OBJECTIVE:To assess the added diagnostic value of magnetoencephalographic source imaging (MSI) beyond conventional magnetic resonance imaging (MRI) and fluorodeoxyglucose-positron emission tomography (FDG-PET) in localizing the epileptogenic zone, with stereo-electroencephalography (SEEG) and surgical resection serving as reference standards. METHODS:Among 101 patients prospectively enrolled with drug-resistant focal epilepsy in the EPIMAGE study to assess the diagnostic yield of non-invasive multimodal imaging (MSI, MRI, FDG-PET), those undergoing SEEG and/or surgery were analyzed to compare imaging with SEEG seizure-onset zone (SOZ) or resection zone. We employed binomial generalized linear mixed models (GLMMs) to evaluate the detection accuracy of MRI, PET, and MSI, individually and in combination, for identifying the SEEG-defined SOZ and resection zones. We further assessed the spatial concordance between imaging abnormalities and these reference standards. RESULTS:Using SEEG as reference, MSI identified additional SOZ regions beyond MRI in 55.6% of patients, beyond PET in 29.6%, and beyond combined MRI + PET in 33.3%. When the resection zone served as reference, MSI added new localizing value beyond MRI in 55.6% of patients, beyond PET in 29.6%, and beyond MRI + PET in 33.3%. GLMM analysis revealed that bimodal combinations improved detection rates (MRI + PET: 73.7%; MRI + MSI: 81.3%; PET+MSI: 79.8%). The trimodal combination (MRI + PET+MSI) achieved the highest detection probability at 85.3%, significantly higher than MRI, PET, or MSI alone (p = .003, p = .008, and p = .008, respectively). MSI significantly enhanced SOZ detection when added to either MRI (p = .01) or PET (p = .05). SIGNIFICANCE:MSI adds significant localizing value to the presurgical workup of focal epilepsy by expanding the detection of the epileptogenic network beyond the limits of structural MRI and metabolic PET. The primary clinical benefit of MSI lies in its ability to identify additional seizure-onset regions in complex cases, without increasing false-positive localizations. These findings demonstrate that a multimodal approach incorporating MSI optimizes surgical planning by increasing the probability of capturing the full extent of the epileptogenic zone.

Recent growing neuroimaging evidence support that a set of cortical regions - the central autonomic network - is involved in autonomic control, but its functional organization remains unclear. We studied the direct autonomic cardiac effects produced by 1500 direct cortical electrical stimulations in 43 patients with epilepsy (32.8 ± 8.6 years old, 19 females) undergoing intracerebral recordings during presurgical evaluation. The time course of RR interval (RRI) reactivity and its variability were studied. Nearly half (48.6 %, n = 729) of the cortical stimulations resulted in a cardiac response, divided almost equally between bradycardia (24.47 %) and tachycardia (24.13 %), with no difference between right and left stimulations. Bradycardia was marked by an increase in parasympathetic heart control (increase in HF power and decrease in LF/HF ratio), while tachycardia was marked by a predominance in sympathetic heart control (decrease in HF power and increase in LF/HF ratio). We individualized a main network, where evoked bradycardia and tachycardia were strong, consisting of amygdala, posterior insula, frontal mesial premotor/prefrontal cortex, and anterior cingulate. Other brain regions were also involved, but to a lesser degree, with regions mostly in the limbic system and neocortex (sensory-motor/premotor and lateral temporal regions). These results highlight a close relationship between cerebral cortex and heart. Two hierarchically ordered networks were identified. A 'core' autonomic network strongly involved in cardiovascular regulation, consistent with the classical definition of CAN in functional imaging. But also a more 'widespread' autonomic network, both consistent with a major role of the cortex in continuous autonomic cardiac adjustments to high level emotional, cognitive or sensorimotor cortical activities. This study establishes for the first time a functional mapping of cardiac responses evoked by cortical electrical stimulations, and evidenced hierarchically ordered networks that extends the classical model of CAN.

OBJECTIVE:There is currently scarce data on the electroclinical characteristics of epilepsy associated with synapsin 1 (SYN1) pathogenic variations. We examined clinical and electro-encephalographic (EEG) features in patients with epilepsy and SYN1 variants, with the aim of identifying a distinctive electroclinical pattern. METHODS:In this retrospective multicenter study, we collected and reviewed demographic, genetic, and epilepsy data of 19 male patients with SYN1 variants. Specifically, we analyzed interictal EEG data for all patients, and electro-clinical data from 10 epileptic seizures in 5 patients, using prolonged video-EEG monitoring recordings. Inter-ictal EEG functional connectivity parameters and frequency spectrum of the 10 patients over 12 years of age, were computed and compared with those of 56 age- and sex-matched controls. RESULTS:The main electroclinical features of epilepsy in patients with SYN1 were (1) EEG background and organization mainly normal; (2) interictal abnormalities are often rare or not visible on EEG; (3) more than 60% of patients had reflex seizures (cutaneous contact with water and defecation being the main triggers) isolated or associated with spontaneous seizures; (4) electro-clinical semiology of seizures was mainly temporal or temporo-insulo/perisylvian with a notable autonomic component; and (5) ictal EEG showed a characteristic rhythmic theta/delta activity predominating in temporo-perisylvian regions at the beginning of most seizures. Comparing patients with SYN1 to healthy subjects, we observed a shift to lower frequency bands in power spectrum of interictal EEG and an increased connectivity in both temporal regions. INTERPRETATION:A distinct epilepsy syndrome emerges in patients with SYN1, with a rather characteristic clinical and EEG pattern suggesting predominant temporo-insular involvement. ANN NEUROL 2024.

Some of the most important integrative control centers for the autonomic nervous system are located in the brainstem and the hypothalamus. However, growing recent neuroimaging evidence support that a set of cortical regions, named the central autonomic network (CAN), is involved in autonomic control and seems to play a major role in continuous autonomic cardiac adjustments to high-level emotional, cognitive or sensorimotor cortical activities. Intracranial explorations during stereo-electroencephalography (SEEG) offer a unique opportunity to address the question of the brain regions involved in heart-brain interaction, by studying: (i) direct cardiac effects produced by the electrical stimulation of specific brain areas; (ii) epileptic seizures inducing cardiac modifications; (iii) cortical regions involved in cardiac interoception and source of cardiac evoked potentials. In this review, we detail the available data assessing cardiac central autonomic regulation using SEEG, address the strengths and also the limitations of this technique in this context, and discuss perspectives. The main cortical regions that emerge from SEEG studies as being involved in cardiac autonomic control are the insula and regions belonging to the limbic system: the amygdala, the hippocampus, and the anterior and mid-cingulate. Although many questions remain, SEEG studies have already demonstrated afferent and efferent interactions between the CAN and the heart. Future studies in SEEG should integrate these afferent and efferent dimensions as well as their interaction with other cortical networks to better understand the functional heart-brain interaction.

Background and Objectives:Neurodevelopmental disorder with spastic diplegia and visual defect (NEDSDV) is a recently described rare syndrome caused by loss-of-function variations in CTNNB1 gene which includes developmental delay, intellectual deficiency, visual defects, and other features. Startle disease is not present in the classic clinical description and has been reported in only 2 patients so far.Methods:We report 12 cases of patients with NEDSDV who present an exaggerated startle response including 1 patient observed in our department and 11 patients recruited by addressing a questionnaire to the members of the Facebook group of families of patients with a CTNNB1 pathogenic variant. We performed an EMG analysis of this abnormal startle response in 1 patient and a genotype-phenotype analysis of startle response in NEDSDV.Results:All 12 patients presented exaggerated startle responses to an unexpected stimulus. They provoked falls in 8 patients, causing injuries in 3, and 3 patients were afraid to walk. This startle disorder corresponds to atypic hyperekplexia. No genotype to phenotype correlation has been found to differentiate NEDSDV with or without startle disease.Discussion:Our data allow us to refine the phenotypic spectrum of patients affected by CTNNB1-related NEDSDV, suggesting that exaggerated startle reactions may be part of clinical features. A precise questioning on startle disorders should be performed systematically in these patients because they can lead to potentially traumatic falls, while effective treatments are available and can improve quality of life. CTNNB1 study should be considered in patients with startle disease associated with intellectual deficiency.

Background and Objectives Neurodevelopmental disorder with spastic diplegia and visual defect (NEDSDV) is a recently described rare syndrome caused by loss-of-function variations in CTNNB1 gene which includes developmental delay, intellectual deficiency, visual defects, and other features. Startle disease is not present in the classic clinical description and has been reported in only 2 patients so far. Methods We report 12 cases of patients with NEDSDV who present an exaggerated startle response including 1 patient observed in our department and 11 patients recruited by addressing a questionnaire to the members of the Facebook group of families of patients with a CTNNB1 pathogenic variant. We performed an EMG analysis of this abnormal startle response in 1 patient and a genotype-phenotype analysis of startle response in NEDSDV. Results All 12 patients presented exaggerated startle responses to an unexpected stimulus. They provoked falls in 8 patients, causing injuries in 3, and 3 patients were afraid to walk. This startle disorder corresponds to atypic hyperekplexia. No genotype to phenotype correlation has been found to differentiate NEDSDV with or without startle disease. Discussion Our data allow us to refine the phenotypic spectrum of patients affected by CTNNB1-related NEDSDV, suggesting that exaggerated startle reactions may be part of clinical features. A precise questioning on startle disorders should be performed systematically in these patients because they can lead to potentially traumatic falls, while effective treatments are available and can improve quality of life. CTNNB1 study should be considered in patients with startle disease associated with intellectual deficiency.

Although it is now widely accepted that the brain contributes to the autonomic regulation, the cortical autonomic network is not clearly identified. Here, we provide a functional mapping of cardiac responses to brain stimulations. Methods: The cardiac effects of 1504 intracortical stimulations were divided into tachycardia, bradycardia, and no cardiac response according to the magnitude of RR interval reactivity in 44 patients with epilepsy (32.8±8.6 years, 19 women). Bipolar stimulations were performed with an intensity between 0.2–3.5 mA. Generalized Estimating Equation and odd ratio (OR) were used to explore the relationship between cardiac responses and brain regions, independently of sex, age and type, intensity, lateralization of stimulations and number of stimulations per patient. Results: Cardiac responses were induced by 320 stimulations (21.3%), including in 10.7% bradycardia (n=161) and in 10.6% tachycardia (n=159). Bradycardia was frequently and significantly evoked in posterior insula (OR=18.3), frontal motor (OR=7.5) and premotor (OR=8.3) cortex, temporal internal pole (OR=12.1), less frequently in amygdala (OR=5.2), parahippocampus (OR=5.2), anterior insula (OR=4.6), superior temporal cortex (OR=3.5), and hippocampus (OR=2.1). Tachycardia was frequently induced in posterior insula (OR= 26.8), anterior cingulate (OR= 19.5), parietal superior lobule (OR= 12.3), orbitofrontal cortex (OR= 9.0), and temporal internal pole (OR=8.3) and temporal fusiform inferior gyrus (OR=8.0); and less frequently in parahippocampus (OR=5.6), frontal motor cortex (OR=4.9), amygdala (OR=4.0), hippocampus (OR=2.4), anterior insula (OR=2.0), and temporal external pole (OR=2.0). Conclusions: These results illustrate i) brain networks underpinning tachycardia or bradycardia with ii) more extensive brain networks which may also contribute to cardiac autonomic control.

Background: Visceral and emotional sensations (VES) are frequently reported during epileptic seizures. To date, the underlying mechanisms and the location of brain areas involved in the processing of these sensations remain unclear. The aim of our study is to characterize the type and frequency of VES evoked by electrical stimulations performed all over the cortical mantle and to assess whether they might be related to specific brain structures. Methods : We reviewed 12,088 bipolar stimulations performed in 203 patients using stereotactically implanted depth electrodes, during the presurgical evaluation of drug-refractory epilepsy, at Neurological Hospital in Lyon (France). VES were divided into viscero-sensitive (feelings in the throat, thorax or abdomen), viscero-vegetative (flush, nausea, feeling of tachycardia and dyspnea) and viscero-psychic sensations (fear, anxiety). Univariate analysis and then conditional logistic regression were used to assess the association between VES and localization of the stimulated contacts. Results : 543 stimulations evoked VES (4.26%). Stimulations of insulo-limbic structures (amygdala, anterior and posterior insula, anterior and mid-cingulate cortex, hippocampus and parahippocampus) were significantly more associated with VES than those of extra limbic structures (p<0.0001). Preferential implication of certain brain structures, depending on the type of visceral responses was evidenced: temporo-mesial structures (amygdala, hippocampus and parahippocampus) and insula for viscero-sensitive sensations; amygdala, insula and mid-cingulate cortex for viscero-vegetative sensations; temporo-mesial structures and anterior cingulate cortex for emotional sensations. Conclusion : These data can help to localize the epileptogenic zone in seizures with visceral sensations, and also bring insights in the discussion on the mechanisms of interoception.

The functional roles of the insula diverge between its posterior portion (PI), mainly connected with somato-sensory and motor areas, and its anterior section (AI) connected with the frontal, limbic, and cingulate regions. We report intracranial recordings of local field evoked potentials from PI, AI, and the visual fusiform gyrus to a full array of emotional faces including pain while the individuals' attention was diverted from emotions. The fusiform gyrus and PI responded equally to all types of faces, including neutrals. Conversely, the AI responded only to emotional faces, maximally to pain and fear, while remaining insensitive to neutrals. The two insular sectors reacted with almost identical latency suggesting their parallel initial activation via distinct functional routes. The consistent responses to all emotions, together with the absence of response to neutral faces, suggest that early responses in the AI reflect the immediate arousal value and behavioral relevance of emotional stimuli, which may be subserved by "fast track" routes conveying coarse-spatial-frequency information via the superior colliculus and dorsal pulvinar. Such responses precede the conscious detection of the stimulus' precise signification and valence, which need network interaction and information exchange with other brain areas, for which the AI is an essentialhub.

OBJECTIVE:Visceral sensations are bodily symptoms which are component manifestations of emotions frequently reported during epileptic seizures. Nowadays, the underlying mechanism and location of brain areas involved in the processing of these sensations remain unclear. Our objectives were to characterize the type and frequency of visceral and emotional responses evoked by electrical stimulations, to produce a mapping of brain structures involved in their processing, and to assess the link between visceral sensations and emotional feelings.METHODS:We reviewed 12,088 bipolar stimulations performed in 203 patients during the presurgical evaluation of drug refractory epilepsy. Responses to stimulation were divided into viscero-sensitive, viscero-vegetative, and emotional sensations. Univariate analysis and conditional logistic regression were used to assess the association between visceral and emotional sensations and localization of the stimulated contacts.RESULTS:In total, 543 stimulations evoked visceral and emotional sensations. Stimulations of operculo-insulolimbic structures (amygdala, anterior and posterior insula, anterior and mid-cingulate cortex, hippocampus, parahippocampus, temporal pole, frontal and parietal operculum) were significantly more associated with visceral and emotional sensations than all other cortical regions. Preferential implication of certain brain structures, depending on the type of visceral responses was evidenced: temporo-mesial structures, insula, and frontoparietal operculum for viscero-sensitive sensations; amygdala, insula, anterior and mid-cingulate cortex, and temporal pole for viscero-vegetative sensations; temporo-mesial structures, anterior cingulate cortex, and frontal operculum for emotional sensations.INTERPRETATION:Our data can help to guide SEEG explorations when visceral or emotional symptoms are part of the ictal semiology. They also bring some insights into the mechanisms of visceroception and the functional significance of the co-localization of visceral and emotional representations in the human brain.

OBJECTIVE:Electrical stimulations performed in awake patients identified dura mater, venous sinuses, and arteries as pain-sensitive intracranial structures. However, cephalic pain has been only occasionally reported in patients with epilepsy undergoing stereo-electroencephalography (SEEG) stimulations.METHODS:The aim of our study was to investigate whether headache can be triggered by SEEG stimulations and might be related to specific cortical areas. Data were gathered from 16 050 stimulations collected in 266 patients who underwent a SEEG as part of a presurgical assessment of their drug-resistant epilepsy.RESULTS:Two-hundred and eight stimulations (1.3%) evoked headaches. Pain was more frequently described as bilateral (42.31%) than ipsilateral (16.83%) or contralateral (14.42%) to the stimulated hemisphere. Headache was more frequently elicited during stimulation of the insulo-limbic regions such as the anterior and medial cingulate gyrus, the mesial part of temporal lobe, and the insula.CONCLUSION:This study shows that cortical stimulation can evoke headache, mostly during stimulation of the temporo-frontal limbic regions. It suggests that brief epileptic headache can be an epileptic symptom caused by a cortical discharge involving somatic or visceral network and does not reflect only trigemino-vascular activation. Although not specific, the occurrence of a brief epileptic headache may point to a seizure origin in the temporo-frontal limbic regions.

Electrical stimulations of the insula performed during stereo-electro-encephalography (SEEG) reproduce the ictal symptoms observed during the development of insular seizures and are also a unique opportunity to provide a functional mapping of the insular cortex. We provide here a functional mapping of the insular cortex obtained by electrical stimulation, based on our previous work and a review of literature. The most frequent responses to insula stimulation were somatosensory sensations followed by visceral responses. Then, in decreasing order of frequency, auditory sensations, vestibular illusions, speech impairment, gustato-olfactory sensations and motor reactions were evoked. A bipolar organization could be evidenced with a posterior part assigned to somatosensory functions and notably to pain perception; and an anterior part assigned to visceral functions. Although some degree of spatial segregation could be evidenced, there was a clear spatial overlap between the representations of the different types of responses. These data provide a better understanding of physiological insular functions, insula seizures semiology and a prediction of post-surgical deficits. Insula is the only cortical region where stimulations demonstrate such a multi-modal representation, perhaps supporting its integrative functions of polymodal inputs.

Despite numerous studies suggesting the role of insular cortex in the control of autonomic activity, the exact location of cardiac motor regions remains controversial. We provide here a functional mapping of autonomic cardiac responses to intracortical stimulations of the human insula. The cardiac effects of 100 insular electrical stimulations into 47 epileptic patients were divided into tachycardia, bradycardia, and no cardiac response according to the magnitude of RR interval (RRI) reactivity. Sympathetic (low frequency, LF, and low to high frequency powers ratio, LF/HF ratio) and parasympathetic (high frequency power, HF) reactivity were studied using RRI analysis. Bradycardia was induced by 26 stimulations (26%) and tachycardia by 21 stimulations (21%). Right and left insular stimulations induced as often a bradycardia as a tachycardia. Tachycardia was accompanied by an increase in LF/HF ratio, suggesting an increase in sympathetic tone; while bradycardia seemed accompanied by an increase of parasympathetic tone reflected by an increase in HF. There was some left/right asymmetry in insular subregions where increased or decreased heart rates were produced after stimulation. However, spatial distribution of tachycardia responses predominated in the posterior insula, whereas bradycardia sites were more anterior in the median part of the insula. These findings seemed to indicate a posterior predominance of sympathetic control in the insula, whichever the side; whereas the parasympathetic control seemed more anterior. Dysfunction of these regions should be considered when modifications of cardiac activity occur during epileptic seizures and in cardiovascular diseases.

OBJECTIVE:Resective surgery is effective in treating drug-resistant focal epilepsy, but it remains unclear whether improved diagnostics influence postsurgical outcomes. Here, we compared practice and outcomes over 2 periods 15 years apart.METHODS:Sixteen European centers retrospectively identified 2 cohorts of children and adults who underwent epilepsy surgery in the period of 1997 to 1998 (n = 562) or 2012 to 2013 (n = 736). Data collected included patient (sex, age) and disease (duration, localization and diagnosis) characteristics, type of surgery, histopathology, Engel postsurgical outcome, and complications, as well as imaging and electrophysiologic tests performed for each case. Postsurgical outcome predictors were included in a multivariate logistic regression to assess the strength of date of surgery as an independent predictor.RESULTS:Over time, the number of operated cases per center increased from a median of 31 to 50 per 2-year period (p = 0.02). Mean disease duration at surgery decreased by 5.2 years (p < 0.001). Overall seizure freedom (Engel class 1) increased from 66.7% to 70.9% (adjusted p = 0.04), despite an increase in complex surgeries (extratemporal and/or MRI negative). Surgeries performed during the later period were 1.34 times (adjusted odds ratio; 95% confidence interval 1.02-1.77) more likely to yield a favorable outcome (Engel class I) than earlier surgeries, and improvement was more marked in extratemporal and MRI-negative temporal epilepsy. The rate of persistent neurologic complications remained stable (4.6%-5.3%, p = 0.7).CONCLUSION:Improvements in European epilepsy surgery over time are modest but significant, including higher surgical volume, shorter disease duration, and improved postsurgical seizure outcomes. Early referral for evaluation is required to continue on this encouraging trend.

Magnetoencephalography (MEG) records weak magnetic fields outside the human head and thereby provides millisecond-accurate information about neuronal currents supporting human brain function. MEG and electroencephalography (EEG) are closely related complementary methods and should be interpreted together whenever possible. This manuscript covers the basic physical and physiological principles of MEG and discusses the main aspects of state-of-the-art MEG data analysis. We provide guidelines for best practices of patient preparation, stimulus presentation, MEG data collection and analysis, as well as for MEG interpretation in routine clinical examinations. In 2017, about 200 whole-scalp MEG devices were in operation worldwide, many of them located in clinical environments. Yet, the established clinical indications for MEG examinations remain few, mainly restricted to the diagnostics of epilepsy and to preoperative functional evaluation of neurosurgical patients. We are confident that the extensive ongoing basic MEG research indicates potential for the evaluation of neurological and psychiatric syndromes, developmental disorders, and the integrity of cortical brain networks after stroke. Basic and clinical research is, thus, paving way for new clinical applications to be identified by an increasing number of practitioners of MEG.