Dynamical irreversibility, high‐order interactions, and whole‐brain modeling of gamma oscillations in neurodegeneration

Abstract

AbstractBackgroundAbnormal gamma oscillations (γ) have been systematically reported in preclinical animal models of Alzheimer’s disease (AD) and human AD patients. However, little is known about the underlying mechanisms, non‐linear dynamics, and high‐order interactions of γ in dementia.MethodTo bridge this gap, we combined EEG and fMRI with three novel approaches to offer a comprehensive pathophysiological characterization of γ oscillations: We assessed the irreversibility of large‐scale brain dynamics to provide a precise signature capable of distinguishing AD at the global, local and network levels and at different oscillatory regimes (study 1). A high‐order functional connectivity (HOFC) multivariate information theory approach capturing interactions between 3 or more regions across spatiotemporal scales was compared with standard connectivity metrics for dementia characterization (study 2). A whole‐brain semi‐empirical model with a perturbational approach combined EEG, structural connectivity, and atrophy to explain the disrupted high‐order interactions observed in AD (study 3).ResultsStudy 1: AD was associated with a breakdown of temporal irreversibility at the global, local, and network levels at γ and other oscillations. The irreversibility of brain dynamics provided higher accuracy and more distinctive information than classical neurocognitive measures when differentiating AD from controls. Study 2: EEG‐HOFC revealed hypoconnectivity in γ between frontal, limbic, and sensory regions in AD, and large effect sizes, compared to standard pairwise metrics, proving a more accurate and parsimonious characterization of AD and frontotemporal dementia (FTD) patients. Study 3: whole‐brain modeling showed that a combined mechanism involving reduced structural integration (DTI) and hypo‐excitability (altered excitation/inhibition balance) triggered the altered high‐order interaction γ dynamics observed in AD and FTD. A perturbational approach identified physiopathological regions (SFG, MTG, precuneus) deviating the trajectories from disease to a healthy brain state.ConclusionThe present results offer new evidence regarding the pathophysiological link, mechanistic processes, and non‐linear whole‐brain dynamics between altered resting‐state γ rhythms and the characterization of AD and FTD, opening new avenues for dementia research at different levels.