FULL-LENGTH ORIGINAL RESEARCH

BOLD responses related to focal spikes and widespread bilateral synchronous discharges generated in the frontal lobe *†Dongmei An, *Francßois Dubeau, and *Jean Gotman Epilepsia, 56(3):366–374, 2015 doi: 10.1111/epi.12909

SUMMARY

Dongmei An is a research fellow at the Montreal Neurological Institute, and is now working at West China Hospital

Objective: To investigate whether specific frontal regions have a tendency to generate widespread bilateral synchronous discharges (WBSDs) and others focal spikes and to determine the regions most involved when WBSDs occur; to assess the relationships between the extent of electroencephalography (EEG) discharges and the extent of metabolic changes measured by EEG/functional magnetic resonance imaging (fMRI). Methods: Thirty-seven patients with interictal epileptic discharges (IEDs) with frontocentral predominance underwent EEG/fMRI. Patients were divided into a Focal (20 patients) group with focal frontal spikes and a WBSD group (17 patients). Maps of hemodynamic responses related to IEDs were compared between the two groups. Results: The mean number  SD of IEDs in the Focal group was 137.5  38.1 and in the WBSD group, 73.5  16.6 (p = 0.07). The volume of hemodynamic responses in the WBSD group was significantly larger than in the Focal group (mean, 243.3  41.1 versus 114.8  27.4 cm3, p = 0.01). Maximum hemodynamic responses occurred in both groups in the following regions: dorsolateral prefrontal, mesial prefrontal, cingulate, and supplementary motor cortices. Maxima in premotor and motor cortex, frontal operculum, frontopolar, and orbitofrontal regions were found only in the Focal group, and maxima in thalamus and caudate only occurred in the WBSD group. Thalamic responses were significantly more common in the WBSD group (14/17) than in the Focal group (7/20), p = 0.004. Deactivation in the default mode network was significantly more common in the WBSD group (14/17) than in the Focal group (10/20), p = 0.04. Significance: The spatial distribution and extent of blood oxygen level–dependent (BOLD) responses correlate well with electrophysiologic changes. Focal frontal spikes and WBSDs are not region specific in the frontal lobe, and the same frontal region can generate focal and generalized discharges. This suggests that widespread discharges reflect widespread epileptogenicity rather than a focal discharge located in a region favorable to spreading. The thalamus plays an important role in bilateral synchronization. KEY WORDS: EEG/fMRI, BOLD, Focal spikes, Widespread bilateral synchronous discharges.

Accepted December 1, 2014; Early View publication January 20, 2015. *Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada; and †Department of Neurology, West China Hospital, Sichuan University, Chengdu, China Address correspondence to Dr. Jean Gotman, Montreal Neurological Institute, McGill University, 3801 University Street, Room 767, Montreal, QC, Canada H3A 2B4. E-mail: [email protected] Wiley Periodicals, Inc. © 2015 International League Against Epilepsy

Widespread bilateral synchronous discharges (WBSDs) are typically observed in patients with generalized epilepsy, in which synchronized oscillations in thalamocortical circuits are recognized as the key pathophysiologic mechanism.1–3 However, WBSDs are also seen frequently in patients with focal epilepsy, where they are also described as “secondary bilateral synchrony.” This concept, first defined by Tuckel and Jasper, means that the epileptic

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367 BOLD Responses Related to Focal Frontal Spikes and WBSDs discharges originate from a limited cortical area and then rapidly spread bilaterally, usually through the corpus callosum or cortical-thalamocortical circuits.4 WBSDs can originate from various cortical regions; most reported cases of WBSDs arise from a limited area in the frontal lobe, frequently the medial frontal area, but they can also arise from the temporal and parietal lobes.5–8 The specific mechanism of WBSDs remains largely unknown. Are there specific regions in the frontal lobe with a tendency to generate WBSDs, while other frontal regions tend to generate more focal epileptic activity? Does the thalamus behave in WBSDs as it does in generalized epilepsy? Simultaneous electroencephalography/functional magnetic resonance imaging (EEG/fMRI) recording can noninvasively investigate the hemodynamic response over the whole brain at the time of epileptic discharges by measuring the blood oxygenation level–dependent (BOLD) signal. Prior studies demonstrate that EEG/fMRI has the potential clinical utility to delineate the epileptic focus of focal epileptiform discharges and help understand the pathophysiology of generalized spike and waves.2,9–12 BOLD responses related to focal epileptic discharges can be confined to the focus, but can also be present in remote regions.13–15 BOLD responses related to generalized spike and waves are often reported as activation predominantly in the thalamus and deactivations in the default mode network (DMN).2,9,16 There has been no study relating the extent of the EEG discharge and the extent of the BOLD response, as most studies have concentrated on comparing the localization of the maximal EEG response with that of the maximum BOLD response. Examples have been shown where a focal EEG discharge leads to local and remote BOLD responses, and where a widespread EEG discharge in idiopathic generalized epilepsy or in focal epilepsy leads to a focal BOLD change,12,15–17 indicating that the relationship between the extent of the EEG discharge and the extent of the BOLD response is uncertain. In this study, we aimed to investigate whether specific frontal regions generate WBSDs and other focal spikes, and to determine which areas of the frontal lobe and related subcortical structures are involved when WBSDs occur. The use of combined EEG-fMRI allows us to investigate the involvement of subcortical regions at the time of scalp EEG discharges. Another aim of this study was to assess the relationships between the extent of EEG discharges and the extent of corresponding BOLD changes.

Materials and Methods Patients All patients were recruited from the EEG/fMRI database of the Montreal Neurological Hospital and Institute. Consecutive cases with interictal epileptic discharges (IEDs) with frontocentral predominance from April 2006 to April 2013 were included in this study. Patients with idiopathic

generalized epilepsy were excluded. Patients were divided into two groups based on the EEG distribution of IEDs: (1) a Focal group, which included patients having unilateral focal frontocentral spikes with a maximum at electrodes Fp1, F3, C3, F7 or at Fp2, F4, C4, F8; or bi-frontal spikes with a limited spatial extent, for example, involving electrodes Fp1, Fp2, F3, F4; or unilateral hemispheric spikes with a frontocentral predominance; and (2) a WBSD group, which included patients having widespread bilateral synchronous discharges with a frontocentral predominance, with or without a hemispheric predominance. Examples of the different types of pattern are shown in Figures 1–4. Each patient signed an informed consent in accordance with the regulation of the research ethics board of the Montreal Neurological Hospital and Institute. EEG/fMRI acquisition EEG was continuously recorded inside a 3T MRI scanner (Trio; Siemens, Erlangen, Germany) with 25 MR compatible scalp electrodes placed according to 10–20 (reference FCz) and 10–10 (F9, T9, P9, F10, T10, P10) electrode systems, using a BrainAmp system (Brain Products, Munich, Germany, 5 kHz sampling). A T1-weighted anatomic image was first acquired (until July 2008: 1-mm slice thickness; 256 9 256 matrix; echo time [TE], 7.4 msec; repetition time [TR], 2,300 msec; flip angle 30 degrees; and from July 2008: 1-mm slice thickness; 256 9 256 matrix; TE, 4.18 msec; TR, 2,300 msec; flip angle 9 degrees), and used for superimposition with functional images. Then functional data were acquired with a T2*-weighted echo planar imaging (EPI) sequence (until July 2008: TR, 1.75 s; TE, 30 msec; 64 9 64 matrix; 25 slices; voxel, 5 9 5 9 5 mm; flip angle 90 degrees; and from July 2008: TR, 1.9 s; TE, 25 msec; 64 9 64 matrix; 33 slices; voxel, 3.7 9 3.7 9 3.7 mm; flip angle 90 degrees). Each EPI run lasts for about 6 min. The total recording time for each patient was 60–90 min. EEG processing MR gradient artifacts were corrected offline with BrainVision Analyzer.18 Ballistocardiogram artifacts were removed by independent component analysis.19 IEDs similar to those recorded during clinical monitoring (outside the scanner) were marked, and IEDs with the same distribution but different morphology were grouped. In the WBSD group, the IEDs with a focal distribution, occurring in addition to WBSDs, were marked and included in the fMRI analysis, but the corresponding results were not included in the subsequent analysis. EEG/fMRI processing The method is identical to that used in previous studies.9,11,14,20 fMRI images were motion corrected and smoothed (6-mm full width at half maximum) using software from the Brain Imaging Center of the Montreal NeuroEpilepsia, 56(3):366–374, 2015 doi: 10.1111/epi.12909

368 D. An et al.

Figure 1. Patient 2 from the Focal group. EEG (bipolar montage) showed Fp1, F3, F7 spikes. BOLD responses: maximum activation in left frontopolar region, t = 9.77. Deactivation in right posterior insula and occipital regions. Epilepsia ILAE

logical Institute (http://www.bic.mni.mcgill.ca/software/). Temporal autocorrelations were accounted for by fitting an autoregressive model of order 1 according to the methods of Worsley et al.,21 and low frequency drifts were modeled with a third-order polynomial fitting to each run.21 Timing and duration of each IED were built as a regressor and convolved with four hemodynamic response functions (HRF) peaking at 3, 5, 7, and 9 s.20 This approach was shown to be more sensitive than using the canonical HRF20 and has been used in many studies. Motion parameters were modeled as confounds. All regressors were included in the same general linear model in the fMRI analysis (fMRIstat).21 For each event type, a statistic t-map was created for each regressor using the other regressors as confounds. A combined t-map was created by taking, at each voxel, the maximum t-value from the four t-maps based on four HRFs. The single combined t-map was used for the subsequent analysis. To be significant, a response required five contiguous voxels having a t-value > 3.1, corresponding to p < 0.05, corrected for multiple comparisons (family-wise error rate) due to the number of voxels and the four HRFs.20 In the t-maps, a yellow-red scale corresponds to positive BOLD responses (activation) and a blue-white scale to negative responses Epilepsia, 56(3):366–374, 2015 doi: 10.1111/epi.12909

(deactivation). Responses outside the brain were excluded and BOLD responses in the ventricles were excluded using a mask, as they are often interpreted as artifactual findings. For the Focal group, responses related to unilateral focal frontal or frontocentral spikes, to bifrontal spikes with a limited extent, and to unilateral hemispheric spikes; for the WBSD group, responses to WBSDs with frontocentral predominance were studied. The correspondence between scalp electrode location and brain regions used the anatomic location of standard electrode locations.22,23 Statistical analysis The following results were compared between the Focal and WBSD groups: 1. Location of the BOLD response with the maximum t-value in the frontal lobe, visually identified following the subdivision of the frontal lobe based on the description by Bancaud and Talairach24; 2. volume of BOLD responses, activation or deactivation corresponding to the spike field. The spike field, the region considered to be the spike generator, was estimated at the sublobar level by visual inspection of the scalp EEG. The approach of a visual matching of the EEG spike field with

369 BOLD Responses Related to Focal Frontal Spikes and WBSDs

Figure 2. Patient 7 from the Focal group. EEG (average reference) showed Fp2, F4, C4, Fz, Cz spikes. BOLD responses: bilateral supplementary motor area and middle cingulate, R > L, maximum t = 5.49. Deactivation in bilateral superior temporal gyrus. Epilepsia ILAE

BOLD responses has been used in many EEG/fMRI studies.10,14,15 The volume was measured by multiplying the number of contiguous voxels above the threshold by the voxel size; 3. presence of a thalamic response (activation or deactivation); 4. presence of deactivation in the DMN. Statistical analysis was performed with SPSS software (Chicago, IL, U.S.A.). Means and standard deviations were calculated for all continuous variables. t-Test was used for comparison of volume of BOLD responses between the Focal and WBSD groups. Corrected chi-square test and Fisher’s exact test were used to explore the differences in frequency of thalamic BOLD responses and deactivation in DMN, between the two groups. The level of statistical significance was set at p < 0.05 (two-sided).

Results Forty-six patients having IEDs with a frontocentral predominance were included for EEG/fMRI study: four

patients had large movement artifact during the scan, which prevented further data analysis, and five did not show clear IEDs during the fMRI scan. Therefore, 37 patients were included for this study. The Focal group consisted of 20 patients: 13 with focal frontal spikes and 7 with bifrontal spikes or hemispheric spikes with a frontocentral predominance. Seventeen patients belonged to the WBSD group. Nine of 20 patients in the Focal group were lesional according to anatomic MRI findings, and 6 of 17 in the WBSD group were lesional (p = 0.07). Detailed clinical and EEG/ fMRI information for the Focal group is given in Table S1, and for the WBSD group in Table S2. BOLD responses Volume of responses In the Focal group, the mean number of IEDs acquired during scanning was 137.5  38.1 (range 18–716). All patients showed significant BOLD responses related to IEDs. Eighteen patients showed both activation and Epilepsia, 56(3):366–374, 2015 doi: 10.1111/epi.12909

370 D. An et al.

Figure 3. Patient 10 from the WBSD group. EEG (bipolar montage) showed widespread bilateral synchronous discharges with a right side predominance. BOLD response: bilateral frontal lobe (R > L), cingulate gyrus, and right thalamus, maximum in right mesial prefrontal cortex, t = 26.8. Deactivation in default mode network, mostly posteriorly, bilateral temporal lobe, posterior insula, and occipital region. Epilepsia ILAE

deactivation, and two patients showed only deactivation. The mean volume of BOLD responses was 114.8  27.4 cm3. The mean number of IEDs in the WBSD group was 73.5  16.6 (range 5–214), which is not significantly different from the Focal group (p = 0.07). Most of the IEDs in the WBSD group occurred in bursts, with a mean duration of 4.4  3.0 s. All patients showed significant BOLD responses related to IEDs. All 17 patients showed both activation and deactivation. The volume of BOLD responses was 243.3  41.1 cm3 and significantly larger than that of Focal group (p = 0.01). Localization of cortical responses Examples from the Focal group are shown in Figures 1 and 2, and from the WBSD group in Figures 3 and 4. A summary of the location of the maximum BOLD responses in both groups is listed in Table 1. Within the frontal lobes, maximum BOLD responses occurred in both groups in the following regions: dorsolatEpilepsia, 56(3):366–374, 2015 doi: 10.1111/epi.12909

eral prefrontal, mesial prefrontal, cingulate, and supplementary motor cortices. Maxima in premotor and motor cortex, frontal operculum, frontopolar, and orbitofrontal regions were found only in the Focal group. Maxima in thalamus and caudate only occurred in the WBSD group. In four patients of the Focal group, the maximum BOLD response corresponded to deactivations, while in the remaining 16, the t-max corresponded to activations. In WBSD group, the maximum BOLD responses in the frontal lobe of all patients were activations. Deactivation in DMN Deactivation in the DMN was significantly more common in the WBSD group (14/17 patients, or 82.3%) than in the Focal group (10/20 patients, or 50%) (p = 0.04). Thalamic responses In the WBSD group, 14/17 (82.3%) patients showed thalamic BOLD responses, unilateral in two and bilateral in 12.

371 BOLD Responses Related to Focal Frontal Spikes and WBSDs

Figure 4. Patient 11 from the WBSD group. EEG (bipolar montage) showed widespread bilateral synchronous discharges with a left side predominance. BOLD response: bilateral frontal lobe, maximum in left mesial prefrontal cortex, t = 34.4. Diffuse deactivation in posterior quadrant, bilateral insula, and also the default mode network including the mesial and lateral prefrontal cortex and posterior cingulate. Epilepsia ILAE

Table 1. Summary of location of BOLD response with the maximum t-value in Focal and WBSD groups Location of BOLD response with max. value in the frontal lobe Lateral Frontopolar cortex Orbitofrontal cortex Frontooperculum cortex Dorsolateral prefrontal cortex Premotor cortex Motor cortex Mesial Cingulate gyrus Mesial prefrontal cortex Supplementary motor cortex Subcortical Thalamus Caudate nucleus

Focal group

WBSD group

1 4 2 3 1 1

0 0 0 4 0 0

4 2 2

5 4 1

0 0

2 1

Nine (64.3%) were thalamic activations, four deactivations, and one patient showed both activation and deactivation. In the Focal group, thalamic BOLD responses were significantly less common (7/20, or 35%) compared to the WBSD group (p = 0.004).Two were unilateral and five were bilat-

eral thalamic responses. Of interest, six of seven (or 85.7%) focal patients with thalamic responses were associated with bifrontal or unilateral hemispheric discharges, and, in contrast to the WBSD group, in five of seven (or 71.4%) patients in the Focal group, thalamic BOLD responses were deactivations rather than activations.

Discussion Frontal lobe anatomy and circuitry likely explain the tendency for this region to generate widespread EEG activity, and mesial frontal lobe structures are often believed to be responsible for the phenomenon called “secondary bilateral synchrony.” Using EEG/fMRI method, and with a better spatial resolution than EEG alone, we studied the mechanisms responsible for the generation of focal and widespread epileptiform discharges (WBSDs) in the frontal lobe. First, we found, not surprisingly, that the BOLD responses associated with focal frontal spikes are usually less extensive than those resulting from WBSDs. Second, we demonstrated that the maximum cortical BOLD responses related to focal frontal spikes are distributed widely in the frontal lobe and, hence, no specific subregions of the frontal lobe are more likely to generate focal Epilepsia, 56(3):366–374, 2015 doi: 10.1111/epi.12909

372 D. An et al. spikes. On the other hand, WBSDs are more likely to be observed when the mesial frontal lobe structures and dorsolateral prefrontal cortex are activated (they also occurred with subcortical responses). Thirdly, thalamic responses and deactivation in the DMN are more frequently observed in the WBSD group than in the Focal group, confirming the role of the thalamus in focal epilepsy, as in generalized epilepsy, for brain synchronization. EEG/fMRI recordings serve as an important tool to simultaneously investigate electrophysiologic changes and the underlying concomitant hemodynamic changes. Scalp EEG records electrical activity preferentially from the cortex near the scalp and does not provide reliable information about deep cortical and subcortical structures in the brain. Also, in order to have a better spatial resolution, EEG modeling methodology requires assumptions regarding the type and extent of generators. BOLD responses indirectly reflect neuronal activity throughout the whole brain simultaneously and can evaluate equally the involvement and the extent of the involvement of all brain regions at the time of a scalp EEG event. The first question we wanted to investigate is whether there is a relationship between the extent of the EEG discharge and the extent of the BOLD response. The number and duration of IEDs has been reported to have an effect on the presence and amplitude of the BOLD response,25,26 but the effect of the extent of the EEG discharge on the BOLD response has not been studied systematically. In two previous studies, we reported that hemodynamic changes associated with focal epileptic discharges sometimes occurred at a distance from the focus, suggesting a widespread epileptic network,11,14 but we had not correlated the volume of the BOLD response and the extent of the EEG discharge. The current study demonstrates a good correlation between the extents of the two types of signal: focal EEG activity is usually associated with small volume hemodynamic changes, and widespread EEG changes are usually associated with large hemodynamic responses. The extent of significant BOLD changes in the Focal group is on average less than half that of the WBSD group, and this difference is significant, with p=0.01. The number of IEDs is not likely to have played a role, since the number of discharges in the two groups was not significantly different (the number in the WBDS group was actually smaller than that in the Focal group). The extended BOLD signal changes associated with WBSDs may be related to the longer duration of the EEG abnormalities found in the patients of this group. However, it is not really possible to separate the spatial from the temporal factors because it is the nature of this type of discharge that they often occur in runs or bursts, when spatial extent and duration are correlated. It is also of note that even within the Focal group, BOLD responses associated with a wider spatial EEG distribution, those with bilateral frontocentral or hemispheric epileptic discharges, have a tendency to be larger compared to those with a very focal frontocentral disEpilepsia, 56(3):366–374, 2015 doi: 10.1111/epi.12909

tribution. Although there are clear exceptions, the extent of BOLD changes tends to reflect the extent of EEG changes, thereby reinforcing the coupling between the two types of measurements. Another question we wanted to address was whether the localization of a generator within the frontal lobe is a determining factor for the presence of widespread discharges or bilateral synchrony. In other words, a generator in a frontal area would result in widespread discharges, whereas a generator located in another part of the frontal lobe would tend to generate very localized discharges. Since the original work of Tuckel and Jasper in 1952,4 the concept of secondary bilateral synchrony has been linked with the frontal parasagittal region. A variety of functional imaging methods, including EEG, EEG-fMRI, and magnetoencephalography have indicated that some types of discharge are linked with the concept of secondary bilateral synchrony. These studies, however, have not investigated in what circumstances such a phenomenon occurs and when it does not.27–30 Our results indicate that epileptic discharges that are maximum in mesial prefrontal cortex, cingulate gyrus, and dorsolateral prefrontal cortex are not more likely to lead to widespread bilateral epileptic discharges than to focal discharges. This indicates that it is not the region of maximum epileptic activity that determines if a discharge will be widespread. It must then be that widespread discharges reflect genuinely a wider extent of epileptic tissue, or a more extensive network, than focal discharges. Such a widespread discharge has a spatial resemblance to the generalized spike and wave seen in idiopathic generalized epilepsy and its mechanisms of generation may be similar (see also below discussion on thalamic involvement). On the other hand, widespread bilateral discharges are unlikely to be maximum in the orbitofrontal/frontopolar or motor/premotor cortex; this indicates that epileptic foci in these regions have a tendency to be more restricted, although we have only a few patients with motor/premotor foci and the conclusion for this region must remain tentative. The DMN is considered to be closely related to human attention, and it is deactivated during task-based fMRI studies.31 The default mode state is also commonly suspended during generalized spike-wave discharges, a deactivation that may contribute to the altered consciousness observed during such discharges.2,16,32 EEG/fMRI studies of focal epilepsy also reported deactivation of parts of the DMN.10,11 In this study, deactivation in DMN regions was observed in both Focal and WBSD groups, which is consistent with previous findings. However, we found that widespread discharges were more likely associated with deactivation of the DMN compared to focal frontal spikes. Deactivation of the DMN at the time of epileptic spikes corresponds to a decrease in gamma activity in the DMN regions,33 but the mechanism linking epileptic discharges and the DMN is uncertain.34 More involvement of the DMN may indicate a more important cognitive effect of epileptic discharges.

373 BOLD Responses Related to Focal Frontal Spikes and WBSDs In EEG/fMRI studies focused on the underlying neuronal networks associated with generalized spike and waves in idiopathic generalized epilepsy, a consistent thalamic BOLD response, most often bilateral, symmetrical, and in the form of activation has been revealed,2,3,9 supporting the corticoreticular hypothesis.35 Animal studies demonstrated that the thalamus played a role in focal epilepsy as well, participating either in seizure propagation or synchronization.1,36 Imaging studies showed metabolic or structural thalamic abnormalities in human focal epilepsy.37,38 In addition, the role of the thalamus in focal epilepsy has attracted clinical attention, since deep brain stimulation targeting the thalamus has become an emerging option for patients with drug-resistant epilepsy who are not suitable for resective surgery.39,40 Thalamic BOLD responses were observed in 82.3% of our WBSD patients, consistent with two EEG/fMRI studies investigating WBSDs or secondary bilateral synchrony.14,17 This percentage was significantly higher than that in the Focal group (35%). Another interesting finding is that most of the Focal patients who showed a thalamic BOLD response had bilateral frontal or hemispheric discharges, suggesting that the thalamus plays an important role in the spreading of epileptic activities. These findings also demonstrate that EEG/fMRI can evaluate the involvement of the thalamus during IEDs, which may have clinical utility for screening patients for deep brain stimulation. In addition, thalamic responses at the time of WBSDs often presented in the form of activation, which is similar to findings with generalized spike and waves in patients with idiopathic generalized epilepsy, whereas thalamic responses related to less widespread IEDs in the Focal group often presented as deactivation. This may indicate different thalamic mechanisms in different types of IEDs, which needs further investigation. In summary, the spatial distribution and extent of the electrophysiologic changes correlate well with the extent of BOLD signal changes. WBSDs are more likely to originate in the mesial or dorsolateral frontal lobe rather than in the other frontal regions. On the other hand, focal frontal spikes can be generated from any frontal areas including the mesial and dorsolateral regions. The thalamus seems to play an important role in the bilateral synchronization and spreading of discharges.

Acknowledgments This study was supported by the Canadian Institutes of Health Research (MOP-38079). D. An was supported by the Chinese Scholarship Council. The authors thank Natalja Zazubovits for helping to collect and analyze the data.

Disclosure None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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Supporting Information Additional Supporting Information may be found in the online version of this article: Table S1. BOLD response in the Focal group. Table S2. BOLD response in the WBSD group.

BOLD responses related to focal spikes and widespread bilateral synchronous discharges generated in the frontal lobe.

To investigate whether specific frontal regions have a tendency to generate widespread bilateral synchronous discharges (WBSDs) and others focal spike...
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