Circuit-specific neuromodulation for the treatment of apathy in Alzheimer's Disease

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Apathy is among the most debilitating and the least treatable neuropsychiatric symptoms in Alzheimer’s Disease (AD). Previous studies have highlighted prefrontal-striatal circuits involved in the neuropathogenesis of apathy. Specifically, a dorsal circuit, encompassing dorsolateral prefrontal cortex and dorsal striatum, and instantiating goal-directed planning; and a ventral circuit, encompassing ventromedial prefrontal cortex and ventral striatum, and instantiating motivation/reward valuation. In addition, both circuits are heavily reliant upon dopamine (DA) availability. This proposal will demonstrate that these circuits can be differentially modulated with repetitive Transcranial Magnetic Stimulation (rTMS) in a group of 20 AD patients with apathy. First, advanced estimates of structural and functional connectivity from striatal regions will be used to derive individualized cortical rTMS targets. Next, patients will undergo three experimental sessions on separate days in which they are stimulated at the dorsal circuit target, the ventral circuit target, and a control target. The impact of rTMS will be measured with simultaneous MR-PET scanning which will assess both changes in resting-state functional connectivity (FC) and striatal 11C-raclopride BPND (a proxy of dopamine availability/release). Behavioral changes resulting from stimulation will be assessed with validated apathy and mood measures and with activation on fMRI tasks of planning and reward. We hypothesize that rTMS will preferentially modulate FC and DA availability only in the circuit stimulated and that this will be accompanied by specific changes in executive and motivational aspects of apathy. This work will pollinate larger clinical trials which systematically assess the ability of this intervention to improve apathy in neurodegenerative patients.