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.

Despite ongoing advances in our understanding of local single-cellular and network-level activity of neuronal populations in the human brain, extraordinarily little is known about their "intermediate" microscale local circuit dynamics. Here, we utilized ultra-high-density microelectrode arrays and a rare opportunity to perform intracranial recordings across multiple cortical areas in human participants to discover three distinct classes of cortical activity that are not locked to ongoing natural brain rhythmic activity. The first included fast waveforms similar to extracellular single-unit activity. The other two types were discrete events with slower waveform dynamics and were found preferentially in upper cortical layers. These second and third types were also observed in rodents, nonhuman primates, and semi-chronic recordings from humans via laminar and Utah array microelectrodes. The rates of all three events were selectively modulated by auditory and electrical stimuli, pharmacological manipulation, and cold saline application and had small causal co-occurrences. These results suggest that the proper combination of high-resolution microelectrodes and analytic techniques can capture neuronal dynamics that lay between somatic action potentials and aggregate population activity. Understanding intermediate microscale dynamics in relation to single-cell and network dynamics may reveal important details about activity in the full cortical circuit.

CDKL5 deficiency disorder (CDD) is an X-linked pharmacoresistant neurogenetic disorder characterized by global developmental delays and uncontrolled seizures. Fenfluramine (FFA), an antiseizure medication (ASM) indicated for treating convulsive seizures in Dravet syndrome, was assessed in six patients (five female; 83%) with CDD whose seizures had failed 5-12 ASMs or therapies. Median age at enrollment was 6.5 years (range: 2-26 years). Mean FFA treatment duration was 5.3 months (range: 2-9 months) at 0.4 mg/kg/day (n = 2) or 0.7 mg/kg/day (n = 4; maximum: 26 mg/day). One patient had valproate added for myoclonic seizures. The ASM regimens of all other patients were stable. Among five patients with tonic-clonic seizures, FFA treatment resulted in a median 90% reduction in frequency (range: 86%-100%). Tonic seizure frequency was reduced by 50%-60% in two patients with this seizure type. One patient experienced fewer myoclonic seizures; one patient first developed myoclonic seizures on FFA, which were controlled with valproate. Adverse events were reported in two patients. The patient with added valproate experienced lethargy; one patient had decreased appetite and flatus. No patient developed valvular heart disease or pulmonary arterial hypertension. Our preliminary results suggest that FFA may be a promising ASM for CDD. Randomized clinical trials are warranted.

OBJECTIVE:Paroxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and background EEG oscillations. METHODS:Confounding factors, including the heterogeneous etiology of epilepsies and medication effects, hamper studies on background brain activity in people with epilepsy. To overcome this limitation, we compared genetic data from a genome-wide association study (GWAS) on epilepsy (n = 12 803 people with epilepsy and 24 218 controls) with that from a GWAS on background EEG (n = 8425 subjects without epilepsy), in which background EEG oscillation power was quantified in four different frequency bands: alpha, beta, delta, and theta. We replicated our findings in an independent epilepsy replication dataset (n = 4851 people with epilepsy and 20 428 controls). To assess the genetic overlap between these phenotypes, we performed genetic correlation analyses using linkage disequilibrium score regression, polygenic risk scores, and Mendelian randomization analyses. RESULTS:Our analyses show strong genetic correlations of genetic generalized epilepsy (GGE) with background EEG oscillations, primarily in the beta frequency band. Furthermore, we show that subjects with higher beta and theta polygenic risk scores have a significantly higher risk of having generalized epilepsy. Mendelian randomization analyses suggest a causal effect of GGE genetic liability on beta oscillations. SIGNIFICANCE/CONCLUSIONS:Our results point to shared biological mechanisms underlying background EEG oscillations and the susceptibility for GGE, opening avenues to investigate the clinical utility of background EEG oscillations in the diagnostic workup of epilepsy.

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.

INTRODUCTION/BACKGROUND:In-scanner head motion is a common cause of reduced image quality in neuroimaging, and causes systematic brain-wide changes in cortical thickness and volumetric estimates derived from structural MRI scans. There are few widely available methods for measuring head motion during structural MRI. Here, we train a deep learning predictive model to estimate changes in head pose using video obtained from an in-scanner eye tracker during an EPI-BOLD acquisition with participants undertaking deliberate in-scanner head movements. The predictive model was used to estimate head pose changes during structural MRI scans, and correlated with cortical thickness and subcortical volume estimates. METHODS:). We evaluated the utility of our technique by assessing the relationship between video-based head pose changes during structural MRI and (i) vertex-wise cortical thickness and (ii) subcortical volume estimates. RESULTS:Video-based head pose estimates were significantly correlated with ground truth head pose changes estimated from EPI-BOLD imaging in a hold-out dataset. We observed a general brain-wide overall reduction in cortical thickness with increased head motion, with some isolated regions showing increased cortical thickness estimates with increased motion. Subcortical volumes were generally reduced in motion affected scans. CONCLUSIONS:We trained a predictive model to estimate changes in head pose during structural MRI scans using in-scanner eye tracker video. The method is independent of individual image acquisition parameters and does not require markers to be to be fixed to the patient, suggesting it may be well suited to clinical imaging and research environments. Head pose changes estimated using our approach can be used as covariates for morphometric image analyses to improve the neurobiological validity of structural imaging studies of brain development and disease.

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.