Multimodal characterization of cortical hyperexcitability as a driver of cognitive decline in neurocognitive...

Cognitive impairment is a major source of disability in neurodegenerative conditions, and it is also highly prevalent in autism spectrum disorder and attention-deficit/hyperactivity disorder. Across these conditions, subclinical epileptiform activity and resting-state functional hyperactivity have been repeatedly described, suggesting a shared state of cortical hyperexcitability. The LENDÜLET Neurocognitive Research Project aims to determine the incidence and multimodal characteristics of cortical hyperexcitability in multiple patient populations and to elucidate how hyperexcitability relates to cognitive performance, large-scale network connectivity, sleep-dependent memory consolidation, and tau/amyloid burden.

In a prospective, multimodal observational study, we are recruiting 75 participants per group (patients with mild cognitive impairment, patients with autism spectrum disorder, patients with attention deficit/hyperactivity disorder, and healthy controls; total N = 300) at the National Institute of Psychiatry and Addictology (Budapest, Hungary). All participants are undergoing a harmonized diagnostic protocol including detailed neuropsychological assessment, structural MRI, resting-state functional MRI, and 24-h ambulatory electroencephalography. Patients with neurodegenerative conditions will additionally undergo CSF sampling. Individuals who exhibit markers of cortical hyperexcitability will be invited to an in-ward mechanistic substudy (3-day video-electroencephalography monitoring with repeated neuropsychological paradigms, overnight sleep recordings, and spindle analysis, and serial blood sampling to characterize circadian dynamics of tau and amyloid.

Primary outcome is the incidence and distribution of cortical hyperexcitability in each diagnostic group relative to controls. Secondary outcomes include relationships between hyperexcitability and (a) structural atrophy and white matter integrity; (b) functional connectivity within and between default mode, salience, and attention networks; (c) cerebrospinal and plasma tau/amyloid levels; and (e) domain-specific cognitive performance. The current paper describes the study design, while the results are not reported.

This study will provide the first systematic, multimodal assessment of cortical hyperexcitability across multiple neurocognitive disorders with shared vulnerability to epilepsy and cognitive decline. The resulting biomarker panel may support risk stratification, inform clinical trial design for anti-hyperexcitability interventions, and ultimately enable individualized prevention strategies for cognitive decline.