Human thalamic low-frequency oscillations correlate with expected value and outcomes during reinforcement learning.

Reinforcement-based adaptive decision-making is believed to recruit fronto-striatal circuits. A critical node of the fronto-striatal circuit is the thalamus. However, direct evidence of its involvement in human reinforcement learning is lacking. We address this gap by analyzing intra-thalamic electrophysiological recordings from eight participants while they performed a reinforcement learning task. We found that in both the anterior thalamus (ATN) and dorsomedial thalamus (DMTN), low frequency oscillations (LFO, 4-12 Hz) correlated positively with expected value estimated from computational modeling during reward-based learning (after outcome delivery) or punishment-based learning (during the choice process). Furthermore, LFO recorded from ATN/DMTN were also negatively correlated with outcomes so that both components of reward prediction errors were signaled in the human thalamus. The observed differences in the prediction signals between rewarding and punishing conditions shed light on the neural mechanisms underlying action inhibition in punishment avoidance learning. Our results provide insight into the role of thalamus in reinforcement-based decision-making in humans.

Early identification of seizure freedom with medical treatment in patients with mesial temporal lobe epilepsy and hippocampal sclerosis.

BACKGROUND: Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is usually associated with a poor response to antiseizure medications. We focused on MTLE-HS patients who were seizure free on medication to: (1) determine the clinical factors associated with seizure freedom and (2) develop a machine-learning classifier to better earlier identify those patients. METHODS: We performed a retrospective, multicentric study comparing 64 medically treated seizure-free MTLE-HS patients with 200 surgically treated drug-resistant MTLE-HS patients. First, we collected medical history and seizure semiology data. Then, we developed a machine-learning classifier based on clinical data. RESULTS: Medically treated seizure-free MTLE-HS patients were seizure-free for at least 2 years, and for a median time of 7 years at last follow-up. Compared to drug-resistant MTLE-HS patients, they exhibited: an older age at epilepsy onset (22.5 vs 8.0 years, p < 0.001), a lesser rate of: febrile seizures (39.0% vs 57.5%, p = 0.035), focal aware seizures (previously referred to as aura)(56.7% vs 90.0%, p < 0.001), autonomic focal aware seizures in presence of focal aware seizure (17.6% vs 59.4%, p < 0.001), dystonic posturing of the limbs (9.8% vs 47.0%, p < 0.001), gestural (27.4% vs 94.0%, p < 0.001), oro-alimentary (32.3% vs 75.5%, p < 0.001) or verbal automatisms (12.9% vs 36.0%, p = 0.001). The classifier had a positive predictive value of 0.889, a sensitivity of 0.727, a specificity of 0.962, a negative predictive value of 0.893. CONCLUSIONS: Medically treated seizure-free MTLE-HS patients exhibit a distinct clinical profile. A classifier built with readily available clinical data can identify them accurately with excellent positive predictive value. This may help to individualize the management of MTLE-HS patients according to their expected pharmacosensitivity.

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.

Brain mapping of auditory hallucinations and illusions induced by direct intracortical electrical stimulation.

BACKGROUND: The exact architecture of the human auditory cortex remains a subject of debate, with discrepancies between functional and microstructural studies. In a hierarchical framework for sensory perception, simple sound perception is expected to take place in the primary auditory cortex, while the processing of complex, or more integrated perceptions is proposed to rely on associative and higher-order cortices. OBJECTIVES: We hypothesize that auditory symptoms induced by direct electrical stimulation (DES) offer a window into the architecture of the brain networks involved in auditory hallucinations and illusions. The intracranial recordings of these evoked perceptions of varying levels of integration provide the evidence to discuss the theoretical model. METHODS: We analyzed SEEG recordings from 50 epileptic patients presenting auditory symptoms induced by DES. First, using the Juelich cytoarchitectonic parcellation, we quantified which regions induced auditory symptoms when stimulated (ROI approach). Then, for each evoked auditory symptom type (illusion or hallucination), we mapped the cortical networks showing concurrent high-frequency activity modulation (HFA approach). RESULTS: Although on average, illusions were found more laterally and hallucinations more posteromedially in the temporal lobe, both perceptions were elicited in all levels of the sensory hierarchy, with mixed responses found in the overlap. The spatial range was larger for illusions, both in the ROI and HFA approaches. The limbic system was specific to the hallucinations network, and the inferior parietal lobule was specific to the illusions network. DISCUSSION: Our results confirm a network-based organization underlying conscious sound perception, for both simple and complex components. While symptom localization is interesting from an epilepsy semiology perspective, the hallucination-specific modulation of the limbic system is particularly relevant to tinnitus and schizophrenia.

Intracerebral mechanisms explaining the impact of incidental feedback on mood state and risky choice.

Identifying factors whose fluctuations are associated with choice inconsistency is a major issue for rational decision theory. Here, we investigated the neuro-computational mechanisms through which mood fluctuations may bias human choice behavior. Intracerebral EEG data were collected in a large group of subjects (n=30) while they were performing interleaved quiz and choice tasks that were designed to examine how a series of unrelated feedbacks affect decisions between safe and risky options. Neural baseline activity preceding choice onset was confronted first to mood level, estimated by a computational model integrating the feedbacks received in the quiz task, and then to the weighting of option attributes, in a computational model predicting risk attitude in the choice task. Results showed that (1) elevated broadband gamma activity (BGA) in the ventromedial prefrontal cortex (vmPFC) and dorsal anterior insula (daIns) was respectively signaling periods of high and low mood, (2) increased vmPFC and daIns BGA respectively promoted and tempered risk taking by overweighting gain vs. loss prospects. Thus, incidental feedbacks induce brain states that correspond to different moods and bias the evaluation of risky options. More generally, these findings might explain why people experiencing positive (or negative) outcome in some part of their life tend to expect success (or failure) in any other.

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.

Development and Validation of the 5-SENSE Score to Predict Focality of the Seizure-Onset Zone as Assessed by Stereoelectroencephalography.

Importance: Stereoelectroencephalography (SEEG) has become the criterion standard in case of inconclusive noninvasive presurgical epilepsy workup. However, up to 40% of patients are subsequently not offered surgery because the seizure-onset zone is less focal than expected or cannot be identified. Objective: To predict focality of the seizure-onset zone in SEEG, the 5-point 5-SENSE score was developed and validated. Design, Setting, and Participants: This was a monocentric cohort study for score development followed by multicenter validation with patient selection intervals between February 2002 to October 2018 and May 2002 to December 2019. The minimum follow-up period was 1 year. Patients with drug-resistant epilepsy undergoing SEEG at the Montreal Neurological Institute were analyzed to identify a focal seizure-onset zone. Selection criteria were 2 or more seizures in electroencephalography and availability of complete neuropsychological and neuroimaging data sets. For validation, patients from 9 epilepsy centers meeting these criteria were included. Analysis took place between May and July 2021. Main Outcomes and Measures: Based on SEEG, patients were grouped as focal and nonfocal seizure-onset zone. Demographic, clinical, electroencephalography, neuroimaging, and neuropsychology data were analyzed, and a multiple logistic regression model for developing a score to predict SEEG focality was created and validated in an independent sample. Results: A total of 128 patients (57 women [44.5%]; median [range] age, 31 [13-58] years) were analyzed for score development and 207 patients (97 women [46.9%]; median [range] age, 32 [16-70] years) were analyzed for validation. The score comprised the following 5 predictive variables: focal lesion on structural magnetic resonance imaging, absence of bilateral independent spikes in scalp electroencephalography, localizing neuropsychological deficit, strongly localizing semiology, and regional ictal scalp electroencephalography onset. The 5-SENSE score had an optimal mean (SD) probability cutoff for identifying a focal seizure-onset zone of 37.6 (3.5). Area under the curve, specificity, and sensitivity were 0.83, 76.3% (95% CI, 66.7-85.8), and 83.3% (95% CI, 72.30-94.1), respectively. Validation showed 76.0% (95% CI, 67.5-84.0) specificity and 52.3% (95% CI, 43.0-61.5) sensitivity. Conclusions and Relevance: High specificity in score development and validation confirms that the 5-SENSE score predicts patients where SEEG is unlikely to identify a focal seizure-onset zone. It is a simple and useful tool for assisting clinicians to reduce unnecessary invasive diagnostic burden on patients and overutilization of limited health care resources.

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.

The Insula: A Stimulating Island of the Brain.

Direct cortical stimulation (DCS) in epilepsy surgery patients has a long history of functional brain mapping and seizure triggering. Here, we review its findings when applied to the insula in order to map the insular functions, evaluate its local and distant connections, and trigger seizures. Clinical responses to insular DCS are frequent and diverse, showing a partial segregation with spatial overlap, including a posterior somatosensory, auditory, and vestibular part, a central olfactory-gustatory region, and an anterior visceral and cognitive-emotional portion. The study of cortico-cortical evoked potentials (CCEPs) has shown that the anterior (resp. posterior) insula has a higher connectivity rate with itself than with the posterior (resp. anterior) insula, and that both the anterior and posterior insula are closely connected, notably between the homologous insular subdivisions. All insular gyri show extensive and complex ipsilateral and contralateral extra-insular connections, more anteriorly for the anterior insula and more posteriorly for the posterior insula. As a rule, CCEPs propagate first and with a higher probability around the insular DCS site, then to the homologous region, and later to more distal regions with fast cortico-cortical axonal conduction delays. Seizures elicited by insular DCS have rarely been specifically studied, but their rate does not seem to differ from those of other DCS studies. They are mainly provoked from the insular seizure onset zone but can also be triggered by stimulating intra- and extra-insular early propagation zones. Overall, in line with the neuroimaging studies, insular DCS studies converge on the view that the insula is a multimodal functional hub with a fast propagation of information, whose organization helps understand where insular seizures start and how they propagate.

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.

Anatomical dissociation of intracerebral signals for reward and punishment prediction errors in humans.

Whether maximizing rewards and minimizing punishments rely on distinct brain systems remains debated, given inconsistent results coming from human neuroimaging and animal electrophysiology studies. Bridging the gap across techniques, we recorded intracerebral activity from twenty participants while they performed an instrumental learning task. We found that both reward and punishment prediction errors (PE), estimated from computational modeling of choice behavior, correlate positively with broadband gamma activity (BGA) in several brain regions. In all cases, BGA scaled positively with the outcome (reward or punishment versus nothing) and negatively with the expectation (predictability of reward or punishment). However, reward PE were better signaled in some regions (such as the ventromedial prefrontal and lateral orbitofrontal cortex), and punishment PE in other regions (such as the anterior insula and dorsolateral prefrontal cortex). These regions might therefore belong to brain systems that differentially contribute to the repetition of rewarded choices and the avoidance of punished choices.

Mapping of Language-and-Memory Networks in Patients With Temporal Lobe Epilepsy by Using the GE2REC Protocol.

Preoperative mapping of language and declarative memory functions in temporal lobe epilepsy (TLE) patients is essential since they frequently encounter deterioration of these functions and show variable degrees of cerebral reorganization. Due to growing evidence on language and declarative memory interdependence at a neural and neuropsychological level, we propose the GE2REC protocol for interactive language-and-memory network (LMN) mapping. GE2REC consists of three inter-related tasks, sentence generation with implicit encoding (GE) and two recollection (2REC) memory tasks: recognition and recall. This protocol has previously been validated in healthy participants, and in this study, we showed that it also maps the LMN in the left TLE (N = 18). Compared to healthy controls (N = 19), left TLE (LTLE) showed widespread inter- and intra-hemispheric reorganization of the LMN through reduced activity of regions engaged in the integration and the coordination of this meta-network. We also illustrated how this protocol could be implemented in clinical practice individually by presenting two case studies of LTLE patients who underwent efficient surgery and became seizure-free but showed different cognitive outcomes. This protocol can be advantageous for clinical practice because it (a) is short and easy to perform; (b) allows brain mapping of essential cognitive functions, even at an individual level; (c) engages language-and-memory interaction allowing to evaluate the integrative processes within the LMN; (d) provides a more comprehensive assessment by including both verbal and visual modalities, as well as various language and memory processes. Based on the available postsurgical data, we presented preliminary results obtained with this protocol in LTLE patients that could potentially inform the clinical practice. This implies the necessity to further validate the potential of GE2REC for neurosurgical planning, along with two directions, guiding resection and describing LMN neuroplasticity at an individual level.

Interactive mapping of language and memory with the GE2REC protocol.

Previous studies have highlighted the importance of considering cognitive functions from a dynamic and interactive perspective and multiple evidence was brought for a language and memory interaction. In this study performed with healthy participants, we present a new protocol entitled GE2REC that interactively accesses the neural representation of language-and-memory network. This protocol consists of three runs related to each other, providing a link between tasks, in order to assure an interactive measure of linguistic and episodic memory processes. GE2REC consists of a sentence generation (GE) in the auditory modality and two recollecting (2REC) memory tasks, one recognition performed in the visual modality, and another one recall performed in the auditory modality. Its efficiency was evaluated in 20 healthy volunteers using a 3T MR imager. Our results corroborate the ability of GE2REC to robustly activate fronto-temporo-parietal language network as well as temporal mesial, prefrontal and parietal cortices in encoding during sentence generation and recognition. GE2REC is useful because it: (a) requires simultaneous and interactive language-and-memory processes and jointly maps their neural basis; (b) explores encoding and retrieval, managing to elicit activation of mesial temporal structures; (c) is easy to perform, hence being suitable for more restrictive settings, and (d) has an ecological dimension of tasks and stimuli. GE2REC may be useful for studying neuroplasticity of cognitive functions, especially in patients with temporal lobe epilepsy who show reorganization of both language and memory networks. Overall, GE2REC can provide valuable information in terms of the practical foundation of exploration language and memory interconnection.

Indications, Techniques, and Outcomes of Robot-Assisted Insular Stereo-Electro-Encephalography: A Review.

Stereo-electro-encephalography (SEEG) is an invasive, surgical, and electrophysiological method for three-dimensional registration and mapping of seizure activity in drug-resistant epilepsy. It allows the accurate analysis of spatio-temporal seizure activity by multiple intraparenchymal depth electrodes. The technique requires rigorous non-invasive pre-SEEG evaluation (clinical, video-EEG, and neuroimaging investigations) in order to plan the insertion of the SEEG electrodes with minimal risk and maximal recording accuracy. The resulting recordings are used to precisely define the surgical limits of resection of the epileptogenic zone in relation to adjacent eloquent structures. Since the initial description of the technique by Talairach and Bancaud in the 1950's, several techniques of electrode insertion have been used with accuracy and relatively few complications. In the last decade, robot-assisted surgery has emerged as a safe, accurate, and time-saving electrode insertion technique due to its unparalleled potential for orthogonal and oblique insertion trajectories, guided by rigorous computer-assisted planning. SEEG exploration of the insular cortex remains difficult due to its anatomical location, hidden by the temporal and frontoparietal opercula. Furthermore, the close vicinity of Sylvian vessels makes surgical electrode insertion challenging. Some epilepsy surgery teams remain cautious about insular exploration due to the potential of neurovascular injury. However, several authors have published encouraging results regarding the technique's accuracy and safety in both children and adults. We will review the indications, techniques, and outcomes of insular SEEG exploration with emphasis on robot-assisted implantation.

Intracranial EEG in the 21st Century.

Intracranial electroencephalography (iEEG) has been the mainstay of identifying the seizure onset zone (SOZ), a key diagnostic procedure in addition to neuroimaging when considering epilepsy surgery. In many patients, iEEG has been the basis for resective epilepsy surgery, to date still the most successful treatment for drug-resistant epilepsy. Intracranial EEG determines the location and resectability of the SOZ. Advances in recording and implantation of iEEG provide multiple options in the 21st century. This not only includes the choice between subdural electrodes (SDE) and stereoelectroencephalography (SEEG) but also includes the implantation and recordings from microelectrodes. Before iEEG implantation, especially in magnetic resonance imaging -negative epilepsy, a clear hypothesis for seizure generation and propagation should be based on noninvasive methods. Intracranial EEG implantation should be planned by a multidisciplinary team considering epileptic networks. Recordings from SDE and SEEG have both their advantages and disadvantages. Stereo-EEG seems to have a lower rate of complications that are clinically significant, but has limitations in spatial sampling of the cortical surface. Stereo-EEG can sample deeper areas of the brain including deep sulci and hard to reach areas such as the insula. To determine the epileptogenic zone, interictal and ictal information should be taken into consideration. Interictal spiking, low frequency slowing, as well as high frequency oscillations may inform about the epileptogenic zone. Ictally, high frequency onsets in the beta/gamma range are usually associated with the SOZ, but specialized recordings with combined macro and microelectrodes may in the future educate us about onset in higher frequency bands. Stimulation of intracranial electrodes triggering habitual seizures can assist in identifying the SOZ. Advanced computational methods such as determining the epileptogenicity index and similar measures may enhance standard clinical interpretation. Improved techniques to record and interpret iEEG may in the future lead to a greater proportion of patients being seizure free after epilepsy surgery.

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.

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.

Biallelic PDE2A variants: a new cause of syndromic paroxysmal dyskinesia.

Cause of complex dyskinesia remains elusive in some patients. A homozygous missense variant leading to drastic decrease of PDE2A enzymatic activity was reported in one patient with childhood-onset choreodystonia preceded by paroxysmal dyskinesia and associated with cognitive impairment and interictal EEG abnormalities. Here, we report three new cases with biallelic PDE2A variants identified by trio whole-exome sequencing. Mitochondria network was analyzed after Mitotracker™ Red staining in control and mutated primary fibroblasts. Analysis of retrospective video of patients' movement disorder and refinement of phenotype was carried out. We identified a homozygous gain of stop codon variant c.1180C>T; p.(Gln394*) in PDE2A in siblings and compound heterozygous variants in young adult: a missense c.446C>T; p.(Pro149Leu) and splice-site variant c.1922+5G>A predicted and shown to produce an out of frame transcript lacking exon 22. All three patients had cognitive impairment or developmental delay. The phenotype of the two oldest patients, aged 9 and 26, was characterized by childhood-onset refractory paroxysmal dyskinesia initially misdiagnosed as epilepsy due to interictal EEG abnormalities. The youngest patient showed a proven epilepsy at the age of 4 months and no paroxysmal dyskinesia at 15 months. Interestingly, analysis of the fibroblasts with the biallelic variants in PDE2A variants revealed mitochondria network morphology changes. Together with previously reported case, our three patients confirm that biallelic PDE2A variants are a cause of childhood-onset refractory paroxysmal dyskinesia with cognitive impairment, sometimes associated with choreodystonia and interictal baseline EEG abnormalities or epilepsy.

Relationship between direct cortical stimulation and induced high-frequency activity for language mapping during SEEG recording.

OBJECTIVE: The authors assessed the clinical relevance of preoperative task-induced high-frequency activity (HFA) for language mapping in patients with refractory epilepsy during stereoelectroencephalography recording. Although HFA evaluation was described as a putative biomarker of cognition, its clinical relevance for mapping language networks was assessed predominantly by studies using electrocorticography (ECOG). METHODS: Forty-two patients with epilepsy who underwent intracranial electrode implantation during both task-induced HFA and direct cortical stimulation (DCS) language mapping were evaluated. The spatial and functional relevance of each method in terms of specificity and sensitivity were evaluated. RESULTS: The results showed that the two methods were able to map classic language regions, and a large and bilateral language network was obtained with induced HFA. At a regional level, differences were observed between methods for parietal and temporal lobes: HFA recruited a larger number of cortical parietal sites, while DCS involved more cortical temporal sites. Importantly, the results showed that HFA predicts language interference induced by DCS with high specificity (92.4%; negative predictive value 95.9%) and very low sensitivity (8.9%; positive predictive value 4.8%). CONCLUSIONS: DCS language mapping appears to be more appropriate for an extensive temporal mapping than induced HFA mapping. Furthermore, induced HFA should be used as a complement to DCS to preselect the number of stimulated sites during DCS, by omitting those reported as HFA-. This may be a considerable advantage because it allows a reduction in the duration of the stimulation procedure. Several parameters to be used for each method are discussed and the results are interpreted in relation to previous results reported in ECOG studies.