P17. Early Huntington’s disease patients demonstrate micro-structural and functional connectivity changes in motor and basal ganglia-thalamic networks

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Two distinct anatomical otolith pathways within the thalamo-cortical vestibular network were proposed in patients with thalamic infarctions who presented with contra- or ipsiversive tilts of the subjective visual vertical (SVV) (Dieterich and Brandt, 1993; Baier et al., submitted for publication). Aim of this study was to investigate the dendato-thalamo-cortical pathways in association with otolith dysfunction by means of DTI (diffusion tensor imaging) based on the regions found in a recent patient study using statistical lesion-behavior mapping (Baier et al., submitted for publication). Methods: Twenty-four healthy volunteers (11 females; aged 20– 4 years, mean age 28.2 ± 6.3 years) were measured in a 3 Tesla MRI (Erlangen, Siemens, Verio). The data was analyzed with FSL. For the examination of the dendato-thalamo-cortical pathways we calculated voxelbased DTI tractography between the dendate nuclei, vestibular nuclei, the thalamic regions defined in the patients with thalamic infarctions (Baier et al., submitted for publication) and the cortex. Results: At group level the data-driven DTI tractography showed that the dendato-thalamo-cortical pathways connected to ipsiversive SVV tilts projected ipsilaterally from the dendate and vestibular nuclei to the cortex via the caudate nucleus. Thalamus regions connected to contraversive SVV tilts received input from the contralateral cerebellar hemispheres, the dendate and vestibular nucleus crossing either in the pons or mesencephalon and reaching the cortex via the putamen. Discussion: These data verify that there are two distinct anatomical otolith signal-processing pathways within a dendato-thalamo-cortical vestibular network. This supports results of earlier PET- and fMRI-studies with caloric and galvanic stimulation in humans (Dieterich and Brandt, 2008). Therefore, our data support the existence of two functionally distinct dendato-thalamo-cortical vestibular pathways leading - when damaged - either to a vestibular tone imbalance to the ipsiversive or to the contraversive side. Acknowledgements: Supported by the Support Program for Research and Teaching (FöFoLeLMU), Graduate School of Systemic Neuroscience (GSN), the German Foundation for Neurology (Deutsche Stiftung Neurologie) and the German Federal Ministry of Education and Research (German Center for Vertigo and Balance Disorders -IFBLMU, Grant code 01 EO 0901).

we want to compare high-resolution 3D-US with 2D-US for the examination of the median nerve. Methods: In 22 healthy probands 3D-US of both median nerves was performed by 2 examiners (Ex1, Ex2) using an 18 MHz linear transducer (Toshiba Aplio 500) connected to the Curefab CS (Curefab Technologies GmbH, Munich, Germany). A single virtual 3D-stack of the ventral forearm ranging from the distal wrist crease to 20 cm in proximal direction was generated. Subsequently, cross section area (CSA) of each median nerve was determined by common 2D-US in 3 randomly assigned distances (1–20 cm) proximal to the distal wrist crease. Finally, for each median nerve CSA was measured in the 3D-stack at the same distances as for 2D-US. Furthermore, quality of 3D-US was evaluated with a semi-quantitative scale (1: good quality, nerve and fibre structures can be depicted axially and horizontally; 2: sufficient quality, CSA measurement is possible, but horizontal visualisation of fibre structures is limited by blurry view or too much artefacts; 3: poor quality, CSA measurement is not possible). While 3D-US of the median nerve was done by 2 examiners, CSA measurements and evaluation of quality were done by 1 examiner. Results: CSA of the median nerve from 3D-US was 0.8 mm2 (Ex1) respectively 0.5 mm2 (Ex2) smaller than CSA obtained by 2D-US. Applying intraclass correlation coefficient, interrater agreement was moderate with 0.68. 88% of CSA from 3D-US differed by just ±1 mm2 between examiners. Quality assessment showed a good quality of 3D-data in 55% (Ex1) and 45% (Ex2), a sufficient quality in 39% and 48% and a poor quality with missing CSA analysis in just 6% respectively 7%. Furthermore, for 2D- and 3D-US, there was a significant inverse correlation between the distance from the wrist and the median nerve’s CSA (Pearson r = 0.32–0.36, each p < 0:05). Conclusion: Although it is technically challenging to scan the median nerve over a distance of 20 cm without interruption, 3D-US showed a moderate to good agreement with conventional 2D-US examination. Contrary to 2D-US, 3D-US allows measurements of CSA exactly perpendicular to the nerve’s course, thus yielding more accurate results. Therefore, we propose, that 3D-US of nerves is a promising diagnostic tool to minimise time effort by separating data acquisition from subsequent data analysis since the virtual 3D-stack contains all information for a profound offline evaluation; in addition 3D-US facilitates comparability of follow-up examinations.

References

doi:10.1016/j.clinph.2015.04.135

Baier B, Conrad J, Stephan T, Kirsch V, Vogt T, Wilting J, Müller-Forell W, Dieterich M (submitted) Vestibular Thalamus: Two distinct graviceptive pathways. submitted. Dieterich M, Brandt T. Thalamic infarctions: differential effects on vestibular function in the roll plane (35 patients). Neurology 1993;43:1732–40. Dieterich M, Brandt T. Functional brain imaging of peripheral and central vestibular disorders. Brain 2008;131:2538–52. Lopez C, Blanke O. The thalamocortical vestibular system in animals and humans. Brain Res Rev 2011;67:119–46. doi:10.1016/j.clinph.2015.04.134

P15. Evaluation and comparison of 3D-ultrasound of the median nerve with common 2D-ultrasound—J. Pelz, M. Busch, A. Weinreich, D. Saur (Universitätsklinikum Leipzig, Klinik und Poliklinik für Neurologie, Leipzig, Germany) Background: Ultrasound is still regarded as an imaging modality that considerably depends on the examiner’s experience. Additionally, storage of only single images or short video sequences restricts re-evaluation and repeated measurements. While 3D-ultrasound (3D-US) might overcome these limitations, its use is currently mainly hampered by relatively low image quality. Here,

P17. Early Huntington’s disease patients demonstrate micro-structural and functional connectivity changes in motor and basal ganglia-thalamic networks—H.-P. Müller a, J. Kassubek a, G. Grön b, M. Gorges a, G.B. Landwehrmeyer a, S.D. Süßmuth a, M. Orth a (a University of Ulm, Department of b Neurology, Ulm, Germany, University of Ulm, Section Neuropsychology and Functional Imaging, Department of Psychiatry, Ulm, Germany) Introduction: In Huntington’s disease (HD), cerebral white matter changes have been reported in a number of studies using diffusion tensor imaging (DTI) or T1-weighted magnetic resonance imaging (MRI). A key question is how brain structure changes (both grey and white matter) influence brain function. Intrinsic functional connectivity (ifc) MRI investigates intrinsic connectivity networks (ICN), i.e. large-scale distributed functionally coupled brain regions observed in the absence of a specific task. The objective of our study was to integrate structural connectivity data as assessed by DTI with ifcMRI changes in order to obtain a comprehensive picture of structural and functional changes with an emphasis on motor and basal ganglia thalamic networks.

Society Proceedings / Clinical Neurophysiology 126 (2015) e63–e170

Methods: Thirty-five early HD subjects (TFC stage 1 and 2) and 32 age- and sex-matched healthy controls underwent3T-MRI (T1w, DTI and ifcMRI sequences). DTI and ifcMRI data analyses were performed using the Tensor Imaging and Fiber Tracking (TIFT) software (Müller et al., 2007) for complementary DTI fiber tracking (FT) and ifcMRI data analysis. For the motor ICN ifcMRI analyses, the dominant M1 was used as the seed, for the basal ganglia-thalamic ICN the thalamus was used. In addition, the cortico-spinal tract (CST) and the thalamocortical pathway were used for comparisons at the group level. Results: Structural connectivity measured by DTI at the group level showed an increase of FA values in the basal ganglia as well as FA reductions in the external and internal capsule, in parts of the thalamus, and in subcortical white matter. Intrinsic functional connectivity (brain function) showed hyper-connectivity in the motor ICN, i.e. the insula was less connected in HD than in controls. The basal ganglia-thalamic ICN connectivity differed between HD and controls in the insula and the basal ganglia in both hemispheres. Conclusion: At the group level, we confirmed microstructural changes identified in previous DTI studies in HD (e.g. (Rosas et al., 2006)). There is evidence that the insula becomes disconnected from the motor cortex. The caudatum seems to lose its functional integration with widely distributed cortical areas (basal ganglio-thalamic ICN). Abnormal connectivity of the insula and caudatum may be relevant in the emergence of clinical signs of HD. Acknowledgements: This work was partially supported by the European Union under the Seventh Framework programme PADDINGTON Project, Grant Agreement No.261358, and the European Huntington’s Disease Network (EHDN), project 070 PADDINGTON. References Müller H-P, Unrath A, Ludolph AC, Kassubek J. Preservation of diffusion tensor properties during spatial normalization by use of tensor imaging and fiber tracking on a normal brain database. Phys Med Biol 2007;52:N99–109. Rosas HD, Tuch DS, Hevelone ND, Zaleta AK, Vangel M, Hersch SM, et al. Diffusion tensor imaging in presymptomatic and early Huntington’s disease: selective white matter pathology and its relationship to clinical measures. Mov Disord 2006;21:1317–25. doi:10.1016/j.clinph.2015.04.136

P18. Pattern of ‘resting-state’ functional hyperconnectivity in Amyotrophic lateral sclerosis reflects neuropathological disease stages—I. Röll, M. Gorges, H.-P. Müller, D. Lulé, A.C. Ludolph, J. Kassubek (University of Ulm, Department of Neurology, Ulm, Germany) Background: Autopsy-controlled studies in Amyotrophic lateral sclerosis (ALS) proposed a 4-stage sequential spreading of the underlying TDP-43 pathology (Brettschneider et al., 2013). Recently the in vivo transfer of the neuropathological stages by use of tract of interest-based diffusion-tensor-imaging (DTI) has been performed (Kassubek et al., 2014). Based upon the DTI findings, we have expanded the imaging approach by complementary investigation of ifc-fMRI in order to trace the pathology spreading in well-defined intrinsic functional connectivity networks (ICNs). Methods: We used a 3.0T resting state-fMRI protocol for 76 ALS patients and 28 healthy controls. The preprocessing followed standardized procedures including motion correction, MNI normalization, spatial filtering, temporal linear detrending and bandpass filtering. ICNs were identified utilizing the seed-based approach (Gorges et al., 2014). These ICNs comprised the motor (neuropathological stage 1), frontoparietal, frontal executive and brainstem

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(stage 2), basal ganglia (stage 3), and hippocampal (stage 4) networks; we used the visual ICN as reference. Results: ALS patients compared with healthy controls demonstrated a large-scale pattern of increased functional connectivity (hyperconnectivity) in all networks with the exception of the reference network. More specifically, the hyperconnectivity pattern extended spatially into adjacent brain structures following the neuropathological spreading. The hyperconnectivity in stage 1 extended into frontal areas, in stage 2 into prefrontal and postcentral areas, in stage 3 into prefrontal and postcentral areas, and in stage 4 within the hippocampal formation. Moreover, the disease stages as observed in vivo by DTI significantly correlated with increasing functional connectivity in the ICNs. Conclusion: Ifc-fMRI provides a promising approach to functionally trace pathological spreading in ALS. As recently suggested (Douaud et al., 2011), the loss of the inhibitory influence may be most likely attributable to the pattern of hyperconnectivity in ALS. With increasing stages of disease, hyperconnectivity seems to spread sequentially into more frontal and postcentral regions following the neuropathological spreading. References Brettschneider et al. Ann Neurol 2013;74:20–38. Douaud et al. Brain 2011;134:3470–9. Gorges et al. Biomed Res Int 2014;2014:947252. Kassubek et al. Brain 2014;137:1733–40. doi:10.1016/j.clinph.2015.04.137

P19. The brain’s default mode is associated with executive oculomotor deficits in Parkinson’s disease—M. Gorges, H.-P. Müller, A.C. Ludolph, E. Pinkhardt, J. Kassubek (University of Ulm, Department of Neurology, Ulm, Germany) Introduction: Eye movements provide a valuable window into complex forms of human behavior. Impaired eye movement control in patients with Parkinson’s disease (PD) has been consistently demonstrated besides the well-known motor symptoms (Pinkhardt and Kassubek, 2011). Saccadic intrusions are a common oculomotor manifestation in PD and interrupt smooth pursuit and fixation during tracking a ’jumping’ target (visually guided reactive saccades) (Pinkhardt and Kassubek, 2011; Gorges et al., 2014). The default mode network (DMN) as observed with ’resting-state’ functional MRI is crucially involved in higher cognitive processes such as attention (Buckner et al., 2008). We hypothesized that prevalence of saccadic intrusions in patients with PD reflects executive deficits which are closely associated with intrinsic functional connectivity (iFC) within the DMN. Methods: The analysis was based on 31 patients with PD and 22 age-matched healthy controls. We acquired ’resting-state’ functional MRI (3 Tesla; BOLD-sensitive T2⁄-sequence) and video-oculographic recordings (VOG, Eye-Link I operating on 250 Hz sampling rate) of smooth pursuit eye movements and visually guided reactive saccades. ’Resting-state’ functional MRI analysis followed standardized procedures (Gorges et al., 2014) with the DMN computed by seeding the posterior cingulate cortex (Buckner et al., 2008). The posterior cingulate cortex is known to be both a major node of the DMN (Buckner et al., 2008) and to play a critical role in eye movement control (Olson et al., 1996). Both smooth pursuit gain as a measure for saccadic intrusions and the saccadic intrusion rate during reactive saccades were analyzed in patients vs. controls and correlated with iFC within the DMN. Results: VOG analysis revealed a significantly higher prevalence of saccadic intrusions during smooth pursuit (p < 0.001) and reactive