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 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.

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.

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.

[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.

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.

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.

Silence is golden: transient neural deactivation in the prefrontal cortex during attentive reading.

It is becoming increasingly clear that attention-demanding tasks engage not only activation of specific cortical regions but also deactivation of other regions that could interfere with the task at hand. At the same time, electrophysiological studies in animals and humans have found that the participation of cortical regions to cognitive processes translates into local synchronization of rhythmic neural activity at frequencies above 40 Hz (so-called gamma-band synchronization). Such synchronization is seen as a potential facilitator of neural communication and synaptic plasticity. We found evidence that cognitive processes can also involve the disruption of gamma-band activity in high-order brain regions. Intracerebral electroencephalograms were recorded in 3 epileptic patients during 2 reading tasks. Visual presentation of words induced a strong deactivation in a broad (20-150 Hz) frequency range in the left ventral lateral prefrontal cortex, in parallel with gamma-band activations within the reading network, including Broca's area. The observed energy decrease in neural signals was reproducible across patients. It peaked around 500 ms after stimulus onset and appeared subject to attention-modulated amplification. Our results suggest that cognition might be mediated by a coordinated interaction between regional gamma-band synchronizations and desynchronizations, possibly reflecting enhanced versus reduced local neural communication.

Ictal clinical and scalp-EEG findings differentiating temporal lobe epilepsies from temporal 'plus' epilepsies.

Temporal 'plus' epilepsies are characterized by seizures involving a complex epileptogenic network including the temporal lobe and the closed neighboured structures such as the orbito-frontal cortex, the insula, the frontal and parietal operculum and the temporo-parieto-occipital junction. Temporal 'plus' epilepsies are currently identified by means of intracerebral electrodes but whether their diagnosis can be suspected non-invasively has not been evaluated yet. The aim of this retrospective study was to address this issue in 80 consecutive patients who were thought to suffer from non-lesional temporal lobe seizures which finally proved, on the basis of stereotactic intracerebral EEG (SEEG) recordings, to be 'purely' temporal (TL group, n = 58) or temporal 'plus' (T+ group, n = 22). Our results showed that the two groups of patients were difficult to differentiate on the basis of general clinical features or MRI data. Even the presence of hippocampal sclerosis did not distinguish the two groups. Conversely, both ictal clinical symptoms and scalp-EEG findings significantly differentiated TL from T+ patients. Patients with TL epilepsies more frequently presented an ability to warn at seizure onset (P = 0.003), an abdominal aura (P = 0.05), gestural automatisms (P = 0.04) and a post-ictal amnesia (P = 0.02). Patients suffering from T+ epilepsies more frequently had gustatory hallucinations (P = 0.02), rotatory vertigo (P = 0.02) and auditory illusions (P = 0.02) at seizure onset; they exhibited more frequently contraversive manifestations of the eyes and/or head (P = 0.001), piloerection (P = 0.03) and ipsilateral tonic motor signs (P = 0.05), and they were more often dysphoric in the post-ictal phase (P = 0.0001). Cluster analysis mainly indicated that some associations of symptoms were relevant for differentiating TL cases from T+ cases. Interictal EEG of T+ patients more frequently exhibited bilateral or precentral abnormalities, while ictal EEG more frequently pointed over the anterior frontal, temporo-parietal and precentral regions. Neither TL interictal spikes, nor TL ictal EEG onset, allowed us definitely to rule out the possibility of T+ epilepsies. Our findings may be useful for identifying, among patients suffering from 'atypical' non-lesional TL epilepsies, those who should undergo invasive recordings before surgery.

[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.

[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.

[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.

[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.

[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.

[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.

Intracerebral recordings of nocturnal hyperkinetic seizures: demonstration of a longer duration of the pre-seizure sleep spindle.

OBJECTIVE: Nocturnal frontal lobe epilepsy (NFLE) seizures occur primarily during non-rapid eye movement sleep stage 2. We observed in several patients rhythms of same localization and frequency as sleep spindles, immediately preceding and sometimes continuing at seizure onsets. We aimed to study the link between sleep spindles and seizure onsets. METHODS: We used intracerebral stereo-EEG ictal recordings of two MRI-negative patients with clinically defined NFLE. For each of the six studied seizures, sustained activity in the frontal sleep spindle frequency (12Hz) was observed around seizure onset. The duration of this pre-seizure sleep spindle was compared to that of the 10 preceding sleep spindles. RESULTS: The pre-seizure sleep spindles were clearly of longer duration than the "interictal" sleep spindles for all seizures. This sustained pre-seizure 12Hz activity could be differentiated from normal awakenings, and showed no spatial relation to the ictal onset. CONCLUSIONS: We demonstrated a functional alteration of the sleep spindle-generating thalamocortical loop concomitant with the seizure onsets. This defect may also be involved in seizure generation. SIGNIFICANCE: A thalamic participation in NFLE pathogenesis is likely in our two patients. The study of additional patients will allow to evaluate the role of the thalamocortical circuits in NFLE.

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.

Stereo-electroencephalography methodology: advantages and limits.

Since January 1990, 70 patients with medically intractable partial epilepsy underwent a stereo-EEG investigation in our center. We first described technical requirements, and gave an overview of the variety of the explored cerebral regions and implantation patterns realized, pointing out the low rate of morbidity (1.4%). The three-dimensional epileptogenic zone thus defined led to a tailored individualized surgical excision in 60 patients, while 9 are waiting for surgery and the remaining 1 has been excluded (1.4%). Conceptual and technical aspects of the stereo-EEG methodology were discussed in order to underline its peculiarities in the field of "depth recordings", and more generally among the broader group of "invasive" procedures.

Hemiplegia in posterior cerebral artery occlusion.

We report 4 patients with hemiplegia due to a posterior cerebral artery occlusion. Associated clinical signs were aphasia, alexia or a neglect syndrome, hemianopia, and hemisensory loss. Hemiplegia was due to infarction in the lateral midbrain. The level of the occlusion in the posterior cerebral artery may be located distal to the junction with the posterior communicating artery.

Intracranial EEG and human brain mapping.

This review is an attempt to highlight the value of human intracranial recordings (intracranial electro-encephalography, iEEG) for human brain mapping, based on their technical characteristics and based on the corpus of results they have already yielded. The advantages and limitations of iEEG recordings are introduced in detail, with an estimation of their spatial and temporal resolution for both monopolar and bipolar recordings. The contribution of iEEG studies to the general field of human brain mapping is discussed through a review of the effects observed in the iEEG while patients perform cognitive tasks. Those effects range from the generation of well-localized evoked potentials to the formation of large-scale interactions between distributed brain structures, via long-range synchrony in particular. A framework is introduced to organize those iEEG studies according to the level of complexity of the spatio-temporal patterns of neural activity found to correlate with cognition. This review emphasizes the value of iEEG for the study of large-scale interactions, and describes in detail the few studies that have already addressed this point.