Hippocampal-Subregion Mechanisms of Repetitive Transcranial Magnetic Stimulation Causally Associated with Amelioration of Episodic Memory in Amnestic Mild Cognitive Impairment

Background: Altered hippocampal subregions (HIPsub) and their network connectivity relate to episodic memory decline in amnestic mild cognitive impairment (aMCI), which is significantly limited by over-dependence on correlational associations. Objective: To identify whether restoration of HIPsub and its network connectivity using repetitive transcranial magnetic stimulation (rTMS) is causally linked to amelioration of episodic memory in aMCI. Methods: In the first cohort, analysis of HIPsub grey matter (GM) and its functional connectivity was performed to identify an episodic memory-related circuit in aMCI by using a pattern classification approach. In the second cohort, this circuit was experimentally modulated with rTMS. Structural equation modeling was employed to investigate rTMS regulatory mechanism in amelioration of episodic memory. Results: First, in the first cohort, this study identified HIPsub circuit pathology of episodic memory decline in aMCI patients. Second, in the second cohort, restoration of HIPc GM and its connectivity with left middle temporal gyrus (MTG.L) are causally associated with amelioration of episodic memory in aMCI after 4 weeks of rTMS. Especially important, the effects of HIPc GM changes on the improvement of episodic memory were significantly mediated by HIPc connectivity with MTG.L changes in aMCI. Conclusion: This study provides novel experimental evidence about a biological substrate for the treatment of the disabling episodic memory in aMCI patients. Correction of breakdown in HIPc structure and its connectivity with MTG can causally ameliorate episodic memory in aMCI.