Enhancement of Hippocampal Plasticity Using Repetitive Transcranial Magnetic Stimulation

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Emerging evidence indicates that dysfunction of hippocampal synaptic plasticity, which precedes neuronal degeneration during the progression of Alzheimer's disease (AD), underlies the hallmark cognitive impairment. Although there are currently no effective disease modifying treatments for AD, recent preclinical studies in animal models of AD have suggested that repetitive transcranial magnetic stimulation (rTMS) promotes hippocampal synaptic plasticity and, ultimately, improves learning and memory abilities. In this application, we will utilize MRI-based neuronal connectivity maps as a guide to precisely propagate the neuronal excitation elicited by the superficial rTMS pulse to the hippocampus. The premise of this image-guided approach is supported by both previously published research in healthy adults and our pilot data in individuals with amnestic mild cognitive impairment (aMCI). Our preliminary findings demonstrate that applying a single dose of rTMS over a superficial brain region that is structurally connected to the hippocampus can transiently modulate hippocampal activity and enhance associative memory function. The specific aims of this project are to 1) determine the behavioral effect of hippocampal rTMS on memory function, 2) verify MRI-guided rTMS effects on hippocampal functional connectivity; and 3) develop a personalized, image-guided hippocampal rTMS protocol. Sixty individuals with aMCI will be enrolled in the double-blind, randomized, sham-controlled, crossover study with three rTMS conditions: excitatory stimulation, inhibitory stimulation, and sham stimulation. Each participant will complete 10 stimulation sessions for each condition with a 4-week interval between conditions to avoid potential carry-over effects. Building on preliminary data, here we will rigorously test our hypothesis that active rTMS protocols have a stronger modulation effect on both memory function and hippocampal functional connectivity, compared with sham rTMS in individuals with aMCI. Furthermore, data acquired from aims 1 and 2 will be used to develop statistical models to predict responses to rTMS intervention. The proposed research uses interventions grounded in precision medicine to provide an innovative platform that integrates MRI (including functional MRI and diffusion-tensor imaging) and rTMS to improve memory function in individuals with aMCI. This project represents a critical step in developing a non-invasive hippocampal stimulation protocol that should greatly benefit patients with Alzheimer's disease.