Faculty Bibliography

Bridging clinical and basic research is increasingly recognized as a priority in the epilepsy field, yet opportunities for integration remain limited by the time, space, and financial constraints of scientific meetings. To address this gap, the Research Task Force of the Young Epilepsy Section of the International League Against Epilepsy (ILAE-YES) organized a free global webinar series designed to promote translational dialogue and provide accessible research education for early-career clinicians, researchers, and physician-scientists. Based on a preliminary ILAE-YES community survey, eight topics of high interest were selected: (1) epigenetics, (2) EEG biomarkers, (3) ictogenesis, (4) thalamo-cortical network, (5) sudden unexpected death in epilepsy, (6) neurodegeneration and seizures, (7) seizure-related brain damage, and (8) neuromodulation therapy. From March to June 2025, eight live Zoom webinars were held, each featuring expert speakers representing both basic science and clinical perspectives, with recordings made available as unlisted YouTube videos to ensure on-demand access. A total of 1199 individuals from 116 countries registered, 63.2% from low- and middle-income countries. Live attendance averaged 50 participants per session, and the mean session duration was 71.6 min, including an average of 16 min of discussion. Post-session feedback was obtained from 285 respondents; overall satisfaction was high, with 93.3% rating their experience as 4 or 5 on a 5-point Likert scale. Speaker satisfaction was similarly high (95.4%), and 80.0% reported gaining new research ideas. Although access to YouTube and Google Forms may have limited participation in some regions, the series provided an inclusive and globally accessible platform. These findings demonstrated that free, discussion-focused online webinars represent a scalable, low-cost, and reproducible educational model that can effectively promote international engagement and integration between clinical and basic epilepsy research, aligning with the ILAE's global educational mission and complementing WHO IGAP priorities on capacity building and equitable access to knowledge. PLAIN LANGUAGE SUMMARY: Bringing together basic science and clinical research is important for improving epilepsy care, but many researchers have limited opportunities to learn across these fields. We organized a free global webinar series that helped early-career clinicians and researchers learn about epilepsy research by combining scientific talks with clinical perspectives and open discussion. More than 1100 participants from over 100 countries joined, and most reported high satisfaction and gaining new research ideas. These results show that free, discussion-based online webinars can provide an accessible way to support research education and international learning in epilepsy.

INTRODUCTION/BACKGROUND:The long-standing cholinergic hypothesis posits that cholinergic signaling is uniformly deficient in Alzheimer's disease (AD) and Down syndrome (DS). We tested the hypothesis that this deficiency occurs primarily late in disease, while early stages involve excessive cholinergic signaling, with distinct implications for memory. METHODS:Tg2576 (AD model; n = 38), Ts65Dn (DS model; n = 14), and wild-type (WT; n = 17) mice at young (3 to 4 months) and old (>14 months) ages received treatments to reduce cholinergic signaling (medial septum chemogenetic inhibition, muscarinic antagonist scopolamine) or enhance it (acetylcholinesterase inhibitor donepezil). Memory assessments used novel object recognition. RESULTS:Anticholinergic manipulations restored memory in young Tg2576 and Ts65Dn mice but impaired age-matched WT mice. Conversely, donepezil improved the memory of old Tg2576, Ts65Dn, and WT but not young Tg2576 and Ts65Dn animals. DISCUSSION/CONCLUSIONS:These findings refine and challenge the cholinergic hypothesis, revealing for the first time a functional shift from cholinergic hyperactivity driving early cognitive impairment to late-stage degeneration requiring enhancement.

High-frequency oscillations (HFOs) were discovered more than 20 years ago, and since then they have been studied intensively in the context of epilepsy. HFOs encompass a broad spectrum of oscillations, typically ranging from 80 Hz to several kHz, that include both normal and pathological oscillations, documented in people with epilepsy and animal models. HFOs have drawn considerable attention due to their prominent roles in epileptogenesis, ictogenesis, and functional organization of epileptic tissue. We provide historical background on HFOs in epilepsy and summarize the current state of knowledge, synthesizing clinical and basic science content from the Third International Workshop on HFOs in Epilepsy. Over the years, the field has evolved from single-center analysis of HFOs on invasive electroencephalographic recordings to recent multicenter studies and meta-analysis, which have tempered the conviction or hope that HFOs are uniform, "one event fits all," stand-alone biomarkers. Instead, association of HFOs with other electrophysiological phenomena such as interictal spikes, seizures, and signal features like entropy have highlighted new ways to identify epileptogenic tissue. Advances in recording and analytical tools have significantly expanded their potential applications in both clinical and basic science settings. Several recent publications focus on how scalp HFOs can illuminate disease propensity, severity, and therapy responses. Moreover, it was recently discovered that HFOs are also present in experimental models of Alzheimer's disease, and research is ongoing regarding their relations to the HFOs found in epilepsy. Together, these developments highlight that HFOs represent an evolving research area, with significant inroads made over the years. Yet, key gaps in knowledge remain, and we propose five benchmark areas that warrant future research and advancement.

This article reflects key themes and discussions from the American Epilepsy Society Annual Meeting 2025, Epilepsy and Aging Special Interest Group (SIG) session entitled "Multimodal Biomarkers of Epilepsy in Older Adults." The perspectives presented here are intended to highlight emerging priorities for the field. Epilepsy in older adults is the fastest-growing segment of the epilepsy population worldwide. Despite rising incidence, prevalence, and substantial morbidity, care for late-onset epilepsy (LOE) remains anchored to a seizure-centric framework that inadequately addresses the broader consequences of seizures in later life. Older adults with LOE face markedly increased risks of dementia, mortality, and stroke, yet are frequently excluded from epilepsy and Alzheimer's disease (AD) clinical trials. Patient-centered outcomes, including cognition, sleep, function, and quality of life, remain underprioritized. In this article, we argue that LOE requires multimodal biomarkers and multidisciplinary care. We contend that LOE should be reframed as a biologically meaningful warning signal of network vulnerability and overlapping brain pathology, rather than a late-life complication to be managed pragmatically. Cognitive dysfunction is common, heterogeneous, and often precedes overt neurodegenerative diagnoses, positioning cognition as an early clinical signal. Neuroimaging and electrophysiological evidence further place LOE along a continuum intersecting cardiovascular risk factors, sleep disruption, and AD biology, challenging traditional silos between epilepsy and dementia care. We argue for greater inclusion of older adults in antiseizure medication trials and for the inclusion of individuals with epilepsy in AD clinical trials. We propose a brain-health-centered framework for LOE that integrates longitudinal electroencephalography, particularly sleep-inclusive strategies, routine cognitive screening with targeted neuropsychological assessment, neuroimaging, vascular and sleep risk evaluation, and selective use of neurodegenerative biomarkers when clinically actionable. Together, these shifts move care beyond seizure counting toward a comprehensive brain-health model aligned with the realities of aging epilepsy.

Pyramidal cells (PCs) of hippocampal area CA2 exhibit increased excitability in temporal lobe epilepsy (TLE) and in mouse models of TLE. In epileptic mice, selective inhibition of CA2 PCs reduces chronic seizures. Here we asked if activating CA2 PCs increases seizures. Mice expressing Cre recombinase in CA2 PCs (Amigo2-Cre mice) were injected with the convulsant pilocarpine to induce a period of severe seizures (status epilepticus, SE), which leads to chronic seizures after 3-4 weeks (epilepsy). Epileptic mice were injected with a Cre-dependent adeno-associated virus (AAV) to express an excitatory designer receptor exclusively activated by designer drug (eDREADD; hM3Dq) in dorsal CA2 bilaterally and implanted with subdural EEG electrodes. After recovery, mice were recorded continuously using video and EEG for 6 weeks, 3 weeks with drinking water containing the eDREADD activator clozapine-N-oxide (CNO) and 3 weeks without CNO. CA2 activation with CNO caused a significant increase in seizure frequency and duration. Seizures occurred in clusters (many seizures per day over several consecutive days) and mice given water with CNO had a greater maximum number of seizures per day during a cluster compared to water without CNO. CNO had no significant effect in control mice. In naïve Amigo2-Cre mice expressing hM3Dq, pre-treatment with CNO before pilocarpine administration shortened the latency to SE and increased EEG power at the start of SE. Taken together with prior findings, the results suggest that CA2 is a control point for regulating seizures in the pilocarpine mouse model of TLE.

Advanced EEG technology has revealed that epileptiform activity occurs more frequently in Alzheimer's disease (AD) than previously recognized, prompting debate over the utility of EEG in AD diagnostics. Yet, unlike epilepsy, epileptiform activity is not always observed in AD, leading to skepticism. Historically, this absence has been attributed to limited recording depth or insufficient recording duration. We tested an alternative hypothesis that certain types of epileptiform activity, specifically high-frequency oscillations (HFOs, defined as 250-500Hz fast ripples), inhibit interictal spikes (IIS), which are currently used to assess hyperexcitability clinically. We recorded wideband (0.1-500Hz) hippocampal local field potentials in three AD (Tg2576, Presenilin 2^-/-, Ts65Dn Down syndrome model) and two epilepsy (intrahippocampal kainic acid, pilocarpine) mouse models during wakefulness and sleep. In both AD and epilepsy, HFOs consistently outnumbered IIS across behavioral states, age and recording contact. However, IIS and HFOs showed divergent relationships: a negative correlation between their rates was observed only in AD, in contrast to a positive correlation in epilepsy. HFOs preceded IIS at much shorter intervals in epilepsy than in AD. Co-occurrence of IIS with ripples did not differ between AD and epilepsy. These findings reveal a novel dissociation between clinically-relevant EEG biomarkers in AD and epilepsy. In AD, HFOs may inhibit IIS, which could lead to underestimation of hyperexcitability and hinder patient stratification for anti-seizure therapies. While non-invasive HFO detection remains challenging, we stress the need for wideband EEG/MEG, particularly in AD, to assess the full extent of hyperexcitability and biomarker interactions that would otherwise remain undetected.

INTRODUCTION/BACKGROUND:Alzheimer's disease (AD) dementia has near full penetrance in adults with Down syndrome (DS) and is strongly linked to late-onset myoclonic epilepsy in Down syndrome (LOMEDS). However, promising biomarkers of epileptogenicity, such as high-frequency oscillations (HFOs >250 Hz), have not been studied. This study is the first to use wideband polysomnography in DS to investigate if HFOs occurred and preceded AD dementia and LOMEDS. METHODS:Wideband (0.1 to 500 Hz, 2048 Hz) polysomnography was performed using the international 10-20 system. HFOs were automatically detected during slow-wave sleep, followed by manual review. RESULTS:Fourteen individuals with DS and five age-matched euploid controls were studied, with all DS cases showing HFOs. HFOs emerged before AD dementia and LOMEDS and showed hemispheric lateralization in asymptomatic but not symptomatic AD dementia cases. A trend toward increasing HFO rates with age in DS warrants further confirmation. DISCUSSION/CONCLUSIONS:HFOs are promising biomarkers that may predict symptomatic AD dementia in adults with DS. HIGHLIGHTS/CONCLUSIONS:Wideband polysomnography reveals a new electrical abnormality in DS. HFOs precede AD dementia in DS. The occurrence of HFOs in DS is independent of an epilepsy diagnosis. HFOs showed hemispheric lateralization in asymptomatic DS cases. A trend of increased HFO rate with advancing age warrants further investigation.

INTRODUCTION/BACKGROUND:Down syndrome (DS) is a genetic form of Alzheimer's disease (AD), with a high prevalence of sleep disorders, but data in adults with DS and dementia are lacking. We aim to assess sleep in adults with DS across the AD continuum. METHODS:We studied 78 healthy controls and 229 adults with DS (154 asymptomatic, 25 with prodromal AD, and 75 with AD) with subjective sleep measures and objective nocturnal polysomnography. RESULTS:Adults with DS presented worse sleep quality and higher prevalence of unnoticed obstructive sleep apnea (OSA) than controls. Sleep disruption and OSA severity increased across the AD continuum. Age-related decreases in slow-wave sleep and rapid eye movement sleep were more pronounced in the DS group. Subjective sleep measures did not capture sleep disorders. CONCLUSIONS:In DS, AD is linked to worse sleep disturbances and altered architecture. However, longitudinal studies are needed to clarify directionality and disease progression. HIGHLIGHTS/CONCLUSIONS:Down syndrome (DS) is associated with increased slow-wave sleep (SWS) and reduced rapid eye movement (REM) sleep. Obstructive sleep apnea prevalence increases along the Alzheimer's disease continuum in DS. Age-related decreases in SWS and REM sleep are accelerated in DS. Subjective sleep measures do not detect sleep disturbances in adults with DS.