40Hz Gamma Oscillations as a Biomarker and Therapeutic Modality for Cognitive Functions

Abstract

This dissertation aims to elucidate the efficacy of 40Hz gamma oscillations as a biomarker and their potential value as a therapeutic modality. The research is structured into three distinct chapters. Chapter I investigates the alterations in 40Hz gamma oscillations and the underlying mechanisms in vitamin D-deficient mouse models. Chapter II examines the changes in gamma oscillations within Alzheimer’s disease mouse models and explores the therapeutic intervention mechanisms of transcranial direct current stimulation. Finally, Chapter III demonstrates the superiority of game-based cognitive-responsive 40Hz auditory stimulation compared to conventional 40Hz auditory stimulation and validates its effects on cognitive enhancement in healthy elderly individuals. In Chapter I, I investigated the impact of vitamin D deficiency (VDD) on gamma oscillations. VDD is a recognized risk factor for schizophrenia and is closely correlated with symptom severity. Patients with schizophrenia exhibit abnormal gamma-band oscillations (GBO), characterized by increased spontaneous GBO and decreased evoked GBO. However, the direct effect of VDD on GBO has remained largely unknown. Our results demonstrate that VDD mouse models exhibit reduced evoked GBO and increased spontaneous GBO, accompanied by sensory gating deficits and a reduction in perineuronal nets (PNNs). These alterations in gamma oscillations were further validated in a PNN digestion model induced by chondroitinase ABC (chABC) injection. Consequently, these findings suggest that VDD may increase the risk of schizophrenia and aggravate its associated cognitive symptoms. In Chapter II, I investigated the therapeutic mechanisms of transcranial direct current stimulation (tDCS) for AD, focusing on 40Hz gamma oscillations. As a non-invasive neuromodulation technique, tDCS has gained significant attention for its potential in treating various neuropsychiatric disorders. Although recent studies have demonstrated that tDCS can mitigate cognitive decline and reduce amyloid-beta (Aβ) levels in Alzheimer’s disease (AD) mouse models, the precise underlying mechanisms remain poorly understood. Utilizing the 5xFAD mouse model, I observed that a two-week regimen of anodal tDCS treatment significantly improved cognitive function and reduced Aβ plaque deposition. Furthermore, I identified that the deficits in evoked 40Hz gamma oscillations and myelination levels observed in AD mice were restored following the two-week tDCS intervention. These findings suggest that remyelination and the subsequent restoration of gamma oscillations play a critical role in the therapeutic mechanisms of tDCS for the treatment of Alzheimer’s disease. In Chapter III, I evaluated the cognitive enhancement effects of task-contingent 40Hz auditory stimulation in healthy older adults. While 40Hz sensory stimulation research has centered on Alzheimer's disease pathology, its efficacy in cognitively intact populations remains underexplored. Building on the state-dependent nature of gamma entrainment and the thalamocortical resonance properties of 40Hz oscillations, I implemented a game-based task-contingent stimulation paradigm in which 40Hz auditory stimuli were precisely synchronized to discrete cognitive events within a card- matching task. Using a 2×2 factorial design separating stimulation frequency specificity and delivery timing across four groups, our results demonstrated that task-contingent 40Hz stimulation produced the greatest improvements in working memory as measured by the Digit Span Test, while task-uncoupled delivery of the same stimulus failed to surpass passive stimulation alone — suggesting that temporal misalignment between external stimulation and endogenous gamma activity may actively attenuate entrainment efficacy. Preliminary EEG analysis further revealed greater increases in 40Hz inter-trial coherence and phase-locking value in the task-contingent group. These findings establish task-contingent delivery as a mechanistically superior approach to conventional passive stimulation, offering a practical framework for cognitive enhancement in the healthy aging population.