Abnormal gamma phase-amplitude coupling in the parahippocampal cortex is associated with network hyperexcitability in Alzheimer’s disease

Abstract

While animal models of Alzheimer’s disease (AD) have shown altered gamma oscillations (∼40 Hz) in local neural circuits, the low signal-to-noise ratio of gamma in the resting human brain preclude its quantification via conventional spectral estimates. Phase-amplitude coupling (PAC) indicating the dynamic integration between the gamma amplitude and the phase of low frequency (4-12 Hz) oscillations is a useful alternative to capture the local gamma activity. In addition, PAC is also an index of neuronal excitability as the phase of low frequency oscillations that modulate the amplitude of gamma, effectively regulate the excitability of local neuronal firing. In this study, we sought to examine the local neuronal activity and excitability using gamma PAC, within brain regions vulnerable to early AD pathophysiology—entorhinal cortex and parahippocampus, in a clinical population of patients with AD and age-matched controls. Our clinical cohorts consisted of a well-characterized cohort of AD patients (n=50; age, 60±8 years) with positive AD biomarkers, and age-matched cognitively unimpaired controls (n=35; age, 63±5.8 years). We identified the presence or absence of epileptiform activity in AD patients (AD patients with epileptiform activity, AD-EPI+, n=20; AD patients without epileptiform activity, AD-EPI−, n=30) using long-term electroencephalography (LTM-EEG) and 1-hour long magnetoencephalography (MEG) with simultaneous EEG. Using the source reconstructed MEG data, we computed gamma PAC as the coupling between amplitude of the gamma frequency (30-40 Hz) with phase of the theta (4-8 Hz) and alpha (8-12 Hz) frequency oscillations, within entorhinal and parahippocampal cortices. We found that patients with AD have reduced gamma PAC in the left parahippocampal cortex, compared to age-matched controls. Furthermore, AD-EPI+ patients showed greater reductions in gamma PAC than AD-EPI− in bilateral parahippocampal cortices. In contrast, entorhinal cortices did not show gamma PAC differences either between AD versus control or between AD-EPI− versus AD-EPI+. Our findings demonstrate the specific regional patterns of altered gamma oscillations within medial temporal cortex regions vulnerable to AD pathophysiology indicating possible region-specific vulnerabilities of network hyperexcitability. Greater deficits in AD-EPI+ suggested that reduced gamma PAC is a sensitive index of network hyperexcitability in AD patients. Collectively, the current results emphasize the importance of investigating the role of neural circuit hyperexcitability in early AD pathophysiology and explore its potential as a modifiable contributor to AD pathobiology.