Faculty Bibliography

Interictal epileptiform discharges (IEDs) can impair memory. The properties of IEDs most detrimental to memory, however, are undefined. We studied the impact of temporal and spatial characteristics of IEDs on list learning. Subjects completed a memory task during intracranial EEG recordings including hippocampal depth and temporal neocortical subdural electrodes. Subjects viewed a series of objects, and after a distracting task, recalled the objects from the list. The impacts of IED presence, duration, and propagation to neocortex during encoding of individual stimuli were assessed. The effects of IED total number and duration during maintenance and recall periods on delayed recall performance were also determined. The influence of IEDs during recall was further investigated by comparing the likelihood of IEDs preceding correctly recalled items vs. periods of no verbal response. Across 6 subjects, we analyzed 28 hippocampal and 139 lateral temporal contacts. Recall performance was poor, with a median of 17.2% correct responses (range 10.4-21.9%). Interictal epileptiform discharges during encoding, maintenance, and recall did not significantly impact task performance, and there was no significant difference between the likelihood of IEDs during correct recall vs. periods of no response. No significant effects of discharge duration during encoding, maintenance, or recall were observed. Interictal epileptiform discharges with spread to lateral temporal cortex during encoding did not adversely impact recall. A post hoc analysis refining model assumptions indicated a negative impact of IED count during the maintenance period, but otherwise confirmed the above results. Our findings suggest no major effect of hippocampal IEDs on list learning, but study limitations, such as baseline hippocampal dysfunction, should be considered. The impact of IEDs during the maintenance period may be a focus of future research.

Depression is associated with adverse outcomes in epilepsy but is undertreated in this population. Project UPLIFT, a telephone-based depression self-management program, was developed for adults with epilepsy and has been shown to reduce depressive symptoms in English-speaking patients. There remains an unmet need for accessible mental health programs for Hispanic adults with epilepsy. The purpose of this study was to evaluate the feasibility, acceptability, and effects on depressive symptoms of a culturally adapted version of UPLIFT for the Hispanic community. Hispanic patients with elevated depressive symptoms (n = 72) were enrolled from epilepsy clinics in New York City and randomized to UPLIFT or usual care. UPLIFT was delivered in English or Spanish to small groups in eight weekly telephone sessions. Feasibility was assessed by recruitment, retention, and adherence rates and acceptability was assessed by self-reported satisfaction with the intervention. Depressive symptoms (PHQ-9 scores) were compared between study arms over 12 months. The mean age was 43.3±11.3, 71% of participants were female and 67% were primary Spanish speakers. Recruitment (76% consent rate) and retention rates (86-93%) were high. UPLIFT participants completed a median of six out of eight sessions and satisfaction ratings were high, but rates of long-term practice were low. Rates of clinically significant depressive symptoms (PHQ-9 ≥5) were lower in UPLIFT versus usual care throughout follow-up (63% vs. 72%, 8 weeks; 40% vs. 70%, 6 months; 47% vs. 70%, 12 months). Multivariable-adjusted regressions demonstrated statistically significant differences at 6 months (OR = 0.24, 95% CI, 0.06-0.93), which were slightly reduced at 12 months (OR = 0.30, 95% CI, 0.08-1.16). Results suggest that UPLIFT is feasible and acceptable among Hispanic adults with epilepsy and demonstrate promising effects on depressive symptoms. Larger trials in geographically diverse samples are warranted.

We describe the spatiotemporal course of cortical high-gamma activity, hippocampal ripple activity and interictal epileptiform discharges during an associative memory task in 15 epilepsy patients undergoing invasive EEG. Successful encoding trials manifested significantly greater high-gamma activity in hippocampus and frontal regions. Successful cued recall trials manifested sustained high-gamma activity in hippocampus compared to failed responses. Hippocampal ripple rates were greater during successful encoding and retrieval trials. Interictal epileptiform discharges during encoding were associated with 15% decreased odds of remembering in hippocampus (95% confidence interval 6-23%). Hippocampal interictal epileptiform discharges during retrieval predicted 25% decreased odds of remembering (15-33%). Odds of remembering were reduced by 25-52% if interictal epileptiform discharges occurred during the 500-2000-ms window of encoding or by 41% during retrieval. During encoding and retrieval, hippocampal interictal epileptiform discharges were followed by a transient decrease in ripple rate. We hypothesize that interictal epileptiform discharges impair associative memory in a regionally and temporally specific manner by decreasing physiological hippocampal ripples necessary for effective encoding and recall. Because dynamic memory impairment arises from pathological interictal epileptiform discharge events competing with physiological ripples, interictal epileptiform discharges represent a promising therapeutic target for memory remediation in patients with epilepsy.

OBJECTIVE:Brain functions such as perception, motor control, learning, and memory arise from the coordinated activity of neuronal assemblies distributed across multiple brain regions. While major progress has been made in understanding the function of individual neurons, circuit interactions remain poorly understood. A fundamental obstacle to deciphering circuit interactions is the limited availability of research tools to observe and manipulate the activity of large, distributed neuronal populations in humans. Here we describe the development, validation, and dissemination of flexible, high-resolution, thin-film (TF) electrodes for recording neural activity in animals and humans. APPROACH/METHODS:We leveraged standard flexible printed-circuit manufacturing processes to build high-resolution TF electrode arrays. We used biocompatible materials to form the substrate (liquid crystal polymer; LCP), metals (Au, PtIr, and Pd), molding (medical-grade silicone), and 3D-printed housing (nylon). We designed a custom, miniaturized, digitizing headstage to reduce the number of cables required to connect to the acquisition system and reduce the distance between the electrodes and the amplifiers. A custom mechanical system enabled the electrodes and headstages to be pre-assembled prior to sterilization, minimizing the setup time required in the operating room. PtIr electrode coatings lowered impedance and enabled stimulation. High-volume, commercial manufacturing enables cost-effective production of LCP-TF electrodes in large quantities. MAIN RESULTS/RESULTS:Our LCP-TF arrays achieve 25× higher electrode density, 20× higher channel count, and 11× reduced stiffness than conventional clinical electrodes. We validated our LCP-TF electrodes in multiple human intraoperative recording sessions and have disseminated this technology to >10 research groups. Using these arrays, we have observed high-frequency neural activity with sub-millimeter resolution. SIGNIFICANCE/CONCLUSIONS:Our LCP-TF electrodes will advance human neuroscience research and improve clinical care by enabling broad access to transformative, high-resolution electrode arrays.

We evaluated baseline sudden unexpected death in epilepsy (SUDEP) knowledge and counseling practices among national and international adult neurology trainees with a 12-question online survey. The survey was emailed to all 169 U.S. neurology residency program directors and select international neurology/epilepsy program leaders. Program leaders were asked to distribute the survey link to adult neurology trainees. There were 161 respondents in the U.S. and 171 respondents outside the U.S. The latter were from 25 Latin American, European, Asian, and African countries. More than 90% of all trainees reported familiarity with SUDEP definition. Familiarity with SUDEP risk factors and mitigation measures ranged from 56% to 67% across these groups, with international trainees slightly more familiar with risk factors (67% vs. 61% in U.S.) but less familiar with mitigation measures (56% vs. 63% in U.S.). Approximately half of national (49%) and international (54%) trainees rarely or never counseled patients on SUDEP. Less than half of national (44%) and international (41%) trainees were educated about SUDEP. Many U.S. and adult neurology trainees remain unfamiliar with SUDEP risk factors and mitigation measures. Sudden unexpected death in epilepsy counseling falls below recommended standards. We suggest that worldwide neurology training programs' leaderships consider improving SUDEP education targeted at adult neurology trainees.

OBJECTIVE:To identify the molecular signaling pathways underlying sudden unexpected death in epilepsy (SUDEP) and high-risk SUDEP compared to epilepsy control patients. METHODS:For proteomics analyses, we evaluated the hippocampus and frontal cortex from microdissected post-mortem brain tissue of 12 SUDEP and 14 non-SUDEP epilepsy patients. For transcriptomics analyses, we evaluated hippocampus and temporal cortex surgical brain tissue from mesial temporal lobe epilepsy (MTLE) patients: 6 low-risk and 8 high-risk SUDEP as determined by a short (< 50 seconds) or prolonged (≥ 50 seconds) postictal generalized EEG suppression (PGES) that may indicate severely depressed brain activity impairing respiration, arousal, and protective reflexes. RESULTS:In autopsy hippocampus and cortex, we observed no proteomic differences between SUDEP and non-SUDEP epilepsy patients, contrasting with our previously reported robust differences between epilepsy and non-epilepsy control patients. Transcriptomics in hippocampus and cortex from surgical epilepsy patients segregated by PGES identified 55 differentially expressed genes (37 protein-coding, 15 lncRNAs, three pending) in hippocampus. CONCLUSION/CONCLUSIONS:The SUDEP proteome and high-risk SUDEP transcriptome were similar to other epilepsy patients in hippocampus and frontal cortex, consistent with diverse epilepsy syndromes and comorbidities associated with SUDEP. Studies with larger cohorts and different epilepsy syndromes, as well as additional anatomic regions may identify molecular mechanisms of SUDEP.

BACKGROUND:Many electroencephalography (EEG) based seizure detection paradigms have been developed and validated over the last two decades. The majority of clinical approaches use scalp or intracranial EEG electrodes. Scalp EEG is limited by patient discomfort and short duration of useful EEG signals. Intracranial EEG involves an invasive surgical procedure associated with significant risk making it unsuitable for widespread use as a practical clinical biometric. A less invasive EEG monitoring approach, that is between invasive intracranial procedures and noninvasive methods, would fill the need of a safe, accurate, chronic (ultra-long term) and objective seizure detection method. We present validation of a continuous EEG seizure detection paradigm using human single-channel EEG recordings from subcutaneously placed electrodes that could be used to fulfill this need. METHODS:Ten-minute long sleep, awake and ictal EEG epochs obtained from 21 human subjects with subscalp electrodes and validated against simultaneous iEEG recordings were analyzed by three experienced clinical neurophysiologists. The 201subscalp EEG time series epochs where classified as diagnostic for awake, asleep, or seizure by the clinicians who were blinded to all other information. Seventy of the epochs were classified in this way as representing seizure activity. A subject specific seizure detection algorithm was trained and then evaluated offline for each patient in the data set using the expert consensus classification as the gold standard. RESULTS:The average seizure detection performance of the algorithm across 21 subjects exceeded 90 % accuracy: 97 % sensitivity, 91 % specificity, and 93 % accuracy. For 19 of 21 patient datasets the algorithm achieved 100 % sensitivity. For 15 of 21 patients, the algorithm achieved 100 % specificity. For 13 of 21 patients the algorithm achieved 100 % accuracy. COMPARISON/UNASSIGNED:No comparable published methods are available for subgaleal EEG seizure detection. CONCLUSIONS:These findings suggest that a simple seizure detection algorithm using subcutaneous EEG signals could provide sufficient accuracy and clinical utility for use in a low power, long-term subcutaneous brain monitoring device. Such a device would fill a need for a large number of people with epilepsy who currently have no means for accurately quantifying their seizures thereby providing important information to healthcare providers not currently available.

Image labeling using convolutional neural networks (CNNs) are a template-free alternative to traditional morphometric techniques. We trained a 3D deep CNN to label the hippocampus and amygdala on whole brain 700 μm isotropic 3D MP2RAGE MRI acquired at 7T. Manual labels of the hippocampus and amygdala were used to (i) train the predictive model and (ii) evaluate performance of the model when applied to new scans. Healthy controls and individuals with epilepsy were included in our analyses. Twenty-one healthy controls and sixteen individuals with epilepsy were included in the study. We utilized the recently developed DeepMedic software to train a CNN to label the hippocampus and amygdala based on manual labels. Performance was evaluated by measuring the dice similarity coefficient (DSC) between CNN-based and manual labels. A leave-one-out cross validation scheme was used. CNN-based and manual volume estimates were compared for the left and right hippocampus and amygdala in healthy controls and epilepsy cases. The CNN-based technique successfully labeled the hippocampus and amygdala in all cases. Mean DSC = 0.88 ± 0.03 for the hippocampus and 0.8 ± 0.06 for the amygdala. CNN-based labeling was independent of epilepsy diagnosis in our sample (p = .91). CNN-based volume estimates were highly correlated with manual volume estimates in epilepsy cases and controls. CNNs can label the hippocampus and amygdala on native sub-mm resolution MP2RAGE 7T MRI. Our findings suggest deep learning techniques can advance development of morphometric analysis techniques for high field strength, high spatial resolution brain MRI.

OBJECTIVE:People with epilepsy experience increased rates of sexual dysfunction, often affecting quality of life. Sexual dysfunction may result from the underlying disorder, antiseizure or other medications, or comorbid psychosocial factors. This study evaluated the incidence and clinical associations of sexual dysfunction in adult epilepsy patients. METHODS:89 epilepsy patients 18 years and older admitted to the New York University Comprehensive Epilepsy Center epilepsy monitoring unit between 2016 and 2018 completed a survey on sexual functioning. The survey included demographic, clinical, and sexual functioning information with a validated measure of sexual function (the Arizona Sexual Experiences Scale (ASEX). RESULTS:Of 89 surveys completed, 15 (16.9 %) patients had discussed sexual functioning with a medical professional and 20 (22.5 %) reported sexual dysfunction. For the group, the mean ASEX score was 13.6 (SD 4.8). 59 (66.3 %) participants reported not being asked about sexual health by their doctor or nurse practitioner in the last year. The two independent predictors of sexual dysfunction were self-identifying as overweight/obese (OR 6.1, CI 1.4-26.5, P = 0.02) or taking strong enzyme-inducing antiseizure medications (OR 7.8, CI 1.4-44.9, P = 0.02). Other factors such as age, relationship status, duration of epilepsy, the presence of depression or anxiety, cardiovascular risk factors, and opioid/stimulant use, did not predict sexual dysfunction. SIGNIFICANCE/CONCLUSIONS:Our study showed that sexual dysfunction is common in epilepsy patients but infrequently discussed by medical professionals. Two modifiable risk factors, being overweight or taking strong enzyme-inducing antiseizure medications, were independently associated with sexual dysfunction, suggesting interventions to potentially improve sexual health.

OBJECTIVE:Ataluren is a compound that reads through premature stop codons and increases protein expression by increasing translation without modifying transcription or mRNA stability. We investigated the safety and efficacy of ataluren in children with nonsense variants causing Dravet Syndrome (DS) and CDKL5 Deficiency Syndrome (CDD). METHODS:This single-center double-blind, placebo-controlled crossover trial randomized subjects to receive ataluren or placebo for 12 weeks (period 1), a 4-week washout, then another 12-week treatment (period 2). The primary outcome was ataluren's safety profile. The secondary outcome measures were (1) changes in convulsive and/or drop seizure frequency and (2) changes in minor seizure types during ataluren treatment compared to placebo. Exploratory objectives assessed changes in cognitive, motor, and behavioral function as well as quality of life during ataluren therapy. RESULTS:We enrolled seven subjects with DS and eight subjects with CDD. Three treatment-related adverse events (AE) occurred during the blinded phases. Two subjects withdrew due to AE. Ataluren was not effective in reducing seizure frequency or improving cognitive, motor, or behavioral function or quality of life in subjects with either DS or CDD due to nonsense variants. Limitations included a small sample size and 12-week treatment phase, possibly too short to identify a disease-modifying effect. SIGNIFICANCE/CONCLUSIONS:There was no difference between ataluren and placebo; ataluren is not an effective therapy for seizures or other disorders in children with DS or CDD due to nonsense variants. There were no drug-related serious AE during the double-blind period, consistent with ataluren's favorable safety profile in larger studies. (Funded by Epilepsy Foundation, Dravet Syndrome Foundation, Finding A Cure for Seizures and Epilepsy and PTC Therapeutics, Inc.; ClinicalTrials.gov number, NCT02758626).