Biophysical basis of alpha rhythm disruption in Alzheimer’s disease

Abstract

Alpha is one of the most prominent rhythms (7.5-12.5 Hz) detected in electroencephalography (EEG) during wakeful relaxation with closed eyes. In response to elevated ambient acetylcholine levels, a subclass of thalamic pacemaker cells generate alpha. This rhythm is intrinsic to the cell and is robustly orchestrated by an interplay of hyperpolarization activated cyclic nucleotide gated channels(HCN) and calcium-ion channels. It has been shown that decreased expression of HCN channels is correlated to Alzheimer's Diseased (AD). In early stages of AD, alpha is known to be down-regulated and lowered in coherence. We use this well characterized and quantified rhythm to understand the changes in ion channel properties that lead to disruption of alpha as seen in AD in a biophysically detailed network model of the thalamo-cortical circuit that generates the alpha-rhythm. Our computational model allows us to explore the causal links between alpha rhythms, HCN channels and amyloid-beta aggregation. The most commonly used drugs(acetylcholinesterase inhibitors) in AD increase the duration and level of acetylcholine and provide temporary symptomatic relief in some cases. Our simulations show how increasing acetylcholine can provide rescue for a small range of aberrant HCN expression. We hypothesize that reduced alpha rhythm frequency and coherence is a result of down-regulated HCN expression, rather then compromised cholinergic modulation(as is currently thought). The model predicts that lowering of the alpha-rhythm can modify the network activity in the thalamo-cortical circuit and lead to an increase in the inhibitory drive to the thalamus.