Resting state network energy abnormalities in Alzheimer’s disease mouse model and the reversal through central thalamic deep brain stimulation

Abstract Alzheimer’s disease (AD) disrupts intrinsic brain activity, particularly within the Papez and cortico-thalamo-hippocampal circuits, contributing to cognitive decline. Despite extensive research, AD remains incurable, and effective therapies are limited. This study investigates how AD alters brain-state organization and whether central thalamic deep brain stimulation (CT-DBS) modulates these alterations. Resting-state fMRI data were collected from 26 wild-type mice (WT group), 26 AD mice without treatment (AD without CT-DBS group), and 26 AD mice receiving CT-DBS (AD with CT-DBS group). A maximum entropy model (MEM) was used to estimate energy values for each group across the 64 possible brain states defined by six brain regions: prefrontal cortex (PFC), caudate putamen (CPu), thalamus (THA), hypothalamus (HT), entorhinal cortex (EC), and hippocampus (Hipp). To characterize group-associated differences in brain-state organization, MEM-derived energy values were compared across corresponding brain-state configurations among the WT, AD without CT-DBS, and AD with CT-DBS groups. The AD without CT-DBS group showed differences in MEM-derived energy values across multiple single- and multi-regional state configurations, including the CPu, Hipp, THA, EC-Hipp, THA-HT, and HT-Hipp. These findings indicate altered organization of network configurations in AD. The AD with CT-DBS group showed energy values shifting toward WT-like patterns, suggesting a partial shift toward WT-like network organization following stimulation. CT-DBS was associated with a partial shift of AD-associated network configurations toward WT-like patterns within Papez and cortico-thalamo-hippocampal circuits, and energy-state analysis provides a quantitative framework for assessing circuit-level effects of neuromodulation in AD.