Magnetoencephalography in Neurosurgery

REVIEW

MAGNETOENCEPHALOGRAPHY IN NEUROSURGERY

Jyrki P. Makela, M.D., Ph.D.BioMag Laboratory,Engineering Centre,Helsinki University Central Hospital,Helsinki, Finland, andBrain Research Unit,Low Temperature Laboratory,Helsinki University of Technology,Espoo, Finland

Nina Forss, M.D., Ph.D.Brain Research Unit,Low Temperature Laboratory,Helsinki University of Technology,Espoo, Finland, andDepartment of ClinicalNeurosciences,Helsinki University Central Hospital,Helsinki, Finland

Juha Jaaskelainen, Prof.Department of Neurosurgery,Kuopio University Hospital,Kuopio, Finland

Erika Kirveskari, M.D., Ph.D.Brain Research Unit,Low Temperature Laboratory,Helsinki University of Technology,Espoo, Finland, andDepartment of ClinicalNeurophysiology,Helsinki University Central Hospital,Helsinki, Finland

Antti Korvenoja, M.D.Functional Brain Imaging Unit,Helsinki Brain Research Center,Medical Imaging Center,University of Helsinki,Helsinki, Finland

Ritva Paetau, M.D., Ph.D.Department of Clinical Neurophysiology,Helsinki University Central Hospital,and Department ofPediatric Neurology,Hospital for Childrenand Adolescents,University of Helsinki,Helsinki, Finland

Reprint requests:Jyrki P. Makela, M.D., Ph.D.,BioMag Laboratory,Engineering Centre,Helsinki University Central Hospital,Haartmaninkatu 4,P.O. Box 340,FIN-00029 HUS, Helsinki, Finland.Email: [email protected]

Received, July 18, 2005.

Accepted, June 8, 2006.

OBJECTIVE: To present applications of magnetoencephalography (MEG) in studies ofneurosurgical patients.METHODS: MEG maps magnetic fields generated by electric currents in the brain, andallows the localization of brain areas producing evoked sensory responses and spon-taneous electromagnetic activity. The identified sources can be integrated with otherimaging modalities, e.g., with magnetic resonance imaging scans of individual patientswith brain tumors or intractable epilepsy, or with other types of brain imaging data.RESULTS: MEG measurements using modern whole-scalp instruments assist in tailor-ing individual therapies for neurosurgical patients by producing maps of functionallyirretrievable cortical areas and by identifying cortical sources of interictal and ictalepileptiform activity. The excellent time resolution of MEG enables tracking of com-plex spaciotemporal source patterns, helping, for example, with the separation of theepileptic pacemaker from propagated activity. The combination of noninvasive map-ping of subcortical pathways by magnetic resonance imaging diffusion tensor imagingwith MEG source localization will, in the near future, provide even more accuratenavigational tools for preoperative planning. Other possible future applications ofMEG include the noninvasive estimation of language lateralization and the follow-upof brain plasticity elicited by central or peripheral neural lesions or during the treat-ment of chronic pain.CONCLUSION: MEG is a mature technique suitable for producing preoperative “roadmaps” of eloquent cortical areas and for localizing epileptiform activity.

KEY WORDS: Epilepsy surgery, Language lateralization, Magnetoencephalography, Pain, Plasticity,Preoperative functional localization, Stereotactic radiation therapy

Neurosurgery 59:493-511, 2006 DOI: 10.1227/01.NEU.0000232762.63508.11 www.neurosurgery-online.com

Magnetoencephalography (MEG), thedetection of magnetic fields pro-duced by neuronal activity in the

cortex, was pioneered in 1968 (15). The firstrecordings depicted magnetic � rhythm with asingle-channel induction coil magnetometer.The necessary signal averaging was triggeredby simultaneously recorded electroencepha-lography (EEG). The design and constructionof special rooms shielding recordings fromambient magnetic fields, the introduction of gra-diometers measuring magnetic field gradientsinstead of the actual field, and the developmentof radiofrequency and direct-current supercon-ducting quantum interference devices (SQUIDs)increased the sensitivity of the MEG method,making feasible the direct detection of sponta-neous activity, as well as evoked fields time-locked to somatosensory, auditory, and visualstimuli in the late 1970s (48).

The potential of MEG in clinical practicewas first demonstrated by systematic studiesof patients with different epilepsies (6, 7, 80).In these studies, the data were obtained se-quentially by moving a one-sensor instrumentover the head. Simultaneously measured EEGspikes were triggers for detection of epilepticspikes in the MEG signal from sequential mea-surements at different sites, resulting in fieldmaps of more than 1000 averaged spikes (7).These formidable efforts demonstrated sourcelocations of rolandic spikes and activation inthe opposite hemisphere 20 ms later (6), aswell as multiple sources of epileptiform activ-ity (7). The accuracy of locating the centralsulcus by somatosensory evoked fields, ascompared with direct cortical recordings, wasdemonstrated in 1988 (119). The coregistrationof the source localization of functional corticalareas with anatomic magnetic resonance im-

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aging (MRI), sometimes called magnetic source imaging,paved the way for the use of MEG in preoperative planning inpatients with brain lesions (31, 56). Early on, the need formultichannel detectors was obvious for appropriate clinicalusage (80) and has led to the development of instrumentscovering the whole scalp (1, 132).

The introduction of whole-scalp MEG instruments (Fig. 1) in1993 (1, 132) has been a major breakthrough in patient studies.These instruments make simultaneous recording of magneticactivity over the entire head surface feasible. This is usefulbecause short recording times increase the reliability of resultsby decreasing subject fatigue. Possible inaccuracy caused byrepetitive probe positioning is also avoided. The sources andspread of individual epileptiform activities are detected with asingle measurement. Moreover, eloquent cortical areas of dif-ferent modalities can also be located within a single session.

In 1993, the comments on the report of applicability of MEGfunctional landmarks in tumor patients stated that the tech-nology of biomagnetism with respect to the brain has, atvarious times, both enticed and disappointed neurosurgeons,and that the potential clinical utility of this method of func-tional localization needs to be explored (31). In this review, weevaluate whether or not the next decade of the development ofMEG applications in neurosurgery, making use of whole-scalpinstruments, has provided such clinical utility.

Physiological Background of MEG

MEG picks up tiny magnetic fields (Table 1) produced bythe brain’s electric activity in a completely noninvasive man-ner. MEG and EEG are generated mainly by dipolar currentsassociated with dendritic excitatory and inhibitory postsynap-tic potentials. The propagating action potentials appear aspairs of current dipoles, forming quadrupole sources; theirmagnetic fields diminish as 1/r3 with the distance r, as com-pared with the 1/r2 behavior of the current dipole. The mag-netic field detectable outside the head is produced by intra-cellular current flow in the active neurons, whereas EEG isdetermined by distribution of extracellular volume currents,generated by the intracellular currents (48).

A considerable number of neurons functioning synchro-nously generate the magnetic field outside the head. Thedendrites of pyramidal neurons aligned in parallel are consid-ered as the main contributors to MEG and EEG signals fromthe cerebral cortex. About 104–105 synchronous postsynapticpotentials produce a dipole moment of 10 nAm, a typicalequivalent dipole for auditory responses (48). Comparison ofmagnetic fields elicited in tissue slices with the results derivedfrom a mathematical model of the pyramidal cells suggests acrucial role for apical dendrites in the generation of late syn-aptic magnetic fields (86).

The comparison of human evoked magnetic fields withepicortical evoked potentials and intracortical responses fromawake monkeys yields information about the source structureof evoked fields. In monkeys, a complex relationship existsbetween surface evoked potentials, recorded directly abovethe activated cortex, and intracortical currents (118). This in-dicates that the surface deflections display a sum of the com-plete laminar current source density profile, weighted by thestrength of the current sources and sinks, and the distancefrom the recording site (118). Thus, it is clear that the currentdipole model is a simplification of a complex sequence ofactivation in the cortex, and that the source activity underly-ing the evoked fields is composed of multiple neuronal events.

MEG Technology

The monitoring of brain activity by MEG requires extremelysensitive sensors made superconductive by liquid helium, anddata acquisition in purpose-built shielded rooms cutting outthe ambient magnetic fields to obtain the best-quality signals.

FIGURE 1. A, patient seated under the whole-scalp magnetometer. B,schematic representation of the sensors covering the whole scalp. C, digiti-zation of an anatomic landmark with a pointer. The indicator coils forlocating the head position are digitized similarly. D, identification of thelandmark site from the anatomic MRI scan for the overlay of MEG andMRI coordinate systems.

TABLE 1. Magnitudes of magnetic fields (in femtotesla)

Magnetic resonance imaging 1,000,000,000,000,000 (�1T)Earth’s magnetic field 100,000,000,000Magnetocardiogram 100,000Brain alpha rhythm 1000Brain evoked fields 100Sensitivity of magnetometers 10Shielded room thermal noise 1

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The strengths of detected signals are measured in picoteslaor femtotesla levels (Table 1). Signals of this strength mayarise, e.g., from moving metal traces in the patient’s hairdye as well. However, the MEG signals are robust in com-parison with brain noise and, when present, are evidentwithout sophisticated signal analysis (besides averaging).The magnetic signals are usually detected with gradiom-eters that are insensitive to a spatially uniform backgroundfield, but respond to field changes generated by the nearbybrain. Planar gradiometers detect the largest signal abovethe strongest local current, where the field gradient reachesits peak (Fig. 2). This feature eases data interpretation. Thenumber of active sources can often be estimated directlyfrom the measured data. Axial gradiometers and magne-tometers produce maxima and minima of the signals somecentimeters from the activated brain area, producing a morecomplex image of activation, particularly when severalbrain areas are activated simultaneously. Magnetometersare more sensitive to deep brain sources than gradiometers.Unfortunately, they are also more sensitive to ambient noise(38).

MEG Signal Processing

Epileptic discharges produce MEG activity with a signal-to-noise ratio sufficient to allow reliable analysis without signalaveraging. When sensory responses or motor activations arestudied, signal averaging is needed. The signal-to-noise ratiocan be improved by digital signal processing, e.g., digitalfiltering, coherence analysis, or spatial filtering. In studies ofevoked responses, the averaged signals are often low-passfiltered digitally to suppress the high-frequency noise. Most ofthe signal energy in spontaneous brain activity is often con-centrated on relatively narrow bandwidths, and the signal-to-noise ratio is often high enough for the source analysis ofunaveraged spontaneous activity after bandpass filtering. Thecooperative behavior of brain regions and muscles can bestudied by calculating cross-correlations or coherence spectraacross MEG and EMG signals (16, 108). Spatial filters arebased on an assumption that the target signal distributiondiffers from those of environmental noise, biological artifacts,or brain activity outside the function studied (47). These filtersallow the removal or suppression of noise subspace, caused bycardiac activity (53), the source of magnetocardiography.

MEG Source Modeling

MEG detects magneticfields generated by currentstangential to the head sur-face, or by tangential compo-nents of the oblique currents,generated in cortical sulciharboring about two-thirdsof the cortex. MEG is insensi-tive to radial currents presentin gyral crowns, which dom-inate the EEG signals (48).From the measured field, it ispossible, by making appro-priate assumptions, to calcu-late backwards the activatedbrain area. In interpretingMEG data, one is dealingwith the electromagnetic in-verse problem, i.e., with thecalculation of the source cur-rents responsible for the mea-sured extracranial magneticfield. This problem has nounique solution. Conse-quently, a priori assumptionsof the source structure arenecessary in the interpreta-tion of MEG data. Sourcemodels, such as equivalentcurrent dipoles, are needed.The location, magnitude, andorientation of the active area

FIGURE 2. An example of MEG source analysis with a 2-dipole model. Left, auditory evoked magnetic fieldsrecorded with a 122-sensor device to 1-kHz tones presented to the subject’s right ear once every 4 seconds. The headis viewed from above and the helmet surface has been flattened to show the responses from the whole head simulta-neously; the nose points upwards. The responses in the boxes are shown in enlarged form in the inserts. In theamplitude scale, fT refers to femtotesla and the unit fT/cm indicates that the field derivatives are measured as afunction of distance. Top right, the magnetic field pattern over the head at the peak of the response. White indi-cates the magnetic flux into and gray out of the head. The field patterns are drawn on the helmet-shaped inner sur-face of the instrument. The center of the arrow depicts the location of the equivalent current dipole; arrow direc-tion indicates the current orientation. Bottom middle, dipole strength versus time curves, indicating the timebehavior of the active areas in the left (LH) and right (RH) hemispheres. Q denotes the dipole moment; the good-ness of fit (g) indicates how well the model explains the measured data. More than 90% of the measured field isexplained with the two dipoles at the peak of the response. The response peaks earlier in the left than in the righthemisphere, demonstrating contralateral dominance of the auditory cortical activation. Bottom right, the auditoryevoked field (AEF) sources projected on an MRI surface rendering, viewed from above. To show the supratemporalsurface, frontal lobes have been digitally sectioned from the image. Modified from (87).



in the brain can then be found reliably by using non-linearleast-squares optimization methods (47), provided that theassumption of current dipoles is valid. This requires that theneural currents are confined to a small region of the cortex.Importantly, these assumptions match with the physiologicalreality, in the localization of early somatosensory cortical ac-tivation, where the MEG source location estimates agree withdirect intraoperative localization within the range of measure-ment accuracy (89, 110). In MEG signal processing, the sourcelocation tells the approximate center of gravity of the activatedarea, not its extent. The time behavior of the brain area mod-eled by the dipole can then be illustrated with a millisecondscale by applying a time-varying dipole model (Fig. 2). Thisapproach corresponds to an idea of small patches of the cortexactivated sequentially or simultaneously. If the same experi-ment is repeated, the locations, amplitudes and orientations ofthe sources may differ slightly owing to differences in instru-mental noise and ongoing background activity (47). Confi-dence limits of dipole parameters are calculated to estimatethis variability (48).

In clinical applications, the MEG device coordinate systemneeds to be related to the anatomic head-based coordinate sys-tem of the subject’s head. This is usually accomplished by attach-ing three or more head position indicator coils on known scalplocations and by calculating the head position from magneticsignals produced by weak currents at the coils in relation toanatomic landmarks (Fig. 1) (47). Naturally, accuracy at thisphase is of prime importance in preoperative measurements,because errors in the transformation of the coordinates are di-rectly reflected as the inaccuracy of the final results. Similarproblems exist, however, in alternative brain mapping methods.For example, in functional MRI (fMRI), the functional images aredistorted owing to susceptibility effects and, likewise, need to becoregistered with structural MRI scans, although both imagesmay be obtained within the same session.

The excellent temporal resolution of MEG allows thefollow-up of brain activation sequences. For example, it isfeasible to study the progression of somatosensory activationfrom the primary sensory cortex at 20 ms onwards to second-ary somatosensory and posterior parietal cortices at about 90to 110 ms (41), or to identify the pacemaker area and second-ary spread patterns of rapidly generalizing epileptic dis-charges (39, 93).

Other ways to model sources of MEG signals, such as mini-mum norm or minimum current estimates (MCE), are oftenmore useful in analyzing widespread activation patterns related,for example, to speech perception or reading (65). In these ap-proaches, it is assumed that the sources are distributed within avolume or surface, and various estimation techniques are thenused to find the most plausible source distribution. The selectedvolume may be defined as the whole brain or be restricted to thecerebral cortex determined from MRI scans (47). The “hot spots”depicted by MCE (Fig. 3) illustrate the smallest currents neededto produce the measured magnetic field in a triangle mesh rep-resenting the convexial cortex. One can also study the activationstrength as a function of time within these “hotspots” (126).

However, the size of the activated region in the source imagesneed not relate to the actual dimensions of the source. Without anextremely high signal-to-noise ratio, the claims of defining theextent of a source giving rise to the MEG signal are unrealistic(47).

Methodological Problems and Solutions

The development of MEG applications in neurosurgery ishandicapped by the scarcity of MEG systems. At present,there are approximately 100 whole-head MEG installationsworldwide. An MEG unit with the shielded room and themagnetometer costs more than two million dollars. Extensiveresearch and development is carried out in the industry tolower the cost of acquiring an MEG unit. After installation, themain running expense is the cost of liquid helium and therelated logistics. A modern MEG system requires a weeklytransfer of about 80 L of liquid helium, and annual usageapproaches 5000 L. In the United States, the American MedicalAssociation has granted a Current Procedural Terminologycode for presurgical functional mapping and epilepsy local-ization, stabilizing the economical basis of MEG units.

FIGURE 3. Top, multidipole model for responses to left-sided dorsalpenile nerve electric stimuli showing field maps of primary somatosensory(SI) activation in the head midline and secondary somatosensory (SII) acti-vation in the left hemisphere. Bottom, minimum current estimates of thesame responses. The areas modeled with current dipoles display activity inminimum current estimates at corresponding latencies. The source loca-tions of dorsal penile nerve responses in the mesial cortex of the healthysubjects did not differ from those to tibial nerve stimulation, suggestingthat sources of dorsal penile nerve responses are not useful as functionallandmarks in patients with parasagittal tumors. Modified from (88).

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Magnetic Artifacts

MEG signals are extremely tiny and the recordings aresensitive to artifacts produced by moving magnetic materials.In studies of patients, possibilities for such disturbancesabound. Dental materials, shunts needed to treat hydroceph-alus, clips closing aneurysms or tiny lid springs needed totreat the lid lag in facial paresis may all be magnetic or becomeso after MRI scans are performed. Occasionally, ferromagneticdust owing to drilling in a previous neurosurgical operationmay produce disturbances lowering signal quality. In studiesof patients with epilepsy, magnetic electrodes, including sphe-noidal electrodes, or magnetic leads may produce severe dis-turbances. Vagal nerve stimulators or pacemakers may renderMEG recordings useless. These problems can occasionally beprevented by selecting electrodes and instrumentation care-fully. Demagnetization by special instruments may turn out tobe helpful in some cases. Occasionally, filtering of the signalsor the exclusion of the most affected channels may facilitatethe analysis.

Computational removal of background noise from artifactsowing to moving magnetic objects is developing quickly. Thesignal space separation algorithm allows the recognition ofmagnetic signals from different subspaces, e.g., from the headand its surroundings (122). Removal of the signals statisticallysimilar signals in both subspaces removes the artifacts gener-ated even in close vicinity of the sensors (121). This methodsuppresses artifacts generated by electric stimulation of sub-thalamic electrodes in Parkinsonian patients (Fig. 4), expand-ing the MEG applications into studies of effects of deep brainstimulation.

Movements

As in any functional imaging method, subject movementduring data acquisition can seriously affect the data usability.The detection of head movements during the MEG measure-ment is crucial for the accuracy of the MEG source localiza-tion. Whereas adult patients are usually highly motivated andremain motionless, with about 1 mm standard deviation of themeasured head positions (127), movements may increase in-accuracy in pediatric measurements. Continuous head posi-tion monitoring has been developed to monitor the position ofthe patient’s head during MEG recordings (127), although it isnot yet widely applied in clinical use. The accuracy of thesource localization will increase further with these applica-tions, particularly in pediatric neurology.

Deep Basal Sources

Detecting epileptic activity in the mesial temporal cortexand deep orbitofrontal cortices directly by MEG is difficult(79, 136) because gradiometers are relatively insensitive todeep sources. Indirect information about mesial temporalorigin is obtained from the dipole source orientation (4).New MEG instruments also contain magnetometers, whichare more sensitive to deep sources, but, unfortunately, alsoto noise. The “brain noise” in magnetic measurements isclearly stronger in the low, rather than high, frequencyrange. Consequently, the relative signal-to-noise ratio inmagnetometers is better for signals having high-frequencycomponents (Parkkonen and Curio, personal communica-tion, 2000). We have tested the usefulness of magnetometersin detecting deep sources by measuring brainstem auditoryevoked fields, containing high-frequency components, withgradiometers and magnetometers. Whereas the gradiom-eter signals were in the noise range, magnetometers dis-played a clear response, with dipolar field patterns at thepeak latency of the wave V of brainstem auditory evokedpotentials. The estimated source areas agreed with previousknowledge concerning generators of the brainstem auditoryevoked activity (96). This holds some promise for the de-tection of high-frequency mesial epileptic spikes in a data-driven manner from MEG signals as well.

Current Neurosurgical Applications

Both evoked responses and spontaneous MEG rhythms (42)can be used to create functional maps by superimposing thesource locations of the evoked fields and spontaneousrhythms on the subject’s MRI scans of the brain. MEG pro-vides fairly accurate data on individual patients, as verified bydirect intraoperative mapping. There is no need for responseaveraging over patients, which would blur individual differ-ences and diminish clinical applicability. The noninvasivenessof MEG allows repeated recordings when desired. However,long-term recordings are difficult with the present MEG tech-nology.

FIGURE 4. A, auditory evoked fields recorded during bilateral 130-Hzstimulation of subthalamic nucleus electrodes in a patient with Parkin-son’s disease. B, fields after subtraction of artifacts by signal space separa-tion with temporal extension. The source localizations from the filtereddata agreed with the values of healthy subjects (Fig. 2).



Preoperative Localization of Functional Areas

For most patients who harbor mass lesions of the brain, MRIscans, in conjunction of clinical data, provide sufficient infor-mation for the selection of appropriate neurosurgical ap-proaches. In a subset of patients, however, the lesion (e.g.,neoplasm, cavernous hemangioma, or arteriovenous malfor-mation) is located within or near eloquent cortices, or hascaused such a distortion of neuroanatomy that it is not possi-ble to determine the topography of eloquent areas in relationto the mass lesion. In these patients, functional mapping ofeloquent brain areas is a valuable adjunct to preoperativeplanning (12, 30, 66, 70, 89). MEG provides one modality forfunctional mapping with excellent temporal and reasonablespatial accuracy. Central sulcus localization and the mappingof auditory and visual cortices are feasible with MEG.

Presurgical Planning

The identification of MEG sources, displayed in three-dimensional (3-D) MRI surface rendering, aids in pinpointingfunctionally irretrievable areas before neurosurgery, thus as-sisting in presurgical planning to find the optimal “surgicalcorridor” to the lesion (30, 56, 89). For example, the orientationto subcortical tumors is facilitated by appropriate functionallandmarks (Fig. 5). These landmarks may encourage opera-tions in cases in which key cortical areas are displaced, butunaffected, by tumor masses, suggest the selection of alterna-tive treatment strategies in patients with tumor invasion intocrucial cortical regions, and facilitate maximal resection intumors abutting the eloquent cortex (33). Preoperative discus-sion with the patient on surgical alternatives (e.g., tradingbetween the amount of resection and the possible functionaldeficit) is also made more accurate. This is not possible if thefunctional cortical areas are localized only by recordings dur-ing the operation. A case report described an operation wherethe available preoperative functional localization by MEG wasnot used in presurgical planning because of preference forintraoperative localization in identifying the functional cortex.However, technical difficulties prevented cortical mapping,and anatomic landmarks were used instead. A severe postop-erative deficit resulted from misidentification of the motorcortex (2).

Orientation During Surgery

The orientation in a limited field of view of the brain avail-able during surgery is facilitated by 3-D reconstructions ofbrain anatomy, including cortical veins, and with superim-posed functional landmarks (Fig. 6). In addition, the selectionof stimulation sites or the adequate grid position for intraop-erative monitoring of evoked potentials during awake craniot-omies is speeded up by functional landmarks, which serve as“intraoperative road maps” for the most efficient stimulationand recording sites (46, 89, 110).

Central Sulcus Localization

The most common application of functional mapping is thelocalization of the central sulcus. The sources of the somato-sensory evoked fields (SEFs) to median nerve stimuli arelocated in the posterior wall of the central sulcus (119). Theprimary motor cortex, to be particularly protected duringoperations, is on its anterior wall. Motor evoked fields, re-corded by time locking of MEG signal with movements, iden-tify the motor cortex directly, but are complex to interpretbecause of concomitant somatosensory activity (106). Correlo-grams between electromyography (EMG) and cortical sponta-neous MEG during wrist or ankle extension (108) also yieldfast localization of the motor strip in some patients (Fig. 7).Statistically significant MEG-EMG coherence for hand and legrepresentations are detected in approximately two out of threepatients, independently confirming the SEF localization of thecentral sulcus. The combined use of several functional land-marks adds accuracy for the central sulcus localization andincreases the probability of detecting possible methodologicalerrors (89).

Detection of Functional Tissue within the Tumor

Gliomas grow diffusely, and functional tissue may persistwithin the tumorous growth (17). This may, in part, explainrelatively mild functional deficits in these patients. Evidencefor functional activity within the tumor has been obtained byMEG recordings in 8 to 18% of the patients with a glioma(111). However, effects of source extension on the point-likesingle dipole calculation may produce localization, even into ametastasis, which does not contain functional tissue (89).

Comparison with Intraoperative Recordings

Preoperative functional localization with MEG generallyagrees with direct intraoperative mapping of the somatosen-sory and motor cortical areas. Approximately 200 cases of SEFsource localizations and intraoperative cortical mapping havebeen published, with a satisfactory concordance (30, 31, 34, 35,51, 56, 66, 67, 89, 106, 110, 115, 119), suggesting that handlingof the inverse problem in dipole modeling matches the neu-rophysiological reality. The reported mean concordance ofabout 10 mm (89, 106, 110) needs to be related to methodolog-ical factors of intraoperative localization. For example, SEFsources are typically located within sulci, and cortical stimu-lation and recordings are performed from the visible gyralsurface. No clear information exists about the spread of thestimulation current within the cortex. Schiffbauer et al. (110)observed that the same response to cortical stimulation wasobtained from sites with spatial variation of 11 � 1 mm.Moreover, the diameter of electrodes and intercontact dis-tances in cortical grids used to record intracortical SEPs do notallow exact comparisons. The obtained accuracy, however,compares favorably with the 25-mm accuracy of expert esti-mations of the motor cortex localization based on MRI gyralmorphology. The maximum difference from operating room

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FIGURE 7. A, preoperative 3-D surface renderings with superimposedveins of the brain of a patient with a right parasagittal frontal glioma.Owing to edema, the anatomic landmarks were poorly visible in thispatient. Sources of responses to right and left median (hand SI) and lefttibial nerve stimulation (foot SI) and source of MEG-EMG coherence forthe left wrist extension (hand MI) are superimposed on the surface ren-dering. B, intraoperative photograph showing venous structure and stimu-lation sites used to define the motor cortex location. The arrows in theMRI surface rendering and in the photograph indicate the same vein bifur-cation. The distance between the estimated source of maximum MEG-EMG coherence and the site producing hand movement in stimulation was6 mm. Modified from (89).

FIGURE 5. A, top left, 3-D surface rendering of the brain of a patientwith a subcortical cavernous hemangioma (arrow), including corticalveins and sources of SEFs and AEFs. A, bottom left, a section of the 3-Dsurface rendering is removed to reveal the hemangioma. A, right, a coro-nal MRI section showing the source of the median nerve SEF (top) and asagittal section showing the source of the AEF 100-milliseconds response(bottom). The tumor is below the median nerve source and posterior tothe AEF source. In combination with the sulcal pattern, this finding indi-cates the tumor projection to the cortical surface, readily identified duringthe exposure of the cortex. The arrows show the approximate location ofthe subcortical tumor. Instead of the originally planned stereotacticapproach, a sulcal route, avoiding cortical lesion, was selected for tumorremoval. Modified from (89). B, enlarged section of the 3-D surface ren-dering of a patient (top left), intraoperative photograph without (centerleft) and with (bottom left) the SEP recording grid. During operation,the details of the 3-D surface rendering were easily identified. The arrowsshow the approximate location of the subcortical tumor. B, right, intraop-erative SEPs from eight electrodes. The electrode numbers are indicated onthe grid. Polarity reversal of SEP at 23 milliseconds (vertical line) occursbetween Electrodes 3 and 7 (Electrodes 3, 4, and 8 are under the dura).Modified from (89).

FIGURE 6. A, preoperative 3-D surface rendering of the brain of apatient with a left parietal GII oligoastrocytoma. The equivalent currentsources of responses to median nerve SEFs (hand SI), tibial nerve SEFs(foot SI), lip-SEFs (lip SI) and AEFs (auditory cortex) are displayed onthe surface. B, postoperative surface rendering of the patient. In additionto SEF and AEF sources, sources of MEG-EMG coherences for the rightwrist (hand MI) and ankle extensions (foot MI) are displayed on the sur-face. The surgeon has successfully avoided damage to the somatosensorycortex. C, enlarged section of 3-D MRI surface rendering. D, correspond-ing brain surface during surgery. The veins are readily identifiable andallow both the localization of the compressed somatosensory cortex and thetumor area (vein bifurcation over the tumor is marked with an arrow).Intraoperative cortical stimulation and somatosensory evoked potentialrecordings confirmed the preoperative localization of the central sulcus.Modified from (89).



findings in the group of neurosurgeons was 48 mm in thisstudy (125).

Combination with Neuronavigation

MEG landmarks can also be incorporated into image-guided stereotactic methods for more precise navigation dur-ing operation (35, 106, 110). Schiffbauer et al. (110), usingneuronavigation, calculated a 21 � 2 mm 3-D difference be-tween preoperative SEF localization and intraoperative stim-ulation sites. Additional problems for pre- and intraoperativesite comparison may be introduced by neuronavigation. Thecortical surface shifts 5 to 10 mm after dural opening duringthe surgery. The main shift direction follows gravity, and itseffect on the brain depends on the head position during theoperation (107). The largest shift sometimes occurs near thecenter of the craniotomy, which is usually the brain region ofgreatest interest (44), and probably increases the differencebetween pre- and intraoperative source areas. Depicting sur-face veins in combination with 3-D brain structures and func-tional landmarks provides visual feedback for intraoperativeorientation (89). This may alleviate problems in neuronaviga-tion caused by brain tissue movement during surgery.

Prediction of Complications

The distance between MEG landmarks and the operatedregion, covarying with the distance between the lesion marginand the edge of the functional cortical area, may reflect rela-tive risk of complications (46). Risk analysis based on MEGfunctional localization in selection of patients for radiother-apy, biopsy, or tumor removal have been suggested to im-prove patient outcome as compared with similar patientstreated without magnetic source imaging (2). In 119 patientswith gliomas, 46% were not considered for surgery because oftumor invasion of eloquent cortex indicated by MEG sourcelocalization. Fifty-four percent of the patients were operatedand 6% experienced neurological deterioration. This comparesfavorably with functionally significant or permanent deficitsin 17 to 20% of the operated patients reported previously (33).However, there is no Class I evidence of improved outcomesusing MEG risk profiling.

MEG and Epilepsy Surgery

In patients with intractable epilepsy and no clear-cut ana-tomic lesions, the accurate preoperative identification of epi-leptic foci and their relation to areas of the eloquent cortexwould enhance possibilities for successful epilepsy surgery.MEG recordings give information about both these aspects.MEG seems to be particularly beneficial in the study of pa-tients with non-lesional neocortical epilepsy and in patientswith large lesions, in which it may provide unique informa-tion on the epileptogenic zone in relation to the lesion (5, 10,64, 98, 99). Sources of epileptic spikes can be integrated intoneuronavigation systems as easily as those of the evokedfields (49). The preoperative localization of eloquent corticescan be made with the same methods in epileptic patients as in

patients with brain tumors (123), and their relation to epilepticzone can be visualized (Fig. 8). Furthermore, well-establishedphysiological landmarks, such as sources of early mediannerve SEFs and auditory evoked fields, provide confidence insuccess of the MEG-MRI overlay in location of epileptic zones.

Sensitivity of MEG in Epilepsy

Although methodological properties limit feasible record-ing times in epileptic patients, the average sensitivity of MEGfor specific electric activity has been found to be 70% in aseries of 455 patients going through presurgical epilepsy eval-uation. Information crucial for final decision making was ob-tained in 10% of the patients (116). Similar general sensitivitiesof 79 (99) or 73% (63) have been reported in smaller series. Theyield was 92% in patients with extratemporal and 50% inpatients with medial temporal lobe epilepsy (63). When pa-tients were on subtherapeutic anticonvulsant levels and sleepwas encouraged, the yield in temporal lobe epilepsies ap-proached 100% (4). Abnormal slow wave activity may alsooccur in the vicinity of the epileptogenic area, although the

FIGURE 8. MEG signals from a triggered epileptic seizure. The patienthas partial epilepsy with seizures triggered by touching of the left gum orcorner of the mouth, inducing left facial jerking. The whole seizure fromthe channel showing the maximum signal in the right hemisphere isdepicted in the box above. Bottom, sections A, B, and C show the devel-opment of the seizure as well as activity in the corresponding region in theleft hemisphere in enlarged form. Before the seizure onset, spikes emergemore frequently and become polyphasic in the right frontoparietal region.No notable activity over the left hemisphere is seen during the first 6 sec-onds. Afterwards, the spike discharge spreads to the left side as well. Afterthe seizure, interictal spikes are absent. The sources of epileptic activity(spikes) cluster to the face motor cortex representation area. Sources ofmedian nerve SEFs and AEFs are shown to indicate irretrievable areas.Modified from (29).

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yield is not as high as in locating epileptic spikes. The MEGsources of this activity were concordant with the consensusfinding, based on other evaluation methods, concerning thepresumed epileptiform region in 48% of the patients, as oftenas ictal noninvasive video EEG monitoring (32). Combiningsource localization of the abnormal slow wave activity withinterictal epileptiform spikes enhanced localization of the af-fected hemisphere in patients with temporal epilepsy (25).

Epileptiform Activity in Different Lesions

MEG has demonstrated which of the multiple cavernomasis related to epileptic tissue (117). In these patients, MEG alsodetected epileptic foci with no spatial relation to cavernomas,encouraging the stereotactic radiation of the epileptic zonerather than cavernoma removal (117). The epileptogenic activ-ity of gliomas (100), arteriovenous malformations (83), andfocal cortical dysplasias (9, 84) has been evaluated by MEG. Intuberous sclerosis patients with multiple lesions, MEG iden-tified the epileptiform tubers (133). Reevaluation of epilepti-form areas pinpointed by MEG sources using MRI scans witha high spatial resolution has identified previously undetectedanatomic cortical lesion in about 20% of the studied patients(82). If no epileptiform activity is displayed in MEG in patientswith lesions and epileptic seizures, lesionectomy may be theonly required procedure (49).

Prediction of Outcome

High correlation of the resection volume with the brainregion containing MEG sources of epileptic spikes (26, 36) oronset zones of epileptiform MEG (9) predict favorable out-come in epilepsy surgery. Regions displaying scatteredsources instead of source clusters of epileptic spikes may beepileptogenic and should be studied by electrocortigography(ECoG) (49). If source clusters are located in the nonresectableeloquent cortex, residual seizures remain probable (49).

Modeling Spread of Epileptiform Activity with MEG

In addition to locating interictal spike sources, MEG de-scribes the temporal sequence of spike propagation if multi-dipole models are applied in the data analysis. We can oftenfollow the spread of epileptic activity from one hemisphere toanother (Fig. 8) or within a hemisphere (Fig. 9). The identifi-cation of the earliest source of epileptic activity adds reliabilityto localization of the epileptogenic zone (39, 72, 93, 135).

Ictal Recordings

Ictal measurements are possible in several types of epilepsy(Fig. 8), although body movements may render the signalnon-analyzable. However, the initiation of the epileptiformdischarges may be detected before the onset of body move-ments. This was the case in six out of seven cases (23). Sourcesof interictal spikes were found to be in the same area as thesources of ictal spikes in two small series of patients (113, 124),whereas ictal MEG produced localizing information superiorto interictal MEG in three out of six patients (23). New more

comfortable gantries, allowing patients to be studied in thesupine position, make ictal recordings more feasible.

Comparison with Invasive EEG Recordings

Invasive video EEG monitoring has been the “gold stan-dard” for defining the epileptogenic cortex before surgery.MEG source localization guides the positioning of intraoper-ative ECoG grids (23, 77). It may be particularly useful in thedetection of epileptic activity after lesionectomy or unsuccess-ful removal of the epileptic zone, because dural adhesionsmay hamper the insertion of subdural electrode grids in thesepatients (58). Ictal MEG recordings produced localizationequivalent or superior to invasive EEG in five out of sixpatients (23). Comparisons of preoperative MEG findings withECoG have occasionally found almost complete matches (69,92), whereas some others report lower values (77). The patientpopulations have been quite variable, and the location of theseizure focus probably affects the degree of correlation be-tween MEG and invasive EEG recordings. There is no con-vincing evidence that MEG is able to replace invasive EEGmonitoring, although it has been suggested that combinationof MEG with positron emission tomography (69) or ictalsingle-photon emission computed tomography (62) couldachieve this target. In rare instances, MEG may localize epi-leptogenic areas not found by other noninvasive tests (77).However, a risk of initiating useless invasive EEG tests toevaluate further potentially false MEG results needs to beconsidered in each case.

MEG and Stereotactic Radiotherapy Planning

Stereotactic radiation therapy with high single doses is suit-able for lesions with sharp boundaries. When applying high

FIGURE 9. Spread patterns of interictal spikes in a patient with focal-onset seizures. A, six-dipole fit of four consecutive interictal spikes showthe earliest activity in the right inferior temporal (RIT) area, followed bysecondary spikes at several right-hemisphere locations within 60 millisec-onds. B, MRI surface reconstruction showing spike clusters (from severalinterictal spikes) corresponding to the set of six dipoles displayed in A. Asmall xanthoastrocytoma was found at the site of the earliest RIT activity.Its removal resulted in seizure freedom. RPO, right parieto-occipital;RmPO, right medial parieto-occipital; Rsyl, right sylvian; RpSyl, rightposterior sylvian; RT, right temporal; RF, right frontal activation.



doses, it is important to avoid radiation damage to the sur-rounding intact brain areas. If the lesion is located close toeloquent brain areas, MEG localization can provide usefulinformation for the dose planning (Fig. 10) (3). The localizationof epileptic focus with MEG may guide the gamma kniferadiosurgery in the treatment of epilepsy (114).

Emerging Applications

MEG Localization and Subcortical Pathways

Intraoperative electrical stimulation of the white mattertracts to sensorimotor and language areas may improve therisk-benefit ratio in the surgery of low-grade gliomas invadingeloquent regions (20). Combined MEG source localization and

3-D anisotropy contrast imaging allows such optimizationpreoperatively. The eloquent motor pathway (55), the anat-omy of the optic radiation, and the functional localization ofthe primary visual cortex (50) have been visualized in thismanner, allowing an accurate preoperative planning of thetumor surgery.

Hemispheric Lateralization and Localization ofLanguage-related Cortices

Lateralization of Speech and Memory

Detection of language lateralization is important in somepresurgical evaluations. Hemispheric language dominance isassessed by the Wada test, injection of amobarbital separatelyinto the right and left internal carotid arteries to stop thefunction of one hemisphere at a time. Concomitantly, thelanguage and memory functions of the non-anesthetizedhemisphere are tested. However, because the procedure in-volves a risk of serious complications, is sensitive to the cross-flow of amobarbital to the other hemisphere, and poses diffi-culties in interpretation, particularly when verbal memory istested (60), a reliable noninvasive test for language dominancewould be highly desirable.

Estimations of language lateralization with MEG havemainly been based on calculations of sequential single equiv-alent current dipole sources accounting for late auditoryevoked field (AEF) components (150–700 ms after stimulusonset) elicited in both hemispheres by a recognition memorytask for spoken words (94) or by listening synthesized vowelsounds (120). In a series of 100 patients, a recognition memorytask produced AEFs not applicable to laterality analysis in15% of the patients; complete agreement with Wada test wasobtained in 87% of the remaining patients (94). Similar agree-ment has been observed in native Spanish-speaking patients(74). Although a single dipole model is an obvious oversim-plification of complex cortical processing related to the recog-nition memory of words, consistent activity in the perisylvianauditory areas detected by this method may provide usefuldata for preoperative planning (94). Listening to synthesizedvowel sounds produced late responses, the sources of whichlateralized to the left hemisphere in 85% of the patients withleft-hemisphere sites essential for language in intraoperativecortical stimulation, and to the right side in patients withright-hemisphere predominance in the Wada test (120). Moresimple tests, based on stronger 100-ms AEF in the dominantauditory cortex for speech than non-speech stimuli, have beendeveloped (37, 59, 97). However, these new tests have not yetbeen compared with the Wada test.

Silent naming of visually presented pictures suppressesspontaneous MEG activity in the 8 to 50 Hz range. The later-ality of stronger suppression in the inferior frontal gyrusregion was congruent with the result of the Wada test in 95%of the patients (45). The suppression of spontaneous 7 to 12 Hzactivity in ECoG recordings during silent naming in sitesfound to be essential for language in direct cortical stimulationhas been reported, but in temporoparietal, not in inferior

FIGURE 10. Data from a patient with a residual occipital meningioma.The tumor was located close to the visual cortex, but the patient had novisual symptoms. To prevent damage of the visual cortex, visual evokedfields (A and B) to pattern reversal checkerboard stimulus presented sepa-rately to four visual field quadrants were recorded for preoperative local-ization of the visual cortex. One of the visual evoked field sources (redcircle) was in the immediate vicinity of the tumor. The radiosurgery doseplan (C) was designed according to the results of functional mapping toavoid the visual evoked field source area. During a 1-year follow-upperiod, the patient did not develop any visual symptoms.

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frontal regions (91). Thus, this promising approach to lan-guage lateralization requires further studies.

Speech Localization within Hemispheres

The preoperative localization of speech-related areas withinthe hemispheres would be beneficial in planning surgery insome patients. The sources of 100-ms AEFs (N100m) reside inthe supratemporal auditory cortex (40, 87). This localization isuseful, particularly in the left temporal lobe, because the leftauditory cortex is often surrounded by the language-relatedcortex (90). Current MEG techniques cannot directly identifythe whole set of speech-related cortical areas. However, wecan study subsets of language functions; for instance, MEGactivations related to reading or listening words or sentences,or to naming objects (109). MEG deflections elicited by visu-ally presented words forming sentences have been describedin the vicinity of the left auditory cortex at about 400 millisec-onds after the word onset (43). Anomalous words endingsentences activate the left perisylvian cortex more stronglythan the words producing expected endings. Although thesource modeling of the widespread activity related to lan-guage tasks requires expertise, it may produce useful func-tional landmarks (Fig. 11). It is obvious that modeling of thespeech-related brain activity by current dipoles shows onlysome parts of the network related to reading, speech produc-tion, and perception.

MEG in Plasticity and Pain Studies

Reorganization of cortical functions may explain why somelow-grade gliomas invading eloquent structures produce little

or no neurological deficit at the phase in which they presentwith seizures. Eloquent areas may be redistributed around thetumor, or the function disturbed by the tumor is compensatedwith activity in remote areas within the same or oppositehemisphere (17). Taking into account such reshaping of func-tional areas in planning of surgery is probably beneficial toobtain the best possible quality of life after operation (18).Extensive practice or lack of use of a certain body part maychange the cortical organization. Objective means to predictpotential for rehabilitation and to follow its course would beuseful in the follow-up of neurosurgical patients. Detectingthese developments obviously provides new vistas for MEGfunctional mapping.

Somatosensory Plasticity

Redistribution of somatosensory representation has beendescribed in MEG source locations of patients with arterio-venous malformations reaching the central sulcus region. TheSEF sources were atypical in approximately 30% of the pa-tients and were shifted to the opposite hemisphere in 10%(131). However, the shifts to the opposite hemisphere occurredin sources of SEFs to lip stimulation, known to have bilateralrepresentation in healthy subjects as well. Less marked SEFsource reorganizations have been described in patients withTaylor-type cortical dysplasia in the vicinity of the centralsulcus (13). Cortical representations of fingers have also beenshown to differentiate after the treatment of syndactyly inMEG source analysis (81). Moreover, the amputation of thearm modifies SEF sources in a manner indicating plasticchanges in the primary sensory cortex (27).

Auditory Plasticity

The operation of acoustic neuromas may cause deafness inthe operated ear. This accurately timed lesion allowsfollow-up of the reorganization of the adult auditory systemduring recovery from operation. After acoustic neuroma op-erations leading to deafness in the operated ear, N100m AEFsfor the healthy ear stimulation were initially delayed anddampened in both hemispheres. However, they recoveredtowards normal values during the 1-year follow-up periodafter the operation (129). These changes varied from one pa-tient to another, owing, at least in part, to the details of thedisease process (128). AEFs were also modified towards nor-mal values after the rehabilitation of hearing by operativetreatment of unilateral conductive hearing loss (130). No sys-tematic shifts of N100m source locations were observed inthese experiments; this emphasizes the importance of the ex-cellent temporal resolution of MEG in detecting these changes.

Cognitive Alterations by Tumors

Low-grade gliomas cause subtle cognitive deficits, such asdisturbances in attention, executive functions, recognitionmemory, or verbal fluency (19). Altered functional connectiv-ity, assessed by synchronization likelihood of spontaneousMEG signals, has been described in patients with brain tu-

FIGURE 11. A, preoperative 3-D surface rendering of a patient withrecurrence of a left temporal glioma operated 3 years previously. Thesources of N400 responses (word 450 ms, word 567 ms) to semantic sur-prises are superimposed on the 3-D reconstruction. B, enlarged section ofthe 3-D reconstruction. C, intraoperative view showing the curved vein(arrows) in both the reconstruction and the photograph. Speech produc-tion was completely prevented during stimulation of Site 2, close to thesource of the 100-millisecond AEF (right auditory). Stimulation of Sites 1,3, and 5 produced severe disturbances of repeating a word list. Stimula-tion of Site 6 produced motor difficulties in repeating words. Mild dys-lexia was elicited by stimulation of Site 7. Stimulation of Site 8 producedword repetition difficulties, but no problems in reading. Stimulation ofSite 9 did not affect speech.



mors, and its contribution to global cognitive deficits has beensuggested (8).

Chronic Pain

Modifications of SEF sources also occur in association withchronic pain without nerve deafferentation (54, 76, 102). Inpatients with complex regional pain syndrome (CRPS), expe-riencing persistent unilateral pain of the upper extremity, thedistance between SI representations of the thumb and the littlefinger as measured by SEF source localization was signifi-cantly smaller in the affected than healthy hemisphere. Fur-thermore, abnormal ipsilateral SEFs developed in associationwith the mirror-like spread of CRPS from one upper limb toanother during a 3-year follow-up period (28). Such reorgani-zation may provide objective correlates of perceived pain.These changes are, at least to some extent, reversible, suggest-ing that rehabilitation should be targeted for regaining theorderly somatotopic arrangement at the SI cortex (75).

Motor cortex stimulation is used to relieve pain in somechronic pain syndromes. As the motor representations of dif-ferent body parts are identified and localized with MEG (108),preoperative MEG recordings may improve targeting of thestimulation to the desired part of the motor strip. Signs ofmotor dysfunction are frequently detected in chronic painpatients, suggesting functional connections between pain andthe motor system. Acute pain modulates the MEG activity ofthe motor cortex in healthy subjects (105). Both A-�- andC-fiber stimuli elicited long-lasting attenuation of the motorcortex spontaneous activity, indicating a prolonged excitationof the motor cortex in association with acute pain. In accor-dance, altered reactivity of the motor cortex spontaneous MEGsuggests decreased inhibition of the motor cortex in CRPSpatients (54). This is in line with recent transcranial magneticstimulation studies showing hyperexcitability of the motorcortex in CRPS (22, 112). The new artifact rejection methods(121) will pave the way for studies of these spontaneousactivity changes in patients also having electrical stimulatorsto treat chronic pain.

Comparison of MEG with EEG

EEG signals, applied in studies of neurosurgical patients fordecades, are also generated by neuronal currents. However,there are advantages in MEG compared with EEG when spa-tially accurate localization is required (Table 2). Electric fieldsare blurred by the cranium and scalp, whereas magnetic fieldsare not affected. Consequently, whereas a homogeneous one-sphere conductor is used to model the head in MEG sourceanalysis, a three-sphere model is needed in EEG. Moreover,conductivities of each tissue layer are difficult to estimate inindividual subjects, and cranial defects, such as those resultingfrom previous operations, may affect them strongly. MEG issensitive to current components tangential to the head surface,whereas EEG reflects both radial and tangential components.MEG is more sensitive to cortical activity, because MEG ismore attenuated than EEG when the distance from the head

surface increases. These factors allow easier modeling for ac-tivity underlying MEG. In other words, MEG sees fewer cur-rents than EEG, but modeling of MEG signals requires lessassumptions and calculations (48). MEG can also be measuredquickly with whole-head instruments. To gain similar spatialsampling with EEG, a time-consuming fixation of more than300 electrodes would be required.

MEG and EEG signals look qualitatively similar (Fig. 8), andthe knowledge of different epileptiform phenomena, based onvisual pattern recognition and collected since the beginning ofEEG studies, can be used in MEG signal analysis. However,source modeling provides information not available in tradi-tional EEG. In 113 consecutive patients undergoing epilepsysurgery, MEG was able to localize the resected region in 72%,and noninvasive video-EEG in 40% of the patients (99). In aprospective, consecutive cohort of 70 candidates for epilepsysurgery, MEG data could not be evaluated because of exces-sive magnetic artifacts in three patients. Of the remainingpatients, the sensitivity to detect interictal epileptiform activ-ity was 72% for 306-sensor MEG and 61% for the simultaneous70-channel EEG. MEG recorded epileptiform activity in one-third of the EEG-negative patients, particularly in patientswith lateral neocortical epilepsy or cortical dysplasia (61).

In localization of somatosensory evoked potential sourcesusing dipole modeling in non-operated patients with braintumors, variability within one recording session was 18 � 10mm, and the discrepancy between preoperative source eval-uation and operating room findings was 18 mm (125), clearlyexceeding the estimates of 1-cm accuracy of SEF source local-ization in patients.

MEG may be useful in detecting epileptic activity deep inthe sulci, masked in EEG by more superficial radial activity inthe gyri (78), e.g., in Landau-Kleffner syndrome (Fig. 12), inwhich the spike activity typically resides deep in the Sylvianfissure (52, 93). Consequently, the simultaneous recording ofMEG and EEG signals, and the use of both methods in mod-eling the epileptiform activity is crucial for a complete view ofthe epileptogenic zone. In particular, combined MEG-EEGrecordings are essential in childhood epileptic encephalopa-thies, in which rapidly generalizing spike-wave dischargescarry a high risk for permanent intellectual development.Combined MEG and EEG can identify the source areas andtheir activation sequences, thereby helping to select childrenwith a single pacemaker area and a prospect for good outcomeafter surgery (9, 71, 85, 93).

Comparison of MEG Source Localization with Resultsfrom fMRI

fMRI is widely available for preoperative functional local-ization. Studies performed using fMRI do not show the am-biguities introduced to MEG by the neuromagnetic inverseproblem (Table 2). In anesthetized cats immobilized with ahead holder, fMRI is able to resolve function, even at thecortical column level (21). The spatial specificity, however,depends on the applied imaging technique (73). A typical

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resolution in fMRI studies of the presurgical mapping hasranged from 3 to 4 mm in a plane with 5 to 6-mm slicethickness (134). Problems related to statistical thresholding ofthe signals, necessary to dissociate true activations from spu-rious ones, pose problems when individual patients are stud-ied. Blood oxygenation level dependent (BOLD) signals de-tected by fMRI differ significantly between individuals andthe use of absolute thresholds is, therefore, questionable (60).Concerns have also been raised about possible differences inneurovascular coupling between patients and control subjects.The BOLD response in the vicinity of the tumor may notreflect the neuronal signal as accurately as it does in healthytissue (18). Furthermore, geometric distortions and the signalloss occur in inferior frontal and medial temporal lobes duringfMRI aquisition (103).

fMRI provides information about the location of the somato-motor strip in about 90% of the patients (68). Several studieshave reported an excellent match between fMRI and intraop-erative central sulcus localization, but discrepancies have alsobeen reported (24, 51, 104), and tasks resulting in more specificactivation patterns have been requested (95, 104). Comparisonof SEF source location and the somatosensory activation infMRI in the same subjects has shown a 15 � 5 mm difference(66), which may exceed the gyral width. The fMRI and MEGlocalization of the central sulcus in patients with tumors in thevicinity of the central sulcus were discordant in approximately20% of the affected hemispheres. The MEG localizations wereconfirmed by intraoperative SEP recordings (51). Our resultsfrom applying both fMRI and SEFs in central sulcus localiza-tion of patients with brain tumors parallel these findings (67).

TABLE 2. Advantages and disadvantages of magnetoencephalography compared with functional magnetic resonance imaging,electroencephalography, and intraoperative monitoring/electrocorticographya

Purpose MEG fMRI EEG IOM/ECoG

General Direct measure of neuronalactivation

Excellent spatial resolution Direct measure of neuronalactivation

Accurate when correctlyapplied

Excellent temporalresolution

Extent of the active area Widely available Does not require modeling

Good spatial resolution Widely available Excellent temporalresolution

Invasive

Completely noninvasive Anatomical MRI scan inthe same session

Completely noninvasive No preoperativeinformation

Limited availability Poor temporal resolution Poor spatial resolution Prolongs operationsMagnetic artifacts maydisturb

Movement artifactsThresholding of theactivation

Source modeling complex Narrow field of view

Movement artifacts Depicts metabolic changesrelated to neuronalactivation

CS localization Identification of sensoryversus motor cortex

Availability AvailabilityPrevious operations worsenspatial resolutionMRI alignment needed

Direct identification of themotor stripRisk of intraoperativeseizures

SI localization needs nocooperation by the patient

Activation of severalsensorimotor areas

MRI alignment needed MRI alignment needed

Epilepsy Direct measure ofepileptiform activation

Difficulties in ictalrecordings

Direct measure ofepileptiform activation

May pinpoint the focus

Allows follow-up of spread EEG-triggered fMRIactivation not wellunderstood

Ambulatory recordingsavailablePrevious operations worsenspatial resolution

Limited area for recording

Difficulties in ictalrecordings

Dural adhesions hamper

aMEG, magnetoencephalography; fMRI, functional magnetic resonance imaging; EEG, electroencephalography; IOM, intraoperative neurophysiological monitoring;ECoG, electrocortigography; MRI, magnetic resonance imaging; CS, central sulcus. For comparisons of the MEG method with positron emission tomography, seereferences 11 and 14. Disadvantages are indicated by italics.



As fMRI integrates brain activity over a period of severalseconds, it reveals the whole cortical network participating inthe processing of external stimuli or a task. Limited resolutionin the time domain may, therefore, result in difficulties inseparating the primary areas of interest from secondary pro-cessing areas. Strong fMRI activations in non-primary areasmay, therefore, sometimes confound the interpretation of ac-tivation maps (67). This drawback is avoided in MEG mea-surements detecting cortical activity with millisecond tempo-ral accuracy, thus allowing the separation of the primarysomatosensory cortex from secondary activations (41).

The detection of language and memory lateralization toreplace intracarotid amobarbital procedure has been a focusof several fMRI studies (60, 103). Recent fMRI studies havedemonstrated an agreement of about 90% with results fromsimultaneous Wada tests, and also a significant correlationbetween presurgical fMRI and postsurgical outcome forfMRI imaging of frontal language areas (60). The progressin this field has been quicker in fMRI than in MEG, proba-bly owing to the much wider availability of fMRI than MEGtechnique. However, it has been emphasized that fMRI is amarker of activation and does not show whether the acti-vated area is necessary for language production (60, 103). Itremains to be seen whether the excellent temporal resolu-

tion of MEG assists in pinpointing the cortical regions cru-cial for speech processing from subprocesses less critical forthe preservation of these functions. A recent study (57)suggests that fMRI depicts better frontal speech-relatedactivity, whereas receptive language-related areas in thetemporal lobe are more prominent in MEG source analysis.Combination of both methods demonstrated dissociatedexpressive and receptive language functions, as verified byWada test and postoperative findings (57). The task designaffects the neurosurgical relevance of obtained fMRI acti-vation (101). Standardized series of activation paradigmsare desirable in fMRI studies of language lateralization andrepresentation in the brain (60). This is certainly true forMEG studies of language as well.

CONCLUSION

The presurgical localization of key cortical areas and thelocalization of epileptic foci before epilepsy surgery are thetwo main neurosurgical MEG applications so far. WithMEG recordings, it is usually possible to identify bodyrepresentations in the somatosensory and motor corticespreoperatively in patients with brain tumors in close vicin-ity of the sensorimotor strip. At present, MEG producesmost easily interpretable functional landmarks in the vicin-ity of the central sulcus. Mapping of speech-related activa-tions may prove useful in planning and executing opera-tions. However, rigorous intraoperative controls are stillneeded to validate this conjecture.

MEG source clusters of interictal epileptic spikes havebeen shown to correlate well with the electrocorticography-based localization of the ictal epileptogenic zone. In addi-tion, the millisecond time resolution allows the detection ofthe spread of epileptiform activity in some patients, furtherincreasing the reliability in finding the cortical sites respon-sible for the onset of epileptic activity. It is clear, however,that MEG is only a part of multifaceted clinical evaluationderiving information from all available sources for the ben-efit of the patient. The relative weight of MEG in thisevaluation depends on clinical details of each individualpatient.

The past decade has produced a vivid view of possibleapplications of MEG in neurosurgery. However, even themain applications of MEG, localization of epileptic foci andfunctional mapping of eloquent areas, have not been assessedin detail with randomized control groups including shammeasurements to display effects on clinical outcome. Larger,prospective studies of the clinical impact of MEG investiga-tions are still needed. The emergence of the whole head in-struments in hospital settings is making such research increas-ingly more feasible.

MEG is still an expensive installation, and its use requirespersonnel with experience to interpret the results. In contrast,fMRI acquisition is possible with most modern MRI scannersalready present in most centers performing neurosurgery, andpersonnel using MRI for anatomic imaging may perform fMRI

FIGURE 12. MEG source dynamics of bilateral Sylvian spike-waves of a6-year-old child experiencing acquired epileptic aphasia of childhood(Landau-Kleffner syndrome). A, in contrast to bilaterally simultaneous orleft-onset spikes in EEG (not shown), the source activations of right syl-vian (Rsyl) MEG spikes peaked 10 ms earlier than the left sylvian (Lsyl)cortex. A horizontal source in the right sylvian cortex (Rsylh) peaked laterthan the Lsyl source. B, dipole locations and orientations superimposed onthe patient’s coronal and sagittal MRI slices. White cutlines indicate thesection level. Language skills of the patient displayed clear recovery aftermultiple subpial transsections in the depths of the right sylvian cortex.The apparent false lateralization derived from EEG signals was caused bystronger radial than tangential current contribution to EEG. Convexialspikes, originating from Rsylh source and dominating the EEG signal inthe right hemisphere, peaked later than the MEG spikes in the fissural cor-tex. Thus, the earliest EEG spikes in the right hemisphere reflected propa-gated instead of pacemaker activity.

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with little extra training. However, MEG has unique proper-ties in depicting somatomotor cortical function, as well as indetecting sources and the spread of epileptic activity in indi-vidual patients. Furthermore, MEG provides informationcomplementary to that available with fMRI, EEG, or othersources and is, therefore, a useful tool for research as well asfor routine clinical measurements. Neurosurgical units partic-ipating in both these activities would particularly benefit froma MEG unit.

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AcknowledgmentsThis study was supported by the Academy of Finland. Riitta Hari made

valuable comments on the manuscript. Minna Vihla, Ph.D. helped to correct theEnglish language.

COMMENTS

Makela et al., who have pursued magnetoencephalography (MEG)applications for several years, are world leaders in this technol-

ogy. This is a comprehensive review of their own work, includingpresent applications and future possibilities. Today, the most impor-tant applications seem to be functional localization and mapping ofepileptic activity. These applications can be improved. MEG technol-ogy also offers possibilities of improving studies of neurological re-covery, establishing prognoses, etc.

This review sparked curiosity and imagination because initial dif-ficulties with accuracy seem minimalized as long as the cost still limitswidespread use. One fascinating quality of neurosurgery is the inter-section of mind and matter, and this technology provides complemen-tary imaging of this dichotomy.

Tiit MathiesenTom BrismarStockholm, Sweden

In this review, the authors discuss the technology of MEG and itsrelevance to neurosurgery. Although the ability to detect magnetic

fields produced by neuronal activity in the cortex has been availablefor decades, it has not found widespread use in neurosurgery. In fact,most neurosurgeons have never used this technology in clinical prac-tice, and few are entirely familiar with the scientific basis and clinicalpotential of MEG. In this review, the authors discussed the history,scientific background, and current and future applications of MEG.The additional information with regards to functional localizationfrom MEG may ultimately prove to be an important adjuvant to moretraditional imaging and preoperative workups.

Charles Y. LiuLos Angeles, California

Our group has used MEG in neurosurgical planning since 1993.Localization of sensory and motor areas were transferred to

stereotactic magnetic resonance imaging (MRI) reconstructions andprovided information for surgical approaches that avoided these im-portant areas. Later, we confirmed with interoperative electrophysi-ology that what we were identifying on MEG were, in fact, the sameregions that were identified electrophysiologically at stereotactic cra-niotomy (1). However, we do not use MEG much anymore for surgicalplanning because good quality functional MRI data is available. Thereason for this was not because functional MRI was “better” thanMEG, but rather because we could obtain functional MRI informationand anatomical information within a single study during stereotacticdatabase acquisition. The MEG unit was (and still is) in anotherbuilding and, with the availability of functional MRI, had a low addedbenefit over the hassle factor, at least at our institution. We arepresently evaluating the use of MEG in localizing epileptic foci andagree with the authors that this may prove to be valuable. Nonethe-

MÄKELÄ ET AL.


less, this review makes valid points and lists other applications forMEG that will be of interest to neurosurgeons.

Patrick J. KellyNew York, New York

1. Rezai AR, Hund M, Kronberg E, Zoneshayn M, Cappell J, Ribary U, Kall B,Llinas R, Kelly PJ: The interactive use of magnetoencephalography in stereo-tactic image-guided neurosurgery. Neurosurgery 39:92–102, 1996.

MEG has been used as a clinical neurosurgical tool for more thana decade. The most common clinical application of MEG has

involved functional mapping of the sensory and motor cortex andepileptic foci. The introduction and routine use of functional MRI inneurosurgical practice, however, has limited the growth and thedream of having “a MEG in every neurosurgical center.” The authors,from one of the most experienced MEG groups, review the evolutionof MEG systems and discuss the current application in neurosurgery.

From a functional imaging standpoint, MEG clearly has uniquecharacteristics that cannot be replicated by other imaging modalities,such as positron emission tomography and functional MRI. The su-perior temporal resolution of MEG allows neuronal processes occur-ring on a millisecond time scale to be mapped. This unsurpassed timeresolution feature of MEG can facilitate tracking of multiple sources ofelectrical activity. Noninvasive mapping of deep sulcal epileptiformactivity, not visible on electroencephalography, can also be considereda unique characteristic of MEG. Functional mapping of eloquent cor-tex adjacent to vascular lesions, a task which may be difficult to dowith functional MRI because of its dependence on blood flow as itssignal, is another area in which MEG may always remain superior.

Regrettably, the high cost of these systems will likely limit their useto large epilepsy centers, which may be able to justify the acquisitionof such a system on clinical means alone. Other large academic centersmay be able to use an MEG system in a mixed clinical/academicmode. The possibility, not discussed by the authors, that MEG may be

used to identify and characterize thalamocortical dysrhythmia (1), anabnormal coherent MEG rhythm occurring in a number of neurolog-ical disorders, may promote its use for functional neurosurgical ap-plications, including lesioning and deep brain stimulation. Additionalemerging applications of MEG in chronic pain, brain plasticity, lan-guage localization, auditory processing and cognitive function willfurther advance the utility of MEG systems.

Ali R. RezaiCleveland, OhioAlon Y. MogilnerGreat Neck, New York

1. Llinas, RR, Ribary U, Jeanmonod D, Kronberg E, Mitra PP: Thalamocorticaldysrhythmia: A neurological and neuropsychiatric syndrome characterizedby magnetoencephalography. Proc Natl Acad Sci USA 96:15222–15227, 1999.

Magnetic source imaging promises to be an important addition toneurosurgery. Its promise lies both as a tool of mapping neural

pathways, localizing the neuroanatomical substrates mediating func-tion, and as a means of localizing epileptoform events in the brain. Thehope is that one day it may be possible to circumvent invasive mon-itoring, such as depth electrodes and grids, to localize the sources ofepilepsies. To date, the cross correlation of these modalities is increas-ingly convincing, but we have not yet reached the point where MEGcan totally replace the need for intracranial recordings in difficultcases. With expansion of the indications, it may be possible that MEGcould play an important adjunct to functional MRI and other tests inlocalizing speech and language function, as well as memory reserve.Thus, the potential for MEG is large, and time will tell whether or notit fulfills its promise as a tool in neuroscience and as an adjunct inneurosurgery.

Andres M. LozanoToronto, Canada



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Magnetoencephalography in Neurosurgery

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