Understanding the mechanisms of lateral parietal memory modulation in Mild Cognitive Impairment

The application of transcranial magnetic stimulation (TMS) to lateral parietal cortex has shown promise in improving episodic memory in older adults with Mild Cognitive Impairment (MCI). Previous work has suggested that such improvements are achieved by activating hippocampus at a distance with TMS, though this explanation is incomplete. We hypothesized that the mnemonic benefits arise from an additional mechanism: the modulation of semantic representations. Nineteen participants with amnestic MCI received either active intermittent theta-burst stimulation (iTBS) to angular gyrus or control vertex stimulation over three consecutive days while viewing object stimuli and completing relational memory encoding tasks during fMRI, followed by conceptual and perceptual recognition memory tests. We found that active TMS (relative to control TMS) significantly modulated conceptual memory performance. Using Representational Similarity Analysis with semantic embeddings derived from a large language model, we examined how TMS affects neural representations in inferior parietal lobule and hippocampus. We found that TMS enhanced semantic representational strength in inferior parietal lobule and reduced representational strength in hippocampus. Surprisingly, both effects supported successful memory. Neural pattern similarity analyses suggested that reduced hippocampal similarity supported successful memory, perhaps by promoting pattern separation mechanisms. These findings demonstrate that parietal TMS modulates semantic processing in a region-specific manner, by strengthening semantic integration at the stimulation site while promoting representational differentiation in medial temporal regions. This work advances our mechanistic understanding of memory neuromodulation and has implications for the optimization of therapeutic interventions in age-related memory disorders.