Neurophysiology, Neuropsychology, and Epilepsy, in 2022: Hills We Have Climbed and Hills Ahead. Neurophysiology in epilepsy.

Since the discovery of the human electroencephalogram (EEG), neurophysiology techniques have become indispensable tools in our armamentarium to localize epileptic seizures. New signal analysis techniques and the prospects of artificial intelligence and big data will offer unprecedented opportunities to further advance the field in the near future, ultimately resulting in improved quality of life for many patients with drug-resistant epilepsy. This article summarizes selected presentations from Day 1 of the two-day symposium "Neurophysiology, Neuropsychology, Epilepsy, 2022: Hills We Have Climbed and the Hills Ahead". Day 1 was dedicated to highlighting and honoring the work of Dr. Jean Gotman, a pioneer in EEG, intracranial EEG, simultaneous EEG/ functional magnetic resonance imaging, and signal analysis of epilepsy. The program focused on two main research directions of Dr. Gotman, and was dedicated to "High-frequency oscillations, a new biomarker of epilepsy" and "Probing the epileptic focus from inside and outside". All talks were presented by colleagues and former trainees of Dr. Gotman. The extended summaries provide an overview of historical and current work in the neurophysiology of epilepsy with emphasis on novel EEG biomarkers of epilepsy and source imaging and concluded with an outlook on the future of epilepsy research, and what is needed to bring the field to the next level.

A machine learning approach to explore cognitive signatures in patients with temporo-mesial epilepsy.

We aimed to identify cognitive signatures (phenotypes) of patients suffering from mesial temporal lobe epilepsy (mTLE) with respect to their epilepsy lateralization (left or right), through the use of SVM (Support Vector Machine) and XGBoost (eXtreme Gradient Boosting) machine learning (ML) algorithms. Specifically, we explored the ability of the two algorithms to identify the most significant scores (features, in ML terms) that segregate the left from the right mTLE patients. We had two versions of our dataset which consisted of neuropsychological test scores: a "reduced and working" version (n = 46 patients) without any missing data, and another one "original" (n = 57) with missing data but useful for testing the robustness of results obtained with the working dataset. The emphasis was placed on a precautionary machine learning (ML) approach for classification, with reproducible and generalizable results. The effects of several clinical medical variables were also studied. We obtained excellent predictive classification performances (>75%) of left and right mTLE with both versions of the dataset. The most segregating features were four language and memory tests, with a remarkable stability close to 100%. Thus, these cognitive tests appear to be highly relevant for neuropsychological assessment of patients. Moreover, clinical variables such as structural asymmetry between hippocampal gyri, the age of patients and the number of anti-epileptic drugs, influenced the cognitive phenotype. This exploratory study represents an in-depth analysis of cognitive scores and allows observing interesting interactions between language and memory performance. We discuss implications of these findings in terms of clinical and theoretical applications and perspectives in the field of neuropsychology.

A real-time marker of object-based attention in the human brain. A possible component of a "gate-keeping mechanism" performing late attentional selection in the Ventro-Lateral Prefrontal Cortex.

The decision to process an incoming stimulus attentively - and to trigger a follow-up cascade of high-level processes - is strategic for the human brain as it becomes transiently unavailable to subsequent stimulus processing. In this study, we set to identify brain networks that carry out such evaluations. We therefore assessed the time-course of neural responses with intracerebral EEG in human patients during an attentional reading task, contrasting to-be-attended vs. to-be-ignored items. We measured High-Frequency Activity [50-150 â€‹Hz] as a proxy of population-level spiking activity and we identified a crucial component of a Gate-Keeping Mechanism bilateral in the mid-Ventro-Lateral Prefrontal Cortex (VLPFC), at the interplay of the Ventral and Dorsal Attention Networks, that selectively reacts before domain specialized cortical regions that engage in full stimulus analysis according to task demands.

Synchrotron X-ray microtransections: a non invasive approach for epileptic seizures arising from eloquent cortical areas.

Synchrotron-generated X-ray (SRX) microbeams deposit high radiation doses to submillimetric targets whilst minimizing irradiation of neighboring healthy tissue. We developed a new radiosurgical method which demonstrably transects cortical brain tissue without affecting adjacent regions. We made such image-guided SRX microtransections in the left somatosensory cortex in a rat model of generalized epilepsy using high radiation doses (820 Gy) in thin (200 µm) parallel slices of tissue. This procedure, targeting the brain volume from which seizures arose, altered the abnormal neuronal activities for at least 9 weeks, as evidenced by a decrease of seizure power and coherence between tissue slices in comparison to the contralateral cortex. The brain tissue located between transections stayed histologically normal, while the irradiated micro-slices remained devoid of myelin and neurons two months after irradiation. This pre-clinical proof of concept highlights the translational potential of non-invasive SRX transections for treating epilepsies that are not eligible for resective surgery.

The concept of temporal 'plus' epilepsy.

The concept of temporal 'plus' epilepsy (T+E) is not new, and a number of observations made by means of intracerebral electrodes have illustrated the complexity of neuronal circuits that involve the temporal lobe. The term T+E was used to unify and better individualize these specific forms of multilobar epilepsies, which are characterized by electroclinical features primarily suggestive of temporal lobe epilepsy, MRI findings that are either unremarkable or show signs of hippocampal sclerosis, and intracranial recordings which demonstrate that seizures arise from a complex epileptogenic network including a combination of brain regions located within the temporal lobe and over closed neighbouring structures such as the orbitofrontal cortex, the insulo-opercular region, and the temporo-parieto-occipital junction. We will review here how the term of T+E has emerged, what it means, and which practical consideration it raises.

[Adult patients treated for focal epilepsy with antiepileptic drugs (AEDs) in combination in France: description according to the 2009 ILAE definition of AED resistance (ESPERA study)]. / Patients adultes traités par une association d'antiépileptiques pour une épilepsie focale en France: description et mode de prise en charge selon les nouveaux critères de définition de la pharmacorésistance (étude ESPERA).

AIMS: To describe the adult population treated with antiepileptic drugs (AEDs) in combination for focal epilepsy according to the definition of AED resistance proposed by the International League Against Epilepsy (ILAE) in 2009 and to evaluate its implementation in current practice. METHODS: ESPERA was a multicenter, observational, cross-sectional study with a clinical data collection covering the past 12 months conducted by neurologists. Classifications according to AED responsiveness established by investigators for each enrolled patient were revised by two experts. RESULTS: Seventy-one neurologists enrolled 405 patients. Their mean age was 42.7 years (sex-ratioM/F 0.98). According to the investigators, 60% of epilepsies were drug-resistant, 37% drug-responsive and 3% had an undefined drug-responsiveness. After revision of experts, 71% of epilepsies were classified as drug resistant, 22% as responsive and 7% as undefined. Among the participating neurologists, 76% have made at least one error in classifying their patients according to the 2009 ILAE definition of AED resistance. Because of epilepsy, 24% of patients (age≤65) were inactive and 42% could not drive (respectively 29 and 49% of patients with AED resistant epilepsy). Half of patients had at least one other chronic condition. Number of prescribed drugs in combination and health care resource utilisation were significantly higher in patients with drug-resistant epilepsies than in patients with drug responsive epilepsies. CONCLUSION: ESPERA study shows that the use of new definition of drug-resistance in everyday practice seems difficult without any additional training and that the social and professional disability is frequent in adults with focal epilepsies treated with polytherapy.

Rehabilitation of verbal memory by means of preserved nonverbal memory abilities after epilepsy surgery.

We present a patient with epilepsy who underwent left anterior temporal cortex resection, sparing the hippocampus, to stop drug-refractory seizures. Given that one year after surgery the patient showed verbal memory difficulties, we proposed a short (twelve weeks) and intensive (two times a week) training based on visual imagery strategies as the nonverbal memory abilities were preserved. Neuropsychological and fMRI assessments were performed before and after rehabilitation to evaluate the cognitive progress and cerebral modifications induced by this rehabilitation program. Our results showed that the rehabilitation program improved both scores for verbal memory and the everyday quality of life. Changes in cerebral activity highlighted by fMRI suggest that the program might have facilitated the development of compensatory strategies, as reflected by the shift of activation from the anterior to the posterior cerebral network during a verbal memory task. One year after the rehabilitation program, the patient reported using mental imagery in everyday life for routine and professional activities. Although supplementary evidence is necessary to increase the robustness of these findings, this case report suggests that an efficient rehabilitation program is feasible and (a) should be based on the individual cognitive profile and on the preserved cognitive abilities, (b) can be short but intensive, (c) can be applied even months after the lesion occurrence, and (d) can induce a positive effect which may be sustainable over time.

Turning visual shapes into sounds: early stages of reading acquisition revealed in the ventral occipitotemporal cortex.

The exact role of the left ventral occipitotemporal cortex (VOTC) during the initial stages of reading acquisition is a hotly debated issue, especially regarding the comparative effect of learning on early stimulus-dependent vs. later task-dependent processes. We show that this controversy can be solved with high-temporal resolution intracerebral EEG recordings of the VOTC. We measured High-Frequency Activity (50-150 Hz) as a proxy of population-level spiking activity while participants learned Japanese Katakana symbols, and found that learning primarily affects top-down/task-dependent neural processing, after a few minutes only. In contrast, adaptation of early bottom-up/stimulus-dependent processing takes several days to adapt and provides the basis for fluent reading. Such evidence that two consecutive stages of neural processing, stimulus- and task-dependent are differentially affected by learning, can reconcile seemingly opposite hypotheses on the role of the VOTC during reading acquisition.

High-frequency oscillations (HFOs) in clinical epilepsy.

Epilepsy is one of the most frequent neurological diseases. In focal medically refractory epilepsies, successful surgical treatment largely depends on the identification of epileptogenic zone. High-frequency oscillations (HFOs) between 80 and 500Hz, which can be recorded with EEG, may be novel markers of the epileptogenic zone. This review discusses the clinical importance of HFOs as markers of epileptogenicity and their application in different types of epilepsies. HFOs are clearly linked to the seizure onset zone, and the surgical removal of regions generating them correlates with a seizure free post-surgical outcome. Moreover, HFOs reflect the seizure-generating capability of the underlying tissue, since they are more frequent after the reduction of antiepileptic drugs. They can be successfully used in pediatric epilepsies such as epileptic spasms and help to understand the generation of this specific type of seizures. While mostly recorded on intracranial EEGs, new studies suggest that identification of HFOs on scalp EEG or magnetoencephalography (MEG) is possible as well. Thus not only patients with refractory epilepsies and invasive recordings but all patients might profit from the analysis of HFOs. Despite these promising results, the analysis of HFOs is not a routine clinical procedure; most results are derived from relatively small cohorts of patients and many aspects are not yet fully understood. Thus the review concludes that even if HFOs are promising biomarkers of epileptic tissue, there are still uncertainties about mechanisms of generation, methods of analysis, and clinical applicability. Large multicenter prospective studies are needed prior to widespread clinical application.

Directed differential connectivity graph of interictal epileptiform discharges.

In this paper, we study temporal couplings between interictal events of spatially remote regions in order to localize the leading epileptic regions from intracerebral EEG (iEEG). We aim to assess whether quantitative epileptic graph analysis during interictal period may be helpful to predict the seizure onset zone of ictal iEEG. Using wavelet transform, cross-correlation coefficient, and multiple hypothesis test, we propose a differential connectivity graph (DCG) to represent the connections that change significantly between epileptic and nonepileptic states as defined by the interictal events. Postprocessings based on mutual information and multiobjective optimization are proposed to localize the leading epileptic regions through DCG. The suggested approach is applied on iEEG recordings of five patients suffering from focal epilepsy. Quantitative comparisons of the proposed epileptic regions within ictal onset zones detected by visual inspection and using electrically stimulated seizures, reveal good performance of the present method.

Comparison of five directed graph measures for identification of leading interictal epileptic regions.

Directed graphs (digraphs) derived from interictal periods of intracerebral EEG (iEEG) recordings can be used to estimate the leading interictal epileptic regions for presurgery evaluations. For this purpose, quantification of the emittance contribution of each node to the rest of digraph is important. However, the usual digraph measures are not very well suited for this quantification. Here, we compare the efficiency of recently introduced local information (LI) measure and a new measure called total global efficiency with classical measures like global efficiency, local efficiency and node degree. For evaluation, the estimated leading interictal epileptic regions based on five measures are compared with seizure onset zones obtained by visual inspection of epileptologists for five patients. The comparison revealed the superior performance of the LI measure. We showed efficiency of different digraph measures for the purpose of source and sink node identification.

Anxiety and depression in psychogenic movement disorder and non-epileptic seizures: a prospective comparative study.

OBJECTIVE: This study compared anxiety and depression in patients presenting with psychogenic non-epileptic seizures (PNES) with those suffering from psychogenic movement disorders (PMD) to assess the link between these psychiatric pathologies and neurological symptoms. METHODS: This clinically descriptive, prospective study involved consecutive patients who fulfilled the clinical and video-EEG criteria for PNES and PMD, and who were recruited over an 18-month period. Semi-structured (according to DSM-IV criteria) psychiatric interviews and self-evaluation using the Beck Depression Inventory and Spielberger State-Trait Anxiety Inventory were carried out. Clinical follow-up was conducted 8-12 months after the first evaluation. RESULTS: A total of 17 patients were recruited: nine presented with PNES; and eight had PMD. Both patient groups had similar demographic and clinical data as well as depression and personality disorders. Although not statistically significant, there was a trend towards an increased prevalence of a familial medical history of epilepsy and a higher incidence of anxiety disorders among patients with PNES. CONCLUSION: The data from this prospective study underscore the clinical and psychiatric similarity between PNES and PMD patients. Further studies involving a larger number of subjects should confirm, from a statistical point of view, the differences suggested in the present investigation and, in particular, the greater incidence of anxiety disorders in PNES patients and the presence of an epileptic parent as a risk factor for PNES.

SPM analysis of ictal-interictal SPECT in mesial temporal lobe epilepsy: relationships between ictal semiology and perfusion changes.

A combination of temporo-limbic hyperperfusion and extratemporal hypoperfusion was observed during complex partial seizures (CPS) in temporal lobe epilepsy (TLE). To investigate the clinical correlate of perfusion changes in TLE, we analyzed focal seizures of increasing severity using voxel-based analysis of ictal SPECT. We selected 26 pre-operative pairs of ictal-interictal SPECTs from adult mesial TLE patients, seizure-free after surgery. Ictal SPECTs were classified in three groups: motionless seizures (group ML, n=8), seizures with motor automatisms (MA) without dystonic posturing (DP) (group MA, n=8), and seizures with DP with or without MA (DP, n=10). Patients of group ML had simple partial seizures (SPS), while others had CPS. Groups of ictal-interictal SPECT were compared to a control group using statistical parametric mapping (SPM). In ML group, SPM analysis failed to show significant changes. Hyperperfusion involved the anteromesial temporal region in MA group, and also the insula, posterior putamen and thalamus in DP group. Hypoperfusion was restricted to the posterior cingulate and prefrontal regions in MA group, and involved more widespread associative anterior and posterior regions in DP group. Temporal lobe seizures with DP show the most complex pattern of combined hyper-hypoperfusion, possibly related both to a larger spread and the recruitment of more powerful inhibitory processes.

[Basal ganglia deep-brain stimulation for treatment of drug-resistant epilepsy: review and current data]. / La stimulation cérébrale profonde des ganglions de la base comme traitement des épilepsies pharmacorésistantes: revue et données actuelles.

The surgical treatment of intractable epilepsies involving eloquent areas of the cortex is still challenging. Deep-brain stimulation could be an alternative to resective surgery because it can modulate the remote control systems of epilepsy, such as the thalamus and basal ganglia. The surgical experience acquired in the field of movement disorder surgery and the low morbidity of this technic could allow one to apply DBS to intractable epilepsies, such as generalized, motor and bitemporal epilepsies. Here we discuss the main experimental and clinical data reported so far in the literature and taken from our own experience.

[The epileptogenic zone]. / La zone épileptogène.

The definition of the epileptogenic zone is a concept proposed by Jean Bancaud and Jean Talairach based on the anatomical, electrical and clinical correlations established from stereoelectroencephalographic recordings. They believed the epileptogenic zone to be the "region of the beginning and the primary organization" of ictal discharges. The opinion of North American authors is different: the epileptogenic zone is the "what to remove area" to produce freedom from seizures. This surgical definition assumes postsurgical validation. The aim of this paper is to show how to define the epileptogenic zone from all the stereoelectroencephalographic recording data.

[Medicoeconomic assessment of epilepsy surgery in adults with medically intractable partial epilepsy. Three-year outcomes from a multicenter French cohort]. / Evaluation médicoéconomique de la chirurgie des épilepsies partielles pharmacorésistantes de l'adulte. Résultats à trois ans d'une étude prospective multicentrique française.

PURPOSE: To compare resective surgery and medical therapy in a cost-effectiveness analysis in a multicenter cohort of adult patients with partial intractable epilepsy. POPULATION AND METHODS: Adult patients with partial, medically intractable, potentially operable epilepsy were eligible and followed every year over five years. Effectiveness was defined as one year without seizure. The long-term costs and effectiveness were extrapolated over the patients' lifetime with a Markov model. Productivity (indirect costs) and quality of life (QOLIE-31, SEALS) were also assessed. Changes before and after surgery were compared between the two groups. RESULTS: Two hundred and eighty-nine patients were included (119 with surgery, 161 medically treated, six not eligible, three lost to follow-up). One year after surgery, 81% of the patients were seizure-free; at two and three years, this rate was 78%. In the medical group, these rates were 10, 18, and 15%, respectively. The cost of the explorations was euro 8464; including surgery, it was euro 19,700. In the medical group, the average annual direct costs were between 3500 and euro 6000. At two years after surgery, the annual direct cost decreased to euro 2768, at three years, it was euro 1233, predominately antiepileptic drug costs. Surgery became cost-effective between seven and eight years. In the surgical group, all the quality-of-life scores improved at one year after surgery and were stable during the second and third years. CONCLUSION: Surgical therapy was cost-effective at the middle term even though indirect costs were not considered.

[Epileptic seizure and migraine visual aura: revisiting migralepsy]. / Aura visuelle migraineuse et crise épileptique: la migralepsie revisitée.

INTRODUCTION: The term of "migralepsy" has been proposed to define migraine-triggered epileptic seizures. Although already reported in the literature for more than fifty years, a number of observations remain debatable because of possible confusion between migraine and epileptic seizure clinical manifestations, including hemifield visual hallucinations, digestive signs and severe headache. OBSERVATION: We report on the case of a young patient suffering from both diseases, in whom a visual aura preceded either migraine attacks or epileptic generalized tonic-clonic seizure. Subtle modification in the primitive visual hallucination, which suddenly contained colored figures and was accompanied by fear before a prolonged loss of contact, suggested a continuum between migraine aura and epileptic seizure in this patient. Brain MRI was normal and EEG showed some sharp waves in the right posterior area. CONCLUSION: The presence of a neurophysiological continuum between migrainous aura and epileptic seizure is supported by this observation of "migralepsy". Recent findings from genetic and epidemiological studies further support this link.

[Epilepsy surgery in children: from a multidisciplinary network to the creation of an expertise and care centre]. / Chirurgie des épilepsies de l'enfant: du fonctionnement en réseau à la création d'un centre d'expertise et de soins.

We report on the experience of a network created in 1994 to evaluate children with drug-resistant epilepsies who are candidates for surgical treatment. The network includes epilepsy units from several university hospitals in France that decided to share not only their clinical expertise to better respond to the need for a multidisciplinary approach of epilepsy surgery in children, but also all the technical and human resources available in the various teams. This mode of operation has certainly provided concrete proof of its efficacy since it undoubtedly facilitated, and even accelerated, access to optimal presurgical evaluation and epilepsy surgery for hundreds of children. However, after 10 years of this very enriching practice it became evident that our approach was certainly necessary but not sufficient. It is estimated that every year in France nearly 500 children are candidates for surgical treatment, and following a presurgical evaluation, 50% of them could be operated on. Today, only 150-200 children have access to a presurgical evaluation every year. This is a highly paradoxical situation since, even if the human suffering component that such a situation generates is set aside, the direct and indirect life-time costs for every 100 nonoperated patients is estimated at 40 million euros. As a result of our cumulated experience, in 2004 we proposed a different operating model with the creation of an expertise center that will combine not only medical care services provided by a fully equipped multidisciplinary team, but also a pole of applied clinical and fundamental research, a medicosocial center managed by a lay association and an industrial development pole. The project has been recently validated by the Ministry of Health and is supported by a number of national and regional institutions. The Institute for Children and Adolescents with Epilepsy--IDEE--is designed to accelerate diagnostic procedures and, when indicated, access to optimal presurgical evaluation, while also serving as a model for a medical and economic evaluation of epilepsy care in children.

[Temporal disconnection as an alternative treatment for intractable temporal lobe epilepsy: techniques, complications and results]. / Déconnexion du lobe temporal dans les épilepsies temporales pharmacorésistantes: techniques, complications et résultats.

Temporal lobe epilepsy (TLE) is the most common form of intractable partial epilepsy in adults. Surgery (lobectomy or amygdalohippocampectomy) is effective in most patients. However, some complications can occur and brain shift, hematoma into the post operative cavity and occulomotor nerve palsy have been reported due to the surgical technic. We report the technique, safety and efficacy of temporal disconnection in nonlesional TLE. Forty-seven patients (18 males, 29 females; handedness: 12 left, 33 right; aged 35 years+/-10; mean duration of epilepsy: 24+/-10 years) underwent temporal disconnection (20 left, 27 right) guided by neuronavigation. Sixteen patients (35 %) underwent additional presurgical evaluation with SEEG. The outcome was assessed using Engel's classification. At the two-year follow-up, 85 % of the patients were seizure-free (Engel I), 26 (58 %) of whom were Ia. Postoperative persistent morbidity included mild hemiparesis (n=1), mild facial paresis (n=1), quadranopsia (n=23) and hemianopia (n=1). Verbal memory worsened in 13 % of cases when the disconnection was performed in the dominant lobe. MRI follow-up showed two cases of nonsymptomatic thalamic or pallidal limited ischemias, two cases of temporal horn-cystic dilatation, one requiring surgical reintervention without sequelae. There was one case of postoperative phlebitis. In the seizure-free patient group, postoperative EEG showed interictal temporal spikes at three months, one year and two years located in the anterior temporal region. Temporal disconnection is effective, prevents the occurrence of subdural cyst and hematomas in the temporal cavity, prevents the occurrence of oculomotor palsy, and limits the occurrence of quadranopsia. However, comparative studies are required to evaluate temporal disconnection as an alternative to lobectomy in nonlesional TLE.

Brain mapping of digestive sensations elicited by cortical electrical stimulations.

The aim of the study was to obtain a comprehensive map of cortical areas from where digestive sensations during intracerebral electrical stimulations (ES) in epileptic patients are elicited. Direct cortical ESs were performed in 339 medically intractable epileptic patients selected to presurgical evaluation using chronically stereotaxically implanted intracerebral electrodes and audio-video-EEG monitoring system. Digestive sensations were electrically induced on 723 different anatomical sites in 172 subjects (51%). According to the exclusion criteria, the final analysis includes 174 relevant stimulations evoked in 87 patients. The reported sensations referred predominantly to the upper part of the digestive tract including the epigastria and area over the periumbilical (n = 83; 48%), retrosternal (n = 17; 10%), pharyngeal (n = 31; 18%) and oral (n = 18; 10%) regions. The temporal pole (BA 38), hippocampus, amygdala and anterior cingulate cortex (ACC; BA 24/BA 32) were the typical anatomical locations connected with epigastric sensations. Retrosternal sensations were preferentially related to the ACC, while oro-pharyngeal sensations were most related to the suprasylvian opercular cortex and the insula. Cortical ESs are followed by a great variability of induced digestive and associated symptoms corresponding to a widely distributed cortical network of visceral sensation processing, in which the limbic and paralimbic structures play a critical role.