Circuit-based multi-focal neurostimulation to target depression and memory in older adults with Alzheimer's dementia

About This Grant

Project Summary: In older adults with mild dementia due to Alzheimer’s disease (AD), difficulties with instrumental activities of daily living stem not only from memory loss, but also from co-occurring depressive symptoms (DEP). DEP + AD is highly prevalent and major driver of disability in older adults, yet most patients with this combination of symptoms do not derive meaningful benefit from current treatments. There is a pressing need to develop safe, multi-component interventions designed to maximize functional capacity in this vulnerable population by simultaneously targeting memory and DEP. It is now well established that depressive and memory symptoms arise from altered function within specific brain circuits, and, that different types of transcranial electrical stimulation (tES) can target these brain circuits to provide symptomatic relief to this population. Parallel lines of preliminary evidence specifically suggest that transcranial direct current stimulation targeting left prefrontal cortex (tDCSPFC) can improve depressive symptoms in people with major depressive disorder, whereas transcranial alternating current stimulation targeting the left angular gyrus (tACSAG) at gamma frequency (40Hz) can improve episodic memory in people with moderate dementia. At the same time, technological advances now allow researchers to: (1) study and optimize multi-channel stimulation montages (i.e., electrode placement and current parameters) using individualized electric field (E-field) modeling; (2) target multiple brain networks simultaneously within a single montage; (3) implement active-sham protocols that enhance double-blinding and control for potential peripheral stimulation effects; and (4) deliver stimulation at home utilizing a remotely monitored caregiver-led administration that has been found to be safe and effective, while increasing treatment access, relieving patients of travel burden, and limiting geographical selection bias. Building upon these preliminary studies and advances, we propose to conduct a phase II, randomized, sham-controlled, double-blinded, parallel-arm trial. The first aim of this study is to assess the separate and combined effects of tACSAG at gamma frequency and tDCSPFC on memory, depressive symptoms, and instrumental activities of daily living in DEP + AD. The second aim is to determine how much of the clinical effects on memory on the one hand, and DEP on the other hand, depend upon the amount of the E- field induced respectively in the left angular gyrus and the left dorsolateral prefrontal cortex, as assessed by individualized E-field high-resolution modelling. The third aim will assess intervention-related changes in brain activity using resting-state EEG. This project aims to demonstrate that tACS and tDCS can be effectively integrated into a single, scalable home-based intervention to maximize functional gains in older adults with mild dementia due to AD + DEP. It will also provide insights into the specificity of brain network-symptom mapping and lay the ground for the development of a highly scalable personalized optimization of stimulation interventions in future trials.