Faculty Bibliography

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.

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: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.

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.

High frequency oscillations (HFOs) are being incorporated into the presurgical evaluation of patients with epilepsy and also represent a rapidly evolving field in basic epilepsy research. Animal models have been pivotal in uncovering the mechanisms underlying HFOs and their role in epilepsy. In this review, we provide an overview of HFOs recorded in animal models, highlighting their relevance not only to epilepsy but also to neuropsychiatric and Alzheimer's diseases, suggesting a broader role in brain disorders. Then we explore recent advances, including innovative computational methods for the automated detection and analysis of HFOs. Building on this analysis, we propose guidelines for HFO identification and reporting with translational potential from animal models to humans. Finally, we discuss existing knowledge gaps and outline future directions for research in this rapidly evolving field.

Electroencephalography (EEG) has been instrumental in epilepsy research for the past century, both for basic and translational studies. Its contributions have advanced our understanding of epilepsy, shedding light on the pathophysiology and functional organization of epileptic networks, and the mechanisms underlying seizures. Here we re-examine the historical significance, ongoing relevance, and future trajectories of EEG in epilepsy research. We describe traditional approaches to record brain electrical activity and discuss novel cutting-edge, large-scale techniques using micro-electrode arrays. Contemporary EEG studies explore brain potentials beyond the traditional Berger frequencies to uncover underexplored mechanisms operating at ultra-slow and high frequencies, which have proven valuable in understanding the principles of ictogenesis, epileptogenesis, and endogenous epileptogenicity. Integrating EEG with modern techniques such as optogenetics, chemogenetics, and imaging provides a more comprehensive understanding of epilepsy. EEG has become an integral element in a powerful suite of tools for capturing epileptic network dynamics across various temporal and spatial scales, ranging from rapid pathological synchronization to the long-term processes of epileptogenesis or seizure cycles. Advancements in EEG recording techniques parallel the application of sophisticated mathematical analyses and algorithms, significantly augmenting the information yield of EEG recordings. Beyond seizures and interictal activity, EEG has been instrumental in elucidating the mechanisms underlying epilepsy-related cognitive deficits and other comorbidities. Although EEG remains a cornerstone in epilepsy research, persistent challenges such as limited spatial resolution, artifacts, and the difficulty of long-term recording highlight the ongoing need for refinement. Despite these challenges, EEG continues to be a fundamental research tool, playing a central role in unraveling disease mechanisms and drug discovery.

A long-standing theory for Alzheimer's disease (AD) has been that deterioration of synapses and depressed neuronal activity is a major contributing factor. We review the increasing evidence, in humans and in mouse models, that show that there is often neuronal hyperactivity at early stages rather than decreased activity. We discuss studies in mouse models showing that hyperexcitability can occur long before plaque deposition and memory impairment. In mouse models, a generator of the hyperactivity appears to be the dentate gyrus. We present evidence, based on mouse models, that inhibition of muscarinic cholinergic receptors or medial septal cholinergic neurons can prevent hyperactivity. Therefore, we hypothesize the novel idea that cholinergic neurons are overly active early in the disease, not depressed. In particular we suggest the medial septal cholinergic neurons are overly active and contribute to hyperexcitability. We further hypothesize that the high activity of cholinergic neurons at early ages ultimately leads to their decline in function later in the disease. We review the effects of a prenatal diet that increases choline, the precursor to acetylcholine and modulator of many other functions. In mouse models of AD, maternal choline supplementation (MCS) reduces medial septal cholinergic pathology, amyloid accumulation and hyperexcitability, especially in the dentate gyrus, and improves cognition.

Sodium selenate (SS) activates protein phosphatase 2 (PP2A) and reduces phosphorylated tau (pTAU) and late post-traumatic seizures after lateral fluid percussion injury (LFPI). In EpiBioS4Rx Project 2, a multi-center international study for post-traumatic targets, biomarkers, and treatments, we tested the target relevance and modification by SS of pTAU forms and PP2A and in the LFPI model, at two sites: Einstein and Melbourne. In Experiment 1, adult male rats were assigned to LFPI and sham (both sites) and naïve controls (Einstein). Motor function was monitored by neuroscores. Brains were studied with immunohistochemistry (IHC), Western blots (WBs), or PP2A activity assay, from 2 days to 8 weeks post-operatively. In Experiment 2, LFPI rats received SS for 7 days (SS0.33: 0.33 mg/kg/day; SS1: 1 mg/kg/day, subcutaneously) or vehicle (Veh) post-LFPI and pTAU, PR55 expression, or PP2A activity were studied at 2 days and 1 week (on treatment), or 2 weeks (1 week off treatment). Plasma selenium and SS levels were measured. In Experiment 1 IHC, LFPI rats had higher cortical pTAU-Ser²⁰²/Thr²⁰⁵-immunoreactivity (AT8-ir) and pTAU-Ser^199/202-ir at 2 days, and pTAU-Thr²³¹-ir (AT180-ir) at 2 days, 2 weeks, and 8 weeks, ipsilaterally to LFPI, than controls. LFPI-2d rats also had higher AT8/total-TAU5-ir in cortical extracts ipsilateral to the lesion (WB). PP2A (PR55-ir) showed time- and region-dependent changes in IHC, but not in WB. PP2A activity was lower in LFPI-1wk than in sham rats. In Experiment 2, SS did not affect neuroscores or cellular AT8-ir, AT180-ir, or PR55-ir in IHC. In WB, total cortical AT8/total-TAU-ir was lower in SS0.33 and SS1 LFPI rats than in Veh rats (2 days, 1 week); total cortical PR55-ir (WB) and PP2A activity were higher in SS1 than Veh rats (2 days). SS dose dependently increased plasma selenium and SS levels. Concordant across-sites data confirm time and pTAU form-specific cortical increases ipsilateral to LFPI. The discordant SS effects may either suggest SS-induced reduction in the numbers of cells with increased pTAU-ir, need for longer treatment, or the involvement of other mechanisms of action.