to be identified and compensated for by closed-loop control.

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Involvement of Primary Motor Cortex in Wilson’s Disease Postural Tremor—Suedmeyer M1, Pollok B2, Hefter H3, Gross J4, Wojtecki L5, Butz M6, Timmermann L7, Schnitzler A8 (1Du¨sseldorf; 2Du¨sseldorf; 3 Du¨sseldorf; 4Du¨sseldorf; 5Du¨sseldorf; 6Du¨sseldorf; 7 Du¨sseldorf; 8Du¨sseldorf) Objective: The following study included five Wilson’s disease (WD) patients showing a right-sided postural forearm tremor (4.6 Hz) and addressed the question whether the primary motor cortex (M1) is directly involved in the generation of tremor. Methods: Using a 122-channel whole-head neuromagnetometer and surface EMGs we investigated cerebro-muscular coupling. Postural tremor was observed in a sustained 458 posture of the right-sided forearm. Data were analyzed using Dynamic Imaging of Coherent Sources (DICS), revealing cerebro-muscular coupling between EMG and cerebral activity. Coherent sources were superimposed on individual high-resolution T1-weighted MR images. Phase lags between EMG and cerebral areas showing the strongest coherence were determined by means of a Hilbert transform of both signals. Results: In all patients postural tremor was associated with strong coherence between tremor EMG and activity in the contralateral primary sensorimotor cortex (S1/M1) at tremor or double tremor frequency. Phase lag values between S1/M1 activity and EMG revealed efferent and afferent components in the corticomuscular coupling. Conclusions: Taken together our results indicate that postural tremor in Wilson’s disease is mediated through a pathological oscillatory drive from the primary motor cortex.

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Intraoperative Neurophysiological Monitoring for Endoscopic Transforaminal Lumbar Spine Surgery under General Anesthesia—Suess O1, Brock M2, Suess S3, Theodoros K4 (1Berlin; 2Berlin; 3Berlin; 4Berlin) Percutaneous transforaminal sequestrectomy (PTFES) under endoscopic guidance has proven successful for decompressing lumbar motor nerve roots at the level of the neuroforamen. Nevertheless, nerve root injury is the major complication of this method. For this reason, PTFES has thus far been performed under local anesthesia so that the patient may be questioned about signs of nerve root irritation. A viable alternative seems to be a set-up with the patient under general anesthesia but with the ‘guidance and control’ of intraoperative motor nerve root monitoring (IOM). Twenty-five patients with an intra- or extraforaminal lumbar disc herniation (IHLD/EHLD) were surgically treated by PTFES under general anesthesia and IOM. There were 6 IHLD, 4 EHLD and 15 combined intra- and extraforaminal HLD. Two of them were at L2/3, 9 at L3/4 and 14 at L4/5. Total intravenous anesthesia was

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performed using remifentanil and propofol. Neuromuscular blocking agents were used only for intubation but not during surgery. Motor nerve root activity was recorded by free-run EMG for the nerve root exiting through the intervertebral foramen at the level of surgery as well as the ones immediately cranial and caudal to it. The nerve root was visible through the endoscope in 17 cases (68%), covered by intraforaminal fat in 3 cases (12%) and dislocated by the herniated disc in the remaining 5 cases (20%). EMG monitoring was completely uneventful in 7 of the 25 cases (28%). Three cases (12%) already had spontaneous EMG signals in terms of fibrillation potentials before the actual procedure began. Pathological EMG activity in the form of bursts was observed in 12 (48%) cases. Endoscope placement through the foramen caused single or non-repetitive asynchronous EMG activity in 11 cases (44%). Tonic train activity was recorded in 6 cases (24%). The operation was interrupted immediately when burst or train activity occurred. EMG activity was normalized in all cases by modifying the surgical technique. PTFES under IOM guidance is a safe and easy-to-perform technique if combined with intraoperative neurophysiological monitoring techniques. It has the following advantages for the patient: (a) immediate postoperative mobilization, (b) minimal surgical trauma, (c) minimal operation-induced instability and (d) excellent cosmetic results. General anesthesia reduces intraoperative stress to a minimum, thus enabling patients to derive full benefit from this minimally invasive procedure.

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Navigated Brainstem Monitoring in the Rhomboid Fossa—Sure U1 (1Marburg) Monitoring of cranial nerve function during intrinsic brainstem surgery is crucial in order to avoid iatrogenic morbidity. The combination of neuronavigation and cranial nerve monitoring might offer a tool for the understanding of the sometimes complex anatomy of brainstem nuclei. In an intraoperative environment we have stimulated the surface of the rhomboid fossa in patients suffering from intrinsic brainstem lesions (cavernous malformations). EMG recording of the muscles innervated by the cranial nerve was performed (Nicolet, Germany, Viking IV). Once a nucleus was outlined by this technique, the exact point of stimulation was landmarked within a preoperatively acquired three-dimensional MRI data set by standard neuronavigation (BrainLab, Germany, VectorVision). Accordingly, a map of brainstem function could be established in the rhomboid fossas of 19 patients. On the basis of the mapped functional chart, the decision, as to where to incise the brainstem surface was facilitated. In our series, the excision of the intrinsic lesions was possible in all patients without permanent surgery-related morbidity. Therefore, we believe that this technique is an important tool to visualize, understand, and preserve the complex functional brainstem anatomy, which is often distorted in patients with intrinsic brainstem lesions.

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Functional electrical stimulation-propelled cycling for paraplegics–Measurement of the patient’s force and endurance—Szecsi J1, Krafczyk S2, Fiegel M3, Brandt T4, Straube A5 (1Mu¨nchen; 2Mu¨nchen; 3Mu¨nchen; 4 Mu¨nchen; 5Mu¨nchen) The ergometer training of paraplegics with functional electrical stimulation (FES) can induce cardiovascular adaptation processes

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that allow them to cover useful distances during FES cycling, but only if a minimum amount of mechanical output power is generated. As a rule this cannot be achieved in the case of untrained patients. By concentrating on the work physiological aspect of FEScycling, this study offers a novel approach to comprehension and measurement of the small powers and endurances observed in paraplegics. We also propose definitions for the driving capability and effort of individual patients with respect to a specific type of cycle. Material and Methods: Eight completely paraplegic patients participated in the study (seven untrained and one exceptionally well trained). The isometrical torque profiles of the six stimulated muscle groups were determined with a torque measuring sensor (ATI, Garner, USA), and dynamic power was measured on an ergometer (Motomed-Viva2, Betzenweiler, Germany). Cadence, drag, and covered distance were recorded for each patient during outdoor cycling (FES-tricycle, OVG, Munich, Germany). Results: Graphic representation of the observed cycling situations with respect to the endurance limit showed that FES cycling of the seven untrained (‘weak’) patients took place in the fatigue region, whereas cycling of the trained (‘strong’) patient No. 8 was localized in the steady-state region. While still in the fatigue region, the cycling situations of four weak patients (Nos. 1,2,4 and 6) were situated near the borderline to the steady state region. The proposed measures ‘cycling capability’ and ‘individual effort’ of the patient in a certain cycling situation correlated well with the covered distance (correlation coefficients: 0.92 and 0.79, respectively). Discussion and conclusion: The work physiological approach revealed that the excessive fatigue observed in the untrained paraplegic cyclist can be attributed to the fact that he or she works in the fatigue mode rather than in the steady-state mode. Training under load can bring the performance of some of the paraplegic cyclists (Nos. 1,2,4,6) into the region of steady-state work. The progress of the cyclist can be monitored by the performance measure ‘cycling capability’. Key words: FES cycling, paraplegic, power

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Intraoperative Neurophysiological Monitoring with Motor Evoked Potentials during MCA Aneurysm Surgery—Szelenyi A1, Seifert V2, Flamm E3, Deletis V4 (1Frankfurt; 2Frankfurt; 3New York; 4New York) Introduction: Motor evoked potentials (MEPs) were evaluated during MCA aneurysm surgery. Intraoperative changes of MEPs are correlated to postoperative motor status and neuroradiologial findings. Methods: 70 patients (38 at facility 2, 32 at facility 1; 14 m, 56 f; mean age 54 years) undergoing MCA aneurysm surgery were studied. MEPs were elicited by transcranial electric or direct cortical stimulation with a multipulse anodal stimulation (train of 5 stimuli; single pulse duration 0.5 ms, interstimulus interval 2– 4 ms) and recorded from bilateral thenar, anterior tibialis and contralateral biceps and finger extensor muscles. Permanent or transient loss of MEPs was considered as significant. Motor status was evaluated pre- and immediately postoperatively and at time of hospital discharge. Neuroradiologic lesions were evaluated by comparing pre- and postoperative brain CT scans. Results: In all patients, MEPs were present at the beginning of surgery. In 9 (13%) patients significant MEP changes occurred. 4/9

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patients (44%) with permanent MEP losses had a severe motor deficit without significant improvement in 3 of those 4 patients. In all those 4 patients, brain CT scans demonstrated ischemic lesions within the motor cortex or subcortically. 1/5 patients with transient MEP losses developed a moderate hemiparesis without complete recovery. The remaining 4 patients did not have any motor deficit. 3 patients without intraoperative MEP changes developed a transient slight motor deficit recovering within a week. None of those patients had an ischemic lesion within the primary motor cortex or its pathways. Conclusions: (1) Intraoperatively preserved MEPs always correlate with good motor outcome. A mild postoperative motor deficit-despite preserved MEPs-will recover within the first postoperative week. (2) Transient MEP loss might be followed by a motor deficit, which is slight or transient. (3) The intraoperative permanent loss of MEPs is always followed by a severe motor deficit and neuroradiologic lesions within the motor cortex and motor pathways.

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Acoustic Communication of Emotions: Processing of Emotional Prosody. An Investigation on Single Word Level using fMRI—Szymanowski F1, Schroeder C2, Peschel T3, Rotte M4, Dengler R5 (1Hannover; 2Hannover; 3Hannover; 4Magdeburg; 5Hannover) Perception of emotional prosody plays an important role in every day social life. However, the underlying neuronal circuits are far from being identified. The objective of our study was to find out more about the neuronal networks involved in the processing of emotional speech on the single word level by means of fMRI. 13 young healthy subjects were tested in an auditory oddball paradigm where frequent standard words (‘Anna’, PZ0.7) and infrequent target words (‘Anni’, PZ0.1) were presented via headphones. The subjects had to press a button each time they heard the target word ‘Anni’. Both words, standard and the target, were spoken in a neutral tone. Additionally, infrequent words ‘Anna’ spoken in a happy (PZ0.1) or sad (PZ0.1) tone were presented as emotional oddballs. Functional MR images were acquired for each stimulus and then statistical parametrical maps (SPMs) were calculated for each subject and for a one-sample t-test. The contrasts ‘happy vs. neutral condition’ and ‘sad vs. neutral condition’ revealed activations in the middle gyrus of the temporal lobe and in the frontal opercular cortex bilaterally but with the main focus on the right side, suggesting a lateralization of emotional prosody processing to the right hemisphere already on the single word level. The results are discussed with respect to the relevant literature, the ecological validity and the limits of the experiment.

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Central and Proximal Myelin Damage of Cranial Nerves in Hereditary Neuropathy with Liability to Pressure Palsies—Tackenberg B1, Moeller JC2, Rindock H3, Ko¨nig I4, Shiratori V5, Sommer N6, Oertel WH7, Rosenow F8, Schepelmann K9, Hamer HM10, Bandmann O11 (1Marburg; 2Marburg; 3Marburg; 4 Lu¨beck; 5Marburg; 6Marburg; 7Marburg; 8Marburg; 9Marburg; 10Marburg; 11Sheffield) Objective: We have attempted to provide evidence for central and proximal nerve myelin damage of cranial nerves in hereditary neuropathy with liability to pressure palsies (HNPP).

Methods: Eight patients with the diagnosis of HNPP, which is due to a heterozygous deletion of PMP22 gene, were investigated consecutively. The results of MRI scans of the brain, evoked potential studies (MEP, VEP, AEP), and reflex studies of the motor and sensory cranial nerves (blink reflex, masseter reflex, jawopening reflex) were performed and categorized either as suspicious of myelin damage or normal by means of potential latencies and T2 hyperintensity. The control group for the electrophysiological studies consisted of 48 healthy individuals, matched for age and gender. Results: Four patients showed pathological hyperintense T2 lesions in MRI. MEP studies were suspicious of demyelination in 11/64 measurements (2/135 controls; P!0.0001), evoked potentials showed pathological latencies in 15/42 measurements (9/188 controls; P!0.00001), and finally reflex studies brought up evidence for central as well as peripheral myelin damage in 7 of 24 measurements (4/55 controls; P!0.01). Conclusions: This study provides systematic and significant evidence in a small-sized consecutive population of HNPP patients for functionally relevant myelin damage of the central nervous system and proximal cranial nerves, indicating not only a possible clinical role for diagnosis and prognosis of HNPP, but also a possible role for PMP22 pathology in the central myelin structure in general.

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Maintained Activity of Contralateral SII in Patients with Thalamic Infarction Affecting the VPL—Taskin B1, Jungehu¨lsing GJ2, Blankenburg F3, Ruben J4, Villringer A5 (1Berlin; 2Berlin; 3Berlin; 4Berlin; 5 Berlin) Cortical representations may change when somatosensory input is altered. Here, we investigated the functional consequences of partial central deafferentation of the somatosensory cortex due to a lesion of the ventroposteriolateral nucleus (VPL). We applied event-related functional magnetic resonance imaging (fMRI) during electrical index finger stimulation of the affected and nonaffected side in patients exhibiting contralesional sensory deficits. Six right-handed subjects (age 60–68 years) with non-acute (O 60 days) solitary unilateral thalamic infarctions participated in the study. For localization of lesions, images at high spatial resolution using a T1-weighted inversion recovery sequence were acquired. In all patients the lesions were found to involve the VPL. Imaging was performed on a 1.5 T scanner using a T2*-weighted BOLDsensitive echoplanar sequence (TRZ2 s, TEZ60 ms, voxel size 4!4!5 mm, 16 slices). For somatosensory stimulation, electrical current pulse trains (4 pulses at 7 Hz, duration 200 ms) were delivered scan-triggered to the left and right index finger at a low and a high amplitude (60 presentations each) in a randomized order with a mean interstimulus interval of w6 s. The low and high intensities were equal for both sides and were set closely above sensory and below pain threshold of the non-hypaesthetic side. Analysis of imaging data was performed with SPM99. For the group, statistical parametric maps showed a reduced activation of the contralateral primary somatosensory cortex (SI) in response to stimulation of the affected side. However, no significant difference in activation of the contralateral secondary somatosensory cortex (SII) compared to stimulation of the non-affected side was detected. For the preserved responsiveness of SII in thalamic stroke comparable to that of the contralesional hemisphere,

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possible explanations are a direct thalamocortical input to SII mediating parallel information processing, a non-linear response behavior of SII in serial processing, or reorganizational processes that evolved over time.

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Novel Stimulation Protocols based on Phase Resetting Principles: Applications to Magnetoencephalography and Deep Brain Stimulation—Tass PA1 (1Ju¨lich) Recently, stimulation techniques have been developed which enable one to reliably manipulate synchronization processes between and within oscillatory neuronal populations by means of a coordinated reset of neuronal sub-populations [1, 2]. In addition, a stochastic phase resetting analysis has been developed which makes it possible to detect the corresponding complex responses and transient synchronization and desynchronization processes in experimental data [3]. The talk presents two applications: (i) Visual stimulation in humans: in a full-field pattern reversal task we studied transient synchronization and desynchronization between visual areas V1 and V5 in eight healthy subjects with magnetoencephalography [5,6]. We observed cross-trial (CT) response clustering (i.e., a switching between qualitatively different responses across trials [1,3]) in V1 and/or V5 in all subjects. Our approach shows that, apart from a simple early reset, the visual stimulus causes longlasting (O2 s) coordinated responses in V1 and V5 which escape detection with standard averaging. (ii) Deep brain stimulation (DBS): permanent DBS at high frequencies turned out to be the standard therapy for patients suffering from neurological diseases (e.g., Parkinson’s disease and essential tremor) who do not respond to drug therapy [7]. Standard DBS appears to basically suppress the neuronal firing in relevant target areas. It may cause side effects and its therapeutic effect may vanish in the course of the therapy. To develop milder and more effective DBS techniques, we have applied the novel stimulation methods [2] to 4 tremor patients during electrode implantation. The novel stimulation protocols desynchronize the neuronal firing in the target areas. In all 4 patients the coordinated reset suppressed the peripheral tremor, even if the standard DBS was not effective [4]. References Tass PA. Phys Rev E 2003; 67: 051902. Tass PA. Biol Cybern 2003; 89: 81–88. Tass PA. Phys Rev E 2004; 69: 051909. Tass PA et al. submitted. Barnikol UB et al. in preparation. Tass PA et al. in preparation. Benabid AL et al. The Lancet 1991; 337: 403–406.

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Convulsive Syncopes in a Patient with Carotid Artery Disease—Terborg C1, Heide G2, Axer H3, Joachimski F4, Ko¨hler S5, Witte OW6 (1Jena; 2Jena; 3Jena; 4Jena; 5 Jena; 6Jena) A 67-year-old male with a history of hypertension, diabetes mellitus, and coronary artery disease suffered from repeated faintings after he got up. His wife reported convulsions of all extremities during fainting and immediate reorientation. On

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admission neurological examination showed mild dysarthria, while medical examination results were normal. MR imaging revealed a small infarct in the borderzone between the territory of the right middle and posterior cerebral artery and a marked hypoperfusion of both hemispheres as compared to the cerebellum. Ultrasonographic studies of the cerebral arteries showed bilateral, 95% stenosis of the internal carotid arteries, low cerebral blood flow velocities of both middle cerebral arteries, and collateral blood flow from vertebrobasilar arteries. During a head-up tilt test with monitoring of ECG, blood pressure, and cerebral blood flow velocities of both middle cerebral arteries, two convulsive syncopes following a marked decrease in systolic blood pressure and blood flow velocities occurred. Diastolic blood pressure and heart rate remained unchanged. In patients with syncope, standard autonomic tests provide the differential diagnosis of orthostatic circulatory disorders. In our patient with bilateral high-grade carotid artery stenosis the correct diagnosis was made by simultaneous monitoring of the blood flow velocities of both middle cerebral arteries, revealing a deep decrease during head-up tilt. Repeated syncopes display a critically decreased cerebral blood flow during orthostasis due to a severely impaired cerebral autoregulation. Transcranial Doppler sonography may supplement standard autonomic tests in patients with syncope even in the presence of carotid artery disease.

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Stroke Treatment with rtPA—Are There any Contraindications?—Terborg C1 (1Jena) In the last two decades therapy with recombinant tissue plasminogen activator has been proved the only treatment option in acute ischemic stroke. However, despite unequivocal evidence of patient’s benefit from randomized trials and implementation of thrombolytic therapy in national and international guidelines, the transmission into clinical practice is poor. Only a minority of patients receive thrombolysis with severe consequences on public health and economic resources. Besides scientific uncertainties about indications and contraindications for rtPA treatment, educational and organizational conditions have to be established. Educational aspects comprise public information and a referral system to centers with expertise in thrombolysis. Information of and waiting for a family doctor has been shown to delay adequate therapy. If a patient is admitted to the hospital, immediate clinical diagnosis and cerebral imaging has to be performed to avoid a delay in therapy. Several questions about thrombolysis have to be answered. Can the time window of 3 h after symptoms onset in some patients be widened to six or more hours? What is the role of modern stroke imaging, can MRI enlarge the indication for therapy with rtPA? Can patients with cerebral microangiopathy and older patients be treated? Should patients be treated despite incomplete symptom recovery? Does sopor after stroke increase the bleeding risk? Do patients with a visible infarction more than 1/3 of the territory of the middle cerebral artery on the first CT scan profit from rtPA? What are the indications for intraarterial thrombolysis and who is better treated intravenously? Although thrombolysis has to be carefully indicated, more patients might receive this treatment.

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A Topodiagnostic Investigation on Lesions Causing Body Lateropulsion in the Absence of Clinical Signs of Vestibular Dysfunction—Tho¨mke F1, Iannetti GD2, Cruccu G3, Fitzek S4, Marx JJ5, Urban PP6, Sto¨ter P7, Dieterich M8, Hopf H9 (1Mainz; 2Rom; 3Rom; 4Jena; 5 Mainz; 6Mainz; 7Mainz; 8Mainz; 9Mainz) Background: Body lateropulsion is often seen in patients with lateral medullary infarctions (LMI) and may occur with or without vestibular nucleus involvement. Whether body lateropulsion in LMI sparing the vestibular nucleus is due to a lesion of the lateral vestibulospinal tract (LVST) or the dorsal spinocerebellar tract (DSCT) is still unclear. Patients and Methods: We retrospectively analyzed the clinical files of a group of 258 consecutive patients presenting with clinical signs and symptoms of acute ischemia in the vertebrobasilar territory for body lateropulsion in the absence of clinical signs of vestibular dysfunction. All patients had magnetic resonance imaging (MRI) with biplane T2- and echo planar diffusion-weighted imaging (EPI-DWI) with slice orientation parallel and perpendicular to slices of the stereotactic anatomical atlas of Schaltenbrand and Wahren. Individual slices were normalized and projected into the corresponding slices of the anatomical atlas. Results: We only identified 10 patients, all with unilateral LMI, who had ipsilesional body lateropulsion as the predominant clinical sign. A comparison of the lesion sites in these patients with the lesion sites in a group of 14 patients with brainstem infarctions at the same level but without body lateropulsion revealed an area midway between the end of the DSCT and the beginning of the lower cerebellar peduncle as the crucial area for the occurrence body lateropulsion. Lesion sites of patients with body lateropulsion without limb ataxia were located more dorsomedial than those of patients with limb ataxia, that were more ventro-lateral. Conclusions: We attributed body lateropulsion without limb ataxia to an impairment of vestibulo-spinal postural control, as the dorso-medial sites of the responsible lesions involved the region of the LVST. Body lateropulsion with limb ataxia more likely reflects impaired or absent proprioceptive information, since lesions in these patients involved the DSCT.

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Lateral Medullary Lesions Involving the Spinal Nucleus of the Trigeminal Nerve may Cause Ipsilesional Masseter Reflex Abnormalities—Tho¨mke F1, Marx JJ2, Mika-Gru¨ttner A3, Fitzek S4, Urban PP5, Stoeter P6, Hopf HC7 (1Mainz, 2Mainz, 3Mainz, 4Jena, 5 Mainz, 6Mainz, 7Mainz) Background: Experimental data indicate a suprasegmental influence on the masseter reflex (MassR), which is mediated via the 5th nerve spinal nucleus. To the best of our knowledge, corresponding data in humans is still lacking. Patients and Methods: We retrospectively analyzed the files of 258 consecutive patients with clinical signs and symptoms of acute ischemia in the vertebrobasilar territory for unilateral infarctions caudal to the levels of the motor and main sensory nucleus of the 5th nerve. Biplane T2- and echo planar diffusion-weighted magnetic resonance imaging with slice orientation parallel and perpendicular to slices of a stereotactic anatomical atlas were done in all patients. Individual slices were normalized and the lesions

were projected into the corresponding slices of the anatomical atlas. Results: We identified 39 patients with unilateral infarctions caudal to the level of the 5th nerve motor and main sensory nucleus. Four of these patients had an abnormal delay and 2 a loss of the MassR on the side of the infarction. In all patients, the infarction involved the region of the 5th nerve spinal nucleus at least on one slice. Conclusions: Our findings indicate that medullary brainstem lesions involving the 5th SpN may cause ipsilesional MassR abnormalities. There is experimental evidence for an excitatory projection from the amygdaloid nucleus via the 5th nerve spinal nucleus to masseter motoneurons in the 5th nerve motor nucleus. An interruption of this pathway at the site of the 5th nerve spinal nucleus would be followed by an impaired excitation of masseter motoneurons, which would explain the MassR abnormalities in our patients.

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MRT-Based Morphometry: Confounding Parameters and Sensitivity of Methods—Tittgemeyer M1, von Cramon DY2 (1Leipzig; 2Leipzig) In neurobiological applications, morphometry aims at a description of brain structure from imaging modalities in terms of size, shape, and texture. Such measures may be evaluated by automated statistical techniques and analyzed together with other clinical and experimental parameters. Thereby, morphometry offers promising approaches for an in vivo characterization of many neurological or psychiatric pathologies. A survey of the recent publications only allusively reflects this attractiveness of MR-based morphometry: published findings are heterogeneous, partly contradictory and not always plausible in terms of known neuropathological correlates. Hence, it is necessary to question the sensitivity of the applied methods. Variations in morphometric measurements can reflect differences in image acquisition and analysis techniques, alterations in neuronal and non-neuronal tissue compartments, physiological alterations in brain tissue, and changes in other chemical constituents that make up the living brain. Furthermore, a sound knowledge about the morphological variability of the normal brain is vital for the assessment of volumetric findings. With this contribution we review the sources of variation that can rapidly produce changes in MR-based morphometric measurements, some of greater magnitude than those reported for a specific neuropathology. In particular, we focus on the error in morphometric measurements determined by the MR scanner, as well as on physiological confounds that create the necessity for a better subject control.

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Somatosensory Evoked Potentials (SEP) in Term Newborns with Perinatal Hypoxic-Ischemic Encephalopathy (HIE)—Borges E1, Wenzel D2, Trollmann R3 (1Erlangen; 2Erlangen; 3Erlangen) Aim: The aim of this work was o evaluate the diagnostic value of somatosensory evoked potentials (SEP) in newborns developing perinatal HIE. Patients and Methods: Our prospective study included ten healthy newborns (postconceptional age 38–41 weeks) and ten asphyxiated infants (postconceptional age 38–42 weeks). Perinatal asphyxia was defined as umbilical artery pH K10 mmol/l and

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development of HIE which was evaluated according to the criteria of Sarnat et al. (1976). SEP were performed at the median chronological age of 8.5 days (controls) and 6.0 days (asphyxia group). Cortical responses were recorded at C 3 0 /C 4 0 against Fz (international 10–20 system) and nuchal responses from the second cervical vertebra against a frontolateral electrode (contralateral to the stimulation; stimulation frequency 1.1 Hz, stimulus duration 100 ms). A 1–3000 Hz filter bandpass with 50 Hz knock-out filter was used. At least two (median: four) recordings were performed. The median number of stimuli was 128. Cortical latency (N20) and central conduction time (CCT, interpeak latency N13-N20) were analyzed for both groups. Results (meanGSD): Seven infants developed severe HIE (stage 2–3). There was no significant difference in the degree of metabolic acidosis between patients with HIE stage 2–3 (pH 7.0G 0.1, BE-18G6 mmol/l) compared to mild HIE (pH 7.0G0.1, BE K17G2 mmol/l). Latencies were significantly prolonged in asphyxiated infants compared to healthy controls: N20, 52.0G 7.0 ms in patients with HIE and 38.3G4.7 ms in healthy newborns (P!0.01); CCT, 40.8G8.0 ms and 28.2G4.8 ms, respectively (P!0.01). There was a trend towards longer latencies in infants with HIE stage 2–3 compared to infants with HIE stage 1. No significant relation between UA pH values and SEP latencies could be found in the HIE group. Conclusions: As shown by our data, SEP during early postnatal period are a useful, non-invasive and practicable additional early diagnostic tool in term newborns developing HIE. Our own reference data were in accordance with reports in the literature.

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Cognitive Function and Educational Achievement in Children with Focal Epilepsy and Long-Term Therapy with Oxcarbazepine—Tzitiridou M1, Panou D2, Pauliduo E3, Panteliadis C4 (1Mu¨nchen; 2Thessaloniki; 3 Thessaloniki; 4Thessaloniki) Purpose: In this study, the cognitive function of patients with simple focal and benign childhood epilepsy with centrotemporal spikes and long-term oxcarbazepine therapy was tested by psychometric tests. Materials and Methods: During the period 1998–2003, we tested 43 patients aged 5 8/12–13 9/12 years (mean age at the onset of the therapy 9 2/12 years) and 45 healthy controls, aged 6–14 years. All of them underwent a complete neurological examination, EEG, brain MRI, psychometric tests (WISC-III, BenderSantucci, Illinois test) before treatment. The reexamination took place after 12 and 24 months of therapy. No important side effects were observed. The EEGs showed focal abnormalities, which depended on the type of the epilepsy. The control EEGs were normal. Results: The psychometric test did not show a statistically significant difference in the intelligence quotient among the patients before the administration of the drug and the controls, which demonstrates the important similarity of the samples. In 6/43 patients and 3/45 controls, learning disabilities were observed. The difficulties were localized in the ability for mathematical thought, logical abstractive thinking, long-term and visual short-term memory. The intelligence quotient was normal. The patient group, examined 10–12 months after drug administration, showed a significant improvement on the ability to logical

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abstractive thinking and verbal comprehension. This small improvement is explained by the cognitive maturation, which is accomplished through each child’s biological development. 24 months after the administration of the therapy an improvement on the long-term memory and visuomotor coordination was observed, which shows that the drug did not influence the ability for longterm acquisition. Conclusion: Our results showed that the cognitive functions, which are directly connected to the children’s performance at school, are not influenced as a rule.

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Does the Shape of the Brain Depend on Gravity?— Ugur T1, Schnaudigel S2, Kruggel F3, Fitzek C4, Mentzel HJ5, Witte OW6, Hagemann G7 (1Jena; 2 Jena; 3Leipzig; 4Jena; 5Jena; 6Jena; 7Jena) The estimation of cerebral atrophy in clinical routine is mostly a visual neuroradiological diagnosis depending on a subjective comparison of the cerebrospinal fluid (CSF) space relative to the brain tissue and size of the ventricles. With neuroimaging brain atrophy appears to be accentuated in the frontal lobe regions. This holds true for normal ageing and even more so in most neurodegenerative processes. This finding might be overestimated because of a brain shift caused by position-dependent gravitational influences in the scanner. MRIbased quantitative morphometric techniques like the Brain Image Analysis (BRIAN, MPI/Leipzig) are able to detect intraindividual changes by a three-dimensional matching of images. This pilot study tried to detect subtle intracranial brain movements relative to the skull and deformations of the brain depending on the position of the head in the scanner. A 1.5 T Siemens MRI scanner was used to obtain 3D T1-weighted MRI images. Image analysis was carried out with the BRIAN tool. Consecutive MRI scans of 2 healthy female participants (age: 25, 62 years) were taken in supine, lateral and prone positions. The image quality did not differ with positioning. In a preliminary analysis, distances between defined intracerebral landmarks like the anterior commissure and defined landmarks of extracerebral structures were measured. In order to assess more complex deformations, a non-rigid image registration was applied. The linear analysis revealed no tissue movements relative to gravity. However non-rigid image registration showed subtle cortical deformation in the frontal and occipital regions. The deformations could not be described by a single main vector and, therefore, it is doubtful whether these changes can be attributed to the influence of gravity. This study demonstrates that acquisition of high quality MRI is possible irrespective of the position of the subject in the scanner. The present preliminarily findings suggest that the position of the brain in the skull and the shape of the brain do not grobly depend on gravitational influences. This might result from mechanical obstacles posed by rigid structures like the sinuses, the cerebellar tentorium or the falx. A voxel-based analysis, however, revealed subtle deformations which have to be analyzed further. At present it is unclear whether more pronounced effects would be visible, e.g., with longer intervals between position changes.

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To Reveal the Impact of a Constant Current Repetitive Electrical Epidural Stimulation on Regeneration of the Contused Rat Spinal Cord—Ullrich R1, Wedekind C2, Klug N3 (1Ko¨ln; 2Ko¨ln; 3Ko¨ln) Background: Does repetitive electrical stimulation promote recovery of the rat contused spinal cord? Study Design: an experimental rat model of spinal cord contusion with subsequent therapeutic intervention was usedto reveal the impact of a constant current repetitive electrical epidural stimulation on the regeneration of the contused rat spinal cord. Experiments were performed in the animal laboratory of a University Neurosurgical Department. Methods: Male Sprague–Dawley rats were anesthesized with nembutal applied intraperitoneally and underwent laminectomy at Th 8. The spinal cord was then lesioned by graded epidural compression. Motor and somatosensory evoked potentials from the hind limbs as well as F waves from the sciatic nerves were recorded before and after lesioning of the cord. After that, a stimulation unit was inserted subcutaneously and stimulating electrodes were placed epidurally. The stimuli applied were constant current (14 mA) monophasic pulses at 8 Hz in the treatment group. A control group received an inactive stimulator. The animals were followed clinically and electrophysiologically for a survival period of 3 and 50 days. Results: No significant differences were seen when comparing both groups either with regard to functional outcome or with respect to the electrophysiological results. Clinical testing revealed recovery of hindlimb function from a mean Basso–Beattie– Bresnahan-/Inclined plane test-score of 6.7/3.8 on day 1 to 9.7/4.6 on day 3 and finally to 17/7.6 on day 50. This was accompanied by a significant increase in F-wave amplitudes whereas amplitudes of somatosensory and motor evoked potentials remained significantly depressed. Conclusions: Constant current repetitive epidural stimulation does not enhance functional or electrophysiological recovery in rats after acute spinal cord injury.

Timing of Task-Set Reconfiguration in Frontal and Parietal Cortices—Ullsperger M1, Brass M2, Kno¨sche T3, Phillips NA4 (1Leipzig; 2Leipzig; 3Leipzig; 4Montreal, Quebec) Neuroimaging studies have shown that the inferior frontal junction area (IFJ, near the junction of inferior frontal and inferior precentral sulci) and the intraparietal sulcus are involved in task preparation. Theories based on animal research have assumed that the contribution of the prefrontal cortex is to bias processing in posterior brain regions. If this assumption holds true, one would expect prefrontal cortex activation preceding parietal activation. The present study tested this assumption by combining results from functional magnetic resonance imaging (fMRI) providing high spatial resolution and event-related potentials (ERP) to gain high temporal resolution. We collected ERP data in 19 participants performing a modified task-switching paradigm. In most trials two task cues with a preparation interval in between were presented before the task stimuli. Assigning two different cues to each task enabled us to isolate task-set reconfiguration in the preparation interval. This process was associated with a midline negative ERP deflection peaking around 470 ms after presentation of the task cue. We placed dipoles in regions activated in a previous fMRI study that used the same paradigm (left IFJ, right inferior frontal,

right parietal) and fitted their directions and magnitudes to the ERP effect. The frontal dipoles contributed to the ERP effect earlier than the parietal dipole, providing support for the view that the prefrontal cortex is involved in updating of general task representations and biases relevant stimulus response associations in the parietal cortex.

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Gamma Knife Thalamotomy and Pallidotomy in Medically Intractable Parkinsonian Tremor—Unger F1, Schro¨ttner O2, Unger B3, Bone G4 (1Graz; 2Graz; 3 Graz; 4Graz) Objective: Six patients with advanced Parkinson’s disease (PD) underwent gamma knife radiosurgical procedures between October 1992 and September 1998. Methods: Four patients underwent thalamotomy, one patient was treated with pallidotomy. One patient received caudatotomy and thalamotomy. One woman and 5 men aged between 52 and 84 years (median 68 years) were followed-up over a period between 12 and 82 months (median 49 months) with MR and neurological means (UPDRS). Results: Of the four patients with thalamotomy three showed a good response while one remained stable [Unified Parkinson’s Disease Rating Scale (UPDRS) improvement, off-drug-phase, motor score: 21%]. Ameliorated were the one with combined thalamotomy and caudatotomy (UPDRS: 9%) as well as the patient with pallidotomy (UPDRS: 15%). Severe side effects and complications were not noted, transient effects included one patient with swallowing problems and one with a paraparesis. Neuropsychological testing revealed no treatment morbidity. Conclusion: Gamma knife radiosurgery offers an interesting alternative to other stereotactical procedures with low morbidity and no mortality to a selected group of patients. Thalamotomy (VOA/VIM) for tremor may be a useful treatment for patients at high risk for surgery. More experience is needed before we can make a conclusive judgement.

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Stereotactic Radiosurgery for Hypothalamic Hamartoma—Unger F1, Schro¨ttner O2, Feichtinger M3 (1Graz; 2Graz; 3Graz) Hypothalamic hamartoma are non-neoplastic lesions often characterized by central precocious puberty and gelastic epilepsy. Due to their delicate location, surgery is often unsuccessful and associated with considerable risks. In the presented series, Gamma knife radiosurgery was applied. Four cases (aged between 5 and 13 years) who presented with medically intractable gelastic epilepsy and increasing secondary generalization, abnormal behaviour and precocious puberty (3 cases) are reported. Hypothalamic hamartomas 11–17 mm in size had been diagnosed by MR imaging. Radiosurgical treatment was performed in general anaesthesia with margin doses of 12–14 Gy to the 50–90% isodoses covering volumes of 600–2300 mm3. After follow-up periods of 12 to 68 months, a continuing decrease both in seizure frequency and intensity was noted [outcome according to Engel: II a (3 cases) and III a (1 case)]. All patients are socially reintegrated. MR imaging did not reveal significant changes concerning the size of the lesions. Gamma knife radiosurgery can be an effective and safe alternative treatment modality for HH and is capable of achieving

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good seizure control and improving behavioural disorders in selected cases.

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Cortical Gene Expression after Spreading Depression—Urbach A1, Bru¨hl C2, Divanach A3, Witte OW4 (1Jena; 2Jena; 3Jena; 4Jena) Cortical spreading depression (SD) plays an important role during migraine aura and stroke. In focal cerebral ischemia, peri-infarct depolarizations (PD), a phenomenon consistent with SD in normal brain, cause expansion of the infarct size within the ischemic penumbra. Otherwise, preconditioning with SD can modulate the outcome of an ischemic injury: when SD occurs more than a day before ischemia, injury is reduced. A number of previous studies showed that gene expression changed after experimentally induced stroke. The aim of this study was to investigate the impact of SDs on the pathophysiological processes after ischemic brain injury at the gene expression level. 7G2 repetitive SDs were induced in rat occipital cortex by topical application of 3 M KCl. Control animals were treated with 3 M NaCl which does not induce SDs. Gene expression has been analyzed in ipsilateral hindlimb cortex 3 h, 24 h, 7 d and 30 d after first KCl/NaCl application using Affymetrix RAE230 arrays. Time-dependent gene expression profiles showed highest differential gene expression at 3 h, decreasing successively at later time points. Some of the 3 h and 24 h data are in agreement with previously published PCR studies of single genes after SD and studies concerning post-stroke gene expression changes: among others immediate early genes, genes for neurotrophic factors and their receptors, stress response proteins and genes involved in inflammatory response are regulated. Surprisingly, we found various genes that are differently expressed 30 d after SD, indicating an influence of PD on delayed processes in non-infarcted ipsilateral cortex. At present the impact of this late differential gene expression is ambiguous. Nevertheless, one possible mechanism may be an influence on cortical reorganization. For further evaluation of the microarray data a representative selection of genes will be verified by real-time RT-PCR.

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Absence of Muscle Spindles in Human Facial Muscles—Urban PP1, Bohl J2, Abrao L3, Stofft E4 (1Mainz; 2Mainz; 3Mainz; 4Mainz) Background: It has not previously been clarified if human facial muscles possess either typical muscle spindles, spindle-like structures or no spindles at all. Methods: Six patients from the Institute of Anatomy were used to investigate the Mm. orbiculares oculi and orbiculares oris. The age ranged from 53 to 91 years; three were males, three females. The specimens were imbedded in paraffin and examined in serial sections. Muscles were prepared for histological (HandE and Elastica van Gieson) and immunohistochemical (protein S-100, neurofilaments, and PGP 9.5) stainings. Results: All biopsies showed skeletal muscle fibers with some discrete alterations according to age. In some regions there were many small peripheral nerve fibers in close vicinity to muscle; but spindle-like structures with intrafusal fibers could not be detected. There were no signs of a sensorimotor double innervation of striated muscle fibers.

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Discussion: Previous investigators came to conflicting results regarding the absence or presence of muscle spindles in human facial muscles. However, in previous studies serial sections and immunohistochemical investigations had not been performed. Our observation of lacking muscle spindles in the facial muscles has several clinical and neurophysiological implications: (1) Pathological central muscle spindle afferent processing is assumed in the pathophysiology of dystonia. Although botulinum toxin leads to a denervation of muscle spindles its effect in the treatment of facial dystonias cannot be related to that. (2) A central facial paresis shows no signs of spasticity even in the chronic stage. Spasticity results in part from abnormal spinal processing of proprioceptive input mediated by Ia afferents. Thus, the absence of muscle spindles in the facial muscles may explain the lack of spasticity in these muscles. (3) In contrast to limb muscles, electrical facial and trigeminal nerve stimulations do not evoke silent periods and facial muscles show no facilitation of magnetic evoked potentials by vibration stimuli. Both phenomena are mediated by Ia afferents and their absence can be explained by the lack of muscle spindles.

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Breathing and Swallowing Pattern Abnormalities in Multiple Sclerosis—Urban PP1, Zahn M2, Schranz S3, Rolke R4, Glassl O5, Pittermann P6, Dieterich M7 (1Mainz; 2Mainz; 3Mainz; 4Mainz; 5Mainz; 6Mainz; 7 Mainz) Background: Recent data suggest a high prevalence of dysphagia and recurrent aspiration in moderately and severely disabled multiple sclerosis patients. Methods: The study participants included 60 healthy subjects, median age 47 years and 20 moderately to severe disabled patients with multiple sclerosis, presenting with a median EDSS of 5.75 (median age 48 years). A 2-channel computer-assisted system was used to obtain concurrent respiratory and submental surface electromyography signals. Subjects were seated in an upright position and asked to swallow boluses of 5, 10 and 25 ml water and 5 ml applesauce presented in random order. Eight swallows of each bolus volume and viscosity were recorded. For each swallow, (1) the latency between the onset of swallowing and swallowing apnea (SA); (2) the duration of each SA; (3) the duration of the submental activity, and (4) the pattern of breathing before and after each SA was evaluated. Results: In healthy subjects and patients a total of 2.560 swallows was performed. The latencies between the onset of swallowing and SA were significantly reduced in MS patients. In the patient group the durations of SA and submental activity were significantly prolonged (ANOVA, P!0.001) at all bolus volumes and correlated significantly (rZ0.76, P!0.0001). Expiration/inspiration before SA occurred in healthy subjects in 87.3%/12.7% and in patients in 89.4%/10.6% (n.s.). Expiration/inspiration after SA occurred in healthy subjects in 98.9%/1.1% and in patients in 93.0%/7.0% (P!0.0001). The difference was highly significant at all bolus volumes and viscosities. Conclusion: Our study confirms that the great majority of swallowing apneas in healthy subjects are followed by expiration. However, in multiple sclerosis patients the SA is followed by inspiration more frequently than expected which might increase the risk of aspiration or laryngeal penetration. Furthermore, the durations of SA and submental swallowing activity are

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significantly increased. The prolonged SA duration most probable reflects a protective mechanism owing to the prolonged swallowing activity in multiple sclerosis patients. Our findings indicate a disturbed temporal coordination between respiration and swallowing in multiple sclerosis patients.

research has been done in amyotrophic lateral sclerosis and in infarction patients. The latter is particularly striking since the utility of this method for assessing residual capacities of affected motor areas seems rather obvious.

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Trigemino-Hypoglossal Silent Period—A New Pontomedullary Brainstem Reflex—Urban PP1, Pittermann P2, Kirchhoff I3, Wahlmann U4 (1Mainz; 2Mainz; 3 Mainz; 4Mainz) Introduction: Inhibitory connections between neurons of the sensory trigeminal nucleus and the hypoglossal nucleus have been described in the cat (Tomioka et al., 1999). We investigated if these inhibitory pontomedullary projections are also present in man by applying a newly developed stimulation and recording technique. Methods: In a preliminary study we examined 14 healthy subjects (9 males, 5 females, age: 42G13 years) with a specially designed enoral stimulation and recording device. The device allowed unilateral electrical stimulation of the trigeminal (V2) innervated palatal mucosa and simultaneous recording of the electromyographic activity from both halves of the tongue using surface electrodes. The stimulation intensity was at least 5-fold the perception threshold and was increased up to a maximum of 20 mA. During stimulation the subject pressed his/her tongue against the recording device. Five recordings were registered and the electromyographic activity was averaged and rectified. Results: The examination was well tolerated by all subjects without adverse events. In all subjects we observed one bilateral suppression period of tongue muscle activity following unilateral electrical stimulation of the mucosal V2 afferents. The silent period started at 41.1G4.7 ms and ended at 82.4G12.5 ms. The mean duration of the silent period was 41.4G10.2 ms. Conclusion: Analogously to animal studies, we demonstrated that inhibitory pontomedullary projections between sensory neurons of the enoral endings of the 2nd trigeminal nerve and hypoglossal neurons are also present in man. The silent period was bilaterally organized and showed, in contrast to the exteroceptive suppression of masseter muscle activity, only one suppression period. The trigemino-hypoglossal silent period is most probably a nociceptive protection reflex and further investigations in patients with defined brainstem lesions have to clarify its diagnostic relevance.

Malfunctions of Central Control of Movement Studied with Slow Brain Potentials in Neurological Patients— Verleger R1 (1Lu¨beck) Studies are reviewed that used movement-related EEG potentials to investigate impairments of movement control in neurological patients. The EEG potentials reviewed are the Bereitschaftspotential (BP), contingent negative variation (CNV), and components of the lateralized readiness potential (LRP). Patient groups included in this review are patients with infarction of the middle cerebral artery, Parkinson’s disease, cerebellar disease, and amyotrophic lateral sclerosis. A rich body of evidence has been collected on Parkinson’s disease, and somewhat less on cerebellar atrophy, contributing to an understanding of the impairments caused by these diseases. In contrast, not much

Antibodies in Myasthenia Gravis and Related Disorders—Vincent A1 (1Oxford) Myasthenia gravis (MG) is caused in the majority of cases by circulating autoantibodies to the nicotinic muscle acetylcholine receptor (AChR). Several studies have now documented a higher incidence of AChR-positive MG in both men and women over age 60 years than among younger individuals (Vincent et al. JNNP in press). Since MG can be misdiagnosed as stroke or motor neuron disease in the elderly, it is likely that there is considerable underdiagnosis of MG in this age group. Fetal AChR antibodies and arthrogryposis maternal antibodies to the fetal isoform of the AChR are found in rare cases of arthrogryposis multiplex congenital. They cross the placenta and cause paralysis in the developing fetus leading to joint contractures and other deformities. Seronegative myasthenia gravis antibodies to AChRs are present in about 85% of patients with generalized disease. Antibodies to the muscle specific receptor tyrosine kinase, MuSK, are found in 0–70% of SNMG patients; those with MuSK antibodies often present with predominant ocular and bulbar weakness, or neck extensor weakness, and may be more difficult to treat effectively with conventional immunosuppression (Vincent et al. Lancet Reviews Neurology 2002). Plasma or serum from SNMG patients may also inhibit the function of AChR expressed on TE671 cells, or on the subline that expresses adult AChRs. The effect appears to be indirect, perhaps acting on another muscle surface receptor that activates a second messenger system leading to reduced AChR function. This plasma factor is not an IgG and co-purifies with IgM (Plested et al. Neurology 2002), and its target is unknown. Voltage-gated ion channels and CNS disease antibodies to the voltage-gated calcium and potassium channels are found in Lambert Eaton myasthenic syndrome and acquired neuromyotonia, respectively. Recently, we have detected very high levels of VGKC antibodies in an increasing number of patients with ‘limbic’ encephalitis. Many do not have evidence of peripheral neuromuscular involvement but show high signal intensity in the temporal lobe(s), seizure activity and low plasma sodium levels. These patients, who typically do not have an associated tumor, may do well after long-term immunosuppression (Vincent et al. Brain 2004).

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Explorative Analysis of fMRI Data: Why Functional PCA should Usually be Preferred to ICA—Viviani R1, Groen G2, Walter H3 (1Ulm; 2Ulm; 3Ulm) Independent component analysis (ICA [1]) has been proposed as an exploratory technique for fMRI data. Unfortunately ICA generates many components with little information about how to select from them. Here we propose a new technique, functional PCA, to retrieve the signal associated to the experimental paradigm in an explorative setting. ICA posits a linear model in which the observed images Y (each column being an image) are linear combinations M of independent non-Gaussian signal sources P: YZMP The distributional nature of ICA’s assumptions makes it

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an excellent explorative technique in general. However, its application to fMRI time series is problematic since the omission of an error term appears inappropriate in this context. A large number of ICA components will be generated out of noise. Furthermore, there is certainly some dependency between fMRI signals sampled at adjacent time points. While this latter point does not invalidate the ICA model, it points to an aspect of the data that is missing from its assumption set. If we can assume that the signal of interest is relatively ‘smooth’, it is appropriate to attempt to separate the signal from undesired high-frequency variance by carrying out a penalty fit voxel-by-voxel with the amount of penalty estimated through generalized cross-validation [2]. This corresponds to a model of the form Y 0 ZXP 0 CE 0 where each column of X is a smooth eigenfunction, each row of P 0 is a component image, and E 0 is a rough error term. Functional PCA exploits advanced techniques to carry out the eigenanalysis directly on the fitted functions [3], harnessing the information implicit in the smoothness assumption to pull out the signal of interest and place it in the first few components. Fig. 1, left shows the screenplot of the PCA on an fMRI dataset generated in a twoback working memory task in a 6-blocks design [4], indicating that only one component can be considered a genuine signal. On the right, the image of the component loading on the left DLPFC. Fig. 2 shows the eigenfunctions retrieved in 11 datasets obtained with the same task. In 10 datasets the first eigenfunction retrieved the experimental signal, in 1 dataset the second eigenfunction. References McKeown et al. Human Br Mapping 1998; 6:160–188. Wahba Spline Models for Observational Data. Philadelphia: SIAM, 1990. Ramsay and Silverman Functional Data Analysis. Berlin: Springer, 1997. Walter et al. Cortex 2003; 39: 897–911.

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Preoperative Visualization of Cortical Veins by 3D Reconstruction of Magnetic Resonance Images (MRI): Correlation with Intraoperative Findings—Vollmar C1, Jordan N2, Winkler PA3, Pfluger T4, Noachtar S5 (1Mu¨nchen; 2Mu¨nchen; 3Mu¨nchen; 4Mu¨ nchen; 5 Mu¨nchen) The topography of the superficial cortical veins shows a high interindividual variation. Brain pathologies may cause additional displacement. We aimed to preoperatively visualize the exact anatomic localization of the veins with regards to the lesion and the planned neurosurgical resections. We included 23 patients with MRI-documented brain lesions in the study. Structural MRI (1.5 T) was acquired with a slice thickness of 1.2 mm and an in-plane resolution of 1.0 mm. In addition, contrast-enhanced venous MRA was recorded using 64 slices with 2 mm thickness. Interactive image registration of both datasets was performed on a Picker voxelQ workstation. Manual segmentation of the brain was done prior to 3D reconstruction of the combined dataset using volume rendering techniques. Digital intraoperative photographs were acquired and all surgically relevant veins were identified by the neurosurgeon. Semitransparent superimposition of photographs and 3D reconstructions was used to evaluate the quality of the preoperative reconstructions. The spatial accuracy of the image registration procedure was 0.8 mm. Preoperative 3D image processing correctly visualized 78.2% of the surgically relevant veins. Intraoperatively documented veins were missed in 11.7% by the 3D images. False positive findings in 3D images occurred in

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4.5% and in 2.2% arterial vessels were mistaken as veins. The preoperative visualization of cortical veins via MRI and MRA is an accurate and reliable method, which helps to plan and modify cortical resections.

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Pseudo Learning and Real Learning and its Contributions to the Posterior Frontomedian Cortex (pFMC)—Volz KG1, Schubotz RI2, von Cramon DY3 (1Leipzig; 2Leipzig; 3Leipzig) The posterior frontomedian cortex (pFMC) was identified as being involved in decision conflict due to knowledge deficits (Volz et al., 2004a). The present study used functional magnetic resonance imaging (fMRI) to investigate if activation within the pFMC is reduced only by increasing knowledge (real learning, RL) , or also by increasing the frequency of positive feedback without any gain in knowledge (pseudo learning, PL). In a simple forcedchoice paradigm participants were naive about valid decision rules and asked to search for valid ones. In the RL condition participants were provided with valid feedback information, in contrast to the PL condition. Here, a pseudo learning effect was simulated by gradually increasing positive feedback according to a learning model that was derived from pilot data. Functional MRI data showed that both RL and PL in contrast to an absolute certain decision in a control task resulted in significant activation within the pFMC, the inferior frontal junction area, precuneus, intraparietal sulcus, and cerebellum. A significant increase in the BOLD response within the pFMC was also observed when directly contrasting pseudo learning trials with real learning trials, when contrasting negative feedback trials with positive feedback trials in the real learning condition, and when testing for the interaction learning task (PL, RL) by feedback quality (positive, negative). By employing a condition which controlled for feedback confidence, it was assured that differences in pFMC activation were not misleadingly attributed in this respect. Based on the present results, we suggest pFMC activation to reflect the subjective experience of uncertainty regardless of the objective feedback information. Moreover, we conclude that uncertainty in decision making is modulated by the experienced status of knowledge rather than by the amount of positive outcomes.

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Constraint-Induced Movement Therapy (Taub’s Training) for Stroke Patients with Pareses of Different Severity Levels—Vorwerk L1, Miltner WHR2, Liesbisch U3, Taub E4 (1Jena; 2Jena; 3Jena; 4Birmingham) The ‘Constraint-Induced Movement Therapy’ is a therapy to treat motoric disorders caused by stroke or other brain damages. It is a behaviorally oriented program, which is based on the principles of learning psychology. The theoretical background of the therapy is described in a theory called ‘Learned Nonuse’. It assumes, that a part of the motoric disablement of stroke patients is not caused by the neurological damage but can be ascribed to a conditioned suppression of behavior. The aim of the therapy is therefore to overcome the ‘Learned Nonuse’ and to transfer the motoric skills, which have been reacquired through the training, in everyday life. In total, 64 patients who suffered from motoric impairment of the upper extremity after stroke have been examined. Depending on the degree of the motoric impairment, patients were divided into a

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group called ‘less strongly affected’ and a group called ‘strongly affected’. The assignment to the two groups took place after selfdefined criteria. The training took place over a period of 10 (‘less strongly affected’) up to 12 (‘strongly affected’) training sessions with a daily training time of about 5 h. During this time, patients had to accomplish various exercises, which had to be conducted solely by the affected extremity. At the same time, movements of the unaffected upper extremity were impeded through the wearing of a splint combined with a loop. This device ensured that the patients also had to use the paralyzed extremity in everyday life in order to conduct motoric actions. Before and after the training intense neuropsychological and motoric diagnostics took place, which were specifically adjusted to the two groups of patients. Results of this diagnostic examination show that the therapy brought about (not only during the training situation itself but also during the accomplishment of everyday tasks) an enhancement of movement quality as well as a heightened use of the paralyzed extremity.

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Source Reconstruction of Evoked Cortical Activity using Current Density Reconstruction within Realistically Shaped Head Models—Waberski TD1, Buchner H2 (1Aachen; 2Recklinghausen) It is well known that source reconstruction techniques based on EEG or MEG data are inferior to fMRI in respect to spatial resolution, but superior concerning the temporal resolution. The present contribution aims to demonstrate the power of modern source reconstruction techniques using standardized, realistically shaped volume conductor models in the spatio-temporal analysis of evoked potentials. A standardized approach of current density reconstruction within a volume conductor model derived from the so-called Montreal wharp brain as implemented in the SPM software will be demonstrated. This approach has the possibility to consider a priori source information, i.e., from functional MRI, to focus the source reconstruction results in respect to the source locations. Using this method, the following exemplary work on source localization and the temporal dynamics of evoked potentials will be demonstrated. The attention effects on median nerve SEP localizes at the contralateral S1 cortex, bilateral temporal, the cingulum and the left parietal cortex. Changes in the electrical activity induced by attention were shown to begin earlier than 100 ms post stimulus. Source reconstruction of the auditory mismatch negativity (MMN) revealed a cingulate source and bilateral temporal generators underlying the MMN. Temporal analysis showed that source activity started at around 130 ms post stimulus within the bilateral temporal gyrus followed by source activity within the cingulum peaking at 220 ms. Source reconstruction of the cortical activity during line bisection judgement revealed 5 source regions, corresponding to those evaluated by a previous fMRI study: right middle occipital gyrus, right superior posterior parietal cortex; bilateral inferior occipital gyrus, and right inferior posterior parietal cortex. Temporal deconvolution presented a sequential activation of these areas starting at the primary visual cortex, followed by the right superior posterior parietal, bilateral inferior occipital cortex and right inferior parietal cortex. In the identification of a network processing spontaneous perceptive reversals of the rotating Necker cube we find support for synchronized neuronal

oscillatory activity in the correlation between visual area V3 and left SMA. In summary, the presented work demonstrates the applicability of analyzing EEG data in actual clinical neurophysiology for ‘functional imaging’ and timing within complex networks of cortical activation.

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Planning Abilities and Prefrontal Cortex: A Parametric efMRI Study with Tower-of-London Task— Wagner G1, Schlo¨sser R2, Sinsel E3, Labadie C4, Mentzel HJ5, Krause W6, Sauer H7 (1Jena; 2Jena; 3 Jena; 4Jena; 5Jena; 6Jena; 7Jena) Objective: Planning abilities are essential for human life, because most of everyday life activities require a coordinated and planful behavior. Patients with damage to the frontal lobes often show noticeable difficulties in the management of everyday situations. Results of previous studies investigating planning abilities with neuroimaging methods were mixed concerning functional dissociation of specific areas within frontal cortex. There are indications that dorsolateral (DLPFC; BA 9/46) and rostrolateral prefrontal cortex (RLPFC; BA 10) are specifically involved in planning (Christoff and Gabriele, 2000). The aim of this study was to differentiate their function. For that purpose we used the Tower-of-London task (TOL) that was often applied to detect frontal impairments. Methods: 17 right-handed healthy subject, 9 men and 8 women, participated in this event-related fMRI study. The TOL task was presented in a pseudo-randomized order and was parametrically varied over the number of moves to plan ahead. To control for irrelevant activations two control conditions were presented, which were matched for the length of single events in the TOL task. For image processing and statistical analyses we used SPM99 and ROI approach. All statistics were corrected for multiple comparisons (PZ0.05). Results: In the categorical contrasts TOL specific activations resulted bilaterally in DLPFC (BA 9/46), in the right VLPFC (BA 47), in the left RLPFC (BA 10) and thalamus, bilaterally in parietal (BA 7, 40) and in premotor cortex (BA 6, 8). Complexity dependent analyses revealed that only the left RLPFC showed a BOLD-signal increase over the four planning levels, which could not be observed in control conditions. Conclusions: The current study provides for a clearer functional differentiation of the prefrontal cortex. With the use of a parametrical event-related fMRI design we have shown that the left RLPFC plays a crucial role for planning abilities. Supported by the German BMBF FKZ01ZZ0105, TMWFK B30701–015/-016, IZKF grants.

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Comparison of Quantified Ipsilateral and Contralateral Head Movements in Patients with Frontal and Temporal Lobe Epilepsies—Wagner P1, Cunha J2, Mauerer C3, Vollmar C4, Feddersen B5, Noachtar S6 (1 Mu¨nchen; 2Mu¨nchen; 3Mu¨nchen; 4Mu¨nchen; 5 Mu¨nchen; 6Mu¨nchen) We have attempted to compare the lateralizing significance of ipsilateral and contralateral head movements during seizures in patients with frontal (FLE) and temporal lobe epilepsy (TLE). We

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inlcuded only EEG and video recorded seizures (nZ45) of patients with temporal lobe (nZ18) and frontal lobe epilepsies (nZ16) considered for resective epilepsy surgery, in whom the camera position was perpendicular to the head facing the camera in an upright position. FLE and TLE were diagnosed based on neuroimaging (MRI, PET, ictal SPECT), and interictal and ictal EEG. Head turning in a reaction to outside stimuli was excluded. Ipsi- and contralateral head versions were defined according to the side of ictal EEG seizure patterns. Head movements were quantified for speed analysis on the videos by selecting the movement of the nose in relation to a defined point on the trunk (25/s) in the inner 908 angle facing the camera. The analysis of the duration was independent of the camera angle. The angular speed, the duration of the movements, and the duration from seizure onset to occurrence of the ipsilateral and contralateral head movements were computed (Mann–Whitney test). Ipsilateral head movement was always preceding contralateral head movement in FLE and TLE. Contralateral head movement occurred significantly earlier in FLE (median 5 sG7.4) than in TLE (median 20 sG16.3) (P! 0.001), whereas ipsilateral head movement occurred similarly early in the seizure evolution in FLE (2 sG5.8) and TLE (3.5 sG 14.2). The duration of the contralateral head movement was significantly longer in TLE (7 sG3.1) than in FLE (4 sG2.3) (P! 0.01). The angular speed of the ipsilateral (7.9 deg/sG8.3 vs. 10.3deg/sG11.5) and contralateral (9.9deg/sG6.6 vs. 11.8deg/sG 9.1) head movements was similar in TLE and FLE. The quantitative analysis of ipsilateral and contralateral head movements shows differences in the movement characteristics and seizure evolution, which provide helpful information for the differentiation of patients with frontal and temporal lobe epilepsies considered for resective epilepsy surgery.

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Cutaneous Sympathetic Vasoconstrictor Function in Multiple System Atrophy and Parkinson’s Disease— Wasner G1, Remien P2, Guballa C3, Hirschner M4, Binder A5, Schattschneider J6, Deuschl G7, Baron R8 (1Kiel; 2Kiel; 3Kiel; 4Kiel; 5Kiel; 6Kiel; 7Kiel; 8Kiel) Introduction: Autonomic disturbances are common features in Parkinson’s disease (PD) and multiple system atrophy (MSA). Innervation of cutaneous vessels by vasoconstrictor neurons is an important pathway of the sympathetic nervous system. It is unclear to what extent this autonomic channel is involved in the two disorders. The aim of this study was to investigate the function of cutaneous sympathetic vasoconstrictor neurons in PD and MSA. To answer the question whether the investigation may be useful as a diagnostic test to distinguish between PD and MSA, the results were compared with the established head-up tilt testing. Methods: The study was performed on 34 patients with PD and on 15 patients with MSA. All patients underwent two different autonomic tests: (1) Head-up tilt-testing was applied as a marker for sympathetic muscle vasoconstrictor outflow. (2) Skin vasoconstrictor test was performed to investigate cutaneous sympathetic activity: skin blood flow was measured with laser Doppler flowmetry during deep inspiratory gasps leading to a vasoconstriction due to activation of sympathetic vasoconstrictor neurones. Results: Orthostatic hypotension defined as a decrease in systolic blood pressure by 20 mm Hg or/and diastolic blood pressure of 10 mm Hg after 3 min of 708 head-up tilting was found in 58% of MSA and 38% of PD patients (P!0.02). A

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disturbed cutaneous sympathetic vasoconstriction in comparison to healthy controls was found in 62% of MSA and 32% of PD patients (P!0.02). Conclusions: The function of sympathetic skin vasoconstrictor neurons was disturbed in about 2/3 of MSA and about 1/3 of PD patients. These results were similar to autonomic failure detected by the head-up tilt testing. The skin vasoconstrictor-test seems to be useful to investigate involvement of cutaneous sympathetic outflow. Supported by the Deutsche Forschungsgemeinschaft (DFG Ba 1921/1-3).

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Combined EEG/fMRI Recordings in Sleep Research— Wehrle R1, Czisch M2, Kaufmann C3, Wetter TC4, Auer DP5, Pollmaecher T6 (1Mu¨nchen; 2Mu¨nchen; 3 Mu¨nchen; 4Mu¨nchen; 5Mu¨nchen; 6Mu¨nchen) Regional activity in the brain and the ability to react to external stimuli undergo fundamental changes during sleep as compared to wakefulness. Most studies so far have used single cell recordings or evoked potentials to uncover these vigilance-dependent alterations. A new and challenging approach is provided by functional magnetic resonance imaging (fMRI). When necessary precautions for patient’s safety are guaranteed, these advanced techniques can be combined with simultaneous electrophysiological recordings like EEG, EOG and EMG, and allow for the noninvasive study of ongoing activity changes in intact brain networks. Our studies targeted the alterations in regional brain activation upon acoustic stimulation across all sleep stages. As thalamocortical connections are vital for processing information from the outside world, and are known to exhibit specific sleeprelated activity changes, we specifically explored these regional activation patterns and the corresponding functional connectivities. Combined fMRI and EEG studies were performed with 12 healthy subjects (6 m/6 f, mean age: 24.5 years). After positioning of the MR compatible electrodes for sleep recording, fMRI sessions of up to 4 h starting after 23:00 h onwards were performed at 1.5 T (GE Signa Echospeed). For fMRI a multi-slice EPI sequence (7 slices, TRZ3 s) parallel to the AC-PC line was used. Once sleep was established according to online polysomnography for at least one minute, scans with additional acoustic stimuli presented in a block design fashion (3 on, 4 off periods of 30 s each) were started. The sleep recordings were postprocessed using an offline artefact correction. Functional MRI experiments were analyzed using SPM99. Compared to classical fMRI signal increases related to stimulus processing during wakefulness, a negative BOLD response upon stimulation is disclosed in different sleep stages in human subjects. The simultaneous EEG data allow us to draw conclusions about changes in sleep stage microstructure and concomitant signal changes in the imaging data, revealing network activity and synchronizations specific for some sleep stages. Making use of the simultaneous recordings, the strong influence of sleep microstructure on fMRI signal changes is demonstrated. Supported by DFG (WE 2250/6–1).

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Topographic Plasticity of Language Sites across Time—Weinert DM 1, Kraus E2, Gottwald B3 (1Plauen; 2Plauen; 3Kiel) Convincing evidence of individual variability in location of language exists from intraoperative cortical stimulation results

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during awake craniotomies in patients with lesions in eloquent areas. However, little information is available about whether the localization of these areas is stable over time or if plastic changes allow a topographic shift of the functional units in the adult brain. The purpose of this investigation was to find out whether the localization of language-associated areas in the inferior frontal gyrus was reproducible in a 23-year-old, right-handed man who presented with a history of febrile seizures and was diagnosed with CT and MRI scans suggesting a left temporal low-grade astrocytoma. Neurological examination was normal. Surgery and reoperation for recurrence 4 years later was performed in local anesthesia with a bone flap of 2.5 cm in diameter to expose the superior temporal gyrus and the perisylvian cortex of the fontal lobe. Brain mapping techniques involved cortical stimulation, electrocorticography for detecting after discharges during stimulation and simultaneous neuropsychological testing including object naming, reading and free talking and the retrieval of newly learnt material. Using a constant-current stimulus isolation unit connected to a bipolar electrode with the tips 2 mm apart stimulation was performed systematically, starting at low current flows and increasing the current up to 20 mA (50 Hz, 0.2 ms). In the first operation reversible speech arrest or slowing of speech during stimulation could be provoked in only two circumscribed small areas in the inferior frontal gyrus, an area which was not infiltrated by the tumor macroscopically and radiographically. These effects were reproducible after tumor removal at the end of the first operation. At reoperation 4 years later the former area of the stimulation effect could be easily identified because the same surgical approach was used. In contrast to the first operation no language site was detectable with stimulation currents up to 20 mA. This area was still free of tumor. The patient showed no aphasia at any time. These results suggest a reorganization of the network involved in the processing of language. However, it cannot be distinguished whether this effect was caused by the temporal tumor or the tumor removal, or whether these plastic changes occur under physiological conditions, too.

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Cerebellar Involvement in Visual On-Line Adaptation of Vertical Stroke Size: A PET Activation Study— Weiss M 1, Schenk T2, Peller M3 , Drzezga A4, Schwaiger M5, Siebner HR6 (1Kiel; 2Durham; 3Kiel; 4 Mu¨nchen; 5Mu¨nchen; 6Kiel) Introduction: Behavioral data suggest that visual feedback can be effectively used for on-line adjustment of letter size during open-loop automated handwriting (Mai et Marquart Exp Brain Res 1999; 128: 224–228). Objective: Our intent was to pinpoint the involvement of the cerebellum in visual on-line adaptation of letter size. Methods: In eight male right-handed subjects (age: 25–39 years), we used H15 2 O positron emission tomography (PET) to measure regional cerebral blood flow (rCBF) during a handwriting task and a control condition (holding the pen). The written trace was recorded using a graphics tablet. Visual feedback of handwriting was continuously provided on a computer screen. In each trial, participants wrote four pairs of ‘l’ (‘ll ll ll ll’) every six seconds. Subjects were asked to match the letter size to the distance between two horizontal lines (w9 mm) using the feedback on the screen. The critical manipulation was an unpredictable change in the gain of vertical feedback during each trial. After the subject had

written the first pair of ‘l’, the gain of vertical feedback was either reduced to 66% (1/3 of the trials), enlarged to 133% (1/3 of the trials) or remained the same (1/3 of the trials). Subjects were asked to maintain stroke size as specified by the horizontal lines. Kinematics of handwriting were analyzed using CS software (MedCom, Munich, Germany). The mean number of inversions in velocity (NIV) was calculated for each scan to quantify the degree of automation. Three scans per condition were acquired in each subject. PET data were analyzed with SPM99 (Wellcome Dept. of Neuroscience, ION, UCL, UK). Using a general linear model, the NIV were treated as a regressor to model the changes in rCBF associated with the mean NIV per scan (P!0.001, uncorrected). Results: Regression analysis revealed a positive linear relationship between the rCBF in several cerebellar clusters and the degree of automation during handwriting (i.e., as indexed by the NIV). These cerebellar areas were located bilaterally in the medial and paramedian aspects of the superior cerebellum. Conclusion: Our findings demonstrate that a high degree of open-loop performance is associated with an increased cerebellar activity during a task requiring rapid integration of visual feedback. This activity pattern points to a significant role of the cerebellum in on-line adjustments of movement amplitude during skilled hand movements.

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Ultra-Late Evoked Potentials Following Stimulation of Tiny Skin Surface Areas in Humans—Weiss T1, Spohn D2, Meyer A3, Miltner WHR4 (1Jena; 2Jena; 3Jena; 4 Jena) C-fiber input to the central nervous system is considered to represent an important antecedent for the experience of secondary pain. Clinically more important, this input is suggested to play a major role in the chronification of pain. However, there are only limited possibilities to investigate this input selectively, i.e., without simultaneous activation of C-fibers. One method that allows the selective activation of cutaneous A- and C-fiber afferents in humans is the stimulation of tiny skin surface areas (about 0.23 mm2). We used this method for stimulation of the dorsum of the left hand and the left foot using a thulium-YAG laser stimulator. 12 volunteers were stimulated while EEG were recorded simultaneously. Additionally, reaction times (RTs), ratings of the perceived intensity of the stimulus, and descriptions of the perceptions (e.g., warm, burning) were registered for each single stimulus. Laser-evoked brain potentials (LEPs) were calculated for shorter and longer RTs on the basis of individual distributions of RTs and interpreted as belonging to A- and C-fibers, respectively. LEPs calculated on the basis of the stimulation of A of shorter RTs showing a waveform typical for late LEPs, i.e.,, a negative peak around 220 ms and a positive peak around 320, ms both with a maximum in Cz. As expected, latencies were longer for foot as compared to hand stimulation. LEPs calculated on the basis of longer RTs show a waveform typical for ultra-late LEPs with two components irrespective from the place of stimulation. A negative component peaked around 920 ms whereas a positive component peaked around 1120 ms. Both components had their maximum at electrode Cz. As expected, latencies were again longer for foot as compared to hand stimulation. However, a different A- and C-fiber stimulation was found for the hand vs. foot distribution of A stimulation. C-fiber responses were significantly more often observed to stimulation to the hand as compared to

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stimulation to the foot. In conclusion, Tm-YAG laser stimulation of tiny skin surface areas offers an opportunity to investigate central nervous responses to selective stimulation of A- and C-fibers in humans at different sites of the body. Supported by IZKF Jena.

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Under which Condition can fMRI Replace the Intracarotid Amobarbital Procedure (IAP) for Presurgical Language Lateralization?—Wellmer J1, Elger CE2, Weis S3, Klaver P4, Linke DB5, Urbach H6, Reul J7, Ruhlmann J8, Kurthen M9, Fernandez G10 (1Bonn; 2Bonn; 3Bonn; 4Bonn; 5Bonn; 6Bonn; 7 Bonn; 8Bonn; 9Bonn; 10Bonn) Introduction: There is a large body of evidence showing that functional magnetic resonance imaging (fMRI) is able to lateralize cortical language representations. Across activation protocols, many studies show good congruence of fMRI-based language lateralization with the gold standard, IAP. However, in up to 25% of patients, fMRI and IAP are discordant. This can be due to a variety of factors. Hence, we developed a simple algorithm that identifies individuals with one strongly dominant hemisphere in whom fMRI can actually replace IAP for language lateralization. Patients and Methods: Forty-five patients with pharmacoresistant epilepsy and suspected atypical language dominance received presurgical language lateralization by fMRI and IAP. For fMRI, we used a semantic-perceptual contrast designed to activate frontal as well as parieto-temporal language areas. It provides an active control condition as well as a continuous performance control. IAP was performed unilaterally on the side of intended surgery. Results: The algorithm: (1) exclusion of patients with possibly BOLD-interfering lesions (nZ8); (2) exclusion of patients with non-compliance or protocol atypical activation patterns (nZ1); (3) identification of unilateral language dominance across both frontal and parieto-temporal activations according to protocol adjusted volumes of interest and lateralization indices resulted in complete congruence and therefore redundance of fMRI and IAP in 16 of 45 patients. Extrapolating lateralization index thresholds for unilateral language dominance defined in this highly selected group of patients to all epilepsy surgery patients who received language fMRI in Bonn between 2000 and 2002 (nZ203) indicates that about two-thirds of IAPs are redundant. Discussion: Without exclusion of interfering factors, fMRIbased language lateralization is error-prone and replacement of IAP by fMRI not recommendable. With the proposed algorithm, however, fMRI is a valuable tool in routine presurgical language lateralization.

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Theoretical reflections about the reciprocal influence of neurotransmitters upon each other—Werner FM1 (1Po¨bneck) In the reticular formation, serotonin and noradrenaline are competitive neurotransmitters in the regulation of the sleep– waking cycle. A balance exists between the two neurotransmitters: serotonin is preponderant during sleep and noradrenaline during wakefulness. Adrenergic neurons transmit an excitatory impulse to glutaminergic neurons via alpha1 receptors. These neurons have an inhibitory effect on serotonergic neurons through NMDA

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receptors. By contrast, serotonergic neurons exert a sleep-inducing and soothing effect through 5-HT1A receptors. These neurons have a postsynaptic excitatory effect upon GABAergic neurons, which presynaptically inhibit adrenergic neurons via GABAA recpetors. This model describes a feedback circuit of the four neurotransmitters that depend on the circadian rhythm. In the pathogenesis of schizophrenia, new research has revealed hyperactivity of dopamine and serotonin in the mesolimbic system. Atypical neuroleptics are D2 and 5-HT2A antagonists are used to treat positive and also negative psychotic symptoms. However, other neurotransmitters, such as glutamate and GABA, are also involved in the pathogenesis of schizophrenia. In animal experiments, glutamate antagonists cause schizophrenic behaviour, which can be relieved by 5-HT2A antagonists. In healthy subjects, a possible neuronal combination could be that dopaminergic neurons would transmit a postsynaptic excitatory impulse to glutaminergic neurons which presynpatically inhibit serotonergic neurons. The serotonergic neurons, in turn, would transmit a postsynpaptic excitatory impulse to GABAergic neurons, which presynaptically inhibit dopaminergic neurons. The presynaptic inhibition prevents hyperactivity of either the dopaminergic or serotonergic system. In schizophrenic patients, 5-HT2A receptors could be localized on dopamine cells so that there is no presynpatic inhibition. Consequently, hyperactivity of dopaminergic and serotonergic neurons is possible. As a result of this, new neuroleptics should have an optimal ratio of D2/5-HT2A receptor occupancy. It is possible that agonism against NMDA and GABAA might improve schizophrenic symptoms.

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Intraoperative Neuromonitoring of Oculomotoric Function during Supra- and Infratentorial Tumor Resections—Wertheimer D1 (1Hamburg) For intraoperative monitoring of motor functions of the oculomotor (III), trochlear (IV) and abducens (VI) nerves usually electromyographic potentials of the musculus rectus inferior, rectus lateralis and obliquus superior are registered. This allows one to recognize not stimulated-induced neuronal activity, which can be an indicator of a functional or structural damage to the cranial nerves. Furthermore, selective electrical stimulation allows the identification of individual cranial nerves. Although intraoperative monitoring of electromyographic potentials of ocular muscles can decrease the probability of neuronal damage, it is seldom used because of the potential risk of lesions to the ocular bulbus during placement of the unipolar needles in the muscles. We have investigated alternative conduction forms with the aim to combine a high selectivity of the biosignal for the different nerves with a low risk of needle placement in order to promote this technique for a larger number of intraoperative investigators. In 30 patients undergoing resection of brain tumors located near the course of cranial nerves III, IV and VI we have performed a neuromonitoring of these nerves. Two unipolar needle electrodes for each conduction were placed subdermally under the bulbus in the lower eyelid, lateral of the bulbus and above the bulbus in the upper eyelid. The registration of not induced potentials was possible in all 30 cases. The amplitudes of the potentials allowed in all cases discrimination between the activity of III and VI. In only 22 of 30 cases was a discrimination of activity of IV possible. In the set-up of electrical stimulation to localize them cranial nerves III and VI were identified and discriminated in 28 of 30 cases,

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nerve IV was identified in 24 of 30 cases. In no case was any pathology as a result of needle placement observed. Intraoperative neuromonitoring of cranial nerves III, IV and VI is feasible by a technique using a conduction mode with near-muscle placement of electrodes. Sensitivity of this method for the identification of cranial nerves III and VI is significantly higher than for cranial nerve IV. The lower success rate for registration of selective activity of vranial nerve IV suggests that this method does not allow us to safely detect functional or structural intraoperative impairment of this nerve. With this limitation the technique presented here still seems to be a safer alternative compared to the traditional mode of intraoperative neuromonitoring of the oculomotor and abducens nerves.

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MRI detection of peripheral nerve denervation and regeneration: correlation with electromyography and histology—Wessig C1, Reiners K2, Koltzenburg M3, Solymosi L4, Toyka KV5, Bendszus M6 (1Wu¨rzburg; 2 Wu¨rzburg; 3Wu¨rzburg; 4Wu¨rzburg; 5Wu¨rzburg; 6 Wu¨rzburg) Background: Acute nerve lesions have been shown to cause hyperintense signals on T2 weighted MRI of the nerve. An animal study using a defined nerve lesion was performed to sequentially study MRI changes in the nerve in comparison to electrophysiological alterations and nerve histology in nerve degeneration and regeneration. Methods: Rat sciatic nerve was compressed by a tight suture which was opened after one week. Serial EMG and motor nerve conduction studies were conducted on the first four days after lesion, on day seven and then in weekly intervals parallel to MRI scanning. On defined time points, sciatic nerves were taken for histology. Results: Nerve hyperintensity on T2 weighted MRI was seen in the thigh already at 24 h after denervation. Progression up to the lower leg level was present after 48 h. Signal changes regressed after four weeks in the thigh, five weeks on the knee level and seven weeks in the lower leg. On EMG, spontaneous activity was found two days after lesion with a proximo-distal gradient which decreased from day 14 in the lower leg and day 35 in the foot. First voluntary activity on EMG occurred about 2 weeks before regression of MRI nerve hyperintensity. Compound muscle action potentials (CMAP) in the foot muscles reappeared seven weeks after lesion, increasing to 80% of the previous values after 13 weeks. On histology, axonal degeneration in the acute phase and, later, nerve oedema were found to parallel MRI changes. Conclusion: MRI is an excellent diagnostic tool to detect acute axonal nerve lesions, showing changes at the time as EMG. In addition, regeneration can be followed by MRI scanning which is in parallel with regression of histological alterations.

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Missing SMA Activation in Self-Initiated Movements after Chronic Prefrontal Traumatic Brain Injury: An Event-Related fMRI Study—Wiese H1, Toennes C2, Nebel K3, de Greiff A4, Gizewski E5, Forsting M6, Stude P7 (1Essen; 2Essen; 3Essen; 4Essen; 5Essen; 6 Essen; 7Essen) Objective: In former studies, we found the Bereitschaftspotential, an EEG component related to the preparation of self-initiated

movements, to be reduced in the acute stage after prefrontal TBI (Wiese et al., Clin Neurophysiol, 2004). However, in the temporal course after the injury a functional reorganization was observed, which resulted in a lateralization of this normally symmetrically distributed component towards the hemisphere contralateral to the movement one year after TBI (Wiese et al., Clin Neurophysiol, accepted). Since the localization of brain regions generating these potentials was not possible, the present study aimed at identifying brain structures involved in the preparation and execution of selfinitiated movements in chronic prefrontal TBI patients. Methods: Eighteen patients with contusions of the frontal lobe were examined. Lesions affected the inferior and dorsolateral prefrontal cortex. During scanning subjects performed selfinitiated movements of their right index finger about every 15 s. 500 T2*-weighted functional images were recorded (EPI, TRZ 1800 ms., TEZ45 ms., 20 slices, slice thicknessZ3.3 mm, matrixZ64!64). Event-related statistical models, including the hemodynamic response function and its temporal derivative, were set up for each subject. For statistical comparison on multi-subjects level, a random effects analysis was calculated. All voxels exceeding a threshold of P!0.05 corrected for multiple comparisons were considered statistically significant. All processing was carried out using SPM99. Results: Significant activations were observed within the left sensorimotor area (BA2, BA4), the left inferior parietal lobe (BA40), the bilateral putamen, the left lateral premotor cortex (BA6), and the left anterior cingulate gyrus (BA24). No significant activation was found within the supplementary motor area (SMA). Conclusions: The SMA has repeatedly been shown to be significantly activated in imaging studies examining self-initiated movements. Most authors also agree that the SMA is a likely generator of the Bereitschaftspotential. The rostral part of the SMA is known to be connected to the prefrontal lobe. This medial route might be disturbed in our patients. Instead, pronounced lateral BA6 and BA40 activations were detected, compensating for the damaged functional network. These results are in good agreement with our previous electrophysiological studies.

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Automated Volumetrics and Methodological Pitfalls in Special Patient Populations—Wilke M1 (1Tu¨bingen) The last decade has seen great advances in the analysis of structural MR images. With the introduction of automated methods of tissue classification and spatial normalization, the userindependent processing of large datasets has become feasible. Instead of the error-prone and extremely time-consuming manual delineation of pre-chosen structures of interest, an automated and unbiased exploration of the whole brain dataset is now possible. Recent methodological advances include a more ‘brain-based’ normalizaton and segmentation scheme or have allowed us to investigate true tissue volume instead of the more abstract concept of tissue density. Also, while numerous studies have proceeded to do voxel-wise analyses (as in the case of voxel-based morphometry, VBM), regional expansion schemes can also be included. Here, we aim at giving an overview over a typical ‘optimized’ processing stream in a widely-used software environment (spm) and highlight some important pitfalls when working with special populations, such as children or elderly subjects. Such populationspecific peculiarities can introduce a substantial bias into the ensuing analyses and thus need to be considered.

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Targeting Prion Protein and Alzheimer’s disease Amyloid Peptide by Peptide Ligands—Willbold D1, Wiesehan K2, Haenel K3, Patt S4, Linke RP5 (1Ju¨lich; 2 Ju¨lich; 3Ju¨lich; 4Jena; 5Martinsried) The presently established models of prion propagation are based on the essential role of the host-encoded prion protein (PrP). Development and progression of the disease implies ongoing conversion of its non-pathological isoform PrPC into its pathological isoform PrPSc. Thus, any stabilization of the PrPC conformation should slow down or inhibit conversion of PrPC into PrPSc. We screened a phage displayed peptide library to ultimately identify high affinity ligands that bind to and stabilize PrPC. A similar approach was used to identify ligands that specifically bind to Alzheimer’s disease (AD) amyloid peptide Abeta(1–42). Applying a mirror image version of a phage display screening allowed us to ultimately identify a 12mer peptide that binds specifically to Abeta(1–42) and consists solely of D-amino acids (D-pep). D-amino acid peptides are known to be less protease sensitive, more resistant to degradation in animals, and less or even not immunogenic at all, as compared with an L-amino acid peptide. D-pep was shown to bind Abeta(1–42) with a dissociation constant in the submicromolar range. Furthermore, in brain tissue sections derived from patients who suffered from Alzheimer’s disease, amyloid plaques were stained specifically with a fluorescencelabeled derivative of D-pep. D-pep was specific for Abeta plaques and did not stain amyloid deposits. Because such D-peptides are considered to consist of peptides other than A, to be rather protease resistant and mostly non-immunogenic, D-pep may be very suitable for use as a probe for the detection of amyloid plaques in living humans or animal models or to search for compounds that are suitable for AD therapy. D-pep may synthetically be combined with any marker employed for physiological detection or medical imaging techniques. Current studies are aimed to find out whether D-pep or derivatives thereof are able to cross the blood-brain barrier and be used for in vivo diagnostic imaging of living brains. Any AD therapeutic approach directed either against amyloid fibril -secretase activities, will have to rely on correct g- or b-formation, or monitoring of the cerebral and cerebrovascular amyloid loads.

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Genetics and Neural Stem and Precursor Cells— Winkler J1 (1Regensburg) The establishment of the three-dimensional cytoarchitecture in the adult brain requires a tight control of neural stem and precursor proliferation, migration and differentiation during development. In particular, a precise guidance of the neuroblasts from their site of origin towards their definitive site of residency is finely regulated. In humans, brain malformations can result from neuronal migration defects of stem and precursor cells. The spectrum of migration disorder severity extends from periventricular heterotopia and subcortical band heterotopia to a complete cortical disorganization, as observed in lissencephaly. Recently, these migration disorders have been linked to mutations in the filaminA, doublecortin and LIS1 genes. Here, we summarize our findings concerning the genetic characteristics of these migration disorders, the functional MRI findings of heterotopic neuroblasts and in vivo/in vitro analysis of the migration-associated gene products. (Supported by the VW- and Fritz Thyssen-Foundation).

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Molecular Differential Diagnosis of HSP with Thin Corpus Callosum—Winner B1, Winkler J2 (1Regensburg; 2Regensburg) Hereditary spastic paraplegia (HSP) with thin corpus callosum (CC) is a rare neurodegenerative disease, classified as a complicated form of spastic paraplegia. Some patients with HSP with thin CC have previously been described with a linkage to chromosome 15q13–15. However, a thin CC has been described in other genetic forms of HSP as well. We report about the clinical, structural, and functional follow-up of patients with HSP and thin CC. Our data show that progressive axonal degeneration occurs in the cortico-cortical projections, the cortico-spinal tract and peripheral nerves in HSP. Moreover we will discuss genetic differential diagnosis of HSP with thin CC. (Supported by TomWahlig-Stiftung, Jena).

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Abilities and Limitations of Synchronization Indexes for Epileptic Seizure Prediction—Winterhalder M1, Schelter B2, Maiwald T3, Brandt A4, Schulze-Bonhage A5, Timmer J6 (1Freiburg; 2Freiburg; 3Freiburg; 4 Freiburg; 5Freiburg; 6Freiburg) Multivariate time series analysis techniques applied to electroencephalography (EEG) recordings enable a detection of interactions between different brain areas. Since several neurons synchronize when a seizure is generated, multivariate time series analysis techniques might yield an increased seizure prediction performance compared to univariate ones. Based on analysis of intracranial EEG data recorded for 21 patients with 24 h of interictal and 2–5 pre-seizure periods (mean 4.2) each, two synchronization indexes originating from the theory of non-linear dynamics are examined. We will discuss limitations of a seizure anticipation and the requirement for seizure prediction. Features characterizing an actual prediction will be presented. Both synchronization indexes are assessed by this concept to show their abilities and limitations for seizure prediction. Furthermore, individual patient results will be compared to group results and the performance for different electrode locations will be presented.

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Measurement of Transcallosal Inhibition in Early Relapsing-Remitting Multiple Sclerosis—Wittstock M1, Zettl UK2, Benecke R3, Wolters A4 (1Rostock; 2 Rostock; 3Rostock; 4Rostock) Early diagnosis of relapsing-remitting multiple sclerosis (RRMS) is important to start immunmodulatory prophylaxis at an early stage in the course of the disease. According to the McDonald criteria [1], magnetic resonance imaging (MRI) is fundamental in detecting spatial and temporal dissemination. An evidenced-based review of the usefulness of evoked potentials in making the diagnosis of RR-MS did not test motor evoked potentials (MEP) [2]. We investigated whether the analysis of transcallosal inhibition (TI) using transcranial magnetic stimulation (TMS) is useful for the early diagnosis of RR-MS. 12 patients (9 female, 34G5 years) with suspected RR-MS were investigated. Inclusion criteria comprised a clinically isolated syndrome (CIS) not demonstrating spatial or temporal dissemination, MRI findings consistent with the diagnosis of MS, but not yet meeting Barkhof

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criteria [3], and occurrence of oligoclonal bands in the cerebrospinal fluid. TMS investigation included routine investigation and measurement of TI (latency, duration, persistence) from both first dorsal interosseus regions. Definite RR-MS was confirmed by further clinical relapses and MRI controls. Mean EDSS was 1G0.4. Clinical presentations were opticus neuritis (nZ6) and sensory symptoms (nZ6). Only 2 patients had motor deficits. A prolongation of central motor latency (CML) could be detected in these and in 2 further patients subclinically. A pathological TI was found in 9 of 12 patients (5 patients without CML prolongation, 11 of 18 hemispheres with TI loss, 1 prolongation of latency [C3 ms], 1 prolongation of duration [C 4 ms]). Periventricular white matter lesions were found in 11 patients, a pericallosal localization only in 4 patients; 3 of the latter patients had a pathological TI. 6 patients with pathological TI had no pericallosal lesions. Measurement of TI by TMS may detect central callosal conduction deficits even in the absence of motor symptoms. TMS may be a useful tool for making the diagnosis of RR-MS in patients with CIS at an early stage of the disease. References McDonald WI. Recommended diagnostic criteria for multiple sclerosis. Ann Neurol 2001; 50: 121–127 Gronseth GS. Practice parameter: the usefulness of evoked potentials in identifying clinically silent lesions in patients with suspected multiple sclerosis. Neurology 2000; 54: 1720–1725 Barkhof F Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 1997; 120: 2059–2069

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Neurophysiological Characterization of Autosomal Dominant Spinocerebellar Ataxia 17—Wolters A1, Walter U2, Benecke R3, Rolfs A4 (1Rostock; 2Rostock; 3 Rostock; 4Rostock) Recently, trinucleotide expansion (critical limit 42G2) has been described in the TATA box binding protein gene in autosomal dominant spinocerebellar ataxia 17 (SCA 17, OMIM 600075). The clinical presentation is very variable with psychiatric disturbance, gait ataxia, dysarthria, bradykinesia and/or dystonia. We neurophysiologically characterized two families with SCA-17 using transcranial magnetic stimulation (TMS) and brain parenchyma sonography (BPS). The two families consisted of 14 individuals with genetically proven SCA-17 (trinucleotide expansion 45 to 54) . 7 family members (4 male, mean age 44G9 years, mean disease duration 8G7 years) were characterized neurophysiologically. Our TMS measures comprised a routine investigation, the contralateral and ipsilateral silent period as well as analysis of short latency intracortical inhibition (PPI 3 ms) and facilitation (PPF 13 ms) using a paired-pulse paradigm. The echogenicity of several brain structures of the basal ganglia and the midbrain was investigated by BPS according to a standardized protocol. All patients showed a moderate to severe dementia and a wide spectrum of clinical symptoms including dyspraxia, atypical Parkinsonism as well as myoclonus, and ataxia in only one case. TMS revealed only one abnormal parameter with loss of PPF 13 ms in 6 patients. BPS demonstrated a reduced echogenicity of the brainstem raphe in all 7 individuals, a hyperechogenicity of the caudat nucleus in 5 patients (with correlation to the severity of dementia), and in all patients a dilatation of the IV ventricle (7.4G1.9 mm). Clinical features of SCA17 comprised a broad spectrum of more psychiatric

and extrapyramidal symptoms than ataxia. A loss of short-latency intracortical facilitation measured by TMS was also reported previously in other types of SCA and may be the expression of a disturbed cerebello-thalamic-cortical connection. Hyperechogenicity of the caudate nucleus in the BPS was described also in other forms of dementia. The hypoechogenicity of the brainstem raphe, a serotonergic nucleus area, was described for patients with unipolar depression. Disturbances in the serotonergic system seem to play a role in patients with SCA suggesting that the hypoechogenicity of the brainstem raphe revealed by BPS may be of pathogenetic importance.

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Effects of Specific Sensorimotor Forelimb Training on Endogenous Stem Cell Proliferation and Differentiation in the Dentate Gyrus after Focal Brain Ischemia—Wurm F1, Grass S2, Kunze A3, Witte OW4, Redecker C5 (1Jena; 2Jena; 3Jena; 4Jena; 5Jena) Neurogenesis is known to occur throughout life in the dentate gyrus of rodents and is modulated by different specific but also unspecific stimuli (e.g., enriched environment). In this study we investigated the effects of specific sensorimotor training on neurogenesis in the dentate gyrus of adult rats after focal brain ischemia. Small cortical photothrombotic infarcts (PT) were induced in the forelimb sensorimotor cortex. We compared one group of animals receiving daily reaching training (RT) of the impaired forelimb with a standard housing group (ST). Every group consisted of lesioned animals (PT) and sham-operated animals (Sham), respectively. We examined cell proliferation and differentiation at two different time points, 10 days and 42 days post surgery. All animals obtained daily injections of the proliferation marker bromodeoxyuridine (BrdU, 50 mg/kg) five times, from day 2 until day 6 post surgery. After 10 days ST-PT as well as RT-PT animals showed a significant increase in total number of BrdU-labeled cells compared with sham-operated controls (ST-Sham, RT-Sham), but there was no difference between trained (RT) and standard housed (ST) animals. At 42 days after the infarct, the RT-PT group revealed about 30% more newborn cells than standard housed animals with cortical infarcts (ST-PT group). However, this training-induced increase was much higher (approx. 100–120%) in the RT-Sham group compared with the ST-Sham group. The neuronal and glial differentiation of these cells was analyzed using confocal microscopy. The present study clearly demonstrates that specific sensorimotor forelimb training significantly increases the survival of new-born progenitor cells in the dentate gyrus after cortical infarcts. Remarkably, these training-induced effects on cell survival are considerably higher in animals without cortical infarcts. Supported by DFG Re1315/3–1 and IZKF Jena.

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Changes in GABAA Receptor Subunit Distribution during Brain Maturation and Aging—Yu ZY 1, Fritschy JM2, Witte OW3, Redecker C4 (1Jena; 2 Zu¨rich; 3Jena; 4Jena) Gamma-aminobutyric acid type A (GABAA) receptors are the most important inhibitory receptors in the central nervous system playing a pivotal role in the regulation of brain excitability. The pentameric receptor is usually composed of different alpha, beta,

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and gamma subunits which modulate the pharmacology of the receptor. Up to now, a diversity of 20 different subunits is known allowing a multitude of adaptive changes under physiological and pathophysiological conditions. In this study, we investigated the expression of five major GABAA receptors subunits (alpha1, alpha2, alpha3, alpha5, gamma2) during brain maturation and ageing in the rat brain. Wistar rats were perfused at day 10, 30, 90, 180, 360, and 540 after birth and immunohistochemistry was performed using antibodies against alpha1, alpha2, alpha3, alpha5, and gamma2 subunits of the GABAA receptor. Morphological and semi-quantitative evaluation of regional optical densities revealed that each of these subunits exhibited age-dependent changes in its regional distribution. During the first postnatal days, subunits alpha2 and alpha5 were abundantly expressed in the cortex whereas only marginal amounts of alpha1 and gamma2 subunits were found in this brain region. In the following weeks the expression of subunits alpha1, alpha2, alpha3, and gamma2 then increased in the cortex and subunit alpha5 in contrast showed a decrease in optical density. After an age of 3 months a continuous down-regulation of subunits alpha3, alpha5, and gamma2 was observed in the cortex whereas subunits alpha1 and alpha2 remained stable on a high expression level. In the hippocampal formation differential temporal alterations in GABAA receptor expression occurred. The present study demonstrates that GABAA receptors show specific changes in subunit composition during brain maturation and ageing. These findings probably contribute to a better understanding of age-related changes in excitability and might further explain the distinct pharmacological effects of different GABAergic drugs in young and elderly patients.

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Artifact-Suppressing Amplifier for EMG Registration during Repetitive Peripheral Magnetic Stimulation (RPMS)—Zehetbauer S1, Angerer B2, Struppler A3 (1Mu¨nchen; 2Mu¨nchen; 3Mu¨nchen) To induce a most physiological proprioceptive inflow to the CNS, the intensity and the repetition frequency of the RPMS are adapted by a closed loop control to induce coordinated movements. For the closed loop control and the quantification of the therapeutic outcome it is necessary to measure the (remaining) voluntary muscle activity, while the RPMS is applied. This is essential, since the patient is advised to assist the induced movements as far as possible. Therefore an RPMS artefact-suppressing EMG amplifier has to be developed to measure the activity of the stimulated muscle during the stimulation. Hereby the stimulation coil is located directly above the two EMG electrodes. Such amplifiers are well-known and established for functional electrostimulation, while artefact-suppressing amplifiers for RPMS are fairly unknown. Because of RPMS impulses, a high (compared to the EMG) voltage is induced into the EMG electrodes. This voltage changes the charge of the skin capacity and therefore the DC offset of the EMG. The induced voltage also elicits an impulse response of the filters in the EMG amplifier. Hence an artefact suppression is necessary, otherwise the amplifier is permanently in saturation since the RPMS impulses are repeated with 20 Hz. The trigger signal for the stimulation device is also used for the artefact suppression. The artefact suppression itself runs on three levels: voltages higher than 1.4 V at the EMG electrodes are filtered by antiparallel diodes independent of the stimulation impulse. If the suppression is triggered, the input to the difference amplifier is

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shorted by two bipolar transistors and the input to the DC offset compensation is grounded. With this suppression unit its is possible to reduce the gap in the measured EMG down to 3 ms. In addition to the artefact suppression, the following requirements (excerpt) are fulfilled in the developed EMG amplifier: selectable amplification gain, bandwidth of 3 Hz to 15 kHz, an anti-aliasing filter with a selectable edge frequency, a 50 Hz band-stop filter and an active shielding (no external pre-amplifier module). Due to a difference amplifier and the artefact suppression the input resistance is at least 500 MOhm and the patient is protected form dangerous high voltages by an isolation barrier (3 kVrms). Also a conventional speaker module is integrated into the designed amplifier.

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Pharmacological Modulation of Plasticity—Ziemann U1, Benilow S2, Alle H3, Korchounov A4, Meintzschel F5, Krakow K6 (1Frankfurt; 2Frankfurt; 3Frankfurt; 4 Frankfurt; 5Frankfurt; 6Frankfurt) Cortical plasticity plays an important role in learning. Understanding of the mechanisms of plasticity would facilitate strategies to improve learning. CNS active drugs can modify plasticity and learning. Here we tested the effects of neuromodulators [dopamine (DA), norepinephrine (NE), serotonin, acetylcholine (ACH)] and, in a different series of experiments, the effects of antiepileptic drugs (AED) on associative long-term potentiation (LTP)-like plasticity and motor learning in eight healthy subjects. LTP was induced by paired associative stimulation (Stefan et al. Brain 2000; 123: 572). Motor learning was investigated in a repeated thumb movement practice protocol (Classen et al. J Neurophysiol 1998; 79: 1117). Single oral doses of the following drugs were tested in a placebo-controlled double-blind crossover design. Neuromodulators: 2 mg of cabergoline (DA agonist), 2.5 mg of haloperidol (DA antagonist), 40 mg of methylphenidate (indirect DA and NE agonist), 1 mg of prazosine (NE antagonist), 100 mg of sertraline (selective serotonin reuptake inhibitor), 8 mg of biperiden (ACH antagonist) and 40 mg of tacrine (ACH agonist). AED: 15 mg of tiagabine (TGB), 20 mg of diazepam (DZP), 1100 mg of gabapentin, 3600 mg of pirazetam, 300 mg of lamotrigine, 100 mg of topiramate, and 3000 mg of levetiracetam (LEV). Drugs were tested in separate sessions at least one week apart in pseudo-randomized and balanced order. LTP and motor learning were enhanced by cabergoline and methylphenidate, but depressed by haloperidol, prazosine and biperiden. Tacrine had no effect on LTP but enhanced motor learning. LTP was depressed by those AED, which enhance gamma-butyric acid (GABA) dependent inhibition (TGB, DZP, in addition LEV) while other AED had no significant effect. The testing of effects of AED on motor learning is work in progress. In conclusion, manipulation of neuromodulatory systems leads to enhancement or depression of LTP and motor learning in the human motor cortex. The congruence of neuromodulatory effects on LTP and motor learning suggests that these two processes share common mechanisms. Neuromodulators may be used to guide cortical plasticity in humans. GABAergic AED interfere negatively with LTP induction and may therefore be detrimental in LTP-dependent learning.

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Short-Latency Afferent Inhibition and Excitation of Primary Motor Cortex in Patients with Focal Hand Dystonia—Ziemann U 1, Kessler K2, Ilic TV3 (1Frankfurt; 2Frankfurt; 3Frankfurt) Sensorimotor integration is abnormal in patients with writer’s cramp (WC), and this may contribute to the movement disorder. The earliest somatosensory input to the primary motor cortex (M1) is the short latency afferent inhibition (SAI), a recently described inhibition of the motor evoked potential (MEP) amplitude when the magnetic stimulus is preceded by a conditioning electrical stimulus to the contralateral median nerve applied 20–26 ms earlier. SAI originates through activation of inhibitory interneurones in M1 and is mediated either via thalamo-cortical projections directly into M1 or through a fast relay via primary sensory cortex (S1). We hypothesized that SAI is abnormal in WC patients. SAI was investigated in 12 patients with simple (nZ6) or dystonic WC and 10 healthy controls. 12 conditioning-test inter-stimulus intervals (ISIs) were tested from K6 to C16 ms in steps of 2 ms around the individual N20 latency and compared to unconditioned trials. MEPs were recorded in two conditions with the abductor pollicis brevis muscle (APB) either relaxed (resting) or slightly contracted (active). In the resting condition, patients and controls showed a similar SAI magnitude at ISI 0 and C2, i.e., when the median nerve stimulus preceded TMS by the individual N20 latency or 2 ms more. In addition, only in the patient group was a significant facilitation at ISIC10 (PZ0.018) found that was significantly more pronounced in the dystonic WC patients (3.2G0.91; nZ5) compared to the simple WC patients (1.9G 0.26; nZ6) (PZ0.017; Mann–Whitney test). In the active condition, patients and controls showed similar SAI at ISI 0 and C2, but no significant facilitation at longer intervals. We show that SAI is normal in patients with WC during muscle rest and contraction. The major discriminating finding between WC and healthy controls was an abnormal MEP facilitation during muscle rest in the WC patients at inter-stimulus intervals of 28–34 ms, most likely reflecting an exaggerated long-latency reflex II (LLR II). We conclude that short-latency somatosensory inhibitory input into M1 is normal in WC, whereas the exaggerated MEP facilitation supports the notion of an abnormal sensorimotor integration of fast excitatory inputs into M1, in particular in those with dystonic rather than simple writer’s cramp. Supported by the Deutsche Forschungsgemeinschaft, DFG KE487/1–1.

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Sleep Deprivation: Effects on Pro-Saccades, MemoryGuided Saccades and Anti-Saccades—Zils E1, Sprenger A2, Gais S3, Kimmig H4, Born J5, Heide W6 (1Lu¨beck; 2Lu¨beck; 3Lu¨beck; 4Lu¨beck; 5Lu¨beck; 6 Celle) In this study we investigated the effect of sleep deprivation on different types of saccadic eye movements, namely reflexive visually-triggered saccades, memory-guided saccades and antisaccades. These types of saccades differ in the extent of voluntary control and hence involve partially different brain structures. This study may reveal parameters and structures being most sensitive to sleep deprivation. Fifteen healthy volunteers participated in one adaptation night and one test night. During the test night half of the

subjects (group 1) slept eight hours in a sleep laboratory, the other subjects (group 2) stayed awake. After four weeks the experiment was repeated with group 1 staying awake, group 2 sleeping. All subjects were tested in the evening before and in the morning after the test night (day 1). Furthermore all subjects were retested after one more night during which all were allowed to sleep (day 2). The tests consisted of a series of reflexive pro-saccades, anti-saccades and memory-guided saccades. Saccadic reaction time, peak velocity, and gain were computed for all saccades. Error rate was computed for the anti-saccade task. Before the test night and on day 2 there were no differences between sleep and sleepdeprivation conditions. All saccades showed a significantly reduced peak velocity on day 1 in the sleep deprivation condition. Surprisingly, pro-saccades had normal reaction times but reduced gain. Memory-guided saccades, however, did show prolonged reaction times with normal gain. Reaction times and gain of antisaccades were not affected. Our data suggest that sleep deprivation does not provoke a general degradation of saccade parameters, but acts on certain parts of the saccadic network.

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The Influence of Biological Rhythms on Sleep–Wake Regulation—Zulley J1 (1Regensburg) The timing of major night-time sleep is governed in a large part by the endogeneous circadian pacemaker. Under conditions of normal daily life, such dependence is reflected in the tendency for major nocturnal sleep to be initiated five to six hours prior to the temperature minimum and terminated shortly after the minimum. For most people, this corresponds roughly to sleep onset times of between 11 pm and midnight, and wake-up times of between about 6 am to 7 am. Because most humans exhibit similar timing in sleep-wake behavior, societal demands have evolved to accommodate such biological timetables. For a small percentage of the population, however, there is a misalignment between the endogeneous clock that governs sleep and the sleep/wake schedule that is desired, or which is regarded as the societal norm. These individuals are said to have circadian rhythm sleep disorders. This class of sleep disorders can be grouped further into two general categories-extrinsic and intrinsic types. Extrinsic types are those in which the disorder is brought on by an alteration in the environment relative to sleep timing, for example, jet lag, or shift work sleep disorder. Circadian rhythm sleep disorders of the intrinsic type are those that occur as a result of the endogeneous clock being altered relative to the (social) environment. That the biological clock can be reset to conform to social schedules, without markedly improving sleep quality, has etiologic implications as well. Alleviation of the rhythm disturbance in the absence of enhanced sleep quality clearly suggests that the sleep disorder aspect of circadian rhythm sleep disorders may include pathophysiology beyond their relationship to the circadian timing system. A current model of sleep regulation hypothesizes that the timing and composition of sleep are controlled by two interacting processes. It is quite likely that circadian rhythm sleep disorders are the result not only of alterations in circadian factors, but also disturbances in so-called Process S, the non-circadian factor proposed by the model. It is also likely that the reverse is true. That is, in sleep disorders such as primary insomnia, it has to be taken into account that these disorders may also be affected by a circadian dysfunctioning. This would suggest that not only Process

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S is altered but the possible deviations of the course of Process C should be considered as a contributing factor to insomnia. As such, a clear differentiation between classification of sleep disorders such as insomnia and as circadian rhythm disorders becomes less evident.

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Reduced Cerebral Glucose Metabolism in Severe Preeclampsia—Zunker P1, Golombeck K2, Czech N3, Reuter M4, von Kaisenberg CS5, Jonat W6, Deuschl G7 (1Arlesheim; 2Kiel; 3Kiel; 4Kiel; 5Kiel; 6Kiel; 7Kiel) Introduction: Patients with pre-eclampsia/eclampsia syndrome reveal alterations in the concentrations of vasoactive hormones, in cerebral hemodynamics, and as recently reported in cerebral glucose metabolism (GM). Since the GM has not been measured absolutely, it is still unclear whether there is a cerebral hypo- or hypermetabolism of glucose and whether the found alterations in GM are related or unrelated to an alteration in cerebral perfusion. Methods and Results: We report on a 30-year-old woman who developed in week 26 of gestation a severe pre-eclampsia. In week 27 a cesarean section was performed and the patient was subjected to cerebral magnet resonance imaging (MRI), magnet resonance angiography (MRA), perfusion SPECT as well as 18-fluoro-2deoxy-D-glucose PET (FDG-PET). MRI on day one postpartum revealed patchy hyperintensities in both hemispheres, and MRA showed a signal loss in the right A1 segment. Perfusion-SPECT at day 2 after delivery revealed inhomogeneous hypoperfusion in the temporal lobe and in the cerebellum. FDG-PET at day 6 obtained reduced GM in the temporal pole, in the mesial temporal structures as well as parietal and occipital in both hemispheres. Discussion: In the present case the cerebral hypoperfusion cannot be attributed to a vascular narrowing in the basal cerebral arteries. Reduced cerebral GM exceeds the areas of cerebral hypoperfusion, which may be caused by an additional cortical deafferentation.

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Reflectory grip force adjustments to sudden loads in children: normal children vs. children with spastic cerebral palsy—Blank R1, von Voss H2 (1 Mu¨nchen, 2 Mu¨nchen) Objective: Reflectory grip force adaptation to sudden loads is important in everyday life. The objective was to study physiological age dependent changes and changes in children with spastic cerebral palsy (CP) during kindergarten age when fine motor functions develop very markedly. Methods: 75 normal children and 103 children with spastic CP (age: 3 to 6 years) were examined. The device was a grip object (200 g) with 3 uniaxial accelerometers in x, y, z-axis and a uni-axial force sensor inside. Below the grip object, a load of additional 100 g was fixed by a wire. This was lifted by the examiner and suddenly dropped down at least 5 times while the child had closed its eyes. Target variables were latency of the early answer (maximum amplitude), latency of the late answer (beginning of the second answer) and force amplitudes of the early and late answer. Results: In normal children, the latencies of the early answer remained fairly unchanged (mZ20 ms), whereas the latencies of the late answer decreased highly significant with age (rZ0,6, from

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MZ80 ms to MZ65 ms). In children with spastic CP, the amplitude of the early answer was often pronounced. The late answers were delayed, and on the non-preferred hands being more affected, this correlated with the degree of hand motor impairment (rZ0,3). Discussion: The study shows that in contrast to adults, children have early answers during sudden load changes. In children with spastic CP, mainly a corticospinal lesion, these are even pronounced. The late latencies decrease with maturation (in spite of considerable anatomical growth at kindergarten age) and with integrity of the corticospinal tract.The early answer may be a sort of H-reflex, which because of the later onset of the main answer can be observed in young children but not anymore in adults with shorter main reponses of reflectory grip force adjustements. The examination takes little time, is non-invasive and highly reliable.

Optimization of simultaneous acquisition of 31P-MRS and surface EMG data during muscle exercise— Rzanny R1, Grassme R2, Reichenbach JR3, Scholle HC4, Kaiser WA5 (1 Jena, 2 Jena, 3 Jena, 4 Jena, 5 Jena) Purpose: 31P-MRS and surface EMG are established methods to investigate metabolic and electrophysiological changes during muscle fatigue. However, the mechanisms of interactions between different components of fatigue are still understood incompletely. Simultaneous measurements with both modalities allow to correlate the results of both techniques. However, the measured signals may be corrupted due to distortions and mutual interferences caused by the measurement equipment. The aim of this study was to optimize data acquisition by reducing signal artifacts and to monitor changes of muscle fatigue by using 31PMRS and EMG simultaneously. Subjects and Methods: Six volunteers (age range 22–26 years) were investigated in a clinical whole body scanner (1.5 T). They performed an exercise of isometric muscle contraction of the lumbar back muscle which corresponds to a modified BieringSo¨rensen test. Measurements were performed for 10 min including 150 s resting phase, 150 s muscle activation and 300 s recovering phase. SEMG was registered at the level of the lumbar vertebrae L4 and L5 with an MR-compatible EMG-system using a bipolar technique. 2D chemical shift imaging (TR/TE/FWZ 715 ms/16 ms/908) was performed simultaneously using a double-tuned 1H/31P-surface coil. Temporal resolution was 30 s per spectroscopic measurement. The transverse slice (thickness: 100 mm) was positioned in the area of the electrodes. Results: Distortions of the EMG-signal were sufficiently reduced to estimate mean frequencies and amplitudes of the EMG signal from the undisturbed parts of the EMG time course. Artifact free 31P spectra were obtained which showed a rapid decrease of PCr to approximately 30% of the resting value during the first measurement of the activation phase. Recovery of PCr took place during the first 150 s after terminating muscle activation. Decreased mean frequencies and increased mean amplitudes of the EMG signals were observed during the working condition. The data were in accordance with results obtained from control EMG measurements without spectroscopic imaging. Conclusions: Simultaneous acquisition of 31P-MRS and EMG data is feasible. Typical metabolic and electrophysiological changes were observed during isometric muscle contraction. Further investigations of different time courses of metabolic

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changes and EMG frequencies and amplitudes associated with different workloads will help to improve the understanding of the underlying mechanisms of muscle fatigue.

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Direct evidence for formation of a movement memory by action observation—Stefan K1, Cohen LG2, Duque J3, Mazzocchio R4, Sawaki L5, Classen J6 (1Wu¨rzburg, 2 Bethesda USA, 3Bethesda USA, 4Bethesda USA, 5 Bethesda USA, 6Wu¨rzburg) Motor practice leads to the formation of elementary motor memories. However, it remains unknown, whether action observation will similarly result in encoding of a memory trace in the primary motor cortex. Twelve right handed subjects (5 women, 34G8 years) participated in three sessions that evaluated the ability of different training interventions to modify the direction of thumb movements elicited by transcranial magnetic stimulation (TMS) of the contralateral primary motor cortex (MI). In two sessions subjects attentively observed videos displaying thumb movements oriented oppositely (observation_antiparallel) or orthoparallel (observation_orthoparallel) to the direction of TMS-evoked thumb movements determined beforehand. In a third session subjects practiced voluntary thumb movements in a direction approximately opposite to the baseline direction (practice_antiparallel). Observation of thumb movements led to an increase in the probability of TMS-evoked movements to fall into the observed movement direction when the displayed movement direction was oriented antiparallel to the baseline direction (from 2.6G0.8% to 9.1G2%, P!0.01). No change in TMS-evoked movement direction was induced when the observed movement direction was orthoparallel to the baseline direction (from 13.6G2.7% to 16.0G7.3%, n.s.). The acceleration of TMS-evoked thumb movements along the principal movement axis changed with observation_antiparallel toward the observed direction, from 0.4G0.0 to 0.1G0.1 m/s2, while no changes were found with observation_orthoparallel. Furthermore, the balance of excitability of muscles participating in the observed movement were altered in favor of the observed movement direction with observation_antiparallel, but not with observation_orthoparallel. Performance of physical movements produced effects qualitatively similar as, yet more pronounced than, observation_antiparallel. These findings may establish a link between the action observation/action execution matching system, as described in non-human primates, and the dynamic representation of movements in human motor cortex that is associated with motor learning. KS was supported by the Akademie der Naturforscher LEOPOLDINA, BMBF-LPD 9901/8–50.

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Disturbance of associative motor cortical plasticity in focal hand dystonia—Weise D1, Schramm A2, Stefan K3, Wolters A4, Reiners K5, Naumann M6, Classen J7 (1Wu¨rzburg, 2Wu¨rzburg, 3Wu¨rzburg, 4Wu¨rzburg, 5 Wu¨rzburg, 6Wu¨rzburg, 7Wu¨rzburg) Maladaptive neuronal plasticity has been implicated in the pathophysiology of dystonia. We employed a recently established model of associative long-term potentiation (LTP) and long-term depression (LTD) to investigate motor cortical plasticity in patients with writer’s cramp. Paired associative stimulation (PAS) was performed by combining repetitively (0.1 Hz, 180 pulses) electric stimulation of the right median (MN) or ulnar (UN) nerve with subsequent transcranial magnetic stimulation (TMS) of the dominant motor cortex at 21.5 ms (MN-PAS21.5; UN-PAS21.5) or 10 ms (MN-PAS10). With MN-PAS21.5 and MN-PAS10, the magnetic coil was placed over the optimal cranial position for eliciting a motor evoked potential (MEP) in the contralateral abductor pollicis brevis muscle (APB). With UN-PAS21.5, the coil was placed over the hot spot for the abductor digiti minimi muscle (ADM). Four to 9 patients with writer’s cramp (age 39G10 y; meanG s.d.) and age and sex-matched controls were studied. Excitability changes were monitored by TMS for up to 85 min after intervention. Following MN-PAS21.5 or UNPAS21.5, MEP amplitudes increased exclusively in the muscle receiving homotopic external PAS stimulation, but not in the muscle which was not stimulated homotopically. By contrast, following either MN-PAS21.5 or UN-PAS21.5, WC-patients exhibited an increase in both APB and ADM-MEP size irrespective of the peripheral or central site stimulated. In WC, the cortical excitability increase developed earlier, its magnitude was larger, and its duration longer, than that observed in the controls. Qualitatively similar observations were made with reversed sign (decrease of excitability) following MN-PAS10. Thus, the range of MEP amplitude modulation was larger in WC than in controls. These findings suggest that in WC, the motor system exhibits a supranormal modifiability in response to associative Hebbian stimulation. Additionally, the normal high topographical specificity of PASinduced plasticity is lost. Our findings confirm, and extend those reported recently by another group (Quartarone et al., 2003). These abnormalities provide a link between repetitive actions and altered sensorimotor representations and may ultimately lead to a better understanding of the pathophysiology of dystonia. Supported by Dystonia Foundation, USA Quartarone A, Bagnato S, Rizzo V, Siebner HR, Dattola V, Scalfari A, et al. Abnormal associative plasticity in the human motor cortex in writer’s cramp. Brain 126: 2586–2596, 2003.