MRI-Guided Transcranial Magnetic Stimulation Effects on Memory, Brain Connectivity, and Brain Perfusion in Mild Cognitive Impairment

Abstract

The urgency to develop a treatment for memory decline in pre-clinical Alzheimer's disease (AD), such as mild cognitive impairment (MCI), has prompted multiple researchers to explore transcranial magnetic stimulation (TMS) as a potential therapeutic approach. However, the outcomes have been mixed. While TMS holds promise as a tool for addressing memory decline, its mechanisms and which protocols are reliable are still the subject of ongoing investigation. In this dissertation, Chapter 1 provides a general introduction to TMS, AD, and MCI, highlighting previous TMS studies that have shown memory improvement. Specifically, we aimed to utilize a time-efficient TMS protocol known as theta-burst stimulation (TBS) across three projects. Chapter 2 features the first TMS treatment study at the University of Arizona. This study was novel in that it involved the use of connectivity-based MRI-guided TMS, with a focus on structural connectivity derived from diffusion-weighted imaging. This allowed the targeting the hippocampus, a deeply-seated memory center of the brain, which is typically beyond the reach of TMS. The results of this study suggested a probable mechanism for TMS, indicating that intermittent TBS (iTBS) stimuli may enhance memory function by transmitting its effects from the superficial cortex to the hippocampus through the inferior longitudinal fasciculus (ILF) white matter tract. Chapter 3 explores a feasibility study where we targeted the dorsolateral prefrontal cortex (DLPFC) in individuals with chemobrain, a type of MCI. This strategy is commonly employed in MCI research to ameliorate poor memory function, and we observed promising results in memory improvement, which led to the development of related superficial frontal stimulation protocols in our lab. Our findings, however, also demonstrated that the mechanism by which TMS on DLPFC enhances memory may not involve the hippocampus, and these findings prompted a departure from this approach. Chapter 4 details our final project, which built upon the stimulation strategy presented in Chapter 2. Here, we incorporated density quantitative values of the human structural connectome and utilized a graph theory approach to identify the optimal cortical stimulation sites in the parietal lobe. In light of the mixed results from previous studies, which often targeted loosely defined parietal lobes, we specifically focused on the superior parietal lobe (SPL) and inferior parietal lobe (IPL). Our discoveries highlighted the superiority of the SPL with iTBS as a more effective and promising stimulation approach with enhanced memory and increased perfusion within hippocampal subfields and regions connected via the ILF. Chapter 5 serves as a discussion that integrates and synthesizes the work presented in the earlier chapters, addressing limitations and highlighting future research directions.