Cross-frequency coupling in cortico-hippocampal networks supports the maintenance of sequential auditory information in short-term memory.

It has been suggested that cross-frequency coupling in cortico-hippocampal networks enables the maintenance of multiple visuo-spatial items in working memory. However, whether this mechanism acts as a global neural code for memory retention across sensory modalities remains to be demonstrated. Intracranial EEG data were recorded while drug-resistant patients with epilepsy performed a delayed matched-to-sample task with tone sequences. We manipulated task difficulty by varying the memory load and the duration of the silent retention period between the to-be-compared sequences. We show that the strength of theta-gamma phase amplitude coupling in the superior temporal sulcus, the inferior frontal gyrus, the inferior temporal gyrus, and the hippocampus (i) supports the short-term retention of auditory sequences; (ii) decodes correct and incorrect memory trials as revealed by machine learning analysis; and (iii) is positively correlated with individual short-term memory performance. Specifically, we show that successful task performance is associated with consistent phase coupling in these regions across participants, with gamma bursts restricted to specific theta phase ranges corresponding to higher levels of neural excitability. These findings highlight the role of cortico-hippocampal activity in auditory short-term memory and expand our knowledge about the role of cross-frequency coupling as a global biological mechanism for information processing, integration, and memory in the human brain.

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.

PIEZO1 expression at the glio-vascular unit adjusts to neuroinflammation in seizure conditions.

Mechanosensors are emerging players responding to hemodynamic and physical inputs. Their significance in the central nervous system remains relatively uncharted. Using human-derived brain specimens or cells and a pre-clinical model of mesio-temporal lobe epilepsy (MTLE), we examined how the mRNA levels of the mechanosensitive channel PIEZO1 adjust to disease-associated pro-inflammatory trajectories. In brain tissue micro-punches obtained from 18 drug-resistant MTLE patients, PIEZO1 expression positively correlated with pro-inflammatory biomarkers TNFα, IL-1ß, and NF-kB in the epileptogenic hippocampus compared to the adjacent amygdala and temporal cortex tissues. In an experimental MTLE model, hippocampal Piezo1 and cytokine expression levels were increased post-status epilepticus (SE) and during epileptogenesis. Piezo1 expression positively correlated with Tnfα, Il1ß, and Nf-kb in the hippocampal foci. Next, by combining RNAscope with immunohistochemistry, we identified Piezo1 in glio-vascular cells. Post-SE and during epileptogenesis, ameboid IBA1 microglia, hypertrophic GFAP astrocytes, and damaged NG2DsRed pericytes exhibited time-dependent patterns of increased Piezo1 expression. Digital droplet PCR analysis confirmed the Piezo1 trajectory in isolated hippocampal microvessels in the ipsi and contralateral hippocampi. The combined examinations performed in this model showed Piezo1 expression returning towards basal levels after the epileptogenesis-associated peak inflammation. From these associations, we next asked whether pro-inflammatory players directly regulate PIEZO1 expression. We used human-derived brain cells and confirmed that endothelium, astrocytes, and pericytes expressed PIEZO1. Exposure to human recombinant TNFα or IL1ß upregulated NF-kB in all cells. Furthermore, TNFα induced PIEZO1 expression in a dose and time-dependent manner, primarily in astrocytes. This exploratory study describes a spatiotemporal dialogue between PIEZO1 brain cell-mechanobiology and neuro-inflammatory cell remodeling. The precise functional mechanisms regulating this interplay in disease conditions warrant further investigation.

Complex visual discrimination is impaired after right, but not left, anterior temporal lobectomy.

The prevailing view in human cognitive neuroscience associates the medial temporal lobes (MTLs) with declarative memory. Compelling experimental evidence has, however, demonstrated that these regions are specialized according to the representations processed, irrespective of the cognitive domain assessed. This account was supported by the study of patients with bilateral medial temporal amnesia, who exhibit impairments in perceptual tasks involving complex visual stimuli. Yet, little is known regarding the impact of unilateral MTL damage on complex visual abilities. To address this issue, we administered a visual matching task to 20 patients who underwent left (N = 12) or right (N = 8) anterior temporal lobectomy for drug-resistant epilepsy and to 38 healthy controls. Presentation viewpoint was manipulated to increase feature ambiguity, as this is critical to reveal impairments in perceptual tasks. Similar to control participants, patients with left-sided damage succeeded in all task conditions. In contrast, patients with right-sided damage had decreased accuracy compared with that of the other two groups, as well as increased response time. Notably, the accuracy of those with right-sided damage did not exceed chance level when feature ambiguity was high (i.e., when stimuli were presented from different viewpoints) for the most complex classes of stimuli (i.e., scenes and buildings, compared with single objects). The pattern reported in bilateral patients in previous studies was therefore reproduced in patients with right, but not left, resection. These results suggest that the complex visual-representation functions supported by the MTL are right-lateralized, and raise the question as to how the representational account of these regions applies to representations supported by left MTL regions.

Decoding the neural dynamics of free choice in humans.

How do we choose a particular action among equally valid alternatives? Nonhuman primate findings have shown that decision-making implicates modulations in unit firing rates and local field potentials (LFPs) across frontal and parietal cortices. Yet the electrophysiological brain mechanisms that underlie free choice in humans remain ill defined. Here, we address this question using rare intracerebral electroencephalography (EEG) recordings in surgical epilepsy patients performing a delayed oculomotor decision task. We find that the temporal dynamics of high-gamma (HG, 60-140 Hz) neural activity in distinct frontal and parietal brain areas robustly discriminate free choice from instructed saccade planning at the level of single trials. Classification analysis was applied to the LFP signals to isolate decision-related activity from sensory and motor planning processes. Compared with instructed saccades, free-choice trials exhibited delayed and longer-lasting HG activity during the delay period. The temporal dynamics of the decision-specific sustained HG activity indexed the unfolding of a deliberation process, rather than memory maintenance. Taken together, these findings provide the first direct electrophysiological evidence in humans for the role of sustained high-frequency neural activation in frontoparietal cortex in mediating the intrinsically driven process of freely choosing among competing behavioral alternatives.

A brain atlas of axonal and synaptic delays based on modelling of cortico-cortical evoked potentials.

Epilepsy presurgical investigation may include focal intracortical single-pulse electrical stimulations with depth electrodes, which induce cortico-cortical evoked potentials at distant sites because of white matter connectivity. Cortico-cortical evoked potentials provide a unique window on functional brain networks because they contain sufficient information to infer dynamical properties of large-scale brain connectivity, such as preferred directionality and propagation latencies. Here, we developed a biologically informed modelling approach to estimate the neural physiological parameters of brain functional networks from the cortico-cortical evoked potentials recorded in a large multicentric database. Specifically, we considered each cortico-cortical evoked potential as the output of a transient stimulus entering the stimulated region, which directly propagated to the recording region. Both regions were modelled as coupled neural mass models, the parameters of which were estimated from the first cortico-cortical evoked potential component, occurring before 80 ms, using dynamic causal modelling and Bayesian model inversion. This methodology was applied to the data of 780 patients with epilepsy from the F-TRACT database, providing a total of 34 354 bipolar stimulations and 774 445 cortico-cortical evoked potentials. The cortical mapping of the local excitatory and inhibitory synaptic time constants and of the axonal conduction delays between cortical regions was obtained at the population level using anatomy-based averaging procedures, based on the Lausanne2008 and the HCP-MMP1 parcellation schemes, containing 130 and 360 parcels, respectively. To rule out brain maturation effects, a separate analysis was performed for older (>15 years) and younger patients (<15 years). In the group of older subjects, we found that the cortico-cortical axonal conduction delays between parcels were globally short (median = 10.2 ms) and only 16% were larger than 20 ms. This was associated to a median velocity of 3.9 m/s. Although a general lengthening of these delays with the distance between the stimulating and recording contacts was observed across the cortex, some regions were less affected by this rule, such as the insula for which almost all efferent and afferent connections were faster than 10 ms. Synaptic time constants were found to be shorter in the sensorimotor, medial occipital and latero-temporal regions, than in other cortical areas. Finally, we found that axonal conduction delays were significantly larger in the group of subjects younger than 15 years, which corroborates that brain maturation increases the speed of brain dynamics. To our knowledge, this study is the first to provide a local estimation of axonal conduction delays and synaptic time constants across the whole human cortex in vivo, based on intracerebral electrophysiological recordings.

Variability of Single Pulse Electrical Stimulation Responses Recorded with Intracranial Electroencephalography in Epileptic Patients.

Cohort studies of brain stimulations performed with stereo-electroencephalographic (SEEG) electrodes in epileptic patients allow to derive large scale functional connectivity. It is known, however, that brain responses to electrical or magnetic stimulation techniques are not always reproducible. Here, we study variability of responses to single pulse SEEG electrical stimulation. We introduce a second-order probability analysis, i.e. we extend estimation of connection probabilities, defined as the proportion of responses trespassing a statistical threshold (determined in terms of Z-score with respect to spontaneous neuronal activity before stimulation) over all responses and derived from a number of individual measurements, to an analysis of pairs of measurements.Data from 445 patients were processed. We found that variability between two equivalent measurements is substantial in particular conditions. For long ( > ~ 90 mm) distances between stimulating and recording sites, and threshold value Z = 3, correlation between measurements drops almost to zero. In general, it remains below 0.5 when the threshold is smaller than Z = 4 or the stimulating current intensity is 1 mA. It grows with an increase of either of these factors. Variability is independent of interictal spiking rates in the stimulating and recording sites.We conclude that responses to SEEG stimulation in the human brain are variable, i.e. in a subject at rest, two stimulation trains performed at the same electrode contacts and with the same protocol can give discrepant results. Our findings highlight an advantage of probabilistic interpretation of such results even in the context of a single individual.

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.

Epileptic spasms are associated with increased stereo-electroencephalography derived functional connectivity in tuberous sclerosis complex.

OBJECTIVE: Epileptic spasms (ES) are common in tuberous sclerosis complex (TSC). However, the underlying network alterations and relationship with epileptogenic tubers are poorly understood. We examined interictal functional connectivity (FC) using stereo-electroencephalography (SEEG) in patients with TSC to investigate the relationship between tubers, epileptogenicity, and ES. METHODS: We analyzed 18 patients with TSC who underwent SEEG (mean age = 11.5 years). The dominant tuber (DT) was defined as the most epileptogenic tuber using the epileptogenicity index. Epileptogenic zone (EZ) organization was quantitatively separated into focal (isolated DT) and complex (all other patterns). Using a 20-min interictal recording, FC was estimated with nonlinear regression, h2 . We calculated (1) intrazone FC within all sampled tubers and normal-appearing cortical zones, respectively; and (2) interzone FC involving connections between DT, other tubers, and normal cortex. The relationship between FC and (1) presence of ES as a current seizure type at the time of SEEG, (2) EZ organization, and (3) epileptogenicity was analyzed using a mixed generalized linear model. Spike rate and distance between zones were considered in the model as covariates. RESULTS: Six patients had ES as a current seizure type at time of SEEG. ES patients had a greater number of tubers with a fluid-attenuated inversion recovery hypointense center (p < .001), and none had TSC1 mutations. The presence of ES was independently associated with increased FC within both intrazone (p = .033) and interzone (p = .011) networks. Post hoc analyses identified that increased FC was associated with ES across tuber and nontuber networks. EZ organization and epileptogenicity biomarkers were not associated with FC. SIGNIFICANCE: Increased cortical synchrony among both tuber and nontuber networks is characteristic of patients with ES and independent of both EZ organization and tuber epileptogenicity. This further supports the prospect of FC biomarkers aiding treatment paradigms in TSC.

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.

How the Human Brain Sleeps: Direct Cortical Recordings of Normal Brain Activity.

OBJECTIVE: Regional variations in oscillatory activity during human sleep remain unknown. Using the unique ability of intracranial electroencephalography to study in situ brain physiology, this study assesses regional variations of electroencephalographic sleep activity and creates the first atlas of human sleep using recordings from the first sleep cycle. METHODS: Intracerebral electroencephalographic recordings with channels displaying physiological activity from nonlesional tissue were selected from 91 patients of 3 tertiary epilepsy centers. Sections during non-rapid eye movement sleep (stages N2 and N3) and rapid eye movement sleep (stage R) were selected from the first sleep cycle for oscillatory and nonoscillatory signal analysis. Results of 1,468 channels were grouped into 38 regions covering all cortical areas. RESULTS: We found regional differences in the distribution of sleep transients and spectral content during all sleep stages. There was a caudorostral gradient, with more slow frequencies and fewer spindles in temporoparieto-occipital than in frontal cortex. Moreover, deep-seated structures showed spectral peaks differing from the baseline electroencephalogram. The regions with >60% of channels presenting significant rhythmic activity were either mesial or temporal basal structures that contribute minimally to the scalp electroencephalogram. Finally, during deeper sleep stages, electroencephalographic analysis revealed a more homogeneous spatial distribution, with increased coupling between high and low frequencies. INTERPRETATION: This study provides a better understanding of the regional variability of sleep, and establishes a baseline for human sleep in all cortical regions during the first sleep cycle. Furthermore, the open-access atlas will be a unique resource for research (https://mni-open-ieegatlas. RESEARCH: mcgill.ca). ANN NEUROL 2020;87:289-301.

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.

Human Anterior Insula Encodes Performance Feedback and Relays Prediction Error to the Medial Prefrontal Cortex.

Adaptive behavior requires the comparison of outcome predictions with actual outcomes (e.g., performance feedback). This process of performance monitoring is computed by a distributed brain network comprising the medial prefrontal cortex (mPFC) and the anterior insular cortex (AIC). Despite being consistently co-activated during different tasks, the precise neuronal computations of each region and their interactions remain elusive. In order to assess the neural mechanism by which the AIC processes performance feedback, we recorded AIC electrophysiological activity in humans. We found that the AIC beta oscillations amplitude is modulated by the probability of performance feedback valence (positive or negative) given the context (task and condition difficulty). Furthermore, the valence of feedback was encoded by delta waves phase-modulating the power of beta oscillations. Finally, connectivity and causal analysis showed that beta oscillations relay feedback information signals to the mPFC. These results reveal that structured oscillatory activity in the anterior insula encodes performance feedback information, thus coordinating brain circuits related to reward-based learning.

Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery.

BACKGROUND: Detailed neuropathological information on the structural brain lesions underlying seizures is valuable for understanding drug-resistant focal epilepsy. METHODS: We report the diagnoses made on the basis of resected brain specimens from 9523 patients who underwent epilepsy surgery for drug-resistant seizures in 36 centers from 12 European countries over 25 years. Histopathological diagnoses were determined through examination of the specimens in local hospitals (41%) or at the German Neuropathology Reference Center for Epilepsy Surgery (59%). RESULTS: The onset of seizures occurred before 18 years of age in 75.9% of patients overall, and 72.5% of the patients underwent surgery as adults. The mean duration of epilepsy before surgical resection was 20.1 years among adults and 5.3 years among children. The temporal lobe was involved in 71.9% of operations. There were 36 histopathological diagnoses in seven major disease categories. The most common categories were hippocampal sclerosis, found in 36.4% of the patients (88.7% of cases were in adults), tumors (mainly ganglioglioma) in 23.6%, and malformations of cortical development in 19.8% (focal cortical dysplasia was the most common type, 52.7% of cases of which were in children). No histopathological diagnosis could be established for 7.7% of the patients. CONCLUSIONS: In patients with drug-resistant focal epilepsy requiring surgery, hippocampal sclerosis was the most common histopathological diagnosis among adults, and focal cortical dysplasia was the most common diagnosis among children. Tumors were the second most common lesion in both groups. (Funded by the European Union and others.).

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.

Epileptogenicity in tuberous sclerosis complex: A stereoelectroencephalographic study.

OBJECTIVE: In tuberous sclerosis complex (TSC)-associated drug-resistant epilepsy, the optimal invasive electroencephalographic (EEG) and operative approach remains unclear. We examined the role of stereo-EEG in TSC and used stereo-EEG data to investigate tuber and surrounding cortex epileptogenicity. METHODS: We analyzed 18 patients with TSC who underwent stereo-EEG (seven adults). One hundred ten seizures were analyzed with the epileptogenicity index (EI). In 13 patients with adequate tuber sampling, five anatomical regions of interest (ROIs) were defined: dominant tuber (tuber with highest median EI), perituber cortex, secondary tuber (tuber with second highest median EI), nearby cortex (normal-appearing cortex in the same lobe as dominant tuber), and distant cortex (in other lobes). At the seizure level, epileptogenicity of ROIs was examined by comparing the highest EI recorded within each anatomical region. At the patient level, epileptogenic zone (EZ) organization was separated into focal tuber (EZ confined to dominant tuber) and complex (all other patterns). RESULTS: The most epileptogenic ROI was the dominant tuber, with higher EI than perituber cortex, secondary tuber, nearby cortex, and distant cortex (P < .001). A focal tuber EZ organization was identified in seven patients. This group had 80% Engel IA postsurgical outcome and distinct dominant tuber characteristics: continuous interictal discharges (IEDs; 100%), fluid-attenuated inversion recovery (FLAIR) hypointense center (86%), center-to-rim EI gradient, and stimulation-induced seizures (71%). In contrast, six patients had a complex EZ organization, characterized by nearby cortex as the most epileptogenic region and 40% Engel IA outcome. At the intratuber level, the combination of FLAIR hypointense center, continuous IEDs, and stimulation-induced seizures offered 98% specificity for a focal tuber EZ organization. SIGNIFICANCE: Tubers with focal EZ organization have a striking similarity to type II focal cortical dysplasia. The presence of distinct EZ organizations has significant implications for EZ hypothesis generation, invasive EEG approach, and resection strategy.

High-Frequency Oscillations in the Normal Human Brain.

OBJECTIVE: High-frequency oscillations (HFOs) are a promising biomarker for the epileptogenic zone. It has not been possible, however, to differentiate physiological from pathological HFOs, and baseline rates of HFO occurrence vary substantially across brain regions. This project establishes region-specific normative values for physiological HFOs and high-frequency activity (HFA). METHODS: Intracerebral stereo-encephalographic recordings with channels displaying normal physiological activity from nonlesional tissue were selected from 2 tertiary epilepsy centers. Twenty-minute sections from N2/N3 sleep were selected for automatic detection of ripples (80-250Hz), fast ripples (>250Hz), and HFA defined as long-lasting activity > 80Hz. Normative values are provided for 17 brain regions. RESULTS: A total of 1,171 bipolar channels with normal physiological activity from 71 patients were analyzed. The highest rates of ripples were recorded in the occipital cortex, medial and basal temporal region, transverse temporal gyrus and planum temporale, pre- and postcentral gyri, and medial parietal lobe. The mean rate of fast ripples was very low (0.038/min). Only 5% of channels had a rate > 0.2/min HFA was observed in the medial occipital lobe, pre- and postcentral gyri, transverse temporal gyri and planum temporale, and lateral occipital lobe. INTERPRETATION: This multicenter atlas is the first to provide region-specific normative values for physiological HFO rates and HFA in common stereotactic space; rates above these can now be considered pathological. Physiological ripples are frequent in eloquent cortex. In contrast, physiological fast ripples are very rare, making fast ripples a good candidate for defining the epileptogenic zone. Ann Neurol 2018;84:374-385.

Critique of the 2017 epileptic seizure and epilepsy classifications.

This article critiques the International League Against Epilepsy (ILAE) 2015-2017 classifications of epilepsy, epileptic seizures, and status epilepticus. It points out the following shortcomings of the ILAE classifications: (1) they mix semiological terms with epileptogenic zone terminology; (2) simple and widely accepted terminology has been replaced by complex terminology containing less information; (3) seizure evolution cannot be described in any detail; (4) in the four-level epilepsy classification, level two (epilepsy category) overlaps almost 100% with diagnostic level one (seizure type); and (5) the design of different classifications with distinct frameworks for newborns, adults, and patients in status epilepticus is confusing. The authors stress the importance of validating the new ILAE classifications and feel that the decision of Epilepsia to accept only manuscripts that use the ILAE classifications is premature and regrettable.