- Email: [email protected]
Chapter 41 Clinical use of magnetoencephalography
Clinical Neurophysiology at the Beginning of the 21s1Century (Supplements 10Clinical Neurophysiology Vol. 53) Editors: Z. Ambler. S. Nevsfmalova, Z. Kadailka,P.M. Rossini © 2000 ElsevierSeience B.V. All rights reserved.
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Chapter 41
Clinical use of magnetoencephalography N. Forss*, N. Nakasato, J. Ebersole, T. Nagamine and R. Salmelin Brain Research Unit, Helsinki University of Technology, SF-02150 Espoo (Finland)
Introduction Cortical magnetic signals are believed to originate from thousands of postsynaptic currents flowing in synchrony within a few square centimeters of cortex. The synchronized intracellular currents of the pyramidal cells generate magnetic fields that can be measured non-invasively outside the head with a very sensitive magnetometer (Hamalainen et al. 1993). In magnetoencephalography recordings (MEG) distribution and reactivity of spontaneous brain oscillations and evoked responses to different external stimuli can be studied. Benefits and drawbacks of MEG in clinical studies
MEG has already proved to be a useful tool in basic brain research, and it is likely to be suitable also for clinical applications. Most importantly, patients are not subjected to radioactive traces, X-rays or powerful magnetic fields, and thus the measurements are truly non-invasive. In addition, MEG recordings are fast and easy to perform. With MEG it is possible to combine excellent
* Correspondence to: Dr. Nina Forss, Brain Research Unit, Helsinki University of Technology, Otakaari 3A, SF02150 Espoo (Finland). E-mail: [email protected]
temporal resolution with reasonably good spatial resolution, because MEG, like EEG, measures directly electromagnetic signals of the brain activity instead of activity related changes in metabolism or blood flow. On the other hand, MEG measurements usually require a magnetically shielded environment and well-trained personnel to take care of measurements and analyses of the data. Further, in MEG recordings the data has to be modeled to achieve accurate localization of active brain areas. Recordings also require co-operation of the patient, at least to some extent, and therefore measurements of disoriented or restless patients can be difficult. However, most of these problems are shared with other brain imaging techniques. MEG has two important clinical applications that are already available; localization of the epileptogenic cortex with respect to functional landmarks and functionally important cortical areas, and preoperative localization of functionally important cortical areas in brain tumor patients. It is most likely that also other clinical applications of MEG will be found, but further research is needed to develop suitable stimulation set-ups and analysis methods to help diagnosis and follow-up of different neurological patient groups. In the following, experiences of MEG recordings in preoperative patient evaluation, localization of epileptogenic foci, and in motor and language disorders are described.
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Anatomo-functional correspondence in the hand sensori-motor cortices revealed by MEG, functional MR imaging and intraoperative cortical stimulation (N, Nakasato, Tohoku University School of Medicine) Anatomical magnetic resonance (MR) imaging can be used to identify the central sulcus (CS) (Ebeling et al. 1989). The somatotopic map of the primary motor cortex has a clear anatomical localization. Functional MR imaging has shown that the motor hand area is located in a knob-like structure shaped like an omega in the axial plane (Yousry et al. 1997). In this presentation, the relation between location of the somatosensory representation area of the hand and anatomical structures were studied using magnetoencephalography (MEG) and functional MR imaging (fMRI). In our previous study (Ohtomo et al. 1996) somatosensory evoked fields (SEFs) were measured to stimuli delivered to the 5 digits in 6 normal subjects, using an MR imaging-linked helmetshaped MEG system with 64 channel axial gradiometers (CTF Systems, Canada). The results revealed that the primary somatosensory cortex of the hand digits is located within one convexity of the posterior bank of the CS. The individual digit dipoles were arranged from lateral inferior to medial superior in the order of thumb to little finger. The dipole positions were curved out towards the anterior, superior and medial directions. The mean separation of the N20 dipole positions was 13.9 mm between the thumb and little finger. In addition, the digit dipole orientations were spread from the anterior horizontal direction to the medial superior direction, almost perpendicular to the CS, in the same order (Fig. I). Subsequently, we found that the convexity, in which the digit N20m sources were located, corresponded to the lateral part of the inverted-omega shape. In our more recent study, SEFs were evoked by stimuli on the thumb, median nerve and ulnar nerve in 5 patients with glioma near the CS. SEFs were recorded with the 64 channel MEG system (CTF Systems, Port Coquitlum, Canada) in 4 patients before surgery, and with the MR imaging-linked helmet-shaped MEG system with 122 channel
planar type gradiometers (Neuromag Co., Ltd., Helsinki, Finland) in one patient after surgery. All 5 patients were also studied with fMRI for motor tasks before surgery (Inoue et aJ. 2000). The presurgical non-invasive functional maps were confirmed by intraoperative cortical stimulation during awake craniotomy in all 5 patients (Nakasato et aJ. 1998), navigated by a frame less stereotaxic system (Viewing Wand, ELEKTA K.K., Kobe, Japan). Fig. 2 illustrates a typical example of functional mapping of the hand area related to the CS anatomy. Before surgery, fMRI during hand grasping indicated highest activation within the precentral knob and along the lateral part of the inverted-omega shape, corresponding to the Superior ,
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Anterior Fig. I. Orientation of the N20m dipole of the somatosensory evoked fields in 10 normal hemispheres. Each bar indicates the averaged N20m directions evoked by stimulus of the contralateral median nerve, ulnar nerve and hand digits (01-05). The mean separation of the N20 dipole positions was 13.9 mm between thumb and little finger (Ohtomo et al. 1996).
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Our findings suggest that the somatotopic localization of the sensori-motor cortex of the hand and digit areas is strongly correlated with the invertedomega shape of the CS. Consequently, awake mapping during surgery is not necessary in most patients with glioma located near the CS if the findings of non-invasive functional mapping, such as MEG and fMR!, are available before surgery. However, intraoperative cortical and subcortical mapping and monitoring of the motor function remain useful and can be performed under general anesthesia (Berger et al. 1990).
MEG in the evaluation of epileptic patients (J. Ebersole, Yale University School of Medicine)
Fig. 2. Functional anatomy in the primary sensori-motor areas of a patient with glioma near the face motor cortex. Note the inverted-omega shaped central sulcus on the axial image. The functional MR imaging signal activated by hand grasping was located in the 'precentral knob' near the center of the inverted-omega shape and the posterior end of the superior frontal sulcus. In contrast, the somatosensory evoked N20m dipoles are localized in the lateral half of the inverted-omega shape.
previous report (Yousry et al. 1997). In magnetic recordings, N20m sources of the SEFs were located along the lateral half of the inverted-omega shape in the order of thumb, median nerve and ulnar nerve from lateral inferior to medial superior positions on the CS. Dipole orientation of the thumb N20m was the most anterior and the ulnar N20m was the most medial and superior. Intraoperative cortical stimulation in the 5 patients with glioma indicated that the thumb sensory cortex was located at the lateral part of the inverted-omega shape.
There is great interest in improving techniques for localizing epileptogenic foci non-invasively, This interest is driven both by economic factors and by an attempt to minimize procedures with possible morbidity. Structural imaging techniques have added much to the evaluation of epileptic conditions in recent years, however, functional localization is still required prior to resective surgery. Functional imaging techniques, such as PET, SPECT, and fMRI, are secondary measures of epileptic activity based on altered glucose metabolism or blood flow/oxygenation. Only MEG and EEG offer direct measurements of epileptic physiology with real-time, millisecond resolution. Source models of these signals have recently been used to determine the origin of this abnormal brain activity. MEG, however, has certain advantages over EEG when used for source modeling; MEG is not distorted by the skull, unlike EEG, and the spatial sampling provided by the new whole-head imaging systems is superior to EEG. Although MEG hardware has significantly improved over the recent years, clinical MEG data analysis procedures have failed to keep pace. Source modeling techniques and interpretation methods are essentially the same as when initially developed. Numerous investigations have shown that MEG source models, such as equivalent current dipoles, can localize the cerebral sources of spikes with considerable accuracy. Commonly MEG
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studies have demonstrated that dipole localization of spikes concurs with other diagnostic findings, such as EEG, both scalp and intracranial, MRI lesions, PET abnormalities, and surgical outcome (Knowlton et al. 1997; Kirchberger et al. 1998; Lamusuo et al. 1999; Paetau et al. 1999; Wheless et al. 1999). The question then is, 'Why has MEG not become a routine tool for the clinical evaluation of epileptic conditions?' The answers are probably several - expense, complexity, and not sufficient usefulness beyond EEG and imaging techniques. Perhaps another other factor constraining MEG's ultimate clinical usefulness are current source modeling techniques and interpretation concepts. Several erroneous ideas about epileptogenic foci have persisted in the MEG literature. It has often been assumed that epileptic spike sources measured by MEG are found in individual sulci. Certainly such a location provides the proper orientation for the generation of a tangential field for which MEG is sensitive. However, recent intracranial EEG studies have shown that the area of cortical sources which produce scalp-recordable EEG fields are quite large, minimally 6 crrr' and commonly up to 20 crrr' or more (Ebersole et al. 1995a; Ebersole 1997a). With sources of such size, the EEG (and MEG) fields from individual sulci tend to cancel because of the opposing orientation of sulcal walls. Gyral cortex is commonly the source of both EEG and MEG spikes. Tangential fields can easily be produced by gyral cortex with the proper orientation. In temporal lobe, for example, basal cortex, temporal tip cortex, and superior temporal plane cortex all have an appropriate orientation for the production of MEG-recordable spikes. Lateral temporal lobe cortex, on the other hand, would produce principally radial fields recordable by EEG, but not necessarily by MEG. Distinguishing among sublobar cortical sources by either technique is thus most easily accomplished by identifying the orientation, as well as location, of equivalent dipoles. The same principles hold for spike sources located in extra-temporal cortex. There has also been a preoccupation with spike modeling only at the instant of maximal MEG field dipolarity. Unfortunately this moment commonly occurs at the peak of the spike, which is several
tens of milliseconds after its onset. By this time the spike source is very likely to be more complicated than it was earlier. Because propagation is very common among epileptic discharges, source models of spike peaks may not reflect spike origins. Clinically, it is more important to determine where a spike starts than where it goes. Using this rationale, it makes sense to model earlier portions of the spike field, even if the signal to noise and dipolarity are less. Similarly, because spikes of all regions tend to propagate it also makes little sense to use only a single dipole model. The moving, single dipole model may be reasonable in cases where the spike source is simple, the spike propagation is unidirectional, and spike propagation is completed before the spike origin repolarizes. Otherwise a complex composite field will result, which will be improperly modeled by a single dipole. Complex, evolving magnetic fields may be better modeled by a spatio-temporal multiple dipole approach. This method can take in the into account a temporal overlap of activity among several sources. It has been shown to be particularly useful for propagating spikes (Ebersole 1994, 1997a,c). As noted above, most previous MEG studies of epilepsy emphasized dipole location when attempting to localize spike sources. Unfortunately, this may lead to erroneous interpretations. For example, MEG dipole models of large temporal lobe sources may be located deep into the actual generating cortex. Without regarding dipole orientation, one assumption can be that such dipoles reflect activity recorded directly from the hippocampus. In most instances this is incorrect. Spike or seizure activity restricted to the hippocampus is unlikely to produce surface-recordable fields because the source is small, deep, and curved in shape, which favors field cancellation. Studies using simultaneous intracranial and scalp EEG, as well as intracranial EEG and MEG, have shown that epileptic activity restricted to the hippocampus does not produce scalp-recordable EEG or MEG signals without intracranial EEG triggering or averaging techniques (Ebersole et al. 1995a; Ebersole 1997a; Knowlton et al. 1997). Instead, it is the common propagation of hippocampal activity to
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entorhinal and basal cortex and from there to temporal tip cortex, which provides sufficient source area. Using 37-, 74-, and most recently 148-channel MEG (BTl Magnes), we have identified 3 distinctive types of temporal lobe spike dipoles and have compared these with the results of MRI imaging and intracranial EEG monitoring in the same patients (Ebersole et al. 1995b; c; Ebersole I997b; c). These dipole patterns are distinguishable by their location, orientation, and propagation pathways. Anterior temporal horizontal dipoles
One group of MEG spikes were modeled by dipoles located in the anterior temporal lobe that had a predominantly horizontal and anteroposterior (AP) orientation. These spikes often had stable magnetic fields over time, suggesting a nonpropagating source. Only cortex of the temporal lobe tip would have the appropriate net orientation for such a dipolar source. Other spikes within this group had fields that evolved over milliseconds. Moving single or multiple spatio-temporal dipole modeling commonly revealed that the earliest magnetic field corresponded to a vertical dipole, which most likely represents activity in the temporal lobe base. Within 30 ms the magnetic field rotated to yield the AP-horizontal dipole orientation characteristic of this spike type. This evolution suggests spike propagation from basal to temporal tip cortex (see Fig. I). MEG spikes of this anterior temporal, AP-horizontal (ATH) class almost always were associated with prominent EEG spikes. The peak of the EEG spike was typically synchronous with or followed the peak of the MEG spike. Voltage topographic maps of the EEG spikes revealed an inferior fronto-temporal negative maximum and a vertex or posterior positive maximum, that is characteristic of the so-called type I spike (Ebersole and Wade 1991; Ebersole 1994). Dipole models of these EEG spikes commonly showed initial orientations that were similar to MEG dipoles, but later in the spike EEG dipoles often took on a more radial orientation. This suggests that some of
these spikes continued to propagate from the temporal tip to the lateral temporal cortex, where they could no longer be appreciated by MEG. Patients having predominantly ATH spikes commonly had ipsilateral hippocampal atrophy on their brain MRIs and had seizures localized to the mesial temporal region on intracranial EEG monitoring. Anterior temporal vertical dipoles
A second group of MEG spikes (ATV) were modeled by dipoles that were also in the anterior temporal region, however, their location was more superior and their orientation was vertical, when modeling the spike peak. Cortex of the anterior superior temporal plane has the appropriate net orientation to be the generator of these spikes. ATV spikes had both stable and evolving fields. In the latter case, dipole models of the earliest magnetic field often had a horizontal orientation similar to the ATH spike group. Subsequently the dipoles rotated to assume the vertical orientation. This progression is consistent with spike propagation from the anterior temporal tip to its superior surface (see Fig. 2). The opposite direction of propagation was also noted in the spikes of some patients. ATV MEG spikes often did not have a distinct EEG counterpart. When they did, it was associated with the horizontal ATH-like component of a propagating spike. Patients with ATV spikes had a 50150 chance of having hippocampal atrophy on MRI, but all of them had seizures beginning in the anterior temporal lobe, including basal or temporal tip cortex. Posterior temporal vertical dipoles
The final group of MEG spikes were modeled by dipoles located superiorly in the mid- to posterior temporal region and having a vertical orientation (PTV). The superior temporal plane is the most likely source for this dipole orientation. PTV spikes usually had stable magnetic fields, but occasionally field rotation suggested localized propagation. PTV spikes were seldom associated with an EEG field (see Fig. 3). Brain MRI findings in these patients
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Fig. 3. Left: a tight cluster of single dipole models of temporal lobe MEG spikes having an anterior temporal location and a horizontal, antero-postero orientation. The temporal tip cortex would have appropriate orientation for such a dipolar source. Right: spatio-temporal, two dipole models of two temporal lobe MEG spikes. The initial spike field is modeled by the vertical dipoles, whereas the later spike peak is modeled by the horizontal, antero-postero dipoles. These changes in spike suggest propagation from temporal basal to temporal tip cortex.
were variable, including lesions, dysplasias, hippocampal atrophy, or normal. Intracranial EEG seizures in this group began principally in lateral temporal neocortex or were unlocalized (Figs. 4-8).
We conclude that MEG can be a clinically useful tool in the evaluation of epileptic patients. Sublobar
Fig. 4. A cluster of single dipole models of temporal lobe MEG spikes having an anterior and superior temporallocation and vertical orientation. Cortex of the anterior superior plane would have an appropriate orientation for such a dipolar source.
Fig. 5. A cluster of single dipole models of temporal lobe MEG spikes having a posterior and superior temporal location and a vertical orientation. Cortex of the posterior superior temporal plane would have an appropriate orientation for such a dipolar source.
Conclusion
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course of the spike. Such MEG analysis may identify among epilepsy surgery candidates those patients who do not need invasive EEG monitoring prior to standard temporal lobectomy and those patients who probably do need such additional investigations. In the latter, MEG dipole modeling can help guide the placement of intracranial electrodes for chronic or intra-operative electrocorticographic recordings.
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Fig. 6. Top: source areas of the N400 semantic response, collected from 10 subjects. Bottom: source waveforms to the 4 different types of sentence-ending words in one subject. Modified from Helenius et al. (1998).
localization of spike sources and propagation patterns within the temporal lobe can be achieved by characterizing MEG spike dipole orientation, as well as location, and its evolution over the time
Recent advances in MEG have given us a better insight into the sites of brain lesions causing movement disturbance, owing to its high spatial resolution. As for the disturbances of voluntary movements, movement-related cortical magnetic field (MRCF) is helpful in detecting the responsible brain lesions, if a patient can perform self-paced movement with the affected body part. Backward averaging of the magnetic field with respect to the movement can
Fig. 7. Cortical activation sequence, collected from 10 subjects, when they were reading aloud single words. The word was shown at time 0 and the vocalization prompt appeared at 800 ms. See text for details. Modified from Salmelin et al. (2000).
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Fig. 8. Responses to vowel (thick curve) and tone sequences (thin curve) in one subject, from single MEG sensors over the left and right temporal lobe (filled squares). The relative response strengths were calculated over the time intervals denoted by the gray bars. Modified from Gootjes et aJ. (l999).
disclose the location of the primary motor area, and its dearrangement or dislocation from the known area. Dissociation of its location from the somatosensory area, in relation to the central sulcus, sometimes supports this evidence. However, the conventional MRCF involves inherent drawbacks for recordings from those who cannot perform brisk movements. For those patients, easier movements such as rapid rate movement at 2 Hz frequency or continuous isometric contraction can assist the source localization for motor cortex. Furthermore, analysis of the background rhythm can be applied to detect motor area, since its change occurs in bilateral areas even with the unilateral movement. Sources of the jerky involuntary movements can also be investigated by jerk-locked back averaging (JLA). In MEG recordings, JLA can differentiate whether the jerky movement is derived from the small cortical region or from the widely-distributed area suggesting subcortical origin. JLA is also useful for detecting the epileptogenic foci when the initiation of the clonic movement can be identified. Further, jerk-locked magnetic field recording can be useful for delineating pathophysiology of involuntary movements.
MEG in language disorders (R. Salmelin, Helsinki University of Technology) Language function encompasses a multitude of subprocesses. Perception may occur via auditory,
visual, or tactile pathways. Comprehension of single words, sentences, or continuous text or discourse may depend on slightly different networks. Semantic and syntactic processing are likely to have partly separate cortical representations. Also, language reception and production are two different things. Production can happen via speech, writing, or signing. One must not forget prosody, the rhythm and intonation, which is a relevant component of speech production and also comprehension. Which aspects of language should one map to 'locate language' for clinical purposes? It would be of paramount importance to know before the MEG measurement if the subject has particular language problems, so one could probe at least those processes. There are several approaches for mapping the language function. One may systematically vary stimuli or tasks and observe the effects in the brain to reveal cortical representation of specific processes such as semantics, phonology, and others. On the other hand, comparison between subjects with normal and impaired language function may help to recognize brain areas and time windows which are relevant or even critical for certain processes. One may study subjects with impairments caused by lesions - aphasics. We have found it particularly interesting to study subjects who have a functional impairment with no clearcut structural abnormalities, such as dyslexics (Salmelin et al. 1996; Helenius et al. 1999a; b) and stuttering subjects (Salmelin et al. 1998; 2000). In the following, 3 examples are given of how we may use MEG to characterize language function. Example 1: reading comprehension
To identify cortical dynamics of reading comprehension, we employed a well-established, so-called N400 paradigm (Kutas and Hillyard 1980), where the subjects are shown sentences which create a very high expectation for a certain final word and one then plays with the appropriateness of that final word in the sentence context. In our sentences the final word was either expected, like in The piano was out of tune, rare
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but semantically possible, like in When the power went out the house became quiet, when it seems that most people would expect dark, totally anomalous, like in The pizza was too hot to sing, or something we call phonological, like in The gambler had a streak of bad luggage, instead of luck, where the first letters looked and sounded the same as those in the expected word (Connolly et al. 1995). While the visual responses were the same for all word types, neuronal populations in the left superior temporal cortex showed the typical N400 behavior, reflecting semantic processing, consistently across subjects (Fig. I). The totally wrong endings resulted in a prominent deflection, peaking at about 400 ms after word onset (Helenius et al. 1998). The signal was significantly smaller for the rare but possible final words and basically flat for the expected words. For this visual reading task, the most pronounced source cluster was in the immediate vicinity of the auditory cortex. In some subjects, the posterior end of the sylvian fissure was also involved. The occasional activation in the right superior temporal cortex was smaller and later than in the left hemisphere. The MEG activation was thus strongly lateralized to the language-dominant left hemisphere in this reading comprehension task.
Example 2: reading words aloud Fig. 2 illustrates the sequence of activation when reading words aloud, with the cortical source waveforms averaged across 10 fluent speakers (Salmelin et aI., 2000). One problem in speech tasks is that vocalization is accompanied by serious artifact signals from face muscles and tongue which mask the brain activity. However, with careful artifact removal, it is possible to analyze the data up to speech onset and even beyond it. Because of the artifacts, we used delayed reading to focus on the preparatory phases. The words were shown for 300 ms. After a blank interval of 500 ms, a question mark appeared, prompting the subject to read the word aloud. The response started about 200 ms later. Like in silent reading, the sources cluster close to the occipital midline and in the left and right occipitotemporal cortices within the first 200
ms. The visual nature of these responses is emphasized by the second response to the question mark. The left superior temporal and inferior parietal responses peak at about 400 ms, as for silent reading. However, in this speech task, there is also activation in the left inferior frontal cortex, approximately Broca's area, starting about 200 ms after word onset. All these responses fade away before the vocalization prompt. The signals depicted in the right-most column begin at about 200-300 ms and persist until actual vocalization and even beyond it. This is reasonable as they arise in the left and right motor cortices and apparently in the supplementary motor area.
Example 3: hemispheric dominance of language function After these examples, one may wonder if it is at all possible to think of language as a lateralized function. Yet, there is no question that in most people language is critically controlled by one hemisphere. Recently, there have been attempts to find simple tests for non-invasive determination of the language-dominant hemisphere. Two groups have used the number of dipolar sources in each hemisphere as the criterion. With visual words as stimuli, dipolar patterns were lateralized to the language-dominant hemisphere, reportedly in agreement with the Wada test (Zouridakis et al. 1998; Papanicolaou et al. 1999). For auditory stimuli, left-hemisphere dominance of dipolar patterns was found for vowels but not for tones (Szymanski et al. 1999). It is, however, unclear whether the more or less dipolar character of the field pattern has any physiological significance. We have recently developed a paradigm where the relative response strengths are compared within each hemisphere, with no need for source modeling (Gootjes et al. 1999). In our approach, the subjects detected targets in tone and vowel sequences. We tested two sequence types, one with 4 stimuli and the other with two stimuli. The target sequence (20% of the stimuli) started and ended with the same vowel or tone. The analysis was performed on the non-targets. Fig. 3 depicts responses to vowels and tones, over the left and right temporal
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cortices. The 4 prominent peaks are responses to the onsets of the 4 stimuli in the sequence. We calculated ratios of the responses to vowels and tones for the first deflection and for the sustained response. Left-hemisphere dominance was detected in all of the 11 subjects, for the sustained response in the two-stimulus task. Comparisons with the Wada test are under way.
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Chapter 41
Clinical use of magnetoencephalography N. Forss*, N. Nakasato, J. Ebersole, T. Nagamine and R. Salmelin Brain Research Unit, Helsinki University of Technology, SF-02150 Espoo (Finland)
Introduction Cortical magnetic signals are believed to originate from thousands of postsynaptic currents flowing in synchrony within a few square centimeters of cortex. The synchronized intracellular currents of the pyramidal cells generate magnetic fields that can be measured non-invasively outside the head with a very sensitive magnetometer (Hamalainen et al. 1993). In magnetoencephalography recordings (MEG) distribution and reactivity of spontaneous brain oscillations and evoked responses to different external stimuli can be studied. Benefits and drawbacks of MEG in clinical studies
MEG has already proved to be a useful tool in basic brain research, and it is likely to be suitable also for clinical applications. Most importantly, patients are not subjected to radioactive traces, X-rays or powerful magnetic fields, and thus the measurements are truly non-invasive. In addition, MEG recordings are fast and easy to perform. With MEG it is possible to combine excellent
* Correspondence to: Dr. Nina Forss, Brain Research Unit, Helsinki University of Technology, Otakaari 3A, SF02150 Espoo (Finland). E-mail: [email protected]
temporal resolution with reasonably good spatial resolution, because MEG, like EEG, measures directly electromagnetic signals of the brain activity instead of activity related changes in metabolism or blood flow. On the other hand, MEG measurements usually require a magnetically shielded environment and well-trained personnel to take care of measurements and analyses of the data. Further, in MEG recordings the data has to be modeled to achieve accurate localization of active brain areas. Recordings also require co-operation of the patient, at least to some extent, and therefore measurements of disoriented or restless patients can be difficult. However, most of these problems are shared with other brain imaging techniques. MEG has two important clinical applications that are already available; localization of the epileptogenic cortex with respect to functional landmarks and functionally important cortical areas, and preoperative localization of functionally important cortical areas in brain tumor patients. It is most likely that also other clinical applications of MEG will be found, but further research is needed to develop suitable stimulation set-ups and analysis methods to help diagnosis and follow-up of different neurological patient groups. In the following, experiences of MEG recordings in preoperative patient evaluation, localization of epileptogenic foci, and in motor and language disorders are described.
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Anatomo-functional correspondence in the hand sensori-motor cortices revealed by MEG, functional MR imaging and intraoperative cortical stimulation (N, Nakasato, Tohoku University School of Medicine) Anatomical magnetic resonance (MR) imaging can be used to identify the central sulcus (CS) (Ebeling et al. 1989). The somatotopic map of the primary motor cortex has a clear anatomical localization. Functional MR imaging has shown that the motor hand area is located in a knob-like structure shaped like an omega in the axial plane (Yousry et al. 1997). In this presentation, the relation between location of the somatosensory representation area of the hand and anatomical structures were studied using magnetoencephalography (MEG) and functional MR imaging (fMRI). In our previous study (Ohtomo et al. 1996) somatosensory evoked fields (SEFs) were measured to stimuli delivered to the 5 digits in 6 normal subjects, using an MR imaging-linked helmetshaped MEG system with 64 channel axial gradiometers (CTF Systems, Canada). The results revealed that the primary somatosensory cortex of the hand digits is located within one convexity of the posterior bank of the CS. The individual digit dipoles were arranged from lateral inferior to medial superior in the order of thumb to little finger. The dipole positions were curved out towards the anterior, superior and medial directions. The mean separation of the N20 dipole positions was 13.9 mm between the thumb and little finger. In addition, the digit dipole orientations were spread from the anterior horizontal direction to the medial superior direction, almost perpendicular to the CS, in the same order (Fig. I). Subsequently, we found that the convexity, in which the digit N20m sources were located, corresponded to the lateral part of the inverted-omega shape. In our more recent study, SEFs were evoked by stimuli on the thumb, median nerve and ulnar nerve in 5 patients with glioma near the CS. SEFs were recorded with the 64 channel MEG system (CTF Systems, Port Coquitlum, Canada) in 4 patients before surgery, and with the MR imaging-linked helmet-shaped MEG system with 122 channel
planar type gradiometers (Neuromag Co., Ltd., Helsinki, Finland) in one patient after surgery. All 5 patients were also studied with fMRI for motor tasks before surgery (Inoue et aJ. 2000). The presurgical non-invasive functional maps were confirmed by intraoperative cortical stimulation during awake craniotomy in all 5 patients (Nakasato et aJ. 1998), navigated by a frame less stereotaxic system (Viewing Wand, ELEKTA K.K., Kobe, Japan). Fig. 2 illustrates a typical example of functional mapping of the hand area related to the CS anatomy. Before surgery, fMRI during hand grasping indicated highest activation within the precentral knob and along the lateral part of the inverted-omega shape, corresponding to the Superior ,
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Our findings suggest that the somatotopic localization of the sensori-motor cortex of the hand and digit areas is strongly correlated with the invertedomega shape of the CS. Consequently, awake mapping during surgery is not necessary in most patients with glioma located near the CS if the findings of non-invasive functional mapping, such as MEG and fMR!, are available before surgery. However, intraoperative cortical and subcortical mapping and monitoring of the motor function remain useful and can be performed under general anesthesia (Berger et al. 1990).
MEG in the evaluation of epileptic patients (J. Ebersole, Yale University School of Medicine)
Fig. 2. Functional anatomy in the primary sensori-motor areas of a patient with glioma near the face motor cortex. Note the inverted-omega shaped central sulcus on the axial image. The functional MR imaging signal activated by hand grasping was located in the 'precentral knob' near the center of the inverted-omega shape and the posterior end of the superior frontal sulcus. In contrast, the somatosensory evoked N20m dipoles are localized in the lateral half of the inverted-omega shape.
previous report (Yousry et al. 1997). In magnetic recordings, N20m sources of the SEFs were located along the lateral half of the inverted-omega shape in the order of thumb, median nerve and ulnar nerve from lateral inferior to medial superior positions on the CS. Dipole orientation of the thumb N20m was the most anterior and the ulnar N20m was the most medial and superior. Intraoperative cortical stimulation in the 5 patients with glioma indicated that the thumb sensory cortex was located at the lateral part of the inverted-omega shape.
There is great interest in improving techniques for localizing epileptogenic foci non-invasively, This interest is driven both by economic factors and by an attempt to minimize procedures with possible morbidity. Structural imaging techniques have added much to the evaluation of epileptic conditions in recent years, however, functional localization is still required prior to resective surgery. Functional imaging techniques, such as PET, SPECT, and fMRI, are secondary measures of epileptic activity based on altered glucose metabolism or blood flow/oxygenation. Only MEG and EEG offer direct measurements of epileptic physiology with real-time, millisecond resolution. Source models of these signals have recently been used to determine the origin of this abnormal brain activity. MEG, however, has certain advantages over EEG when used for source modeling; MEG is not distorted by the skull, unlike EEG, and the spatial sampling provided by the new whole-head imaging systems is superior to EEG. Although MEG hardware has significantly improved over the recent years, clinical MEG data analysis procedures have failed to keep pace. Source modeling techniques and interpretation methods are essentially the same as when initially developed. Numerous investigations have shown that MEG source models, such as equivalent current dipoles, can localize the cerebral sources of spikes with considerable accuracy. Commonly MEG
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studies have demonstrated that dipole localization of spikes concurs with other diagnostic findings, such as EEG, both scalp and intracranial, MRI lesions, PET abnormalities, and surgical outcome (Knowlton et al. 1997; Kirchberger et al. 1998; Lamusuo et al. 1999; Paetau et al. 1999; Wheless et al. 1999). The question then is, 'Why has MEG not become a routine tool for the clinical evaluation of epileptic conditions?' The answers are probably several - expense, complexity, and not sufficient usefulness beyond EEG and imaging techniques. Perhaps another other factor constraining MEG's ultimate clinical usefulness are current source modeling techniques and interpretation concepts. Several erroneous ideas about epileptogenic foci have persisted in the MEG literature. It has often been assumed that epileptic spike sources measured by MEG are found in individual sulci. Certainly such a location provides the proper orientation for the generation of a tangential field for which MEG is sensitive. However, recent intracranial EEG studies have shown that the area of cortical sources which produce scalp-recordable EEG fields are quite large, minimally 6 crrr' and commonly up to 20 crrr' or more (Ebersole et al. 1995a; Ebersole 1997a). With sources of such size, the EEG (and MEG) fields from individual sulci tend to cancel because of the opposing orientation of sulcal walls. Gyral cortex is commonly the source of both EEG and MEG spikes. Tangential fields can easily be produced by gyral cortex with the proper orientation. In temporal lobe, for example, basal cortex, temporal tip cortex, and superior temporal plane cortex all have an appropriate orientation for the production of MEG-recordable spikes. Lateral temporal lobe cortex, on the other hand, would produce principally radial fields recordable by EEG, but not necessarily by MEG. Distinguishing among sublobar cortical sources by either technique is thus most easily accomplished by identifying the orientation, as well as location, of equivalent dipoles. The same principles hold for spike sources located in extra-temporal cortex. There has also been a preoccupation with spike modeling only at the instant of maximal MEG field dipolarity. Unfortunately this moment commonly occurs at the peak of the spike, which is several
tens of milliseconds after its onset. By this time the spike source is very likely to be more complicated than it was earlier. Because propagation is very common among epileptic discharges, source models of spike peaks may not reflect spike origins. Clinically, it is more important to determine where a spike starts than where it goes. Using this rationale, it makes sense to model earlier portions of the spike field, even if the signal to noise and dipolarity are less. Similarly, because spikes of all regions tend to propagate it also makes little sense to use only a single dipole model. The moving, single dipole model may be reasonable in cases where the spike source is simple, the spike propagation is unidirectional, and spike propagation is completed before the spike origin repolarizes. Otherwise a complex composite field will result, which will be improperly modeled by a single dipole. Complex, evolving magnetic fields may be better modeled by a spatio-temporal multiple dipole approach. This method can take in the into account a temporal overlap of activity among several sources. It has been shown to be particularly useful for propagating spikes (Ebersole 1994, 1997a,c). As noted above, most previous MEG studies of epilepsy emphasized dipole location when attempting to localize spike sources. Unfortunately, this may lead to erroneous interpretations. For example, MEG dipole models of large temporal lobe sources may be located deep into the actual generating cortex. Without regarding dipole orientation, one assumption can be that such dipoles reflect activity recorded directly from the hippocampus. In most instances this is incorrect. Spike or seizure activity restricted to the hippocampus is unlikely to produce surface-recordable fields because the source is small, deep, and curved in shape, which favors field cancellation. Studies using simultaneous intracranial and scalp EEG, as well as intracranial EEG and MEG, have shown that epileptic activity restricted to the hippocampus does not produce scalp-recordable EEG or MEG signals without intracranial EEG triggering or averaging techniques (Ebersole et al. 1995a; Ebersole 1997a; Knowlton et al. 1997). Instead, it is the common propagation of hippocampal activity to
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entorhinal and basal cortex and from there to temporal tip cortex, which provides sufficient source area. Using 37-, 74-, and most recently 148-channel MEG (BTl Magnes), we have identified 3 distinctive types of temporal lobe spike dipoles and have compared these with the results of MRI imaging and intracranial EEG monitoring in the same patients (Ebersole et al. 1995b; c; Ebersole I997b; c). These dipole patterns are distinguishable by their location, orientation, and propagation pathways. Anterior temporal horizontal dipoles
One group of MEG spikes were modeled by dipoles located in the anterior temporal lobe that had a predominantly horizontal and anteroposterior (AP) orientation. These spikes often had stable magnetic fields over time, suggesting a nonpropagating source. Only cortex of the temporal lobe tip would have the appropriate net orientation for such a dipolar source. Other spikes within this group had fields that evolved over milliseconds. Moving single or multiple spatio-temporal dipole modeling commonly revealed that the earliest magnetic field corresponded to a vertical dipole, which most likely represents activity in the temporal lobe base. Within 30 ms the magnetic field rotated to yield the AP-horizontal dipole orientation characteristic of this spike type. This evolution suggests spike propagation from basal to temporal tip cortex (see Fig. I). MEG spikes of this anterior temporal, AP-horizontal (ATH) class almost always were associated with prominent EEG spikes. The peak of the EEG spike was typically synchronous with or followed the peak of the MEG spike. Voltage topographic maps of the EEG spikes revealed an inferior fronto-temporal negative maximum and a vertex or posterior positive maximum, that is characteristic of the so-called type I spike (Ebersole and Wade 1991; Ebersole 1994). Dipole models of these EEG spikes commonly showed initial orientations that were similar to MEG dipoles, but later in the spike EEG dipoles often took on a more radial orientation. This suggests that some of
these spikes continued to propagate from the temporal tip to the lateral temporal cortex, where they could no longer be appreciated by MEG. Patients having predominantly ATH spikes commonly had ipsilateral hippocampal atrophy on their brain MRIs and had seizures localized to the mesial temporal region on intracranial EEG monitoring. Anterior temporal vertical dipoles
A second group of MEG spikes (ATV) were modeled by dipoles that were also in the anterior temporal region, however, their location was more superior and their orientation was vertical, when modeling the spike peak. Cortex of the anterior superior temporal plane has the appropriate net orientation to be the generator of these spikes. ATV spikes had both stable and evolving fields. In the latter case, dipole models of the earliest magnetic field often had a horizontal orientation similar to the ATH spike group. Subsequently the dipoles rotated to assume the vertical orientation. This progression is consistent with spike propagation from the anterior temporal tip to its superior surface (see Fig. 2). The opposite direction of propagation was also noted in the spikes of some patients. ATV MEG spikes often did not have a distinct EEG counterpart. When they did, it was associated with the horizontal ATH-like component of a propagating spike. Patients with ATV spikes had a 50150 chance of having hippocampal atrophy on MRI, but all of them had seizures beginning in the anterior temporal lobe, including basal or temporal tip cortex. Posterior temporal vertical dipoles
The final group of MEG spikes were modeled by dipoles located superiorly in the mid- to posterior temporal region and having a vertical orientation (PTV). The superior temporal plane is the most likely source for this dipole orientation. PTV spikes usually had stable magnetic fields, but occasionally field rotation suggested localized propagation. PTV spikes were seldom associated with an EEG field (see Fig. 3). Brain MRI findings in these patients
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Fig. 3. Left: a tight cluster of single dipole models of temporal lobe MEG spikes having an anterior temporal location and a horizontal, antero-postero orientation. The temporal tip cortex would have appropriate orientation for such a dipolar source. Right: spatio-temporal, two dipole models of two temporal lobe MEG spikes. The initial spike field is modeled by the vertical dipoles, whereas the later spike peak is modeled by the horizontal, antero-postero dipoles. These changes in spike suggest propagation from temporal basal to temporal tip cortex.
were variable, including lesions, dysplasias, hippocampal atrophy, or normal. Intracranial EEG seizures in this group began principally in lateral temporal neocortex or were unlocalized (Figs. 4-8).
We conclude that MEG can be a clinically useful tool in the evaluation of epileptic patients. Sublobar
Fig. 4. A cluster of single dipole models of temporal lobe MEG spikes having an anterior and superior temporallocation and vertical orientation. Cortex of the anterior superior plane would have an appropriate orientation for such a dipolar source.
Fig. 5. A cluster of single dipole models of temporal lobe MEG spikes having a posterior and superior temporal location and a vertical orientation. Cortex of the posterior superior temporal plane would have an appropriate orientation for such a dipolar source.
Conclusion
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course of the spike. Such MEG analysis may identify among epilepsy surgery candidates those patients who do not need invasive EEG monitoring prior to standard temporal lobectomy and those patients who probably do need such additional investigations. In the latter, MEG dipole modeling can help guide the placement of intracranial electrodes for chronic or intra-operative electrocorticographic recordings.
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Fig. 6. Top: source areas of the N400 semantic response, collected from 10 subjects. Bottom: source waveforms to the 4 different types of sentence-ending words in one subject. Modified from Helenius et al. (1998).
localization of spike sources and propagation patterns within the temporal lobe can be achieved by characterizing MEG spike dipole orientation, as well as location, and its evolution over the time
Recent advances in MEG have given us a better insight into the sites of brain lesions causing movement disturbance, owing to its high spatial resolution. As for the disturbances of voluntary movements, movement-related cortical magnetic field (MRCF) is helpful in detecting the responsible brain lesions, if a patient can perform self-paced movement with the affected body part. Backward averaging of the magnetic field with respect to the movement can
Fig. 7. Cortical activation sequence, collected from 10 subjects, when they were reading aloud single words. The word was shown at time 0 and the vocalization prompt appeared at 800 ms. See text for details. Modified from Salmelin et al. (2000).
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Fig. 8. Responses to vowel (thick curve) and tone sequences (thin curve) in one subject, from single MEG sensors over the left and right temporal lobe (filled squares). The relative response strengths were calculated over the time intervals denoted by the gray bars. Modified from Gootjes et aJ. (l999).
disclose the location of the primary motor area, and its dearrangement or dislocation from the known area. Dissociation of its location from the somatosensory area, in relation to the central sulcus, sometimes supports this evidence. However, the conventional MRCF involves inherent drawbacks for recordings from those who cannot perform brisk movements. For those patients, easier movements such as rapid rate movement at 2 Hz frequency or continuous isometric contraction can assist the source localization for motor cortex. Furthermore, analysis of the background rhythm can be applied to detect motor area, since its change occurs in bilateral areas even with the unilateral movement. Sources of the jerky involuntary movements can also be investigated by jerk-locked back averaging (JLA). In MEG recordings, JLA can differentiate whether the jerky movement is derived from the small cortical region or from the widely-distributed area suggesting subcortical origin. JLA is also useful for detecting the epileptogenic foci when the initiation of the clonic movement can be identified. Further, jerk-locked magnetic field recording can be useful for delineating pathophysiology of involuntary movements.
MEG in language disorders (R. Salmelin, Helsinki University of Technology) Language function encompasses a multitude of subprocesses. Perception may occur via auditory,
visual, or tactile pathways. Comprehension of single words, sentences, or continuous text or discourse may depend on slightly different networks. Semantic and syntactic processing are likely to have partly separate cortical representations. Also, language reception and production are two different things. Production can happen via speech, writing, or signing. One must not forget prosody, the rhythm and intonation, which is a relevant component of speech production and also comprehension. Which aspects of language should one map to 'locate language' for clinical purposes? It would be of paramount importance to know before the MEG measurement if the subject has particular language problems, so one could probe at least those processes. There are several approaches for mapping the language function. One may systematically vary stimuli or tasks and observe the effects in the brain to reveal cortical representation of specific processes such as semantics, phonology, and others. On the other hand, comparison between subjects with normal and impaired language function may help to recognize brain areas and time windows which are relevant or even critical for certain processes. One may study subjects with impairments caused by lesions - aphasics. We have found it particularly interesting to study subjects who have a functional impairment with no clearcut structural abnormalities, such as dyslexics (Salmelin et al. 1996; Helenius et al. 1999a; b) and stuttering subjects (Salmelin et al. 1998; 2000). In the following, 3 examples are given of how we may use MEG to characterize language function. Example 1: reading comprehension
To identify cortical dynamics of reading comprehension, we employed a well-established, so-called N400 paradigm (Kutas and Hillyard 1980), where the subjects are shown sentences which create a very high expectation for a certain final word and one then plays with the appropriateness of that final word in the sentence context. In our sentences the final word was either expected, like in The piano was out of tune, rare
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but semantically possible, like in When the power went out the house became quiet, when it seems that most people would expect dark, totally anomalous, like in The pizza was too hot to sing, or something we call phonological, like in The gambler had a streak of bad luggage, instead of luck, where the first letters looked and sounded the same as those in the expected word (Connolly et al. 1995). While the visual responses were the same for all word types, neuronal populations in the left superior temporal cortex showed the typical N400 behavior, reflecting semantic processing, consistently across subjects (Fig. I). The totally wrong endings resulted in a prominent deflection, peaking at about 400 ms after word onset (Helenius et al. 1998). The signal was significantly smaller for the rare but possible final words and basically flat for the expected words. For this visual reading task, the most pronounced source cluster was in the immediate vicinity of the auditory cortex. In some subjects, the posterior end of the sylvian fissure was also involved. The occasional activation in the right superior temporal cortex was smaller and later than in the left hemisphere. The MEG activation was thus strongly lateralized to the language-dominant left hemisphere in this reading comprehension task.
Example 2: reading words aloud Fig. 2 illustrates the sequence of activation when reading words aloud, with the cortical source waveforms averaged across 10 fluent speakers (Salmelin et aI., 2000). One problem in speech tasks is that vocalization is accompanied by serious artifact signals from face muscles and tongue which mask the brain activity. However, with careful artifact removal, it is possible to analyze the data up to speech onset and even beyond it. Because of the artifacts, we used delayed reading to focus on the preparatory phases. The words were shown for 300 ms. After a blank interval of 500 ms, a question mark appeared, prompting the subject to read the word aloud. The response started about 200 ms later. Like in silent reading, the sources cluster close to the occipital midline and in the left and right occipitotemporal cortices within the first 200
ms. The visual nature of these responses is emphasized by the second response to the question mark. The left superior temporal and inferior parietal responses peak at about 400 ms, as for silent reading. However, in this speech task, there is also activation in the left inferior frontal cortex, approximately Broca's area, starting about 200 ms after word onset. All these responses fade away before the vocalization prompt. The signals depicted in the right-most column begin at about 200-300 ms and persist until actual vocalization and even beyond it. This is reasonable as they arise in the left and right motor cortices and apparently in the supplementary motor area.
Example 3: hemispheric dominance of language function After these examples, one may wonder if it is at all possible to think of language as a lateralized function. Yet, there is no question that in most people language is critically controlled by one hemisphere. Recently, there have been attempts to find simple tests for non-invasive determination of the language-dominant hemisphere. Two groups have used the number of dipolar sources in each hemisphere as the criterion. With visual words as stimuli, dipolar patterns were lateralized to the language-dominant hemisphere, reportedly in agreement with the Wada test (Zouridakis et al. 1998; Papanicolaou et al. 1999). For auditory stimuli, left-hemisphere dominance of dipolar patterns was found for vowels but not for tones (Szymanski et al. 1999). It is, however, unclear whether the more or less dipolar character of the field pattern has any physiological significance. We have recently developed a paradigm where the relative response strengths are compared within each hemisphere, with no need for source modeling (Gootjes et al. 1999). In our approach, the subjects detected targets in tone and vowel sequences. We tested two sequence types, one with 4 stimuli and the other with two stimuli. The target sequence (20% of the stimuli) started and ended with the same vowel or tone. The analysis was performed on the non-targets. Fig. 3 depicts responses to vowels and tones, over the left and right temporal
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cortices. The 4 prominent peaks are responses to the onsets of the 4 stimuli in the sequence. We calculated ratios of the responses to vowels and tones for the first deflection and for the sustained response. Left-hemisphere dominance was detected in all of the 11 subjects, for the sustained response in the two-stimulus task. Comparisons with the Wada test are under way.
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