Cortical Dysplasia and the mTOR Pathway: How the Study of Human Brain Tissue Has Led to Insights into Epileptogenesis.

Type II focal cortical dysplasia (FCD) is a neuropathological entity characterised by cortical dyslamination with the presence of dysmorphic neurons only (FCDIIA) or the presence of both dysmorphic neurons and balloon cells (FCDIIB). The year 2021 marks the 50th anniversary of the recognition of FCD as a cause of drug resistant epilepsy, and it is now the most common reason for epilepsy surgery. The causes of FCD remained unknown until relatively recently. The study of resected human FCD tissue using novel genomic technologies has led to remarkable advances in understanding the genetic basis of FCD. Mechanistic parallels have emerged between these non-neoplastic lesions and neoplastic disorders of cell growth and differentiation, especially through perturbations of the mammalian target of rapamycin (mTOR) signalling pathway. This narrative review presents the advances through which the aetiology of FCDII has been elucidated in chronological order, from recognition of an association between FCD and the mTOR pathway to the identification of somatic mosaicism within FCD tissue. We discuss the role of a two-hit mechanism, highlight current challenges and future directions in detecting somatic mosaicism in brain and discuss how knowledge of FCD may inform novel precision treatments of these focal epileptogenic malformations of human cortical development.

Transcriptomic profiling of high- and low-spiking regions reveals novel epileptogenic mechanisms in focal cortical dysplasia type II patients.

Focal cortical dysplasia (FCD) is a malformation of the cerebral cortex with poorly-defined epileptogenic zones (EZs), and poor surgical outcome in FCD is associated with inaccurate localization of the EZ. Hence, identifying novel epileptogenic markers to aid in the localization of EZ in patients with FCD is very much needed. High-throughput gene expression studies of FCD samples have the potential to uncover molecular changes underlying the epileptogenic process and identify novel markers for delineating the EZ. For this purpose, we, for the first time performed RNA sequencing of surgically resected paired tissue samples obtained from electrocorticographically graded high (MAX) and low spiking (MIN) regions of FCD type II patients and autopsy controls. We identified significant changes in the MAX samples of the FCD type II patients when compared to non-epileptic controls, but not in the case of MIN samples. We found significant enrichment for myelination, oligodendrocyte development and differentiation, neuronal and axon ensheathment, phospholipid metabolism, cell adhesion and cytoskeleton, semaphorins, and ion channels in the MAX region. Through the integration of both MAX vs non-epileptic control and MAX vs MIN RNA sequencing (RNA Seq) data, PLP1, PLLP, UGT8, KLK6, SOX10, MOG, MAG, MOBP, ANLN, ERMN, SPP1, CLDN11, TNC, GPR37, SLC12A2, ABCA2, ABCA8, ASPA, P2RX7, CERS2, MAP4K4, TF, CTGF, Semaphorins, Opalin, FGFs, CALB2, and TNC were identified as potential key regulators of multiple pathways related to FCD type II pathology. We have identified novel epileptogenic marker elements that may contribute to epileptogenicity in patients with FCD and could be possible markers for the localization of EZ.

One-Stage, Limited-Resection Epilepsy Surgery for Bottom-of-Sulcus Dysplasia.

OBJECTIVE: To determine whether 1-stage, limited corticectomy controls seizures in patients with MRI-positive, bottom-of-sulcus dysplasia (BOSD). METHODS: We reviewed clinical, neuroimaging, electrocorticography (ECoG), operative, and histopathology findings in consecutively operated patients with drug-resistant focal epilepsy and MRI-positive BOSD, all of whom underwent corticectomy guided by MRI and ECoG. RESULTS: Thirty-eight patients with a median age at surgery of 10.2 (interquartile range [IQR] 6.0-14.1) years were included. BOSDs involved eloquent cortex in 15 patients. Eighty-seven percent of patients had rhythmic spiking on preresection ECoG. Rhythmic spiking was present in 22 of 24 patients studied with combined depth and surface electrodes, being limited to the dysplastic sulcus in 7 and involving the dysplastic sulcus and gyral crown in 15. Sixty-eight percent of resections were limited to the dysplastic sulcus, leaving the gyral crown. Histopathology was focal cortical dysplasia (FCD) type IIb in 29 patients and FCDIIa in 9. Dysmorphic neurons were present in the bottom of the sulcus but not the top or the gyral crown in 17 of 22 patients. Six (16%) patients required reoperation for postoperative seizures and residual dysplasia; reoperation was not correlated with ECoG, neuroimaging, or histologic abnormalities in the gyral crown. At a median 6.3 (IQR 4.8-9.9) years of follow-up, 33 (87%) patients are seizure-free, 31 off antiseizure medication. CONCLUSION: BOSD can be safely and effectively resected with MRI and ECoG guidance, corticectomy potentially being limited to the dysplastic sulcus, without need for intracranial EEG monitoring and functional mapping. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that 1-stage, limited corticectomy for BOSD is safe and effective for control of seizures.

Awake Epilepsy Surgery in Patients with Focal Cortical Dysplasia.

BACKGROUND: Awake craniotomy (AC) and direct electric stimulation emerged together with epilepsy surgery >80 years ago. The goal of our study was to evaluate the benefits of awake surgery in patients with drug-resistant epilepsy caused by focal cortical dysplasia (FCD) affecting eloquent areas. METHODS: Our material included 95 patients with drug-resistant epilepsy and FCD, who were operated on between January 2009 and December 2018. These 95 patients were assigned into 3 groups: AC; general anesthesia (GA) with intraoperative neuromonitoring; and GA without intraoperative neuromonitoring. We investigated the following variables: age at surgery, lesion side, eloquent cortex involvement, brain mapping success rate, epilepsy surgery success rate, intraoperative complications, postoperative complications, and intraoperative changes of the preoperative resection plan according to results of the brain mapping by direct electric stimulation. RESULTS: We found statistically significant differences between the AC and GA groups in the mean age at operation, lesion side, eloquent localization, and postoperative transient neurologic deficit. Seizure outcome in the AC was satisfactory (71% complete seizure control) and comparable to the seizure outcome in the GA groups. Our preoperative plan was changed because of functional constraints in 6 patients (43%) operated on during AC. CONCLUSIONS: AC during epilepsy surgery for FCD in eloquent areas may change the preoperative plan. The good rate of postoperative seizure control and the absence of permanent postoperative neurologic deficit in our series is the main proof that AC is a useful tool in patients with FCD involving the eloquent cortex.

Defining the latent period of epileptogenesis and epileptogenic zone in a focal cortical dysplasia type II (FCDII) rat model.

OBJECTIVES: Focal cortical dysplasia type II (FCDII) is one of the most common underlying pathologies in patients with drug-resistant epilepsy. However, mechanistic understanding of FCDII fails to keep pace with genetic discoveries, primarily due to the significant challenge in developing a clinically relevant animal model. Conceptually and clinically important questions, such as the unknown latent period of epileptogenesis and the controversial epileptogenic zone, remain unknown in all experimental FCDII animal models, making it even more challenging to investigate the underlying epileptogenic mechanisms. METHODS: In this study, we used continuous video-electroencephalography (EEG) monitoring to detect the earliest interictal and ictal events in a clustered regularly interspaced short palindromic repeats (CRISPR)-in utero electroporation (IUE) FCDII rat model that shares genetic, pathological, and electroclinical signatures with those observed in humans. We then took advantage of in vivo local field potential (LFP) recordings to localize the epileptogenic zone in these animals. RESULTS: To the best of our knowledge, we showed for the first time that epileptiform discharges emerged during the third postnatal week, and that the first seizure occurred as early as during the fourth postnatal week. We also showed that both interictal and ictal discharges are localized within the dysplastic cortex, concordant with human clinical data. SIGNIFICANCE: Together, our work identified the temporal and spatial frame of epileptogenesis in a highly clinically relevant FCDII animal model, paving the way for mechanistic studies at molecular, cellular, and circuitry levels.

Dysmorphic neurons as cellular source for phase-amplitude coupling in Focal Cortical Dysplasia Type II.

OBJECTIVE: Reliable localization of the epileptogenic zone is necessary for successful epilepsy surgery. Neurophysiological biomarkers include ictal onsets and interictal spikes. Furthermore, the epileptic network shows oscillations with potential localization value and pathomechanistic implications. The cellular origin of such markers in invasive EEG in vivo remains to be clarified. METHODS: In the presented pilot study, surgical brain samples and invasive EEG recordings of seven patients with surgically treated Focal Cortical Dysplasia (FCD) type II were coregistered using a novel protocol. Dysmorphic neurons and balloon cells were immunohistochemically quantified. Evaluated markers included seizure onset, spikes, and oscillatory activity in delta, theta, gamma and ripple frequency bands, as well as sample entropy and phase-amplitude coupling between delta, theta, alpha and beta phase and gamma amplitude. RESULTS: Correlations between histopathology and neurophysiology provided evidence for a contribution of dysmorphic neurons to interictal spikes, fast gamma activity and ripples. Furthermore, seizure onset and phase-amplitude coupling in areas with dysmorphic neurons suggests preserved connectivity is related to seizure initiation. Balloon cells showed no association. CONCLUSIONS: Phase-amplitude coupling, spikes, fast gamma and ripples are related to the density of dysmorphic neurons and localize the seizure onset zone. SIGNIFICANCE: The results of our pilot study provide a new powerful tool to address the cellular source of abnormal neurophysiology signals to leverage current and novel biomarkers for the localization of epileptic activity in the human brain.

Ictal and interictal source imaging on intracranial EEG predicts epilepsy surgery outcome in children with focal cortical dysplasia.

OBJECTIVE: To localize the seizure onset zone (SOZ) and irritative zone (IZ) using electric source imaging (ESI) on intracranial EEG (iEEG) and assess their clinical value in predicting epilepsy surgery outcome in children with focal cortical dysplasia (FCD). METHODS: We analyzed iEEG data from 25 children with FCD-associated medically refractory epilepsy (MRE) who underwent surgery. We performed ESI on ictal onset to localize SOZ (ESI-SOZ) and on interictal discharges to localize IZ (ESI-IZ). We tested whether resection of ESI-SOZ and ESI-IZ predicted good surgical outcome (Engel 1). We further compared the prediction performance of ESI-SOZ and ESI-IZ to those of SOZ and IZ defined using conventional methods, i.e. by identifying iEEG-contacts showing ictal onsets (conventional-SOZ) or being the most interictally active (conventional-IZ). RESULTS: The proximity of ESI-SOZ (p = 0.043, odds-ratio = 3.9) and ESI-IZ (p = 0.011, odds-ratio = 7.04) to resection has higher effect on patients' outcome than proximity of conventional-SOZ (p = 0.17, odds-ratio = 1.7) and conventional-IZ (p = 0.038, odds-ratio = 2.6). Resection of ESI-SOZ and ESI-IZ presented higher discriminative power in predicting outcome (68% and 60%) than conventional-SOZ and conventional-IZ (48% and 53%). CONCLUSIONS: Localizing SOZ and IZ via ESI on iEEG offers higher predictive value compared to conventional-iEEG interpretation. SIGNIFICANCE: iEEG-ESI may help surgical planning and facilitate prognostic assessment of children with FCD-associated MRE.

Sleep related epilepsy in focal cortical dysplasia type 2: Insights from sleep recordings in presurgical evaluation.

OBJECTIVE: To determine the relationship between seizure onset, sleep stage and focal cortical dysplasia type 2 (FCD2) location in sleep related epilepsy (SRE). METHODS: We reviewed scalp video-EEG data of 77 patients with SRE among 130 surgically treated patients with histologically confirmed FCD2. Seizure onset was classified as occurring during NREM, REM and after arousal. RESULTS: Sleep recordings were available for 65 patients (37 males, 7-49 years old). FCD2 was located in frontal lobe in 46 (71%) and in extra-frontal regions in 19, including the temporal lobe in 6. MRI was negative/doubtful in 35 cases. Interictal rhythmic/pseudorhythmic spike rate increased from 31% during waking to 65% during sleep. Seizure onset occurred from NREM in 46 cases (71%), mostly from stage 2, and after arousal in 14 (22%). Seizures occurring from NREM/REM sleep were significantly more frequent in frontal (89%) compared to extra-frontal location (42%), whilst arousal preceded seizure onset more often in extra-frontal (58%) compared to frontal location (7%). CONCLUSIONS: NREM seizure onset is the most common ictal pattern in SRE due to frontal FCD2 whereas preceding arousal points to extra-frontal regions. SIGNIFICANCE: Sleep recordings may help for FCD2 localisation and suggest topography dependent impact on sleep related epileptic networks.

Clinical features and surgical outcomes in young children with focal cortical dysplasia type II.

AIMS: To investigate clinical characteristics and surgery outcomes of young children with focal cortical dysplasia (FCD) type II. METHODS: Young children (onset age ≤6 years) with FCDII who underwent epileptic surgery in Children Epilepsy Center of Peking University First Hospital in 2014-2018 were followed up for at least 6 months after surgery. RESULTS: One hundred and twelve children with FCDII were included, with median age of onset 0.9 years (0.01-5.9), who underwent surgery at 4.1 years old (0.8-16.2). Focal seizures were most frequent (90.2%) and epileptic spasms presented in 23 (20.5%) cases. Epileptic encephalopathy was not uncommon (12.5%), associated with earlier epilepsy onset and higher rate of bilateral onset on ictal EEG (OR = 0.213, 9.059; P = .041, .004). At the last follow-up, 88.4% achieved seizure-free. Before surgery, 49.1% showed moderate/severe developmental delay, associated with earlier seizure onset and higher rate of history of epileptic encephalopathy (OR = 0.740, 5.160, P = .023, .042). For 48 children with preoperatively moderate/severe developmental delay, DQ rank at 6 months postsurgery was improved in only four cases. CONCLUSION: For young children with FCDII, they tend to present with epileptic encephalopathies and show moderate/severe developmental delay before surgery. The seizure outcome was favorable after surgery. For children with preoperatively moderate/severe developmental delay, developmental outcome at 6 months after surgery was not satisfactory.

Low entropy of interictal gamma oscillations is a biomarker of the seizure onset zone in focal cortical dysplasia type II.

OBJECTIVE: Dynamic changes in the regularity of interictal gamma oscillations (GOs, 30-70 Hz) on intracranial electroencephalography (EEG) reflect focal ictogenesis with epileptogenic neuronal synchronization in focal cortical dysplasia (FCD). We investigated whether the regularity of interictal GOs is a biomarker of the seizure onset zone (SOZ) using multiscale entropy analysis. METHODS: We quantified the regularity of interictal GOs using intracranial EEG data from 1164 electrodes in 13 patients with FCD who were seizure-free postoperatively. The regularity of interictal GOs was quantified as entropy values. Low entropy represents high regularity. We standardized entropy values using Z values for each SOZ, resection area (RA), and the region outside the RA. The cutoff Z values, sensitivity, and specificity for detecting each area were calculated using area under the receiver operating characteristics curves (AUCs). RESULTS: Low Z values represent higher regularity of GOs. The cutoff Z value of ≤-2.09 for the SOZ had a sensitivity of 100% and specificity of 97.1% (AUC = 0.992 ±â€¯0.002). The cutoff Z value of ≤-0.12 for the RA had a sensitivity of 54.2% and specificity of 73.8% (AUC = 0.673 ±â€¯0.019). The cutoff Z value of ≥-0.11 for the region outside the RA had a sensitivity of 73.8% and specificity of 54.2% (AUC = 0.673 ±â€¯0.019). CONCLUSIONS: Low entropy of interictal GOs was a reliable biomarker for the SOZ. Maintained high entropy of interictal GOs may be an auxiliary biomarker for nonepileptogenic regions. SIGNIFICANCE: Low entropy of interictal GOs may be a biomarker for the SOZ in FCD type II.

Multiscale Functional Clustering Reveals Frequency Dependent Brain Organization in Type II Focal Cortical Dysplasia With Sleep Hypermotor Epilepsy.

OBJECTIVE: A multiscale functional clustering approach is proposed to investigate the organization of the epileptic networks during different sleep stages and in relation with the occurrence of seizures. METHOD: Stereo-electroencephalographic signals from seven pharmaco-resistant epileptic patients (focal cortical dysplasia type II) were analyzed. The discrete wavelet transform provided a multiscale framework on which a data-driven functional clustering procedure was applied, based on multivariate measures of integration and mutual information. The most interacting functional clusters (FCs) within the sampled brain areas were extracted. RESULTS: FCs characterized by strongly integrated activity were observed mostly in the beta and alpha frequency bands, immediately before seizure onset and in deep sleep stages. These FCs generally included the electrodes from the epileptogenic zone. Furthermore, repeatable patterns were found across ictal events in the same patient. CONCLUSION: In line with previous studies, our findings provide evidence of the important role of beta and alpha activity in seizures generation and support the relation between epileptic activity and sleep stages. SIGNIFICANCE: Despite the small number of subjects included in the study, the present results suggest that the proposed multiscale functional clustering approach is a useful tool for the identification of the frequency-dependent mechanisms underlying seizure generation.

Single stage epilepsy surgery in children and adolescents with focal cortical dysplasia type II - Prognostic value of the intraoperative electrocorticogram.

OBJECTIVE: To evaluate prospectively the informative/prognostic value of epileptic discharges in the post-resection ECoGs of children with drug-resistant epilepsies and Focal Cortical Dysplasia type II (FCD-II). METHODS: Included were consecutive patients with focal epilepsies and suspected FCD-II who were planned for single-stage epilepsy surgery based on non-invasive presurgical evaluation results. Intraoperative ECoGs were recorded using a 32-channel system with strip- and/or grid-electrodes. Spikes were defined as transients with a mainly negative component and duration of 20-70 ms. Fast activity was defined as rhythmic bursts of polyspikes >13 Hz. All ECoGs were analysed visually. The significance of both spikes and fast activity in the post-resection ECoG for seizure outcomes 24 months after surgery was evaluated. RESULTS: Data from 18 patients (five girls) were analysed. 10/18 patients (55.6%) showed spikes in their post-resection ECoGs, five of them showed additional fast activity. 24 months after surgery, 12/18 patients (66.7%) were seizure-free. There was a significant correlation between unfavorable seizure outcomes and fast activity in the post-resection ECoGs (p = 0.009), whereas spikes alone were not predictive (p = 0.502). CONCLUSION: Even when recorded with non-sophisticated techniques, presence of fast activity in post-resection ECoGs might be a valid negative outcome-predictor after surgery in paediatric patients with FCD-II associated drug-resistant epilepsies. SIGNIFICANCE: Fast activity recorded with a relatively simple ECoG equipment seems also to have prognostic significance and by this might be an alternative to HFOs recorded with highly sophisticated and expensive technologies.

Somatic Depdc5 deletion recapitulates electroclinical features of human focal cortical dysplasia type IIA.

Epileptogenic mechanisms in focal cortical dysplasia (FCD) remain elusive, as no animal models faithfully recapitulate FCD seizures, which have distinct electrographic features and a wide range of semiologies. Given that DEPDC5 plays significant roles in focal epilepsies with FCD, we used in utero electroporation with clustered regularly interspaced short palindromic repeats gene deletion to create focal somatic Depdc5 deletion in the rat embryonic brain. Animals developed spontaneous seizures with focal pathological and electroclinical features highly clinically relevant to FCD IIA, paving the way toward understanding its pathogenesis and developing mechanistic-based therapies. Ann Neurol 2018;83:140-146.

Task-induced gamma band effect in type II focal cortical dysplasia: An exploratory study.

OBJECTIVE: Few data are available about the functionality of type II focal cortical dysplasia (FCD). Identification of high-frequency activities (HFAs) induced by cognitive tasks has been proposed as an additional way to map cognitive functions in patients undergoing presurgical evaluation using stereoelectroencephalography (SEEG). However, the repetitive subcontinuous spiking pattern which characterizes type II FCD might limit the reliability of this approach, and its feasibility in these patients remains to be evaluated. METHODS: Seven patients whose magnetic resonance imaging (MRI) data, SEEG data, and/or pathological data were consistent with the diagnosis of type II FCD were included. All patients performed standardized cognitive tasks specifically designed to map task-induced increase of HFA (50 Hz to 150 Hz) at the recorded sites. Electrode contacts which showed an interictal SEEG pattern typical of type II FCD were considered to be localized within the FCD. A site was considered responsive if it was significantly different from baseline in at least one cognitive task. RESULTS: Three of the seven patients (43%) had significant task-induced increase of HFA in the FCD for a total of 15 sites with an interictal SEEG pattern typical of type II FCD. These sites were always localized at the external border of the FCD whereas no HFA response was in the core of FCD. In three of the four other patients, a significant task-induced increase of HFA was observed in a cortical site immediately adjacent to the dysplastic cortex. SIGNIFICANCE: Detection of task-induced HFA remains feasible despite the repetitive subcontinuous spiking pattern which characterizes type II FCD. Depending on the localization of the FCD, some sites of the dysplastic cortex were included in large-scale functional networks. However, these sites were always those closest to the nondysplastic cortex suggesting that persistence of cortical functions might be restricted to a limited part of the FCD.

Value of ictal and interictal epileptiform discharges and high frequency oscillations for delineating the epileptogenic zone in patients with focal cortical dysplasia.

OBJECTIVES: There are different neurophysiological markers of the Epileptogenic Zone (EZ), but their sensitivity and specificity for the EZ is not known in Focal Cortical Dysplasia (FCD) patients. METHODS: We studied patients with FCD who underwent stereoelectroencephalography (SEEG) and surgery. We marked in the SEEG: (a) typical and atypical interictal epileptiform patterns, (b) ictal onset patterns, and (c) rates of ripples (80-250 Hz) and fast ripples (FRs) (>250 Hz). High frequency oscillations were marked automatically during one hour of deep sleep. Surgical outcome was defined as good (Engel I) or poor (Engel II-IV). We computed the sensitivity and, as a measure of specificity, the false positive rate to identify the EZ, and compared them across the different neurophysiological markers. RESULTS: We studied 21 patients, 19 with FCD II. Ictal and typical interictal pattern were the markers with highest sensitivity, while the atypical interictal pattern had the lowest. We found no significant difference in specificity among markers. However, there is a tendency that FRs had the lowest false positive rate. CONCLUSION: The typical interictal pattern has the highest sensitivity. The clinical use of FRs is limited by their low sensitivity. SIGNIFICANCE: We suggest to analyze the typical interictal pattern first. FRs should be analyzed in a second step. If, for instance, a focus with FRs and no typical interictal pattern is found, this area could be considered for resection.

Multinodular and vacuolating neuronal tumors in epilepsy: dysplasia or neoplasia?

Multinodular and vacuolating neuronal tumor (MVNT) is a new pattern of neuronal tumour included in the recently revised WHO 2016 classification of tumors of the CNS. There are 15 reports in the literature to date. They are typically associated with late onset epilepsy and a neoplastic vs. malformative biology has been questioned. We present a series of ten cases and compare their pathological and genetic features to better characterized epilepsy-associated malformations including focal cortical dysplasia type II (FCDII) and low-grade epilepsy-associated tumors (LEAT). Clinical and neuroradiology data were reviewed and a broad immunohistochemistry panel was applied to explore neuronal and glial differentiation, interneuronal populations, mTOR pathway activation and neurodegenerative changes. Next generation sequencing was performed for targeted multi-gene analysis to identify mutations common to epilepsy lesions including FCDII and LEAT. All of the surgical cases in this series presented with seizures, and were located in the temporal lobe. There was a lack of any progressive changes on serial pre-operative MRI and a mean age at surgery of 45 years. The vacuolated cells of the lesion expressed mature neuronal markers (neurofilament/SMI32, MAP2, synaptophysin). Prominent labelling of the lesional cells for developmentally regulated proteins (OTX1, TBR1, SOX2, MAP1b, CD34, GFAPδ) and oligodendroglial lineage markers (OLIG2, SMI94) was observed. No mutations were detected in the mTOR pathway genes, BRAF, FGFR1 or MYB. Clinical, pathological and genetic data could indicate that MVNT aligns more with a malformative lesion than a true neoplasm with origin from a progenitor neuro-glial cell type showing aberrant maturation.

The spectrum of structural and functional network alterations in malformations of cortical development.

Neuroimaging studies of malformations of cortical development have mainly focused on the characterization of the primary lesional substrate, while whole-brain investigations remain scarce. Our purpose was to assess large-scale brain organization in prevalent cortical malformations. Based on experimental evidence suggesting that distributed effects of focal insults are modulated by stages of brain development, we postulated differential patterns of network anomalies across subtypes of malformations. We studied a cohort of patients with focal cortical dysplasia type II (n = 63), subcortical nodular heterotopia (n = 44), and polymicrogyria (n = 34), and compared them to 82 age- and sex-matched controls. Graph theoretical analysis of structural covariance networks indicated a consistent rearrangement towards a regularized architecture characterized by increased path length and clustering, as well as disrupted rich-club topology, overall suggestive of inefficient global and excessive local connectivity. Notably, we observed a gradual shift in network reconfigurations across subgroups, with only subtle changes in focal cortical dysplasia type II, moderate effects in heterotopia and maximal effects in polymicrogyria. Analysis of resting state functional connectivity also revealed gradual network changes, with most marked rearrangement in polymicrogyria; contrary to findings in the structural domain, however, functional architecture was characterized by decreases in both local and global parameters. Diverging results in the structural and functional domain were supported by formal structure-function coupling analysis. Our findings support the concept that time of insult during corticogenesis impacts the severity of topological network reconfiguration. Specifically, late-stage malformations, typified by polymicrogyria, may selectively disrupt the formation of large-scale cortico-cortical networks and thus lead to a more profound impact on whole-brain organization than early stage disturbances of predominantly radial migration patterns observed in cortical dysplasia type II, which likely affect a relatively confined cortical territory.

Characteristics of EEG Seizure-Onset Patterns Recorded From Subdural Electrodes Over MRI-Visible Frontal Focal Cortical Dysplasia Type IIb Lesions.

PURPOSE: Focal cortical dysplasia (FCD) is intrinsically epileptogenic, and an MRI-visible lesion typically constitutes the core part of the epileptogenic zone. We aimed to identify ictal EEG patterns that represent the epileptogenic zone by using subdural electrodes placed over the MRI-visible FCD lesion. METHODS: We selected seven patients with frontal lobe epilepsy caused by pathologically proven FCD type IIb who underwent preoperative intracranial EEG evaluation with subdural electrodes followed by resection surgery with seizure-free outcome. The characteristics of ictal EEG patterns, interictal/ictal high-frequency oscillations, and ictal direct current shifts from intracranial electrodes placed over the MRI-visible lesion were analyzed. RESULTS: Two seizure-onset patterns (low voltage fast activity and fast spike activity) were identified. Low voltage fast activity was seen in all patients with a lateral frontal lesion, and it was always preceded by preictal spikes. Fast spike activity occurred only in patients with a mesial frontal lesion. Interictal/ictal high-frequency oscillations and ictal direct current shifts were seen in all patients. CONCLUSIONS: The epileptogenic zone of frontal FCD type IIb may be characterized by EEG seizure-onset patterns consisting of low voltage fast activity and fast spike activity accompanied by ictal high-frequency oscillations and ictal direct current shifts. Further study is needed to determine whether other seizure-onset patterns exist in patients with FCD type IIb.

Suppression of interictal spikes during phasic rapid eye movement sleep: a quantitative stereo-electroencephalography study.

Tonic and phasic rapid eye movement (REM) sleep seem to represent two different brain states exerting different effects on epileptic activity. In particular, interictal spikes are suppressed strongly during phasic REM sleep. The reason for this effect is not understood completely. A different level of synchronization in phasic and tonic REM sleep has been postulated, yet never measured directly. Here we assessed the interictal spike rate across non-REM (NREM) sleep, phasic and tonic REM sleep in nine patients affected by drug resistant focal epilepsy: five with type II focal cortical dysplasia and four with hippocampal sclerosis. Moreover, we applied different quantitative measures to evaluate the level of synchronization at the local and global scale during phasic and tonic REM sleep. We found a lower spike rate in phasic REM sleep, both within and outside the seizure onset zone. This effect seems to be independent from the histopathological substrate and from the brain region, where epileptic activity is produced (temporal versus extra-temporal). A higher level of synchronization was observed during tonic REM sleep both on a large (global) and small (local) spatial scale. Phasic REM sleep appears to be an interesting model for understanding the mechanisms of suppression of epileptic activity.

Multimodal MRI profiling of focal cortical dysplasia type II.

OBJECTIVE: To characterize in vivo MRI signatures of focal cortical dysplasia (FCD) type IIA and type IIB through combined analysis of morphology, intensity, microstructure, and function. METHODS: We carried out a multimodal 3T MRI profiling of 33 histologically proven FCD type IIA (9) and IIB (24) lesions. A multisurface approach operating on manual consensus labels systematically sampled intracortical and subcortical lesional features. Geodesic distance mapping quantified the same features in the lesion perimeter. Logistic regression assessed the relationship between MRI and histology, while supervised pattern learning was used for individualized subtype prediction. RESULTS: FCD type IIB was characterized by abnormal morphology, intensity, diffusivity, and function across all surfaces, while type IIA lesions presented only with increased fluid-attenuated inversion recovery signal and reduced diffusion anisotropy close to the gray-white matter interface. Similar to lesional patterns, perilesional anomalies were more marked in type IIB extending up to 16 mm. Structural MRI markers correlated with categorical histologic characteristics. A profile-based classifier predicted FCD subtypes with equal sensitivity of 85%, while maintaining a high specificity of 94% against healthy and disease controls. CONCLUSIONS: Image processing applied to widely available MRI contrasts has the ability to dissociate FCD subtypes at a mesoscopic level. Integrating in vivo staging of pathologic traits with automated lesion detection is likely to provide an objective definition of lesional boundary and assist emerging approaches, such as minimally invasive thermal ablation, which do not supply tissue specimen.