Source Connectivity Analysis from MEG and its Application to Epilepsy Source Localization

We report an approach to perform source connectivity analysis from MEG, and initially evaluate this approach to interictal MEG to localize epileptogenic foci and analyze interictal discharge propagations in patients with medically intractable epilepsy. Cortical activities were reconstructed from MEG using individual realistic geometry boundary element method head models. Directional connectivity among cortical regions of interest was then estimated using directed transfer function. The MEG source connectivity analysis method was implemented in the eConnectome software, which is open-source and freely available at . As an initial evaluation, the method was applied to study MEG interictal spikes from five epilepsy patients. Estimated primary epileptiform sources were consistent with surgically resected regions, suggesting the feasibility of using cortical source connectivity analysis from interictal MEG for potential localization of epileptiform activities.     

Dipole Source Analysis May Differentiate Benign Focal Epilepsy of Childhood with Occipital Paroxysms from Symptomatic Occipital Lobe Epilepsy

The aim of the study was to distinguish Benign Focal Epilepsy of Childhood with Occipital Paroxysms (BEOP) from its symptomatic counterpart on the basis of the location of the sources of the interictal EEG spikes. Patients were classified into two groups: idiopathic BEOP and symptomatic occipital lobe epilepsy. Source analysis of the averaged occipital spikes was performed using a homogeneously conducting sphere as the volume conductor model. Results showed a statistically significant difference in the eccentricity, i.e., the distance of the occipital spike focus from the centre of the head. The dipole sources of the occipital spikes in the BEOP group were found to be located more superficially than in the symptomatic group, corresponding in six of the nine cases with a source position estimated to be within the cortical layer just below the skull. The eccentricity of the symptomatic occipital spikes suggests a location deeper than the cortical layer. The results were validated in two patients from the symptomatic group. In one patient the estimated deeper dipole source location corresponded with a deeper location of spike activity observed during ECoG; in the other patient's ECoG, spike activity was observed superficially but over an extended area. The discrepancy between estimated and real location may be explained by the method of dipole source analysis used. It is concluded that the finding of a superficial dipole source location of the occipital spikes provides an indication for the diagnosis BEOP (sensitivity: 67%; specificity: 74%).     

Dipole Localization of Human Induced Focal Afterdischarge Seizure in Simultaneous Magnetoencephalography and Electrocorticography

Localizations were compared for the same human seizure between simultaneously measured MEG and iEEG, which were both co-registered to MRI. The whole-cortex neuromagnetometer localized a dipole in a sphere phantom, co-registered to the MEG sensor array, with an error of 1.4 mm. A focal afterdischarge seizure was induced in a patient with partial epilepsy, by stimulation at a subdural electrocorticography (ECoG) electrode with a known location, which was co-registered to the MRI and to the MEG sensor array. The simultaneous MEG and ECoG during the 30-second seizure was measured and analyzed using the single, moving dipole model, which is the localization model used clinically. The dipole localizations from simultaneous whole cortex 68-channel MEG and 64-channel ECoG were then compared for the repetitive spiking at six different times during the seizure. There were two main regions of MEG and ECoG activity. The locations of these regions were confirmed by determining the location clusters of 8,000 dipoles on ECoG at consecutive time points during the seizure. The mean distances between the stimulated electrode location versus the dipole location of the MEG and versus the dipole location of the ECoG were each about one (1) centimeter. The mean distance between the dipole locations of the MEG versus the dipole locations of the ECoG was about 2 cm. These errors were compared to errors of MEG and ECoG reported previously for phantoms and for somatosensory evoked responses (SER) in patients. Comparing the findings from the present study to those from prior studies, there appeared to be the expected stepwise increase in mean localization error progressing from the phantom, to the SER, to the seizure.     

The Existence of Two Sources in Rolandic Epilepsy: Confirmation with High Resolution EEG, MEG and fMRI

In benign rolandic epilepsy seizure semiology suggests that the epileptic focus resides in the lower sensorimotor cortex. Previous studies involving dipole modeling based on 32 channel EEG have confirmed this localization. These studies have also suggested that two distinct dipole sources are required to adequately describe the typical interictal spikes. Since in benign epilepsy invasive validation is prohibited, this study tries to further establish these results using a multi-modal approach, involving 32 channel EEG, high resolution 84 channel EEG, 151 channel MEG and fMRI. From one patient interictal spikes were recorded and analyzed using the MUSIC algorithm in a realistic volume conductor model. In an fMRI experiment the same patient performed voluntary tongue movements, thus mimicking a typical seizure. Results show that EEG, MEG and fMRI localization converge on the same area in the lower part of the sensorimotor cortex, and that high resolution EEG clearly reveals two distinct sources, one in the post- and one in the pre-central cortex.     

脑磁图在癫痫灶定位中的应用

目的：应用脑磁图（MEG）对癫痫灶进行定位，探讨脑磁图对癫痫灶定位的价值。方法：应用美国4D Vectorview306通道全头型生物磁仪，对21例癫痫患（其中男13例，女8例，年龄3－52岁，平均23．7岁）进行发作间期脑磁图检查。结果：17例测得发作间期棘波，4例未检测到棘波，结论：脑磁图对癫痫灶定位有很高的应用价值。     

Magnetoencephalographic studies on spike foci using a 37-channel biomagnetometer system]

We report the results of a clinical trial of Magnetoencephalography (MEG) on spike foci in patients with epilepsy, which was performed from December 1990 to June 1991 at The University of Tokyo Hospital. Fifty patients with focal epilepsy; 26 primary epilepsy, 24 secondary epilepsy (7 brain tumor, 4 arteriovenous malformation, 4 encephalitis, 3 porencephaly, 2 arachnoid cyst, 1 brain abscess, 1 hemimegaloencephaly, 1 Lance-Adams syndrome, 1 hygroma), and ten normal subjects were enrolled in this study. MEG data were recorded using a 37-channel biomagnetometer system SMI-1001 (BTi Magnes, Biomagnetic Technologies, Inc., San Diego). A simultaneous 19-channel EEG recording with linked-ear reference was also obtained. The overall study was completed safely and none of the normal subjects showed abnormal paroxysmal MEG activity. Two patients showed interictal EEG spikes which would not have been noticed without first noting the presence of corresponding prominent MEG spikes. On the whole, the MEG signal seemed to have a wider frequency bandwidth than EEG. In most cases, the source localization predicted by MEG corresponded well with the EEG findings. The relative accuracy of MEG spike source localization was estimated to be within a cubic centimeter from the cases which showed tightly clustered localization of individual spikes. High-pass filtering reduced interference by superimposed slow wave activity, thereby improving the localization of spike sources. These results demonstrate that 37-channel biomagnetometer system could be a useful tool for analyzing epileptic spike sources.     

Hemodynamic Changes Associated with Interictal Spikes Induced by Acute Models of Focal Epilepsy in Rats: A Simultaneous Electrocorticography and Near-Infrared Spectroscopy Study

Interictal spikes can be generated by blocking GABA_A receptor-mediated inhibition. The nature of the hemodynamic activities associated with interictal spikes in acute models of focal epilepsy based on GABA deactivation has not been determined. We analyzed systemic changes in hemodynamic signals associated with interictal spikes generated by acute models of focal epilepsy. Simultaneous ElectroCorticoGraphy (ECoG) and Near-InfraRed Spectroscopy (NIRS) recordings were obtained in vivo from adult Sprague–Dawley rat brain during semi-periodic focal interictal spikes induced by local cortical application of low doses of Penicillin G (PG) and Bicuculline Methiodide (BM) as GABA deactivation agents. The Finite Impulse Response deconvolution technique was used to estimate the profile of hemodynamic changes in oxyhemoglobin (HbO) and deoxyhemoglobin (HbR) concentrations associated with interictal ECoG spikes in each rat. Our results show that, in both acute models of focal epilepsy, the hemodynamic changes associated with interictal spikes were characterized by pre-spike and post-spike primary NIRS responses, and recovery periods with slight differences in amplitude and latency. The pre-spike period starting at least 2 s prior to the onset of ECoG spikes was characterized by a significant decrease in HbO concomitant with an increase in HbR with respect to baseline. The post-spike primary NIRS response exhibited the expected changes described according to the classical view of neurovascular coupling, i.e., a significant increase in HbO and a significant decrease in HbR in response to interictal spikes. The recovery period was characterized by a decreased HbO signal and an increased HbR signal, followed by a return to baseline. Compared to the BM epilepsy model, the PG model was more stable and showed lower variability in the shape, amplitude and latency of the components of spike-related hemodynamic changes. Our findings support a prominent role for pre-spike hemodynamic changes in the initiation of interictal spikes. The mechanism of interactions between neuronal and vascular networks during the pre-spike period constitutes a complex process, resulting in increased sensitivity of the epileptogenic focus to induce neuronal spiking.     

Comparison of Brain Networks During Interictal Oscillations and Spikes on Magnetoencephalography and Intracerebral EEG

Electromagnetic source localization in electroencephalography (EEG) and magnetoencephalography (MEG) allows finding the generators of transient interictal epileptiform discharges (‘interictal spikes’). In intracerebral EEG (iEEG), oscillatory activity (above 30 Hz) has also been shown to be a marker of neuronal dysfunction. Still, the difference between networks involved in transient and oscillatory activities remains largely unknown. Our goal was thus to extract and compare the networks involved in interictal oscillations and spikes, and to compare the non-invasive results to those obtained directly within the brain. In five patients with both MEG and iEEG recordings, we computed correlation graphs across regions, for (1) interictal spikes and (2) epileptic oscillations around 30 Hz. We show that the corresponding networks can involve a widespread set of regions (average of 10 per patient), with only partial overlap (38 % of the total number of regions in MEG, 50 % in iEEG). The non-invasive results were concordant with intracerebral recordings (79 % for the spikes and 50 % for the oscillations). We compared our interictal results to iEEG ictal data. The regions labeled as seizure onset zone (SOZ) belonged to interictal networks in a large proportion of cases: 75 % (resp. 58 %) for spikes and 58 % (resp. 33 %) for oscillations in iEEG (resp. MEG). A subset of SOZ regions were detected by one type of discharges but not the other (25 % for spikes and 8 % for oscillations). Our study suggests that spike and oscillatory activities involve overlapping but distinct networks, and are complementary for presurgical mapping.     

Magnetoencephalography in pediatric lesional epilepsy surgery

This study was performed to assess the usefulness of magnetoencephalography (MEG) as a presurgical evaluation modality in Korean pediatric patients with lesional localization-related epilepsy. The medical records and MEG findings of 13 pediatric patients (6 boys and 7 girls) with localization-related epilepsy, who underwent epilepsy surgery at Seoul National University Children's Hospital, were retrospectively reviewed. The hemispheric concordance rate was 100% (13/13 patients). The lobar or regional concordance rate was 77% (10/13 patients). In most cases, the MEG spike sources were clustered in the proximity of the lesion, either at one side of the margin (nine patients) or around the lesion (one patient); clustered spike sources were distant from the lesion in one patient. Among the patients with clustered spike sources near the lesion, further extensions (three patients) and distal scatters (three patients) were also observed. MEG spike sources were well lateralized and localized even in two patients without focal epileptiform discharges in the interictal scalp electroencephalography. Ten patients (77%) achieved Engel class I postsurgical seizure outcome. It is suggested that MEG is a safe and useful presurgical evaluation modality in pediatric patients with lesion localization-related epilepsy.     

脑磁图在耐药性癫(癎)术前定位中的价值及影响因素探讨

目的:评价脑磁图(MEG)在耐药性癫癎术前定位中的价值并探讨影响其定位的因素。方法:在47例术前均行MEG,VEEG,MRI检查的耐药性癫癎病例中,以术中皮层脑电图(ECoG)为金标准,比较VEEG和MEG定位准确性,并作影响MEG和VEEG定位的logistic多因素分析。结果:47例颞叶癫癎中,MEG与ECoG完全吻合32例(68％),部分吻合8例(17％);VEEG与ECoG完全吻合18例(38％),部分吻合23例(49％)。MEG与ECoG完全吻合病例明显多于MEG与VEEG吻合例(P <0．05)。MEG定位的多因素分析显示发作频率对MEG定位有影响(P<0．05)。结论:MEG的应用有助于致癎灶的准确定位和手术方式的选择,在难治性颞叶癫癎的术前定位中有重要的临床应用价值。     

Increased Functional MEG Connectivity as a Hallmark of MRI-Negative Focal and Generalized Epilepsy

Epilepsy is one of the most prevalent neurological diseases with a high morbidity. Accumulating evidence has shown that epilepsy is an archetypical neural network disorder. Here we developed a non-invasive cortical functional connectivity analysis based on magnetoencephalography (MEG) to assess commonalities and differences in the network phenotype in different epilepsy syndromes (non-lesional/cryptogenic focal and idiopathic/genetic generalized epilepsy). Thirty-seven epilepsy patients with normal structural brain anatomy underwent a 30-min resting state MEG measurement with eyes closed. We only analyzed interictal epochs without epileptiform discharges. The imaginary part of coherency was calculated as an indicator of cortical functional connectivity in five classical frequency bands. This connectivity measure was computed between all sources on individually reconstructed cortical surfaces that were surface-aligned to a common template. In comparison to healthy controls, both focal and generalized epilepsy patients showed widespread increased functional connectivity in several frequency bands, demonstrating the potential of elevated functional connectivity as a common pathophysiological hallmark in different epilepsy types. Furthermore, the comparison between focal and generalized epilepsies revealed increased network connectivity in bilateral mesio-frontal and motor regions specifically for the generalized epilepsy patients. Our study indicated that the surface-based normalization of MEG sources of individual brains enables the comparison of imaging findings across subjects and groups on a united platform, which leads to a straightforward and effective disclosure of pathological network characteristics in epilepsy. This approach may allow for the definition of more specific markers of different epilepsy syndromes, and increased MEG-based resting-state functional connectivity seems to be a common feature in MRI-negative epilepsy syndromes.     

Magnetoencephalography in clinical epileptology and Epilepsy research

This article reviews the application of magnetoencephalography (MEG) in clinical epileptology and epilepsy research. MEG recordings of interictal as well as ictal epileptiform discharges helped to improve non-invasive localization of epileptic foci in patients with focal epilepsy. Several studies showed good agreement of the localizations obtained from MEG compared with those from invasive electrical recordings. Thus, MEG may become a potentially useful technique in the pre-surgical evaluation of epilepsy patients. As evidenced from studying the penicillin focus in animals and spike propagation in humans, MEG also may contribute to further understand the basic mechanisms of epilepsy and thus may be useful in epilepsy research. Directions of future research include recording from a large number of channels covering a wide area of the head, long-term recording to study mechanisms involved in the transition of interictal to ictal state, and recording of slow magnetic field shifts associated with interictal and ictal epileptiform discharges.     

Magnetoencephalography-guided epilepsy surgery for children with intractable focal epilepsy: SickKids experience.

We introduced magnetoencephalography (MEG)-guided epilepsy surgery for children with intractable focal epilepsy at The Hospital for Sick Children (SickKids) in Toronto, Canada. Surgical candidacy and decisions on surgical procedure for children with intractable focal epilepsy are based on long-term scalp video EEG (VEEG) results, magnetic resonance imaging (MRI) findings, and the distribution of MEG spike sources. After multidisciplinary discussion at the seizure conference, for the patients requiring intracranial VEEG, custom-made subdural electrode grids are designed using three-dimensional MRI superimposed with MEG spike sources to cover the area of clustered MEG spike sources. At the first surgery, neurosurgeons use the intraoperative neuronavigation system to visualize the area of clustered spike dipoles and somatosensory evoked fields on MEG to place the subdural grid and depth electrodes. At the second surgery, the area of seizure onset and active interictal spike discharges on the intracranial VEEG recording, which usually correlates with the zone of clustered MEG spike sources, is resected. This combination leads to successful surgical outcome to control seizures in these challenging paediatric patients. MEG is a useful tool in children with intractable focal epilepsy to determine the surgical candidacy and focal cortical resection to stop seizures.     

Hidden Markov modelling of spike propagation from interictal MEG data

For patients with partial epilepsy, automatic spike detection techniques applied to interictal MEG data often discover several potentially epileptogenic brain regions. An important determination in treatment planning is which of these detected regions are most likely to be the primary sources of epileptogenic activity. Analysis of the patterns of propagation activity between the detected regions may allow for detection of these primary epileptic foci. We describe the use of hidden Markov models (HMM) for estimation of the propagation patterns between several spiking regions from interictal MEG data. Analysis of the estimated transition probability matrix allows us to make inferences regarding the propagation pattern of the abnormal activity and determine the most likely region of its origin. The proposed HMM paradigm allows for a simple incorporation of the spike detector specificity and sensitivity characteristics. We develop bounds on performance for the case of perfect detection. We also apply the technique to simulated data sets in order to study the robustness of the method to the non-ideal specificity-sensitivity characteristics of the event detectors and compare results with the lower bounds. Our study demonstrates robustness of the proposed technique to event detection errors. We conclude with an example of the application of this method to a single patient.     

MEG and EEG Sensitivity in a Case of Medial Occipital Epilepsy

Interictal or ictal events in partial epilepsies may project on scalp EEG contralaterally to the side of the epileptogenic lesion. Such paradoxical lateralization can be observed in case of para-sagittal generators, and is likely due to the spatial orientation of the generator, presenting an oblique projection towards the midline. We present here a case of medial occipital epilepsy investigated using EEG, MEG and stereoelectroencephalography (SEEG). MRI displayed a focal cortical dysplasia in the superior margin of the right calcarine fissure. SEEG demonstrated bilateral medial occipital interictal spikes, with an inversion of polarity at the level of the lesion and a contralateral propagation occurring in 10 ms. Interictal iterative EEG cartographies showed a large posterior field, with a maximum contralateral to the initial generator (EEG paradoxical lateralization). With the same number of channels, interictal iterative MEG cartographies were more precise and more complex than EEG ones, indicating an onset accurately lateralized. A few milliseconds later, MEG cartographies were quadripolar, thus indicating two homotopic active generators. These MEG and EEG cartographies have been reproduced using BESA dipole simulator. Relative merits of MEG and EEG are still debated. With 151 channels, MEG source localizations indicated the right medial occipital area, as demonstrated by SEEG. An investigation with a corresponding number of EEG channels was not performed. After a down sampling to 64 sensors, this precision was lost. MEG and EEG source localization results, both with 64 channels, were quite comparable, indicating both medial occipital areas. However, a careful analysis of MEG/EEG iterative cartographies, performed with the same number of channels in both modalities, demonstrated that, in this configuration, MEG sensitivity was superior to the EEG one, allowing separating two medial occipital sources, characterized in SEEG by a time delay of 10 ms.     

Different patterns of dipole source localization in gelastic seizure with or without a sense of mirth

Dipole source localization corresponding to interictal spikes were estimated using EEG dipole tracing with a realistic three-shell head model in three patients with cryptogenic gelastic epilepsy. The dipole sources in two patients, whose gelastic seizures were accompanied by a subjective feeling of mirth, were estimated in the right or left medio-basal temporal regions. In the other patient, with gelastic seizures without a sense of mirth, the dipole sources were localized in the right frontal region corresponding to the anterior cingulate. The results suggest that the neural activities in hippocampal regions are involved with the generation of gelastic seizures with a sense of mirth and those in the cingulate might be associated with the motor act of laughter.     

脑磁图对致癎灶定位的临床应用价值

目的：探讨脑磁图（MEG）对致痫灶定位的临床应用价值。方法：对临床诊断为癫痫的25例病人进行MEG检查，并与磁共振图（MRI）、脑电图（EEG）及术中脑皮层电图（EcoG）作比较。结果：25例接受MEG检查者中，22（88％）例可确定出致痫灶，其中18例（72％）得到EcoG证实，4例部位不相符。另外3例MEG未发现致痫灶者，深部电极EEG则在颞叶前内侧描记到痫样放电。MEG结果与EcoG对照，符合率为72％。结论：MEG对癫痫患者表浅皮层致痫灶定位具有重要的临床应用价值。     

Interictal spikes: Harbingers or causes of epilepsy?

Interictal spikes are brief paroxysmal electrographic discharges observed between spontaneous recurrent seizures in epileptic patients. The relationship between interictal spikes and the seizures that define acquired epilepsy has been debated for decades. Recent studies using long-term continuous electrographic recordings from the hippocampus and cortex in rats with kainate-induced epilepsy suggest that electrographic spikes, with waveforms similar to interictal spikes, precede the occurrence of the first spontaneous epileptic seizure. These data raise the possibility that spikes might serve as a surrogate marker of ongoing chronic epileptogenesis. Additionally, electrographic spikes might actually contribute to the development and maintenance of the epileptic state (i.e., the increased probability of spontaneous recurrent seizures). Correlational evidence for such a causal relationship has recently also been obtained in an in vitro model of epileptogenesis using organotypic hippocampal slices. Testing for a causal relationship will ultimately require selective anti-spike medications. Although no such agents currently exist, this new preparation is amenable to moderate-throughput screening, which should accelerate their discovery. Anti-spike agents may also be of benefit in ameliorating the cognitive dysfunctions associated with epilepsy, to which spike activity may contribute.     

Localization of the Epileptic Focus by Low-Resolution Electromagnetic Tomography in Patients with a Lesion Demonstrated by MRI

Patients with medically intractable partial epilepsy and well-defined symptomatic MRI lesions were studied using phase-encoded frequency spectral analysis (PEFSA) combined with low-resolution electromagnetic tomography (LORETA). Ten patients admitted to the epilepsy monitoring unit with MRI-identified lesions and intractable partial epilepsy were studied using 31-electrode scalp EEG. The scalp electrodes were located in three-dimensional space using a magnetic digitizer and coregistered with the patient's MRI. PEFSA was used to obtain a phase-encoded scalp map for the ictal frequencies. The ictal generators were obtained from the scalp map using LORETA. In addition, the generators of interictal epileptogenic spikes were identified using time-domain LORETA. The LORETA generators were rostral to the MRI lesion in 87% (7/8) of patients with temporal lobe lesions, but all were located in the mesial temporal lobe in concordance with the patients' MRI lesions. In patients with frontal lobe epilepsy, the ictal generators at the time that the spectral power was maximal localized to the MRI lesions. Eight of 10 patients had interictal spikes, of which 4 were bilateral independent temporal lobe spikes. Only generators of the interictal spikes that were ipsilateral to seizure onset correlated with the ictal generators. LORETA combined with PEFSA of the ictal discharge can localize ictal EEG discharges accurately and improve correlation with brain anatomy by allowing coregistration of the ictal generator with the MRI. Analysis of interictal spikes was less useful than analysis of the ictal discharge.     

Space–time network connectivity and cortical activations preceding spike wave discharges in human absence epilepsy: a MEG study

To describe the spatial and temporal profiles of connectivity networks and sources preceding generalized spike-and-wave discharges (SWDs) in human absence epilepsy. Nonlinear associations of MEG signals and cluster indices obtained within the framework of graph theory were determined, while source localization in the frequency domain was performed in the low frequency bands with dynamic imaging of coherent sources. The results were projected on a three-dimensional surface rendering of the brain using a semi-realistic head model and MRI images obtained for each of the five patients studied. An increase in clustering and a decrease in path length preceding SWD onset and a rhythmic pattern of increasing and decreasing connectivity were seen during SWDs. Beamforming showed a consistent appearance of a low frequency frontal cortical source prior to the first generalized spikes. This source was preceded by a low frequency occipital source. The changes in the connectivity networks with the onset of SWDs suggest a pathologically predisposed state towards synchronous seizure networks with increasing connectivity from interictal to preictal and ictal state, while the occipital and frontal low frequency early preictal sources demonstrate that SWDs are not suddenly arising but gradually build up in a dynamic network.