A Subpopulation of Spikes Predicts Successful Epilepsy Surgery Outcome.

OBJECTIVE: Epileptic spikes are the traditional interictal electroencephalographic (EEG) biomarker for epilepsy. Given their low specificity for identifying the epileptogenic zone (EZ), they are given only moderate attention in presurgical evaluation. This study aims to demonstrate that it is possible to identify specific spike features in intracranial EEG that optimally define the EZ and predict surgical outcome. METHODS: We analyzed spike features on stereo-EEG segments from 83 operated patients from 2 epilepsy centers (37 Engel IA) in wakefulness, non-rapid eye movement sleep, and rapid eye movement sleep. After automated spike detection, we investigated 135 spike features based on rate, morphology, propagation, and energy to determine the best feature or feature combination to discriminate the EZ in seizure-free and non-seizure-free patients by applying 4-fold cross-validation. RESULTS: The rate of spikes with preceding gamma activity in wakefulness performed better for surgical outcome classification (4-fold area under receiver operating characteristics curve [AUC] = 0.755 ± 0.07) than the seizure onset zone, the current gold standard (AUC = 0.563 ± 0.05, p = 0.015) and the ripple rate, an emerging seizure-independent biomarker (AUC = 0.537 ± 0.07, p = 0.006). Channels with a spike-gamma rate exceeding 1.9/min had an 80% probability of being in the EZ. Combining features did not improve the results. INTERPRETATION: Resection of brain regions with high spike-gamma rates in wakefulness is associated with a high probability of achieving seizure freedom. This rate could be applied to determine the minimal number of spiking channels requiring resection. In addition to quantitative analysis, this feature is easily accessible to visual analysis, which could aid clinicians during presurgical evaluation. ANN NEUROL 2023;93:522-535.

Surgical outcome of temporal plus epilepsy is improved by multilobar resection.

OBJECTIVE: Temporal plus epilepsy (TPE) represents a rare type of epilepsy characterized by a complex epileptogenic zone including the temporal lobe and the close neighboring structures. We investigated whether the complete resection of temporal plus epileptogenic zone as defined through stereoelectroencephalography (SEEG) might improve seizure outcome in 38 patients with TPE. METHODS: Inclusion criteria were as follows: epilepsy surgery performed between January 1990 and December 2001, SEEG defining a temporal plus epileptogenic zone, unilobar temporal operations ("temporal lobe epilepsy [TLE] surgery") or multilobar interventions including the temporal lobe ("TPE surgery"), magnetic resonance imaging either normal or showing signs of hippocampal sclerosis, and postoperative follow-up of at least 12 months. For each assessment of postoperative seizure outcome, at 1, 2, 5, and 10 years, we carried out descriptive analysis and classical tests of hypothesis, namely, Pearson χ2 test or Fisher exact test of independence on tables of frequency for each categorical variable of interest and Student t-test for each continuous variable of interest, when appropriate. RESULTS: Twenty-one patients underwent TPE surgery and 17 underwent TLE surgery with a follow-up of 12.4 ± 8.16 years. In the multivariate models, there was a significant effect of the time from surgery on Engel Class IA versus IB-IV outcome, with a steadily worsening trend from 5-year follow-up onward. TPE surgery was associated with better results than TLE surgery. SIGNIFICANCE: This study suggests that surgical outcome in patients with TPE can be improved by a tailored, multilobar resection and confirms that SEEG is mandatory when a TPE is suspected.

Correcting for physiological ripples improves epileptic focus identification and outcome prediction.

OBJECTIVE: The integration of high-frequency oscillations (HFOs; ripples [80-250 Hz], fast ripples [250-500 Hz]) in epilepsy evaluation is hampered by physiological HFOs, which cannot be reliably differentiated from pathological HFOs. We evaluated whether defining abnormal HFO rates by statistical comparison to region-specific physiological HFO rates observed in the healthy brain improves identification of the epileptic focus and surgical outcome prediction. METHODS: We detected HFOs in 151 consecutive patients who underwent stereo-electroencephalography and subsequent resective epilepsy surgery at two tertiary epilepsy centers. We compared how HFOs identified the resection cavity and predicted seizure-free outcome using two thresholds from the literature (HFO rate > 1/min; 50% of the total number of a patient's HFOs) and three thresholds based on normative rates from the Montreal Neurological Institute Open iEEG Atlas (https://mni-open-ieegatlas. RESEARCH: mcgill.ca/): global Atlas threshold, regional Atlas threshold, and regional + 10% threshold after regional Atlas correction. RESULTS: Using ripples, the regional + 10% threshold performed best for focus identification (77.3% accuracy, 27% sensitivity, 97.1% specificity, 80.6% positive predictive value [PPV], 78.2% negative predictive value [NPV]) and outcome prediction (69.5% accuracy, 58.6% sensitivity, 76.3% specificity, 60.7% PPV, 74.7% NPV). This was an improvement for focus identification (+1.1% accuracy, +17.0% PPV; p < .001) and outcome prediction (+12.0% sensitivity, +1.0% PPV; p = .05) compared to the 50% threshold. The improvement was particularly marked for foci in cortex, where physiological ripples are frequent (outcome: +35.3% sensitivity, +5.3% PPV; p = .014). In these cases, the regional + 10% threshold outperformed fast ripple rate > 1/min (+3.6% accuracy, +26.5% sensitivity, +21.6% PPV; p < .001) and seizure onset zone (+13.5% accuracy, +29.4% sensitivity, +17.0% PPV; p < .05-.01) for outcome prediction. Normalization did not improve the performance of fast ripples. SIGNIFICANCE: Defining abnormal HFO rates by statistical comparison to rates in healthy tissue overcomes an important weakness in the clinical use of ripples. It improves focus identification and outcome prediction compared to standard HFO measures, increasing their clinical applicability.

Mapping the Insula with Stereo-Electroencephalography: The Emergence of Semiology in Insula Lobe Seizures.

OBJECTIVE: Insula epilepsy is rare and can be evaluated effectively by Stereotactic intracerebral EEG (SEEG). Many previous studies of insulo-opercular seizures have been unable to separate insular and opercular onset. With adequate sampling of the insula, this study shows this is possible. METHODS: We analyzed intrainsular dynamics and extrainsular propagation in 12 patients with "pure" insula epilepsy (n = 9) or insular and only deepest opercular involvement (n = 3) at seizure onset. Review of semiology defined clinical groups, agglomerative cluster, and principal component analysis of semiological features were performed. Quantitative epileptogenicity, and intrainsular and extrainsular propagation were computed via time frequency analysis and epileptogenicity mapping. RESULTS: Seizure onset patterns were heterogeneous; the seizure onset zone was focal. Seizure onset and first ictal change within insula functional subdivision correlated with aura and reflex component. No paninsular spread occurred; contralateral insular spread was very early. While the discharge was intrainsular, clinical signs related to aura or vegetative signs. Extrainsular propagation was early and related to the emergence of the majority of clinical signs. Cluster analysis found an anterior, intermediate, and posterior insula seizure onset group. The largest principal component separated anterior insula manifestations, including early hypermotor signs, early recovery, and no aura from posterior insula features of early dystonia, early tonic motor features, and sensorimotor aura. INTERPRETATION: Aura is vital to identifying seizure onset and relates to insula functional subdivision. Seizures are heterogenous; extrainsular propagation occurs early, accounting for most of the semiology. With adequate sampling, "pure" insula epilepsy can be identified and focal curative resection is possible. ANN NEUROL 2020;88:477-488.

Prediction of the clinical and naming status after anterior temporal lobe resection in patients with epilepsy.

By assessing the cognitive capital, neuropsychological evaluation (NPE) plays a vital role in the perioperative workup of patients with refractory focal epilepsy. In this retrospective study, we used cutting-edge statistical approaches to examine a group of 47 patients with refractory temporal lobe epilepsy (TLE), who underwent standard anterior temporal lobectomy (ATL). Our objective was to determine whether NPE may represent a robust predictor of the postoperative status, two years after surgery. Specifically, based on pre- and postsurgical neuropsychological data, we estimated the sensitivity of cognitive indicators to predict and to disentangle phenotypes associated with more or less favorable outcomes. Engel (ENG) scores were used to assess clinical outcome, and picture naming (NAM) performance to estimate naming status. Two methods were applied: (a) machine learning (ML) to explore cognitive sensitivity to postoperative outcomes; and (b) graph theory (GT) to assess network properties reflecting favorable vs. less favorable phenotypes after surgery. Specific neuropsychological indices assessing language, memory, and executive functions can globally predict outcomes. Interestingly, preoperative cognitive networks associated with poor postsurgical outcome already exhibit an atypical, highly modular and less densely interconnected configuration. We provide statistical and clinical tools to anticipate the condition after surgery and achieve a more personalized clinical management. Our results also shed light on possible mechanisms put in place for cognitive adaptation after acute injury of central nervous system in relation with surgery.

Hubs disruption in mesial temporal lobe epilepsy. A resting-state fMRI study on a language-and-memory network.

Mesial temporal lobe epilepsy (mTLE) affects the brain networks at several levels and patients suffering from mTLE experience cognitive impairment for language and memory. Considering the importance of language and memory reorganization in this condition, the present study explores changes of the embedded language-and-memory network (LMN) in terms of functional connectivity (FC) at rest, as measured with functional MRI. We also evaluate the cognitive efficiency of the reorganization, that is, whether or not the reorganizations support or allow the maintenance of optimal cognitive functioning despite the seizure-related damage. Data from 37 patients presenting unifocal mTLE were analyzed and compared to 48 healthy volunteers in terms of LMN-FC using two methods: pairwise correlations (region of interest [ROI]-to-ROI) and graph theory. The cognitive efficiency of the LMN-FC reorganization was measured using correlations between FC parameters and language and memory scores. Our findings revealed a large perturbation of the LMN hubs in patients. We observed a hyperconnectivity of limbic areas near the dysfunctional hippocampus and mainly a hypoconnectivity for several cortical regions remote from the dysfunctional hippocampus. The loss of FC was more important in left mTLE (L-mTLE) than in right (R-mTLE) patients. The LMN-FC reorganization may not be always compensatory and not always useful for patients as it may be associated with lower cognitive performance. We discuss the different connectivity patterns obtained and conclude that interpretation of FC changes in relation to neuropsychological scores is important to determine cognitive efficiency, suggesting the concept of "connectome" would gain to be associated with a "cognitome" concept.

Probabilistic mapping of language networks from high frequency activity induced by direct electrical stimulation.

Direct electrical stimulation (DES) at 50 Hz is used as a gold standard to map cognitive functions but little is known about its ability to map large-scale networks and specific subnetwork. In the present study, we aim to propose a new methodological approach to evaluate the specific hypothesis suggesting that language errors/dysfunction induced by DES are the result of large-scale network modification rather than of a single cortical region, which explains that similar language symptoms may be observed after stimulation of different cortical regions belonging to this network. We retrospectively examined 29 patients suffering from focal drug-resistant epilepsy who benefitted from stereo-electroencephalographic (SEEG) exploration and exhibited language symptoms during a naming task following 50 Hz DES. We assessed the large-scale language network correlated with behavioral DES-induced responses (naming errors) by quantifying DES-induced changes in high frequency activity (HFA, 70-150 Hz) outside the stimulated cortical region. We developed a probabilistic approach to report the spatial pattern of HFA modulations during DES-induced language errors. Similarly, we mapped the pattern of after-discharges (3-35 Hz) occurring after DES. HFA modulations concurrent to language symptoms revealed a brain network similar to our current knowledge of language gathered from standard brain mapping. In addition, specific subnetworks could be identified within the global language network, related to different language processes, generally described in relation to the classical language regions. Spatial patterns of after-discharges were similar to HFA induced during DES. Our results suggest that this new methodological DES-HFA mapping is a relevant approach to map functional networks during SEEG explorations, which would allow to shift from "local" to "network" perspectives.

Atlas of the normal intracranial electroencephalogram: neurophysiological awake activity in different cortical areas.

In contrast to scalp EEG, our knowledge of the normal physiological intracranial EEG activity is scarce. This multicentre study provides an atlas of normal intracranial EEG of the human brain during wakefulness. Here we present the results of power spectra analysis during wakefulness. Intracranial electrodes are placed in or on the brain of epilepsy patients when candidates for surgical treatment and non-invasive approaches failed to sufficiently localize the epileptic focus. Electrode contacts are usually in cortical regions showing epileptic activity, but some are placed in normal regions, at distance from the epileptogenic zone or lesion. Intracranial EEG channels defined using strict criteria as very likely to be in healthy brain regions were selected from three tertiary epilepsy centres. All contacts were localized in a common stereotactic space allowing the accumulation and superposition of results from many subjects. Sixty-second artefact-free sections during wakefulness were selected. Power spectra were calculated for 38 brain regions, and compared to a set of channels with no spectral peaks in order to identify significant peaks in the different regions. A total of 1785 channels with normal brain activity from 106 patients were identified. There were on average 2.7 channels per cm3 of cortical grey matter. The number of contacts per brain region averaged 47 (range 6-178). We found significant differences in the spectral density distributions across the different brain lobes, with beta activity in the frontal lobe (20-24 Hz), a clear alpha peak in the occipital lobe (9.25-10.25 Hz), intermediate alpha (8.25-9.25 Hz) and beta (17-20 Hz) frequencies in the parietal lobe, and lower alpha (7.75-8.25 Hz) and delta (0.75-2.25 Hz) peaks in the temporal lobe. Some cortical regions showed a specific electrophysiological signature: peaks present in >60% of channels were found in the precentral gyrus (lateral: peak frequency range, 20-24 Hz; mesial: 24-30 Hz), opercular part of the inferior frontal gyrus (20-24 Hz), cuneus (7.75-8.75 Hz), and hippocampus (0.75-1.25 Hz). Eight per cent of all analysed channels had more than one spectral peak; these channels were mostly recording from sensory and motor regions. Alpha activity was not present throughout the occipital lobe, and some cortical regions showed peaks in delta activity during wakefulness. This is the first atlas of normal intracranial EEG activity; it includes dense coverage of all cortical regions in a common stereotactic space, enabling direct comparisons of EEG across subjects. This atlas provides a normative baseline against which clinical EEGs and experimental results can be compared. It is provided as an open web resource (https://mni-open-ieegatlas. RESEARCH: mcgill.ca).

Direct Recordings from Human Anterior Insula Reveal its Leading Role within the Error-Monitoring Network.

The ability to monitor our own errors is mediated by a network that includes dorsomedial prefrontal cortex (dmPFC) and anterior insula (AI). However, the dynamics of the underlying neurophysiological processes remain unclear. In particular, whether AI is on the receiving or driving end of the error-monitoring network is unresolved. Here, we recorded intracerebral electroencephalography signals simultaneously from AI and dmPFC in epileptic patients while they performed a stop-signal task. We found that errors selectively modulated broadband neural activity in human AI. Granger causality estimates revealed that errors were immediately followed by a feedforward influence from AI onto anterior cingulate cortex and, subsequently, onto presupplementary motor area. The reverse pattern of information flow was observed on correct responses. Our findings provide the first direct electrophysiological evidence indicating that the anterior insula rapidly detects and conveys error signals to dmPFC, while the latter might use this input to adapt behavior following inappropriate actions.

Radiofrequency thermocoagulation of the seizure-onset zone during stereoelectroencephalography.

OBJECTIVE: To assess long-term outcome and identify prognostic factors of radiofrequency thermocoagulation (RFTC) following stereoelectroencephalography (SEEG) explorations in particularly complex cases of focal epilepsy. METHODS: We retrospectively reviewed the medical charts, video-SEEG recordings, and outcomes for 23 patients (aged 6-53 years) treated with SEEG-guided RFTC, of whom 15 had negative magnetic resonance imaging (MRI) findings, and 10 were considered noneligible for resective surgery after SEEG. Two to 11 RFTCs per patient (mean 5) were produced by applying 40-50 V, 75-110 mA current for 10-60 s on SEEG electrode contacts within the epileptogenic region, which was very close to eloquent cortices in 12 cases. The general features, SEEG findings, and RFTC extent of the patients were analyzed to extract potential preoperative predictors of post-RFTC seizure outcomes. RESULTS: After a mean follow-up of 32 months (range 2-119 months), eight patients experienced a ≥50% decrease of seizure frequency after RFTC (R+, 34.8%), of whom one had a sustained seizure freedom and 15 patients did not benefit from RFTC (R-, 65.2%). The presence of an MRI lesion was the only significant predictor of a positive outcome, whereas location of epilepsy, extent of interictal epileptiform discharges (IEDs) and of the seizure onset zone, induction of seizures by electrical stimulation, as well as the ratio of the coagulated sites did not show a significant correlation to the RFTC response. However, (sub-)continuous IEDs were more frequently found in R+ than in R- patients, thus suggesting that this EEG marker of the epileptogenic tissue might predict a positive outcome even in patients without obvious MRI lesion. SIGNIFICANCE: Our study confirms that RFTC, although less effective than resective surgery, can be a reasonable therapeutic option in complex cases where anatomic constraints make impossible any cortical resection. Further prospective studies are needed to better define RFTC indications and to optimize its methodology.

Temporal plus epilepsy is a major determinant of temporal lobe surgery failures.

Reasons for failed temporal lobe epilepsy surgery remain unclear. Temporal plus epilepsy, characterized by a primary temporal lobe epileptogenic zone extending to neighboured regions, might account for a yet unknown proportion of these failures. In this study all patients from two epilepsy surgery programmes who fulfilled the following criteria were included: (i) operated from an anterior temporal lobectomy or disconnection between January 1990 and December 2001; (ii) magnetic resonance imaging normal or showing signs of hippocampal sclerosis; and (iii) postoperative follow-up ≥ 24 months for seizure-free patients. Patients were classified as suffering from unilateral temporal lobe epilepsy, bitemporal epilepsy or temporal plus epilepsy based on available presurgical data. Kaplan-Meier survival analysis was used to calculate the probability of seizure freedom over time. Predictors of seizure recurrence were investigated using Cox proportional hazards model. Of 168 patients included, 108 (63.7%) underwent stereoelectroencephalography, 131 (78%) had hippocampal sclerosis, 149 suffered from unilateral temporal lobe epilepsy (88.7%), one from bitemporal epilepsy (0.6%) and 18 (10.7%) from temporal plus epilepsy. The probability of Engel class I outcome at 10 years of follow-up was 67.3% (95% CI: 63.4-71.2) for the entire cohort, 74.5% (95% CI: 70.6-78.4) for unilateral temporal lobe epilepsy, and 14.8% (95% CI: 5.9-23.7) for temporal plus epilepsy. Multivariate analyses demonstrated four predictors of seizure relapse: temporal plus epilepsy (P < 0.001), postoperative hippocampal remnant (P = 0.001), past history of traumatic or infectious brain insult (P = 0.022), and secondary generalized tonic-clonic seizures (P = 0.023). Risk of temporal lobe surgery failure was 5.06 (95% CI: 2.36-10.382) greater in patients with temporal plus epilepsy than in those with unilateral temporal lobe epilepsy. Temporal plus epilepsy represents a hitherto unrecognized prominent cause of temporal lobe surgery failures. In patients with temporal plus epilepsy, anterior temporal lobectomy appears very unlikely to control seizures and should not be advised. Whether larger resection of temporal plus epileptogenic zones offers greater chance of seizure freedom remains to be investigated.

Correlation of FDG-PET hypometabolism and SEEG epileptogenicity mapping in patients with drug-resistant focal epilepsy.

OBJECTIVE: Interictal [18F]fluorodeoxyglucose-positron emission tomography (FDG-PET) is used in the presurgical evaluation of patients with drug-resistant focal epilepsy. We aimed at clarifying its relationships with ictal high-frequency oscillations (iHFOs) shown to be a relevant marker of the seizure-onset zone. METHODS: We studied the correlation between FDG-PET and epileptogenicity maps in an unselected series of 37 successive patients having been explored with stereo-electroencephalography (SEEG). RESULTS: At the group level, we found a significant correlation between iHFOs and FDG-PET interictal hypometabolism only in cases of temporal lobe epilepsy. This correlation was found with HFOs, and the same comparison between FDG-PET and ictal SEEG power of lower frequencies during the same epochs did not show the same significance. SIGNIFICANCE: This finding suggests that interictal FDG-PET and ictal HFOs may share common underlying pathophysiologic mechanisms of ictogenesis in temporal lobe epilepsy, and combining both features may help to identify the seizure-onset zone.

Neural repetition suppression in ventral occipito-temporal cortex occurs during conscious and unconscious processing of frequent stimuli.

Stimulus repetition can produce neural response attenuation in stimulus-category selective networks within the occipito-temporal lobe. It is hypothesized that this neural suppression reflects the functional sharpening of local neuronal assemblies which boosts information processing efficiency. This neural suppression phenomenon has been mainly reported during conditions of conscious stimulus perception. The question remains whether frequent stimuli processed in the absence of conscious perception also induce repetition suppression in those specialized networks. Using rare intracranial EEG recordings in the ventral occipito-temporal cortex (VOTC) of human epileptic patients we investigated neural repetition suppression in conditions of conscious and unconscious visual processing of words. To this end, we used an orthogonal design manipulating respectively stimulus repetition (frequent vs. unique stimuli) and conscious perception (masked vs. unmasked stimuli). By measuring the temporal dynamics of high-frequency broadband gamma activity in VOTC and testing for main and interaction effects, we report that early processing of words in word-form selective networks exhibits a temporal cascade of modulations by stimulus repetition and masking: neuronal attenuation initially is observed in response to repeated words (irrespective of consciousness), that is followed by a second modulation contingent upon word reportability (irrespective of stimulus repetition). Later on (>300ms post-stimulus), a significant effect of conscious perception on the extent of repetition suppression was observed. The temporal dynamics of consciousness, the recognition memory processes and their interaction revealed in this study advance our understanding of their contributions to the neural mechanisms of word processing in VOTC.

The pivotal role of the supplementary motor area in startle epilepsy as demonstrated by SEEG epileptogenicity maps.

Startle seizures belong to reflex epilepsy syndromes. They usually occur in patients with mental deficiency and showing widely extended cortical lesions, often involving the sensorimotor area. Here we report three cases who did not fulfill these criteria, and in whom stereotactic electroencephalography (SEEG) recordings demonstrated the prominent involvement of the supplementary motor area (SMA). Visual analysis was complemented by time-frequency analysis of SEEG signals using a neuroimaging approach (Epileptogenicity Maps), which showed at seizure onset a significant increase of high frequency oscillations (HFOs, 60-100 Hz) over the premotor and prefrontal areas. Critically, in all cases, the SMA showed ictal HFOs at seizure onset and was included in the surgical resection. All patients became seizure-free after surgery, and histopathological examinations showed no specific lesion. These cases suggest the prominent but not exclusive role of SMA in startle seizures, and highlight the fact that surgery can be considered even in the absence of any magnetic resonance imaging (MRI) lesion.

The long-term effect of vagus nerve stimulation on quality of life in patients with pharmacoresistant focal epilepsy: the PuLsE (Open Prospective Randomized Long-term Effectiveness) trial.

OBJECTIVE: To evaluate whether vagus nerve stimulation (VNS) as adjunct to best medical practice (VNS + BMP) is superior to BMP alone in improving long-term health-related quality of life (HRQoL). METHODS: PuLsE (Open Prospective Randomized Long-term Effectiveness) was a prospective, randomized, parallel-group, open-label, and long-term effectiveness study (conducted at 28 sites in Europe and Canada). Adults with pharmacoresistant focal seizures (n = 112) received VNS + BMP or BMP (1:1 ratio). Medications and VNS parameters could be adjusted as clinically indicated for optimal seizure control while minimizing adverse effects. Primary endpoint was mean change from baseline HRQoL (using Quality of Life in Epilepsy Inventory-89 total score; QOLIE-89). Secondary endpoints included changes in seizure frequency, responder rate (≥50% decrease in seizure frequency), Centre for Epidemiologic Studies Depression scale (CES-D), Neurological Disorders Depression Inventory-Epilepsy scale (NDDI-E), Clinical Global Impression-Improvement scale (CGI-I), Adverse Event Profile (AEP), and antiepileptic drug (AED) load. The study was prematurely terminated due to recruitment difficulties prior to completing the planned enrollment of n = 362. Results for n = 96 who had baseline and at least one follow-up QOLIE-89 assessment (from months 3-12) were included in this analysis. Mixed model repeated measures (MMRM) analysis of variance was performed on change from baseline for the primary and secondary endpoints. RESULTS: Significant between-group differences in favor of VNS + BMP were observed regarding improvement in HRQoL, seizure frequency, and CGI-I score (respective p-values < 0.05, 0.03, and 0.01). More patients in the VNS + BMP group (43%) reported adverse events (AEs) versus BMP group (21%) (p = 0.01), a difference reflecting primarily mostly transient AEs related to VNS implantation or stimulation. No significant difference between treatment groups was observed for changes in CES-D, NDDI-E, AEP, and AED load. SIGNIFICANCE: VNS therapy as a treatment adjunct to BMP in patients with pharmacoresistant focal seizures was associated with a significant improvement in HRQoL compared with BMP alone. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

A spatial perturbation framework to validate implantation of the epileptogenic zone.

Stereo-electroencephalography (SEEG) is the gold standard to delineate surgical targets in focal drug-resistant epilepsy. SEEG uses electrodes placed directly into the brain to identify the seizure-onset zone (SOZ). However, its major constraint is limited brain coverage, potentially leading to misidentification of the 'true' SOZ. Here, we propose a framework to assess adequate SEEG sampling by coupling epileptic biomarkers with their spatial distribution and measuring the system's response to a perturbation of this coupling. We demonstrate that the system's response is strongest in well-sampled patients when virtually removing the measured SOZ. We then introduce the spatial perturbation map, a tool that enables qualitative assessment of the implantation coverage. Probability modelling reveals a higher likelihood of well-implanted SOZs in seizure-free patients or non-seizure free patients with incomplete SOZ resections, compared to non-seizure-free patients with complete resections. This highlights the framework's value in sparing patients from unsuccessful surgeries resulting from poor SEEG coverage.

Efficient "pop-out" visual search elicits sustained broadband γ activity in the dorsal attention network.

An object that differs markedly from its surrounding-for example, a red cherry among green leaves-seems to pop out effortlessly in our visual experience. The rapid detection of salient targets, independently of the number of other items in the scene, is thought to be mediated by efficient search brain mechanisms. It is not clear, however, whether efficient search is actually an "effortless" bottom-up process or whether it also involves regions of the prefrontal cortex generally associated with top-down sustained attention. We addressed this question with intracranial EEG (iEEG) recordings designed to identify brain regions underlying a classic visual search task and correlate neural activity with target detection latencies on a trial-by-trial basis with high temporal precision recordings of these regions in epileptic patients. The spatio-temporal dynamics of single-trial spectral analysis of iEEG recordings revealed sustained energy increases in a broad gamma band (50-150 Hz) throughout the duration of the search process in the entire dorsal attention network both in efficient and inefficient search conditions. By contrast to extensive theoretical and experimental indications that efficient search relies exclusively on transient bottom-up processes in visual areas, we found that efficient search is mediated by sustained gamma activity in the dorsal lateral prefrontal cortex and the anterior cingulate cortex, alongside the superior parietal cortex and the frontal eye field. Our findings support the hypothesis that active visual search systematically involves the frontal-parietal attention network and therefore, executive attention resources, regardless of target saliency.

How silent is silent reading? Intracerebral evidence for top-down activation of temporal voice areas during reading.

As you might experience it while reading this sentence, silent reading often involves an imagery speech component: we can hear our own "inner voice" pronouncing words mentally. Recent functional magnetic resonance imaging studies have associated that component with increased metabolic activity in the auditory cortex, including voice-selective areas. It remains to be determined, however, whether this activation arises automatically from early bottom-up visual inputs or whether it depends on late top-down control processes modulated by task demands. To answer this question, we collaborated with four epileptic human patients recorded with intracranial electrodes in the auditory cortex for therapeutic purposes, and measured high-frequency (50-150 Hz) "gamma" activity as a proxy of population level spiking activity. Temporal voice-selective areas (TVAs) were identified with an auditory localizer task and monitored as participants viewed words flashed on screen. We compared neural responses depending on whether words were attended or ignored and found a significant increase of neural activity in response to words, strongly enhanced by attention. In one of the patients, we could record that response at 800 ms in TVAs, but also at 700 ms in the primary auditory cortex and at 300 ms in the ventral occipital temporal cortex. Furthermore, single-trial analysis revealed a considerable jitter between activation peaks in visual and auditory cortices. Altogether, our results demonstrate that the multimodal mental experience of reading is in fact a heterogeneous complex of asynchronous neural responses, and that auditory and visual modalities often process distinct temporal frames of our environment at the same time.

Long-distance amplitude correlations in the high γ band reveal segregation and integration within the reading network.

Reading sentences involves a distributed network of brain regions acting in concert surrounding the left sylvian fissure. The mechanisms of neural communication underlying the extraction and integration of verbal information across subcomponents of this reading network are still largely unknown. We recorded intracranial EEG activity in 12 epileptic human patients performing natural sentence reading and analyzed long-range corticocortical interactions between local neural activations. During a simple task contrasting semantic, phonological, and purely visual processes, we found process-specific neural activity elicited at the single-trial level, characterized by energy increases in a broad gamma band (40-150 Hz). Correlation analysis between task-induced gamma-band activations revealed a selective fragmentation of the network into specialized subnetworks supporting sentence-level semantic analysis and phonological processing. We extend the implications of our results beyond reading, to propose that gamma-band amplitude correlations might constitute a fundamental mechanism for large-scale neural integration during high-level cognition.

Probabilistic functional tractography of the human cortex.

Single-pulse direct electrical stimulation of cortical regions in patients suffering from focal drug-resistant epilepsy who are explored using intracranial electrodes induces cortico-cortical potentials that can be used to infer functional and anatomical connectivity. Here, we describe a neuroimaging framework that allows development of a new probabilistic atlas of functional tractography of the human cortex from those responses. This atlas is unique because it allows inference in vivo of the directionality and latency of cortico-cortical connectivity, which are still largely unknown at the human brain level. In this technical note, we include 1535 stimulation runs performed in 35 adult patients. We use a case of frontal lobe epilepsy to illustrate the asymmetrical connectivity between the posterior hippocampal gyrus and the orbitofrontal cortex. In addition, as a proof of concept for group studies, we study the probabilistic functional tractography between the posterior superior temporal gyrus and the inferior frontal gyrus. In the near future, the atlas database will be continuously increased, and the methods will be improved in parallel, for more accurate estimation of features of interest. Generated probabilistic maps will be freely distributed to the community because they provide critical information for further understanding and modelling of large-scale brain networks.