Glioma-Induced Alterations in Excitatory Neurons are Reversed by mTOR Inhibition.

Gliomas are highly aggressive brain tumors characterized by poor prognosis and composed of diffusely infiltrating tumor cells that intermingle with non-neoplastic cells in the tumor microenvironment, including neurons. Neurons are increasingly appreciated as important reactive components of the glioma microenvironment, due to their role in causing hallmark glioma symptoms, such as cognitive deficits and seizures, as well as their potential ability to drive glioma progression. Separately, mTOR signaling has been shown to have pleiotropic effects in the brain tumor microenvironment, including regulation of neuronal hyperexcitability. However, the local cellular-level effects of mTOR inhibition on glioma-induced neuronal alterations are not well understood. Here we employed neuron-specific profiling of ribosome-bound mRNA via 'RiboTag,' morphometric analysis of dendritic spines, and in vivo calcium imaging, along with pharmacological mTOR inhibition to investigate the impact of glioma burden and mTOR inhibition on these neuronal alterations. The RiboTag analysis of tumor-associated excitatory neurons showed a downregulation of transcripts encoding excitatory and inhibitory postsynaptic proteins and dendritic spine development, and an upregulation of transcripts encoding cytoskeletal proteins involved in dendritic spine turnover. Light and electron microscopy of tumor-associated excitatory neurons demonstrated marked decreases in dendritic spine density. In vivo two-photon calcium imaging in tumor-associated excitatory neurons revealed progressive alterations in neuronal activity, both at the population and single-neuron level, throughout tumor growth. This in vivo calcium imaging also revealed altered stimulus-evoked somatic calcium events, with changes in event rate, size, and temporal alignment to stimulus, which was most pronounced in neurons with high-tumor burden. A single acute dose of AZD8055, a combined mTORC1/2 inhibitor, reversed the glioma-induced alterations on the excitatory neurons, including the alterations in ribosome-bound transcripts, dendritic spine density, and stimulus evoked responses seen by calcium imaging. These results point to mTOR-driven pathological plasticity in neurons at the infiltrative margin of glioma - manifested by alterations in ribosome-bound mRNA, dendritic spine density, and stimulus-evoked neuronal activity. Collectively, our work identifies the pathological changes that tumor-associated excitatory neurons experience as both hyperlocal and reversible under the influence of mTOR inhibition, providing a foundation for developing therapies targeting neuronal signaling in glioma.

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.

Synaptic hyperexcitability of cytomegalic pyramidal neurons contributes to epileptogenesis in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a developmental disorder associated with epilepsy, autism, and cognitive impairment. Despite inactivating mutations in the TSC1 or TSC2 genes and hyperactive mechanistic target of rapamycin (mTOR) signaling, the mechanisms underlying TSC-associated neurological symptoms remain incompletely understood. Here we generate a Tsc1 conditional knockout (CKO) mouse model in which Tsc1 inactivation in late embryonic radial glia causes social and cognitive impairment and spontaneous seizures. Tsc1 depletion occurs in a subset of layer 2/3 cortical pyramidal neurons, leading to development of cytomegalic pyramidal neurons (CPNs) that mimic dysplastic neurons in human TSC, featuring abnormal dendritic and axonal overgrowth, enhanced glutamatergic synaptic transmission, and increased susceptibility to seizure-like activities. We provide evidence that enhanced synaptic excitation in CPNs contributes to cortical hyperexcitability and epileptogenesis. In contrast, astrocytic regulation of synapse formation and synaptic transmission remains unchanged after late embryonic radial glial Tsc1 inactivation, and astrogliosis evolves secondary to seizures.

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.

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.

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.

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.

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.

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.

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.

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.

Laser ablation is effective for temporal lobe epilepsy with and without mesial temporal sclerosis if hippocampal seizure onsets are localized by stereoelectroencephalography.

OBJECTIVE: Selective laser amygdalohippocampotomy (SLAH) using magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) is emerging as a treatment option for drug-resistant mesial temporal lobe epilepsy (MTLE). SLAH is less invasive than open resection, but there are limited series reporting its safety and efficacy, particularly in patients without clear evidence of mesial temporal sclerosis (MTS). METHODS: We report seizure outcomes and complications in our first 30 patients who underwent SLAH for drug-resistant MTLE between January 2013 and December 2016. We compare patients who required stereoelectroencephalography (SEEG) to confirm mesial temporal onset with those treated based on imaging evidence of MTS. RESULTS: Twelve patients with SEEG-confirmed, non-MTS MTLE and 18 patients with MRI-confirmed MTS underwent SLAH. MTS patients were older (median age 50 vs 30 years) and had longer standing epilepsy (median 40.5 vs 5.5 years) than non-MTS patients. Engel class I seizure freedom was achieved in 7 of 12 non-MTS patients (58%, 95% confidence interval [CI] 30%-86%) and 10 of 18 MTS patients (56%, 95% CI 33%-79%), with no significant difference between groups (odds ratio [OR] 1.12, 95% CI 0.26-4.91, P = .88). Length of stay was 1 day for most patients (range 0-3 days). Procedural complications were rare and without long-term sequelae. SIGNIFICANCE: We report similar rates of seizure freedom following SLAH in patients with MTS and SEEG-confirmed, non-MTS MTLE. Consistent with early literature, these rates are slightly lower than typically observed with surgical resection (60%-80%). However, SLAH is less invasive than open surgery, with shorter hospital stays and recovery, and severe procedural complications are rare. SLAH may be a reasonable first-line surgical option for patients with both MTS and SEEG confirmed, non-MTS MTLE.

Toward a Mechanistic Understanding of Epileptic Networks.

Focal epileptic seizures have long been considered to arise from a small susceptible brain area and spread through uninvolved regions. In the past decade, the idea that focal seizures instead arise from coordinated activity across large-scale epileptic networks has become widely accepted. Understanding the network model's applicability is critical, due to its increasing influence on clinical research and surgical treatment paradigms. In this review, we examine the origins of the concept of epileptic networks as the nidus for recurring seizures. We summarize analytical and methodological elements of epileptic network studies and discuss findings from recent detailed electrophysiological investigations. Our review highlights the strengths and limitations of the epileptic network theory as a metaphor for the complex interactions that occur during seizures. We present lines of investigation that may usefully probe these interactions and thus serve to advance our understanding of the long-range effects of epileptiform activity.

Functional differences among stimulation-identified cortical naming sites in the temporal region.

To preserve postoperative language, electrical stimulation mapping is often conducted prior to surgery involving the language-dominant hemisphere. Object naming is the task most widely used to identify language cortex, and sites where stimulation elicits naming difficulty are typically spared from resection. In clinical practice, sites classified as positive undergo no further testing regarding the underlying cause of naming failure. Word production is a complex function involving multiple mechanisms that culminate in the identification of the target word. Two main mechanisms, i.e., semantic and phonological, underlie the retrieval of stored information regarding word meaning and word sounds, and naming can be hampered by disrupting either of these. These two mechanisms are likely mediated by different brain areas, and therefore, stimulation-identified naming sites might not be functionally equivalent. We investigated whether further testing at stimulation-identified naming sites would reveal an anatomical dissociation between these two mechanisms. In 16 patients with refractory temporal lobe epilepsy (TLE) with implanted subdural electrodes, we tested whether, despite inability to produce an item name, patients could reliably access semantic or phonological information regarding objects during cortical stimulation. We found that stimulation at naming sites in superior temporal cortex tended to impair phonological processing yet spared access to semantic information. By contrast, stimulation of inferior temporal naming sites revealed a greater proportion of sites where semantic access was impaired and a dissociation between sites where stimulation spared or disrupted semantic or phonological processing. These functional-anatomical dissociations reveal the more specific contribution to naming provided by these cortical areas and shed light on the often profound, interictal word-finding deficit observed in temporal lobe epilepsy. Additionally, these techniques potentially lay the groundwork for future studies to determine whether particular naming sites that fall within the margins of the desired clinical resection might be resected without significant risk of decline.

Single unit action potentials in humans and the effect of seizure activity.

Spike-sorting algorithms have been used to identify the firing patterns of isolated neurons ('single units') from implanted electrode recordings in patients undergoing assessment for epilepsy surgery, but we do not know their potential for providing helpful clinical information. It is important therefore to characterize both the stability of these recordings and also their context. A critical consideration is where the units are located with respect to the focus of the pathology. Recent analyses of neuronal spiking activity, recorded over extended spatial areas using microelectrode arrays, have demonstrated the importance of considering seizure activity in terms of two distinct spatial territories: the ictal core and penumbral territories. The pathological information in these two areas, however, is likely to be very different. We investigated, therefore, whether units could be followed reliably over prolonged periods of times in these two areas, including during seizure epochs. We isolated unit recordings from several hundred neurons from four patients undergoing video-telemetry monitoring for surgical evaluation of focal neocortical epilepsies. Unit stability could last in excess of 40 h, and across multiple seizures. A key finding was that in the penumbra, spike stereotypy was maintained even during the seizure. There was a net tendency towards increased penumbral firing during the seizure, although only a minority of units (10-20%) showed significant changes over the baseline period, and notably, these also included neurons showing significant reductions in firing. In contrast, within the ictal core territories, regions characterized by intense hypersynchronous multi-unit firing, our spike sorting algorithms failed as the units were incorporated into the seizure activity. No spike sorting was possible from that moment until the end of the seizure, but recovery of the spike shape was rapid following seizure termination: some units reappeared within tens of seconds of the end of the seizure, and over 80% reappeared within 3 min (τrecov = 104 ± 22 s). The recovery of the mean firing rate was close to pre-ictal levels also within this time frame, suggesting that the more protracted post-ictal state cannot be explained by persistent cellular neurophysiological dysfunction in either the penumbral or the core territories. These studies lay the foundation for future investigations of how these recordings may inform clinical practice.See Kimchi and Cash (doi:10.1093/awv264) for a scientific commentary on this article.

Extraoperative neurostimulation mapping: results from an international survey of epilepsy surgery programs.

OBJECTIVE: Extraoperative electrical stimulation mapping (ESM) to identify functional cortex is performed prior to neurosurgical resection at epilepsy surgery programs worldwide. However, the procedure remains unstandardized, with no established clinical guidelines. We sought to determine the current range in ESM practice parameters across established epilepsy surgery centers. METHODS: We developed and distributed a 31-question survey to 220 epilepsy centers worldwide regarding current practice parameters of ESM. Questions addressed preoperative assessment, technical stimulation parameters, language testing protocols, criteria for identification of positive or negative functional sites, management of mapping complications, and postoperative functional outcome. RESULTS: Survey responses were obtained from 56 centers. These revealed marked practice variability in virtually all aspects of the ESM procedure. These aspects included critical procedure components such as electrical stimulation settings, the types of language functions tested, the operational definition of a language error, size of surgical resection margin, cortical locations mapped for language, testing in the presence of afterdischarges, and medical management of mapping complications. Forty-one percent of centers reported at least one persistent adverse language outcome despite preserving all eloquent sites defined by their stimulation mapping procedure. SIGNIFICANCE: The striking variations in practice across centers are likely to influence mapping results, which directly affect the boundaries of cortical resection and, consequently, might worsen either seizure or functional outcomes. Clearly, adverse functional outcomes occur despite mapping procedures that were perceived to be adequate. Investigation of critical technical and procedural aspects of stimulation mapping is warranted, with the ultimate goal of establishing empirically based practice guidelines to improve the safety and efficacy of ESM and resective epilepsy surgery. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Characteristics and clinical impact of stimulation-evoked seizures during extraoperative cortical mapping.

Extraoperative electrocortical stimulation mapping (ESM) is used to identify functional cortex prior to epilepsy surgery, with the goal of preserving function postoperatively. Although attempts are made to avoid stimulation-evoked seizure activity, the clinical impact of these events with regard to safety, clinical utility, functional outcome, and even disruption to the procedure itself is unknown. We conducted a retrospective review of 57 patients with pharmacoresistant focal epilepsy who underwent intracranial electrode implantation and ESM. Stimulation-evoked seizures (afterdischarges associated with clinical signs or symptoms) occurred in 19 patients (33%). Mapping sessions were disrupted for 11 of these patients (i.e., 19% of the full sample and 58% of the subgroup of patients with stimulation-evoked seizures). Patients who had ESM disruption were no less likely than patients without ESM disruption to be seizure-free at one year (p=0.63) and two years (p=0.57) postoperatively. Among 23 patients who underwent language assessment pre- and postoperatively, 4 (17%) had evoked seizures that disrupted language mapping; these patients were no more likely to show postoperative language declines relative to those who had no ESM disruption (p=0.26). Results suggest that evoked seizures occur frequently during ESM and can disrupt the procedure; however, these events do not appear to adversely affect postoperative outcomes. Nevertheless, attempts should be made to limit stimulation-evoked seizures in order to reduce patient discomfort, increase efficiency, and maximize the utility of ESM.

Features and timing of the response of single neurons to novelty in the substantia nigra.

Substantia nigra neurons are known to play a key role in normal cognitive processes and disease states. While animal models and neuroimaging studies link dopamine neurons to novelty detection, this has not been demonstrated electrophysiologically in humans. We used single neuron extracellular recordings in awake human subjects undergoing surgery for Parkinson disease to characterize the features and timing of this response in the substantia nigra. We recorded 49 neurons in the substantia nigra. Using an auditory oddball task, we showed that they fired more rapidly following novel sounds than repetitive tones. The response was biphasic with peaks at approximately 250 ms, comparable to that described in primate studies, and a second peak at 500 ms. This response was primarily driven by slower firing neurons as firing rate was inversely correlated to novelty response. Our data provide human validation of the purported role of dopamine neurons in novelty detection and suggest modifications to proposed models of novelty detection circuitry.

Ictal high frequency oscillations distinguish two types of seizure territories in humans.

High frequency oscillations have been proposed as a clinically useful biomarker of seizure generating sites. We used a unique set of human microelectrode array recordings (four patients, 10 seizures), in which propagating seizure wavefronts could be readily identified, to investigate the basis of ictal high frequency activity at the cortical (subdural) surface. Sustained, repetitive transient increases in high gamma (80-150 Hz) amplitude, phase-locked to the low-frequency (1-25 Hz) ictal rhythm, correlated with strong multi-unit firing bursts synchronized across the core territory of the seizure. These repetitive high frequency oscillations were seen in recordings from subdural electrodes adjacent to the microelectrode array several seconds after seizure onset, following ictal wavefront passage. Conversely, microelectrode recordings demonstrating only low-level, heterogeneous neural firing correlated with a lack of high frequency oscillations in adjacent subdural recording sites, despite the presence of a strong low-frequency signature. Previously, we reported that this pattern indicates a failure of the seizure to invade the area, because of a feedforward inhibitory veto mechanism. Because multi-unit firing rate and high gamma amplitude are closely related, high frequency oscillations can be used as a surrogate marker to distinguish the core seizure territory from the surrounding penumbra. We developed an efficient measure to detect delayed-onset, sustained ictal high frequency oscillations based on cross-frequency coupling between high gamma amplitude and the low-frequency (1-25 Hz) ictal rhythm. When applied to the broader subdural recording, this measure consistently predicted the timing or failure of ictal invasion, and revealed a surprisingly small and slowly spreading seizure core surrounded by a far larger penumbral territory. Our findings thus establish an underlying neural mechanism for delayed-onset, sustained ictal high frequency oscillations, and provide a practical, efficient method for using them to identify the small ictal core regions. Our observations suggest that it may be possible to reduce substantially the extent of cortical resections in epilepsy surgery procedures without compromising seizure control.