High-gamma modulation language mapping and cognitive outcomes after epilepsy surgery.

OBJECTIVE: We evaluated changes in cognitive domains after neurosurgical lesioning of cortical sites with significant high-gamma power modulations (HGM) during a visual naming task, although these sites were found language-negative on standard-of-care electrical stimulation mapping (ESM). METHODS: In drug-resistant epilepsy patients who underwent resection/ablation after stereo-electroencephalography (SEEG), we computed reliable change indices (RCIs) from a battery of presurgical and 1-year postsurgical neuropsychological assessments. We modeled RCIs as a function of lesioning even one HGM language site, number of HGM language sites lesioned, and the magnitude of naming-related HGM. The analyses were adjusted for 1-year seizure freedom, operated hemispheres, and the volumes of surgical lesions. RESULTS: In 37 patients with 4455 SEEG electrode contacts (1839 and 2616 contacts in right and left hemispheres, respectively), no ESM language sites were lesioned. Patients with lesioning of even one HGM language site showed significantly lower RCIs for Peabody Picture Vocabulary Test (PPVT), working memory, and verbal learning immediate (VLI) scores. RCI declines with higher number of HGM language sites lesioned were seen in PPVT (slope [ß] = -.10), working memory (ß = -.10), VLI (ß = -.14), and letter-word identification (LWI; ß = -.14). No neuropsychological domains improved after lesioning of HGM language sites. Significant effects of the HGM magnitude at lesioned sites were seen on working memory (ß = -.31), story memory immediate (ß = -.27), verbal learning recognition (ß = -.18), LWI (ß = -.16), spelling (ß = -.49), and passage comprehension (ß = -.33). Because working memory was significantly affected in all three analyses, patients with maximal working memory decline were examined post hoc, revealing that all such patients had HGM naming sites lesioned in the posterior quadrants of either hemisphere. SIGNIFICANCE: HGM language mapping should be used as an adjunct to ESM in clinical practice and may help counsel patients/families about postsurgical cognitive deficits.

Adapting dose-response methodology to improve clinical trial design for psychotherapies.

OBJECTIVE: Conventional randomized controlled trials (RCTs) have long served as the foundation of research in clinical psychology; however, most treatments for eating disorders show only modest effects on reduction of symptoms and maintenance of long-term remission. New options for psychotherapy treatment development research, beyond continuing to pursue additive or subpopulation approaches, are needed. METHODS: One option is to apply dose-response designs, which are commonplace in studies of pharmacology, toxicology, and medical research, and characterized by the evaluation of the amount of exposure (dose) to an intervention, and the resulting changes in body function or health (response). RESULTS: Eating disorder interventions are particularly well-suited for dose-response treatment designs. The deadly nature of eating disorders makes it imperative that patients are not turned away for not being "ready" to engage with treatment. By identifying optimal doses, research will likely yield a more parsimonious course of treatment, which will lend itself to reduced costs, greater uptake, and reduced drop-out. DISCUSSION: Limited use of within-subject designs in trials for patients with eating disorders has produced fast-track efficacy studies and omitted key elements in the treatment development pathway. To decrease reliance on RCT's, dose-response methods should be applied as an alternative study design. PUBLIC SIGNIFICANCE: Eating disorders are associated with medical and psychiatric comorbidities, poor quality of life, and high mortality. Access to evidence-based services for patients with eating disorders is limited, and identifying additional effective treatment options can be difficult because of challenges inherent to randomized-controlled trials. This manuscript describes an alternative trial methodology to maximize the information that can be gathered prior to utilizing a standard large-scale efficacy design.

Phase-Transitions in Disgust During Self-Initiated Eating Among Adolescents With Anorexia Nervosa and Related Low-Weight Eating Disorders and Matched Controls.

BACKGROUND: Understanding the emotional context of feeding behavior may help identify causal mechanisms of food avoidance among individuals with anorexia nervosa. Although predominant food avoidance models assume fear of fat drives feeding behavior, disgust may be more theoretically and proximally relevant to moment-to-moment experiences of feeding. This study, therefore, aimed to examine affect and food avoidance using automated affect analysis from facial response by measuring time-specific transitions in disgust during a laboratory eating paradigm. We hypothesized that phase transitions in disgust would distinguish temporally self-initiated eating from food avoidance. METHODS: Sixty-three adolescents with anorexia nervosa or another low-weight eating disorder (LWED) and 27 age- and sex-matched controls were recruited as part of a larger study; 45 patients and 22 controls provided data on autonomous eating and facial affect during a laboratory meal. Dynamic structural equation models quantified moment-to-moment relationships between disgust and feeding behavior. RESULTS: Self-initiated eating was associated with greater increases in disgust, but not fear, intensity among those with LWED relative to control participants and greater disgust intensity predicted lower likelihood of self-initiated eating. DISCUSSION: Phasic transitions in disgust provide moment-to-moment evidence of affective influence on self-initiated eating and lend credibility to the hypothesis that disgust contributes to food avoidance and initiation in individuals with LWED.

"Now We Can Speak": Wheelchair Sport Participation in Areas of Armed Conflict.

This study sought to understand the lived experiences of wheelchair basketball athletes from low- and middle-income countries of recent or current armed conflict and the meaning that they ascribed to their participation. Wheelchair basketball athletes (N = 108) from eight national teams participated in semistructured focus-group interviews. Study data were analyzed thematically using an interpretive descriptive approach. Three themes were developed: "I can do anything I want; not only basketball," self-concept changes through sport participation; "Now they see me as a respectable person," societal belonging through sport; and "I have motivated other disabled people," influence on nonparticipating disabled persons. The findings indicated that participation in wheelchair sports may help disabled persons see themselves as capable individuals on the court and in aspects of daily living, perhaps even peer role models for other disabled persons in their communities and countries.

Comparing electrical stimulation functional mapping with subdural electrodes and stereoelectroencephalography.

OBJECTIVE: Electrical stimulation mapping (ESM) is the clinical standard for functional localization with subdural electrodes (SDE). As stereoelectroencephalography (SEEG) has emerged as an alternative option, we compared functional responses, afterdischarges (ADs), and unwanted ESM-induced seizures (EISs) between the two electrode types. METHODS: Incidence and current thresholds for functional responses (sensory, motor, speech/language), ADs, and EISs were compared between SDE and SEEG using mixed models incorporating relevant covariates. RESULTS: We identified 67 SEEG ESM and 106 SDE ESM patients (7207 and 4980 stimulated contacts, respectively). We found similar incidence of language and motor responses between electrode types; however, more SEEG patients reported sensory responses. ADs and EISs occurred less commonly with SEEG than SDE. Current thresholds for language, face motor, and upper extremity (UE) motor responses and EIS significantly decreased with age. However, they were not affected by electrode type, premedication, or dominant hemispheric stimulation. AD thresholds were higher with SEEG than with SDE. For SEEG ESM, language thresholds remained below AD thresholds up to 26 years of age, whereas this relationship was inverse for SDE. Also, face and UE motor thresholds fell below AD thresholds at earlier ages for SEEG than SDE. AD and EIS thresholds were not affected by premedication. SIGNIFICANCE: SEEG and SDE have clinically relevant differences for functional brain mapping with electrical stimulation. Although evaluation of language and motor regions is comparable between SEEG and SDE, SEEG offers a higher likelihood of identifying sensory areas. A lower incidence of ADs and EISs, and a favorable relationship between functional and AD thresholds suggest superior safety and neurophysiologic validity for SEEG ESM than SDE ESM.

Neuropsychological outcomes after epilepsy surgery: A comparison of stereo electroencephalography and subdural electrodes.

BACKGROUND AND PURPOSE: We analyzed the association of neuropsychological outcomes after epilepsy surgery with the intracranial electrode type (stereo electroencephalography [SEEG] and subdural electrodes [SDE]), and electrical stimulation mapping (ESM) of speech/language. METHODS: Drug-resistant epilepsy patients who underwent comprehensive neuropsychological evaluation before and 1 year after epilepsy surgery were included. SEEG and SDE subgroups were matched by age, handedness, operated hemisphere, and seizure freedom. Postsurgical neuropsychological outcomes (adjusted for presurgical scores) and reliable change indices were analyzed as functions of electrode type and ESM. RESULTS: Ninety-nine patients aged 6-29 years were included with similar surgical resection/ablation volumes in the SEEG and SDE subgroups. Most of the neuropsychological outcomes were comparable between SEEG and SDE subgroups; however, Working Memory and Processing Speed were significantly improved in the SEEG subgroup. Undergoing language ESM was associated with significant improvements in Spelling, Letter-Word Identification, Vocabulary, Verbal Comprehension, Verbal Learning, and Story Memory scores, but a decline in Calculation scores. CONCLUSIONS: Intracranial evaluations with SEEG and SDE are comparable in terms of long-term postsurgical neuropsychological outcomes. Our data suggest that SEEG may be associated with improvements in working memory and processing speed, representing cognitive domains served by spatially distributed networks. Our study also supports wider use of language ESM before epilepsy surgery, preferably using other language tasks in addition to visual naming. Rather than the type of electrode, postsurgical neuropsychological outcomes are driven by whether language ESM was performed or not, with beneficial effects of language mapping.

Epilepsy Milestones 2.0: An updated framework for assessing epilepsy fellowships and fellows.

OBJECTIVE: Accreditation Council for Graduate Medical Education (ACGME)-accredited epilepsy fellowships, like other ACGME accredited training programs, use Milestones to establish learning objectives and to evaluate how well trainees are achieving these goals. The ACGME began developing the second iteration of the Milestones 6 years ago, and these are now being adapted to all specialties. Here, we describe the process by which Epilepsy Milestones 2.0 were developed and summarize them. METHODS: A work group of nine board-certified, adult and pediatric epileptologists reviewed Epilepsy Milestones 1.0 and revised them using a modified Delphi approach. RESULTS: The new Milestones share structural changes with all other specialties, including a clearer stepwise progression in professional development and the harmonized Milestones that address competencies common to all medical fields. Much of the epilepsy-specific content remains the same, although a major addition is a set of Milestones focused on reading and interpreting electroencephalograms (EEGs), which the old Milestones lacked. Epilepsy Milestones 2.0 includes a Supplemental Guide to help program directors implement the new Milestones. Together, Epilepsy Milestones 2.0 and the Supplemental Guide recognize advances in epilepsy, including stereo-EEG, neurostimulation, genetics, and safety in epilepsy monitoring units. SIGNIFICANCE: Epilepsy Milestones 2.0 address the shortcomings of the old Milestones and should facilitate the assessment of epilepsy fellowships and fellows by program directors, faculty, and fellows themselves.

Comparison of outcomes after stereoelectroencephalography and subdural grid monitoring in pediatric tuberous sclerosis complex.

OBJECTIVE: Patients with tuberous sclerosis complex (TSC) epilepsy present with unique clinical challenges such as early seizure onset and high rates of intractability and multifocality. Although there are numerous studies about the safety and efficacy of stereoelectroencephalography (SEEG), this topic has not been studied in TSC patients who have distinct epilepsy profiles. The authors investigated subdural grid (SDG) and SEEG monitoring to determine whether these procedures lead to similar seizure and safety outcomes and to identify features unique to this pediatric population. METHODS: TSC patients who underwent SDG or SEEG placement and a second epilepsy surgery during the period from 2007 to 2021 were included in this single-center retrospective cohort analysis. Various patient, hospitalization, and epilepsy characteristics were collected. RESULTS: A total of 50 TSC patients were included in this study: 30 were included in the SDG cohort and 20 in the SEEG cohort. Baseline weekly seizure count did not significantly differ between the 2 groups (p = 0.412). The SEEG group had a greater mean baseline number of antiepileptic drugs (AEDs) (3.0 vs 2.0, p = 0.003), higher rate of previous surgical interventions (25% vs 0%, p = 0.007), and larger proportion of patients who underwent bilateral monitoring (50% vs 13.3%, p = 0.005). Despite this, there was no significant difference in seizure freedom between the SDG and SEEG cohorts. The mean reduction in seizure count was 84.9% and 47.8% of patients were seizure free at last follow-up (mean 79.4 months). SEEG trended toward being a safer procedure than SDG monitoring, with a shorter mean ICU stay (0.7 days vs 3.9 days, p < 0.001), lower blood transfusion rate (0% vs 13.3%, p = 0.140), and lower surgical complication rate (0% vs 10%, p = 0.265). CONCLUSIONS: In the comparison of the SDG and SEEG cohorts, the SEEG group included patients who appeared to receive more aggressive management and have a higher rate of multifocality, more prior surgical interventions, more AEDs at baseline, and a higher rate of bilateral invasive monitoring. Despite this, the SEEG cohort had similar seizure outcomes and a trend toward increased safety. Based on these findings, SEEG appears to allow for monitoring of a wider breadth of TSC patients given its minimally invasive nature and its relative simplicity for monitoring numerous regions of the brain.

"They're Either Going to Find Ways to Include You or They're Just Kind of Not": Experiences of Students With Orthopedic Impairments in Integrated Physical Education.

This study explored the experiences of students with orthopedic impairments in integrated physical education (PE) classes. An interpretative phenomenological analysis research approach was used, and six students with orthopedic impairments (age = 10-14 years) served as participants. Data sources were semistructured, audiotaped interviews and reflective interview notes. Based on data analysis, three themes were developed-"Without it, they probably would like, just treat me normal," visibility, disclosure, and expectations; "I sit out," limited participation and a lack of modifications/accommodations; and "PE doesn't feel great," social interactions and perception of self. The experiences portrayed throughout these themes highlight the marginalization and lack of access that the participants encountered in their integrated PE classes. The findings indicated that PE professionals working with students with orthopedic impairments may benefit from reflecting on personal biases and their instructional practices in an effort to improve the quality of PE experiences for these students.

A rare case of paediatric astroblastoma with concomitant MN1-GTSE1 and EWSR1-PATZ1 gene fusions altering management.

In a case of astroblastoma, methylation analysis was uninformative, with no clustering with known CNS-HGNET-MN1 cases. Whole genome sequencing however identified a novel MN1-GTSE1 gene fusion (image), confirming the diagnosis of astroblastoma, as well as an EWSR1-PATZ1 gene fusion. Whole genome sequencing, alongside methylation profiling and conventional neuropathology, will continue to lead to improved diagnostics and prognostication for children with brain tumours.

Subtraction ictal SPECT co-registered to MRI (SISCOM) patterns in children with temporal lobe epilepsy.

OBJECTIVE: We evaluated SISCOM patterns and their relationship with surgical outcome in children with temporal lobe epilepsy (TLE) who had undergone a temporal lobe surgery. METHODS: This was an observational study evaluating SISCOM patterns in 40 children with TLE. We classified SISCOM patterns into 4 categories; (i) unilateral anteromesial and/or anterolateral temporal pattern; (ii) unilateral anteromesial and/or anterolateral temporal plus posterior extension pattern; (iii) bilateral anteromesial and/or anterolateral temporal pattern; and (iv) atypical pattern. Determinants of SISCOM pattern and correlation between postoperative outcomes and SISCOM patterns were evaluated. RESULTS: Pattern (i), (ii), (iii), and (iv) were identified in 10 (25%), 14 (35%), 0 (0%), and 16 (40%) patients, respectively. There was no significant correlation between patterns and postoperative outcomes. SISCOM patterns significantly associated with the presence of hippocampal sclerosis and type of focal cortical dysplasia (p-value = 0.048 and 0.036, respectively). Patients with HS had 5 times the odds of having unilateral temporal pattern, compared to patients with other neuropathology (OR = 5, 95% CI 0.92 to 27.08). Patients with FCD type 2 had 9.71 times the odds of having atypical pattern, compared to patients with other types of FCD (OR = 9.71, 95% CI 0.92 to 103.04). Lobar concordance of SISCOM and ictal and interictal scalp EEG significantly correlated with postoperative outcomes (p-value = 0.018 and 0.013, respectively). CONCLUSION: Three SISCOM patterns were seen. Patients with HS had increased odds of having unilateral temporal pattern while patients with FCD type 2 had increased odds of having atypical pattern. However, there was no significant correlation between SISCOM patterns and postoperative outcomes. Lobar concordance of SISCOM and ictal and interictal scalp EEG significantly correlated with postoperative outcome. SIGNIFICANCE: This study shows that the distribution of SISCOM patterns and their relationship with postoperative outcomes in children with TLE are different from adult population. Besides, SISCOM may add only limited diagnostic and prognostic information in children with drug-resistant TLE undergoing epilepsy surgery. Further evaluation to identify patient populations that may benefit from SISCOM is desirable.

Fast Automated Stereo-EEG Electrode Contact Identification and Labeling Ensemble.

INTRODUCTION: Stereotactic electroencephalography (SEEG) has emerged as the preferred modality for intracranial monitoring in drug-resistant epilepsy (DRE) patients being evaluated for neurosurgery. After implantation of SEEG electrodes, it is important to determine the neuroanatomic locations of electrode contacts (ECs), to localize ictal onset and propagation, and integrate functional information to facilitate surgical decisions. Although there are tools for coregistration of preoperative MRI and postoperative CT scans, identification, sorting, and labeling of SEEG ECs is often performed manually, which is resource intensive. We report development and validation of a software named Fast Automated SEEG Electrode Contact Identification and Labeling Ensemble (FASCILE). METHODS: FASCILE is written in Python 3.8.3 and employs a novel automated method for identifying ECs, assigning them to respected SEEG electrodes, and labeling. We compared FASCILE with our clinical process of identifying, sorting, and labeling ECs, by computing localization error in anteroposterior, superoinferior, and lateral dimensions. We also measured mean Euclidean distances between ECs identified by FASCILE and the clinical method. We compared time taken for EC identification, sorting, and labeling for the software developer using FASCILE, a first-time clinical user using FASCILE, and the conventional clinical process. RESULTS: Validation in 35 consecutive DRE patients showed a mean overall localization error of 0.73 ± 0.15 mm. FASCILE required 10.7 ± 5.5 min/patient for identifying, sorting, and labeling ECs by a first-time clinical user, compared to 3.3 ± 0.7 h/patient required for the conventional clinical process. CONCLUSION: Given the accuracy, speed, and ease of use, we expect FASCILE to be used frequently for SEEG-driven epilepsy surgery. It is freely available for noncommercial use. FASCILE is specifically designed to expedite localization of ECs, assigning them to respective SEEG electrodes (sorting), and labeling them and not for coregistration of CT and MRI data as there are commercial software available for this purpose.

Genetic Testing in Epilepsy.

Because of next-generation sequencing and the discovery of many new causative genes, genetic testing in epilepsy patients has become widespread. Pathologic variants resulting in epilepsy cause a variety of changes that can be broadly classified into syndromic disorders (i.e., chromosomal abnormalities), metabolic disorders, brain malformations, and abnormal cellular signaling. Here, we review the available genetic testing, reasons to pursue genetic testing, common genetic causes of epilepsy, the data behind what patients are found to have genetic epilepsies based on current testing, and discussing these results with patients. We propose an algorithm for testing patients with epilepsy to maximize yield and limit costs based on their phenotype (including electroencephalography and magnetic resonance imaging findings), age of seizure onset, and presence of other neurologic comorbidities. Being able to discern which type of genetic testing to order, using that information to give targeted and cost-effective patient care, and interpreting results accurately will be a crucial skill for the modern neurologist.

"My Eyes Have Nothing to Do With How My Legs Move": Individuals With Visual Impairments' Experiences With Learning to Run.

The purpose of this study was to describe the reflections of adults with visual impairments about learning to run during K-12 physical education. An interpretative phenomenological analysis research approach was used, and eight adults (age 22-35 years) with visual impairments served as participants. Primary data sources were semistructured, audiotaped telephone interviews and reflective interview notes. Based on a thematic data analysis process, two themes were developed: (a) "I wouldn't expect anything better from you": running instruction in physical education and (b) "You look like the guy in the crosswalk signal": making up for the shortcomings of physical education. The narratives portraying these themes highlight the lack of instruction that took place in physical education, and the fact that no running instruction occurred at all. These findings indicate that professionals working with individuals with visual impairments should use instructional strategies that will allow for maximum access to learning fundamental movement skills such as running.

Location: A surrogate for personalized treatment of sodium channelopathies.

Voltage-gated sodium channels have been implicated in numerous inherited paroxysmal disorders of the nervous system, muscle, and heart. Our goal is to provide a framework that helps neurologists understand the clinical and treatment implications of sodium channel variants they encounter in clinical practice. This will be accomplished through our objectives of (1) recognizing the relationship between location of a missense sodium channel gene variant and its effect on channel function, and (2) categorizing clinical phenotype based on functional effect of a variant. The relationship between location, function, and treatment response is also discussed. These interactions can be illustrated by the sodium channelopathies seen in people with epilepsy but generalize beyond that disorder. Ann Neurol 2018;83:1-9.

Development of information sharing in language neocortex in childhood-onset drug-resistant epilepsy.

OBJECTIVE: We studied age-related dynamics of information sharing among cortical language regions with electrocorticographic high-gamma modulation during picture-naming and story-listening tasks. METHODS: Seventeen epilepsy patients aged 4-19 years, undergoing extraoperative monitoring with left-hemispheric subdural electrodes, were included. Mutual information (MI), a nondirectional measure of shared information, between 16 pairs of cortical regions of interest, was computed from trial-averaged 70-150 Hz power modulations during language tasks. Impact of age on pairwise MI between language regions and their determinants were ascertained with regression analysis. RESULTS: During picture naming, significant increase in MI with age was seen between pairwise combinations of Broca's area, inferior precentral gyrus (iPreC), and frontal association cortex (FAC); Wernicke's area and posterior association cortex (PAC); and Broca's and Wernicke's areas. During story listening, significant age-related increase in MI was seen between Wernicke's area and either Broca's area, FAC, or PAC; and between Broca's area and FAC. Significant impact of baseline intelligence quotient was seen on the relationship between age and MI for all pairs, except between Broca's area and iPreC. The mean MI was higher during naming compared to listening for pairs including iPreC with Broca's area, FAC, or PAC and was lower for pairs of Wernicke's area or PAC with anterior language regions. SIGNIFICANCE: Information sharing matures with age "within" frontal and temporoparietal language cortices, and "between" Broca's and Wernicke's areas. This study provides evidence for distinct patterns of developmental plasticity within perisylvian language cortex and has implications for planning epilepsy surgery.

A model for visual naming based on spatiotemporal dynamics of ECoG high-gamma modulation.

OBJECTIVE: We studied spatiotemporal dynamics of electrocorticographic (ECoG) high-gamma modulation (HGM) during visual naming. METHODS: In 8 patients, aged 4-19 years, with left hemisphere subdural electrodes, propagation of ECoG HGM during overt visual naming was mapped with trial-averaged time-frequency analysis. Group-level synthesis was performed by transforming all electrodes to a standard space and assigning cortical parcels based on a reference atlas. RESULTS: After image display following cortical parcels were activated: inferior occipital, caudal angular, fusiform, and middle temporal gyri, and superior temporal sulcus [0-400 ms]; rostral pars triangularis (A45r), inferior frontal sulcus, caudal dorsolateral premotor cortex (A6cdl) [300-600 ms]; caudal ventrolateral premotor cortex (A6cvl), caudal pars triangularis (A45c), pars opercularis (A44) [400-800 ms]; primary sensorimotor cortex [600-1400 ms], with most prominent HGM in glossolaryngeal region (A4tl). Lastly, auditory cortex (A41/A42) and superior temporal gyrus (A22) were activated [900 ms-1.4 s]. After 1.5 s, HGM decreased globally, except in ventrolateral premotor cortex. CONCLUSIONS: During visual naming, ECoG HGM shows a sequential but overlapping spatiotemporal course through cortical regions. We provide neurophysiologic validation for a model of visual naming incorporating both modular and distributed cortical processing. This may explain cognitive deficits seen in some patients after surgery involving HGM naming sites outside perisylvian language cortex.

Electrical stimulation mapping of language with stereo-EEG.

OBJECTIVE: We prospectively validated stereo-electroencephalography (EEG) electrical stimulation mapping (ESM) of language against a reference standard of meta-analytic functional magnetic resonance imaging (fMRI) framework (Neurosynth). METHODS: Language ESM was performed using 50 Hz, biphasic, bipolar, stimulation at 1-8 mA, with a picture naming task. Electrode contacts (ECs) were scored as ESM+ if ESM interfered with speech/language function. For each patient, presurgical MRI was transformed to a standard space and coregistered with computed tomographic (CT) scan to obtain EC locations. After whole-brain parcellation, this fused image data were intersected with three-dimensional language fMRI (Neurosynth), and each EC was classified as lying within/outside the fMRI language parcel. Diagnostic odds ratio (DOR) and other indices were estimated. Current thresholds for language inhibition and after-discharges (ADs) were analyzed using multivariable linear mixed models. RESULTS: In 10 patients (5 females), aged 5.4-21.2 years, speech/language inhibition was noted with ESM on 87/304 (29%) ECs. Stereo-EEG language ESM was a valid classifier of fMRI (Neurosynth) language sites (DOR: 9.02, p < 0.0001), with high specificity (0.87) but poor sensitivity (0.57). Similar diagnostic indices were seen for ECs in frontal or posterior regions, and gray or white matter. Language threshold (3.1 ±â€¯1.5 mA) was lower than AD threshold (4.0 ±â€¯2.0 mA, p = 0.0001). Language and AD thresholds decreased with age and intelligence quotient. Electrical stimulation mapping triggered seizures/auras represented patients' habitual semiology with 1 Hz stimulation. CONCLUSIONS: Stereo-EEG ESM can reliably identify cerebral parcels with/without language function but may under detect all language sites. We suggest a 50-Hz stimulation protocol for language ESM with stereo-EEG.

Pharmacogenetics of antiepileptic drug efficacy in childhood absence epilepsy.

OBJECTIVE: To determine whether common polymorphisms in CACNA1G, CACNA1H, CACNA1I, and ABCB1 are associated with differential short-term seizure outcome in childhood absence epilepsy (CAE). METHODS: Four hundred forty-six CAE children in a randomized double-blind trial of ethosuximide, lamotrigine, and valproate had short-term seizure outcome determined. Associations between polymorphisms (minor allele frequency ≥ 15%) in 4 genes and seizure outcomes were assessed. In vitro electrophysiology on transfected CACNA1H channels determined impact of 1 variant on T-type calcium channel responsiveness to ethosuximide. RESULTS: Eighty percent (357 of 446) of subjects had informative short-term seizure status (242 seizure free, 115 not seizure free). In ethosuximide subjects, 2 polymorphisms (CACNA1H rs61734410/P640L, CACNA1I rs3747178) appeared more commonly among not-seizure-free participants (p = 0.011, odds ratio [OR] = 2.63, 95% confidence limits [CL] = 1.25-5.56; p = 0.026, OR = 2.38, 95% CL = 1.11-5.00). In lamotrigine subjects, 1 ABCB1 missense polymorphism (rs2032582/S893A; p = 0.015, OR = 2.22, 95% CL = 1.16-4.17) was more common in not-seizure-free participants, and 2 CACNA1H polymorphisms (rs2753326, rs2753325) were more common in seizure-free participants (p = 0.038, OR = 0.52, 95% CL = 0.28-0.96). In valproate subjects, no common polymorphisms were associated with seizure status. In vitro electrophysiological studies showed no effect of the P640L polymorphism on channel physiology in the absence of ethosuximide. Ethosuximide's effect on rate of decay of CaV 3.2 was significantly less for P640L channel compared to wild-type channel. INTERPRETATION: Four T-type calcium channel variants and 1 ABCB1 transporter variant were associated with differential drug response in CAE. The in vivo P640L variant's ethosuximide effect was confirmed by in vitro electrophysiological studies. This suggests that genetic variation plays a role in differential CAE drug response. Ann Neurol 2017;81:444-453.

Modeling pathogenesis and treatment response in childhood absence epilepsy.

OBJECTIVE: Childhood absence epilepsy (CAE) is a genetic generalized epilepsy syndrome with polygenic inheritance, with genes for γ-aminobutyric acid (GABA) receptors and T-type calcium channels implicated in the disorder. Previous studies of T-type calcium channel electrophysiology have shown genetic changes and medications have multiple effects. The aim of this study was to use an established thalamocortical computer model to determine how T-type calcium channels work in concert with cortical excitability to contribute to pathogenesis and treatment response in CAE. METHODS: The model is comprised of cortical pyramidal, cortical inhibitory, thalamocortical relay, and thalamic reticular single-compartment neurons, implemented with Hodgkin-Huxley model ion channels and connected by AMPA, GABAA , and GABAB synapses. Network behavior was simulated for different combinations of T-type calcium channel conductance, inactivation time, steady state activation/inactivation shift, and cortical GABAA conductance. RESULTS: Decreasing cortical GABAA conductance and increasing T-type calcium channel conductance converted spindle to spike and wave oscillations; smaller changes were required if both were changed in concert. In contrast, left shift of steady state voltage activation/inactivation did not lead to spike and wave oscillations, whereas right shift reduced network propensity for oscillations of any type. SIGNIFICANCE: These results provide a window into mechanisms underlying polygenic inheritance in CAE, as well as a mechanism for treatment effects and failures mediated by these channels. Although the model is a simplification of the human thalamocortical network, it serves as a useful starting point for predicting the implications of ion channel electrophysiology in polygenic epilepsy such as CAE.