Interleaved TMS-fMRI for Hippocampal Stimulation: Modeling Dose-Response Relationship in Amnestic Mild Cognitive Impairment

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Project Summery/Abstract Theta burst stimulation (TBS) is a non-invasive brain stimulation technique that has emerged as a promising therapy for mild cognitive impairment (MCI) and Alzheimer’s disease (AD). However, little effort has been undertaken to optimize the application of TBS for these populations. Previous animal in vitro studies have found that TBS could induce long-term potentiation (LTP) in adult rat hippocampal slices in a dose-dependent manner. The maximum LTP effect was observed after TBS sessions were repeated three times, with a 60-minute break between each session. The dose-response curve was flattened when TBS applications did not have adequate interludes. This points to an array of parameters that must be properly tuned to achieve the desired TBS effects. The purpose of the study is to investigate the effects of spaced TBS at a superficial brain region connected to the hippocampus in individuals with amnestic MCI (aMCI). TBS will be applied inside an MRI scanner interleaved with fMRI to visualize the immediate response to the hippocampal stimulation. Aim 1 of the study will determine the effects of spaced TBS on memory performance and hippocampal function in individuals with aMCI. Aim 2 will establish dose-response relationship of the spaced TBS effect. Thirty-eight individuals with aMCI will be randomly assigned to one of the two TBS groups: active TBS or sham TBS. We hypothesize that 1) the spaced TBS protocol will enhance memory function, strengthen hippocampal functional connectivity, and increase hippocampal activation compared to the sham TBS, and 2) a positive dose-response relationship of the TBS effect will be observed. By leveraging cutting edge MRI-compatible TBS, findings of our innovative study may suggest mechanisms of spaced hippocampal TBS in aMCI. Ultimately, understanding how brain responds to the spaced TBS will enable development of an optimized TBS therapeutic protocol for individuals with MCI and AD.