Cell-type specific and multiscale dynamics of human focal seizures in limbic structures.

The relationship between clinically accessible epileptic biomarkers and neuronal activity underlying the transition to seizure is complex, potentially leading to imprecise delineation of epileptogenic brain areas. In particular, the pattern of interneuronal firing at seizure onset remains under debate, with some studies demonstrating increased firing and others suggesting reductions. Previous study of neocortical sites suggests that seizure recruitment occurs upon failure of inhibition, with intact feedforward inhibition in non-recruited territories. We investigated whether the same principle applies in limbic structures. We analysed simultaneous electrocorticography (ECoG) and neuronal recordings of 34 seizures in a cohort of 19 patients (10 male, 9 female) undergoing surgical evaluation for pharmacoresistant focal epilepsy. A clustering approach with five quantitative metrics computed from ECoG and multiunit data was used to distinguish three types of site-specific activity patterns during seizures, which at times co-existed within seizures. Overall, 156 single units were isolated, subclassified by cell-type and tracked through the seizure using our previously published methods to account for impacts of increased noise and single-unit waveshape changes caused by seizures. One cluster was closely associated with clinically defined seizure onset or spread. Entrainment of high-gamma activity to low-frequency ictal rhythms was the only metric that reliably identified this cluster at the level of individual seizures (P < 0.001). A second cluster demonstrated multi-unit characteristics resembling those in the first cluster, without concomitant high-gamma entrainment, suggesting feedforward effects from the seizure. The last cluster captured regions apparently unaffected by the ongoing seizure. Across all territories, the majority of both excitatory and inhibitory neurons reduced (69.2%) or ceased firing (21.8%). Transient increases in interneuronal firing rates were rare (13.5%) but showed evidence of intact feedforward inhibition, with maximal firing rate increases and waveshape deformations in territories not fully recruited but showing feedforward activity from the seizure, and a shift to burst-firing in seizure-recruited territories (P = 0.014). This study provides evidence for entrained high-gamma activity as an accurate biomarker of ictal recruitment in limbic structures. However, reduced neuronal firing suggested preserved inhibition in mesial temporal structures despite simultaneous indicators of seizure recruitment, in contrast to the inhibitory collapse scenario documented in neocortex. Further study is needed to determine if this activity is ubiquitous to hippocampal seizures or indicates a 'seizure-responsive' state in which the hippocampus is not the primary driver. If the latter, distinguishing such cases may help to refine the surgical treatment of mesial temporal lobe epilepsy.

Distinct signatures of loss of consciousness in focal impaired awareness versus tonic-clonic seizures.

Loss of consciousness is a hallmark of many epileptic seizures and carries risks of serious injury and sudden death. While cortical sleep-like activities accompany loss of consciousness during focal impaired awareness seizures, the mechanisms of loss of consciousness during focal to bilateral tonic-clonic seizures remain unclear. Quantifying differences in markers of cortical activation and ictal recruitment between focal impaired awareness and focal to bilateral tonic-clonic seizures may also help us to understand their different consequences for clinical outcomes and to optimize neuromodulation therapies. We quantified clinical signs of loss of consciousness and intracranial EEG activity during 129 focal impaired awareness and 50 focal to bilateral tonic-clonic from 41 patients. We characterized intracranial EEG changes both in the seizure onset zone and in areas remote from the seizure onset zone with a total of 3386 electrodes distributed across brain areas. First, we compared the dynamics of intracranial EEG sleep-like activities: slow-wave activity (1-4 Hz) and beta/delta ratio (a validated marker of cortical activation) during focal impaired awareness versus focal to bilateral tonic-clonic. Second, we quantified differences between focal to bilateral tonic-clonic and focal impaired awareness for a marker validated to detect ictal cross-frequency coupling: phase-locked high gamma (high-gamma phased-locked to low frequencies) and a marker of ictal recruitment: the epileptogenicity index. Third, we assessed changes in intracranial EEG activity preceding and accompanying behavioural generalization onset and their correlation with electromyogram channels. In addition, we analysed human cortical multi-unit activity recorded with Utah arrays during three focal to bilateral tonic-clonic seizures. Compared to focal impaired awareness, focal to bilateral tonic-clonic seizures were characterized by deeper loss of consciousness, even before generalization occurred. Unlike during focal impaired awareness, early loss of consciousness before generalization was accompanied by paradoxical decreases in slow-wave activity and by increases in high-gamma activity in parieto-occipital and temporal cortex. After generalization, when all patients displayed loss of consciousness, stronger increases in slow-wave activity were observed in parieto-occipital cortex, while more widespread increases in cortical activation (beta/delta ratio), ictal cross-frequency coupling (phase-locked high gamma) and ictal recruitment (epileptogenicity index). Behavioural generalization coincided with a whole-brain increase in high-gamma activity, which was especially synchronous in deep sources and could not be explained by EMG. Similarly, multi-unit activity analysis of focal to bilateral tonic-clonic revealed sustained increases in cortical firing rates during and after generalization onset in areas remote from the seizure onset zone. Overall, these results indicate that unlike during focal impaired awareness, the neural signatures of loss of consciousness during focal to bilateral tonic-clonic consist of paradoxical increases in cortical activation and neuronal firing found most consistently in posterior brain regions. These findings suggest differences in the mechanisms of ictal loss of consciousness between focal impaired awareness and focal to bilateral tonic-clonic and may account for the more negative prognostic consequences of focal to bilateral tonic-clonic.

Multiple sources of fast traveling waves during human seizures: resolving a controversy.

During human seizures organized waves of voltage activity rapidly sweep across the cortex. Two contradictory theories describe the source of these fast traveling waves: either a slowly advancing narrow region of multiunit activity (an ictal wavefront) or a fixed cortical location. Limited observations and different analyses prevent resolution of these incompatible theories. Here we address this disagreement by combining the methods and microelectrode array recordings (N=11 patients, 2 females, N=31 seizures) from previous human studies to analyze the traveling wave source. We find - inconsistent with both existing theories - a transient relationship between the ictal wavefront and traveling waves, and multiple stable directions of traveling waves in many seizures. Using a computational model that combines elements of both existing theories, we show that interactions between an ictal wavefront and fixed source reproduce the traveling wave dynamics observed in vivo We conclude that combining both existing theories can generate the diversity of ictal traveling waves.Significance StatementThe source of voltage discharges that propagate across cortex during human seizures remains unknown. Two candidate theories exist, each proposing a different discharge source. Support for each theory consists of observations from a small number of human subject recordings, analyzed with separately developed methods. How the different, limited data and different analysis methods impact the evidence for each theory is unclear. To resolve these differences, we combine the unique, human microelectrode array recordings collected separately for each theory and analyze these combined data with a unified approach. We show that neither existing theory adequately describes the data. We then propose a new theory that unifies existing proposals and successfully reproduces the voltage discharge dynamics observed in vivo.

The Spatial Reach of Neuronal Coherence and Spike-Field Coupling across the Human Neocortex.

Neuronal coherence is thought to be a fundamental mechanism of communication in the brain, where synchronized field potentials coordinate synaptic and spiking events to support plasticity and learning. Although the spread of field potentials has garnered great interest, little is known about the spatial reach of phase synchronization, or neuronal coherence. Functional connectivity between different brain regions is known to occur across long distances, but the locality of synchronization across the neocortex is understudied. Here we used simultaneous recordings from electrocorticography (ECoG) grids and high-density microelectrode arrays to estimate the spatial reach of neuronal coherence and spike-field coherence (SFC) across frontal, temporal, and occipital cortices during cognitive tasks in humans. We observed the strongest coherence within a 2-3 cm distance from the microelectrode arrays, potentially defining an effective range for local communication. This range was relatively consistent across brain regions, spectral frequencies, and cognitive tasks. The magnitude of coherence showed power law decay with increasing distance from the microelectrode arrays, where the highest coherence occurred between ECoG contacts, followed by coherence between ECoG and deep cortical local field potential (LFP), and then SFC (i.e., ECoG > LFP > SFC). The spectral frequency of coherence also affected its magnitude. Alpha coherence (8-14 Hz) was generally higher than other frequencies for signals nearest the microelectrode arrays, whereas delta coherence (1-3 Hz) was higher for signals that were farther away. Action potentials in all brain regions were most coherent with the phase of alpha oscillations, which suggests that alpha waves could play a larger, more spatially local role in spike timing than other frequencies. These findings provide a deeper understanding of the spatial and spectral dynamics of neuronal synchronization, further advancing knowledge about how activity propagates across the human brain.SIGNIFICANCE STATEMENT Coherence is theorized to facilitate information transfer across cerebral space by providing a convenient electrophysiological mechanism to modulate membrane potentials in spatiotemporally complex patterns. Our work uses a multiscale approach to evaluate the spatial reach of phase coherence and spike-field coherence during cognitive tasks in humans. Locally, coherence can reach up to 3 cm around a given area of neocortex. The spectral properties of coherence revealed that alpha phase-field and spike-field coherence were higher within ranges <2 cm, whereas lower-frequency delta coherence was higher for contacts farther away. Spatiotemporally shared information (i.e., coherence) across neocortex seems to reach farther than field potentials alone.

Long-term outcomes of mesial temporal laser interstitial thermal therapy for drug-resistant epilepsy and subsequent surgery for seizure recurrence: a multi-centre cohort study.

BACKGROUND: Magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) is a minimally invasive alternative to surgical resection for drug-resistant mesial temporal lobe epilepsy (mTLE). Reported rates of seizure freedom are variable and long-term durability is largely unproven. Anterior temporal lobectomy (ATL) remains an option for patients with MRgLITT treatment failure. However, the safety and efficacy of this staged strategy is unknown. METHODS: This multicentre, retrospective cohort study included 268 patients consecutively treated with mesial temporal MRgLITT at 11 centres between 2012 and 2018. Seizure outcomes and complications of MRgLITT and any subsequent surgery are reported. Predictive value of preoperative variables for seizure outcome was assessed. RESULTS: Engel I seizure freedom was achieved in 55.8% (149/267) at 1 year, 52.5% (126/240) at 2 years and 49.3% (132/268) at the last follow-up ≥1 year (median 47 months). Engel I or II outcomes were achieved in 74.2% (198/267) at 1 year, 75.0% (180/240) at 2 years and 66.0% (177/268) at the last follow-up. Preoperative focal to bilateral tonic-clonic seizures were independently associated with seizure recurrence. Among patients with seizure recurrence, 14/21 (66.7%) became seizure-free after subsequent ATL and 5/10 (50%) after repeat MRgLITT at last follow-up≥1 year. CONCLUSIONS: MRgLITT is a viable treatment with durable outcomes for patients with drug-resistant mTLE evaluated at a comprehensive epilepsy centre. Although seizure freedom rates were lower than reported with ATL, this series represents the early experience of each centre and a heterogeneous cohort. ATL remains a safe and effective treatment for well-selected patients who fail MRgLITT.

Seizure onset patterns predict outcome after stereo-electroencephalography-guided laser amygdalohippocampotomy.

OBJECTIVE: Stereotactic laser amygdalohippocampotomy (SLAH) is an appealing option for patients with temporal lobe epilepsy, who often require intracranial monitoring to confirm mesial temporal seizure onset. However, given limited spatial sampling, it is possible that stereotactic electroencephalography (stereo-EEG) may miss seizure onset elsewhere. We hypothesized that stereo-EEG seizure onset patterns (SOPs) may differentiate between primary onset and secondary spread and predict postoperative seizure control. In this study, we characterized the 2-year outcomes of patients who underwent single-fiber SLAH after stereo-EEG and evaluated whether stereo-EEG SOPs predict postoperative seizure freedom. METHODS: This retrospective five-center study included patients with or without mesial temporal sclerosis (MTS) who underwent stereo-EEG followed by single-fiber SLAH between August 2014 and January 2022. Patients with causative hippocampal lesions apart from MTS or for whom the SLAH was considered palliative were excluded. An SOP catalogue was developed based on literature review. The dominant pattern for each patient was used for survival analysis. The primary outcome was 2-year Engel I classification or recurrent seizures before then, stratified by SOP category. RESULTS: Fifty-eight patients were included, with a mean follow-up duration of 39 ± 12 months after SLAH. Overall 1-, 2-, and 3-year Engel I seizure freedom probability was 54%, 36%, and 33%, respectively. Patients with SOPs, including low-voltage fast activity or low-frequency repetitive spiking, had a 46% 2-year seizure freedom probability, compared to 0% for patients with alpha or theta frequency repetitive spiking or theta or delta frequency rhythmic slowing (log-rank test, p = .00015). SIGNIFICANCE: Patients who underwent SLAH after stereo-EEG had a low probability of seizure freedom at 2 years, but SOPs successfully predicted seizure recurrence in a subset of patients. This study provides proof of concept that SOPs distinguish between hippocampal seizure onset and spread and supports using SOPs to improve selection of SLAH candidates.

Single unit analysis and wide-field imaging reveal alterations in excitatory and inhibitory neurons in glioma.

While several studies have attributed the development of tumour-associated seizures to an excitatory-inhibitory imbalance, we have yet to resolve the spatiotemporal interplay between different types of neuron in glioma-infiltrated cortex. Herein, we combined methods for single unit analysis of microelectrode array recordings with wide-field optical mapping of Thy1-GCaMP pyramidal cells in an ex vivo acute slice model of diffusely infiltrating glioma. This enabled simultaneous tracking of individual neurons from both excitatory and inhibitory populations throughout seizure-like events. Moreover, our approach allowed for observation of how the crosstalk between these neurons varied spatially, as we recorded across an extended region of glioma-infiltrated cortex. In tumour-bearing slices, we observed marked alterations in single units classified as putative fast-spiking interneurons, including reduced firing, activity concentrated within excitatory bursts and deficits in local inhibition. These results were correlated with increases in overall excitability. Mechanistic perturbation of this system with the mTOR inhibitor AZD8055 revealed increased firing of putative fast-spiking interneurons and restoration of local inhibition, with concomitant decreases in overall excitability. Altogether, our findings suggest that diffusely infiltrating glioma affect the interplay between excitatory and inhibitory neuronal populations in a reversible manner, highlighting a prominent role for functional mechanisms linked to mTOR activation.

Neuronal Firing and Waveform Alterations through Ictal Recruitment in Humans.

Analyzing neuronal activity during human seizures is pivotal to understanding mechanisms of seizure onset and propagation. These analyses, however, invariably using extracellular recordings, are greatly hindered by various phenomena that are well established in animal studies: changes in local ionic concentration, changes in ionic conductance, and intense, hypersynchronous firing. The first two alter the action potential waveform, whereas the third increases the "noise"; all three factors confound attempts to detect and classify single neurons. To address these analytical difficulties, we developed a novel template-matching-based spike sorting method, which enabled identification of 1239 single neurons in 27 patients (13 female) with intractable focal epilepsy, that were tracked throughout multiple seizures. These new analyses showed continued neuronal firing with widespread intense activation and stereotyped action potential alterations in tissue that was invaded by the seizure: neurons displayed increased waveform duration (p < 0.001) and reduced amplitude (p < 0.001), consistent with prior animal studies. By contrast, neurons in "penumbral" regions (those receiving intense local synaptic drive from the seizure but without neuronal evidence of local seizure invasion) showed stable waveforms. All neurons returned to their preictal waveforms after seizure termination. We conclude that the distinction between "core" territories invaded by the seizure versus "penumbral" territories is evident at the level of single neurons. Furthermore, the increased waveform duration and decreased waveform amplitude are neuron-intrinsic hallmarks of seizure invasion that impede traditional spike sorting and could be used as defining characteristics of local recruitment.SIGNIFICANCE STATEMENT Animal studies consistently show marked changes in action potential waveform during epileptic discharges, but acquiring similar evidence in humans has proven difficult. Assessing neuronal involvement in ictal events is pivotal to understanding seizure dynamics and in defining clinical localization of epileptic pathology. Using a novel method to track neuronal firing, we analyzed microelectrode array recordings of spontaneously occurring human seizures, and here report two dichotomous activity patterns. In cortex that is recruited to the seizure, neuronal firing rates increase and waveforms become longer in duration and shorter in amplitude as the neurons are recruited to the seizure, while penumbral tissue shows stable action potentials, in keeping with the "dual territory" model of seizure dynamics.

Electrically stimulated auras as a potential biomarker of the epileptogenic zone.

Electrocortical stimulation mapping (ESM) is often performed in patients undergoing stereoelectroencephalography (SEEG) prior to epilepsy surgery, with the goal of identifying functional cortex and preserving it postoperatively. ESM may also evoke a patient's typical seizure semiology. The purpose of this study was to determine whether the sites at which typical auras are evoked during ESM are associated with other known clinical and electrophysiologic biomarkers of the epileptogenic zone: the seizure onset zone (SOZ), the early spread zone (ES), and high-frequency oscillations (HFOs). We found that the sites at which auras were provoked were not consistently associated with known biomarkers (p = 0.09). We conclude that evoked auras during ESM may reflect electrical spread rather than true epileptogenicity, and that a larger study is needed to assess their potential value as independent epileptic biomarkers.

Ex vivo multi-electrode analysis reveals spatiotemporal dynamics of ictal behavior at the infiltrated margin of glioma.

The purpose of this study is to develop a platform in which the cellular and molecular underpinnings of chronic focal neocortical lesional epilepsy can be explored and use it to characterize seizure-like events (SLEs) in an ex vivo model of infiltrating high-grade glioma. Microelectrode arrays were used to study electrophysiologic changes in ex vivo acute brain slices from a PTEN/p53 deleted, PDGF-B driven mouse model of high-grade glioma. Electrode locations were co-registered to the underlying histology to ascertain the influence of the varying histologic landscape on the observed electrophysiologic changes. Peritumoral, infiltrated, and tumor sites were sampled in tumor-bearing slices. Following the addition of zero Mg2+ solution, all three histologic regions in tumor-bearing slices showed significantly greater increases in firing rates when compared to the control sites. Tumor-bearing slices demonstrated increased proclivity for SLEs, with 40 events in tumor-bearing slices and 5 events in control slices (p-value = .0105). Observed SLEs were characterized by either low voltage fast (LVF) onset patterns or short bursts of repetitive widespread, high amplitude low frequency discharges. Seizure foci comprised areas from all three histologic regions. The onset electrode was found to be at the infiltrated margin in 50% of cases and in the peritumoral region in 36.9% of cases. These findings reveal a landscape of histopathologic and electrophysiologic alterations associated with ictogenesis and spread of tumor-associated seizures.

Burst suppression uncovers rapid widespread alterations in network excitability caused by an acute seizure focus.

Burst suppression is an electroencephalogram pattern of globally symmetric alternating high amplitude activity and isoelectricity that can be induced by general anaesthetics. There is scattered evidence that burst suppression may become spatially non-uniform in the setting of underlying pathology. Here, we induced burst suppression with isoflurane in rodents and then created a neocortical acute seizure focus with injection of 4-aminopyridine (4-AP) in somatosensory cortex. Burst suppression events were recorded before and after creation of the focus using bihemispheric wide-field calcium imaging and multielectrode arrays. We find that the seizure focus elicits a rapid alteration in triggering, initiation, and propagation of burst suppression events. Compared with the non-seizing brain, bursts are triggered from the thalamus, initiate in regions uniquely outside the epileptic focus, elicit marked increases of multiunit activity and propagate towards the seizure focus. These findings support the rapid, widespread impact of focal epilepsy on the extended brain network.

All-cause mortality and SUDEP in a surgical epilepsy population.

Epilepsy surgery is considered to reduce the risk of epilepsy-related mortality, including sudden unexpected death in epilepsy (SUDEP), though data from existing surgical series are conflicting. We retrospectively examined all-cause mortality and SUDEP in a population of 590 epilepsy surgery patients and a comparison group of 122 patients with pharmacoresistant focal epilepsy who did not undergo surgery, treated at Columbia University Medical Center between 1977 and 2014. There were 34 deaths in the surgery group, including 14 cases of SUDEP. Standardized mortality ratio (SMR) for the surgery group was 1.6, and SUDEP rate was 1.9 per 1000 patient-years. There were 13 deaths in the comparison group, including 5 cases of SUDEP. Standardized mortality ratio for the comparison group was 3.6, and SUDEP rate was 4.6 per 1000 patient-years. Both were significantly greater than in the surgery group (p < 0.05). All but one of the surgical SUDEP cases, and all of the comparison group SUDEP cases, had a history of bilateral tonic-clonic seizures (BTCS). Of postoperative SUDEP cases, one was seizure-free, and two were free of BTCS at last clinical follow-up. Time to SUDEP in the surgery group was longer than in the comparison group (10.1 vs 5.9 years, p = 0.013), with 10 of the 14 cases occurring >10 years after surgery. All-cause mortality was reduced after epilepsy surgery relative to the comparison group. There was an early benefit of surgery on the occurrence of SUDEP, which was reduced after 10 years. A larger, multicenter study is needed to further investigate the time course of postsurgical SUDEP.

Cross-scale effects of neural interactions during human neocortical seizure activity.

Small-scale neuronal networks may impose widespread effects on large network dynamics. To unravel this relationship, we analyzed eight multiscale recordings of spontaneous seizures from four patients with epilepsy. During seizures, multiunit spike activity organizes into a submillimeter-sized wavefront, and this activity correlates significantly with low-frequency rhythms from electrocorticographic recordings across a 10-cm-sized neocortical network. Notably, this correlation effect is specific to the ictal wavefront and is absent interictally or from action potential activity outside the wavefront territory. To examine the multiscale interactions, we created a model using a multiscale, nonlinear system and found evidence for a dual role for feedforward inhibition in seizures: while inhibition at the wavefront fails, allowing seizure propagation, feedforward inhibition of the surrounding centimeter-scale networks is activated via long-range excitatory connections. Bifurcation analysis revealed that distinct dynamical pathways for seizure termination depend on the surrounding inhibition strength. Using our model, we found that the mesoscopic, local wavefront acts as the forcing term of the ictal process, while the macroscopic, centimeter-sized network modulates the oscillatory seizure activity.

Role of paroxysmal depolarization in focal seizure activity.

We analyze the role of inhibition in sustaining focal epileptic seizure activity. We review ongoing seizure activity at the mesoscopic scale that can be observed with microelectrode arrays as well as at the macroscale of standard clinical EEG. We provide clinical, experimental, and modeling data to support the hypothesis that paroxysmal depolarization (PD) is a critical component of the ictal machinery. We present dual-patch recordings in cortical cultures showing reduced synaptic transmission associated with presynaptic occurrence of PD, and we find that the PD threshold is cell size related. We further find evidence that optically evoked PD activity in parvalbumin neurons can promote propagation of neuronal excitation in neocortical networks in vitro. Spike sorting results from microelectrode array measurements around ictal wave propagation in human focal seizures demonstrate a strong increase in putative inhibitory firing with an approaching excitatory wave, followed by a sudden reduction of firing at passage. At the macroscopic level, we summarize evidence that this excitatory ictal wave activity is strongly correlated with oscillatory activity across a centimeter-sized cortical network. We summarize Wilson-Cowan-type modeling showing how inhibitory function is crucial for this behavior. Our findings motivated us to develop a network motif of neurons in silico, governed by a reduced version of the Hodgkin-Huxley formalism, to show how feedforward, feedback, PD, and local failure of inhibition contribute to observed dynamics across network scales. The presented multidisciplinary evidence suggests that the PD not only is a cellular marker or epiphenomenon but actively contributes to seizure activity.NEW & NOTEWORTHY We present mechanisms of ongoing focal seizures across meso- and macroscales of microelectrode array and standard clinical recordings, respectively. We find modeling, experimental, and clinical evidence for a dual role of inhibition across these scales: local failure of inhibition allows propagation of a mesoscopic ictal wave, whereas inhibition elsewhere remains intact and sustains macroscopic oscillatory activity. We present evidence for paroxysmal depolarization as a mechanism behind this dual role of inhibition in shaping ictal activity.

Multiscale recordings reveal the dynamic spatial structure of human seizures.

The cellular activity underlying human focal seizures, and its relationship to key signatures in the EEG recordings used for therapeutic purposes, has not been well characterized despite many years of investigation both in laboratory and clinical settings. The increasing use of microelectrodes in epilepsy surgery patients has made it possible to apply principles derived from laboratory research to the problem of mapping the spatiotemporal structure of human focal seizures, and characterizing the corresponding EEG signatures. In this review, we describe results from human microelectrode studies, discuss some data interpretation pitfalls, and explain the current understanding of the key mechanisms of ictogenesis and seizure spread.

Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy.

OBJECTIVE: Somatic variants are a recognized cause of epilepsy-associated focal malformations of cortical development (MCD). We hypothesized that somatic variants may underlie a wider range of focal epilepsy, including nonlesional focal epilepsy (NLFE). Through genetic analysis of brain tissue, we evaluated the role of somatic variation in focal epilepsy with and without MCD. METHODS: We identified somatic variants through high-depth exome and ultra-high-depth candidate gene sequencing of DNA from epilepsy surgery specimens and leukocytes from 18 individuals with NLFE and 38 with focal MCD. RESULTS: We observed somatic variants in 5 cases in SLC35A2, a gene associated with glycosylation defects and rare X-linked epileptic encephalopathies. Nonsynonymous variants in SLC35A2 were detected in resected brain, and absent from leukocytes, in 3 of 18 individuals (17%) with NLFE, 1 female and 2 males, with variant allele frequencies (VAFs) in brain-derived DNA of 2 to 14%. Pathologic evaluation revealed focal cortical dysplasia type Ia (FCD1a) in 2 of the 3 NLFE cases. In the MCD cohort, nonsynonymous variants in SCL35A2 were detected in the brains of 2 males with intractable epilepsy, developmental delay, and magnetic resonance imaging suggesting FCD, with VAFs of 19 to 53%; Evidence for FCD was not observed in either brain tissue specimen. INTERPRETATION: We report somatic variants in SLC35A2 as an explanation for a substantial fraction of NLFE, a largely unexplained condition, as well as focal MCD, previously shown to result from somatic mutation but until now only in PI3K-AKT-mTOR pathway genes. Collectively, our findings suggest a larger role than previously recognized for glycosylation defects in the intractable epilepsies. Ann Neurol 2018.

Cortical naming sites and increasing age in adults with refractory epilepsy: More might be less.

OBJECTIVE: Critical decisions regarding resection boundaries for epilepsy surgery are often based on results of electrical stimulation mapping (ESM). Despite the potentially serious implications for postoperative functioning, age-referenced data that might facilitate the procedure are lacking. Age might be particularly relevant, as pediatric ESM studies have shown a paucity of language sites in young children followed by a rapid increase at approximately 8-10 years. Beyond adolescence, it has generally been assumed that the language system remains stable, and therefore, potential age-related changes across the adult age span have not been examined. However, increasing age during adulthood is associated with both positive and negative language-related changes, such as a broadening vocabulary and increased word finding difficulty. Because most patients who undergo ESM are adults, we aimed to determine the potential impact of age on the incidence of ESM-identified naming sites across the adult age span in patients with refractory epilepsy. METHODS: We analyzed clinical language ESM results from 47 patients, ages 17-64 years, with refractory dominant-hemisphere epilepsy. Patients had comparable location and number of cortical sites tested. The incidence of naming sites was examined as a function of age, and compared between younger and older adults. RESULTS: Significantly more naming sites were found in older than younger adults, and age was found to be a significant predictor of number of naming sites identified. SIGNIFICANCE: Unlike the developmental changes that coincide with increased naming sites in children, increased naming sites in older adults might signify greater vulnerability of the language system to disruption. Because preservation of language sites can limit the extent of the resection, and thereby reduce the likelihood of seizure freedom, further work should aim to determine the clinical relevance of increased naming sites in older adults.

Postictal clinical and electroencephalographic activity following intracranially recorded bilateral tonic-clonic seizures.

OBJECTIVE: The dynamics of the postictal period, which may demonstrate such dramatic clinical phenomena as focal neurological deficits, prolonged coma and immobility, and even sudden death, are poorly understood. We sought to classify and characterize postictal phases of bilateral tonic-clonic seizures based on electroencephalographic (EEG) criteria and associated clinical features. METHODS: We performed a detailed electroclinical evaluation of the postictal period in a series of 31 bilateral tonic-clonic seizures in 16 patients undergoing epilepsy surgery evaluations for focal pharmacoresistant epilepsy with intracranial electrodes and time-locked video. RESULTS: The postictal EEG demonstrated three clearly differentiated phases as follows: attenuation, a burst-attenuation pattern, and a return to continuous background, with abrupt, synchronized transitions between phases. Postictal attenuation was common, occurring in 84% of seizures in 94% of patients in this study. There was increased power in gamma frequencies (>25 Hz) during postictal attenuation periods relative to preictal baseline in 88% of seizures demonstrating the attenuation pattern (n = 25 seizures, P < 0.002). Such increases were seen in >90% of channels in 13 seizures (52%) and <10% of channels in three seizures (12%). Postictal immobility was seen in 87% of seizures, with either a flaccid (58%) or rigid/dystonic (29%) appearance. Clinical motor manifestations, including focal dystonic posturing, automatisms, head and eye deviation, and myoclonic jerking, continued or emerged within the first minute following seizure termination in 48% of seizures, regardless of EEG appearance. SIGNIFICANCE: Intracranial postictal attenuation, which may be diffuse or focal, is so common that it should be regarded as a ubiquitous feature of bilateral tonic-clonic seizures, rather than an unusual event. The prominence of high-frequency activity coupled with emerging clinical features, including rigid immobility and semiologies such as automatisms, during the postictal period supports the presence of ongoing seizure-related neuronal activity in unrecorded brain regions.

Role of inhibitory control in modulating focal seizure spread.

Focal seizure propagation is classically thought to be spatially contiguous. However, distribution of seizures through a large-scale epileptic network has been theorized. Here, we used a multielectrode array, wide field calcium imaging, and two-photon calcium imaging to study focal seizure propagation pathways in an acute rodent neocortical 4-aminopyridine model. Although ictal neuronal bursts did not propagate beyond a 2-3-mm region, they were associated with hemisphere-wide field potential fluctuations and parvalbumin-positive interneuron activity outside the seizure focus. While bicuculline surface application enhanced contiguous seizure propagation, focal bicuculline microinjection at sites distant to the 4-aminopyridine focus resulted in epileptic network formation with maximal activity at the two foci. Our study suggests that both classical and epileptic network propagation can arise from localized inhibition defects, and that the network appearance can arise in the context of normal brain structure without requirement for pathological connectivity changes between sites.