Anterior-temporal hippocampal network mechanisms of left angular gyrus-navigated rTMS for memory improvement in aMCI: A sham-controlled study

Introduction: Neuro-navigated repetitive transcranial magnetic stimulation (rTMS) of the left angular gyrus has been broadly investigated for the treatment of amnestic mild cognitive impairment (aMCI). Although abnormalities in two hippocampal networks, the anterior -temporal (AT) and posterior -medial (PM) networks, are consistent with aMCI and are potential therapeutic targets for rTMS, the underlying mechanisms of the therapeutic effects of rTMS on hippocampal network connections remain unknown. Here, we assessed the impact of left angular gyrus rTMS on activity in these networks and explored whether the treatment response was due to the distance between the clinically applied target (the group average optimal site) and the personalized target in patients with aMCI. Methods: Sixty subjects clinically diagnosed with aMCI participated in this study after 20 sessions of shamcontrolled rTMS targeting the left angular gyrus. Resting -state functional magnetic resonance imaging and neuropsychological assessments were performed before and after rTMS. Functional connectivity alterations in the PM and AT networks were assessed using seed -based functional connectivity analysis and two -factor repeated measures analysis of variance (ANOVA). We then computed the correlations between the functional connectivity changes and clinical rating scales. Finally, we examined whether the Euclidean distance between the clinically applied and personalized targets predicted the subsequent treatment response. Results: Compared with the sham group, the active rTMS group showed rTMS-induced deactivation of functional connectivity within the medial temporal lobe -AT network, with a negative correlation with episodic memory score changes. Moreover, the active rTMS lowers the interdependency of changes in the PM and AT networks. Finally, the Euclidean distance between the clinically applied and personalized target distances could predict subsequent network lever responses in the active rTMS group. Conclusions: Neuro-navigated rTMS selectively modulates widespread functional connectivity abnormalities in the PM and AT hippocampal networks in aMCI patients, and the modulation of hippocampal-AT network connectivity can efficiently reverse memory deficits. The results also highlight the necessity of personalized targets for fMRI.