Abnormal gamma frequency phase‐amplitude coupling associated with network hyperexcitability in Alzheimer’s Disease

Abstract Background Alzheimer’s disease (AD) carries an increased risk of seizures and subclinical epileptiform activity (Vossel et al. 2016). Network hyperexcitability which is the underlying phenomenon of epileptic manifestations is thought to contribute to AD pathophysiological processes. Recently we demonstrated that greater degree of neural synchronization deficits within 2‐8Hz range of frequency oscillations are sensitive indicators of network hyperexcitability (Ranasinghe et al. 2021). Here, we sought to examine the high frequency gamma band deficits associated with network hyperexcitability in AD patients. Methods Specifically, we quantified Phase Amplitude Coupling (PAC) between the amplitude of gamma oscillations (30‐40Hz); with the phase of 2‐8Hz oscillations) (Figure 1). We used 60s resting‐state magnetoencephalography (MEG) recordings from 48 AD patients (n = 22, with subclinical epileptiform activity, AD‐EPI+; n = 28 without subclinical epileptiform activity, AD‐EPI‐), and 35 age‐matched controls. We computed PAC for each of 68 cortical regions (Desikan et al. 2006) on source‐space reconstructed MEG signal using the mean vector length (Canolty et al. 2006). Results Permutation cluster test was performed for statistical comparisons between AD patients vs. age matched controls, and AD‐EPI+ vs. AD‐EPI‐. Patients with AD showed significantly higher theta (4‐8 Hz)‐gamma coupling in the left parahippocampal and right caudal‐middle frontal regions. Importantly, this increased left parahippocampal theta‐gamma coupling was significantly higher in AD‐EPI+ patients than in AD‐EPI‐. AD‐EPI+ also showed higher alpha (8‐12Hz)‐gamma coupling in the right parahippocampal region compared to AD‐EPI‐ (Figure 2). Conclusion These results not only identify gamma band coupling deficits specifically localized to medial temporal regions which are the earliest affected regions in AD pathophysiology but also delineate the associated vulnerabilities of network hyperexcitability in AD.