Multi-Site Theta-tACS Improves Memory and Language Performance and Associated Local and Remote Functional Connectivity in Mild Cognitive Impairment.

BACKGROUND: While multi-site noninvasive brain stimulation demonstrates enhanced cognitive benefits in mild cognitive impairment (MCI), the efficacy of transcranial alternating current stimulation (tACS) in this paradigm remains unestablished. The study aims were to investigate the therapeutic effects of multi-site tACS on MCI patients and its underlying neural mechanism. METHODS: A parallel, sham-controlled trial was conducted with 60 MCI participants assigned to multi-site tACS (prefrontal gyrus and precuneus), single-site tACS (precuneus), or sham groups. All participants underwent 20 days of 7 Hz tACS concurrent with working memory training. Cognitive assessments and fMRI examinations were performed pre- and post- intervention. Local and remote functional connectivity changes were evaluated using regional homogeneity (Reho) and resting-state network (RSN) analyses, respectively. RESULTS: Multi-site tACS demonstrated superior cognitive improvements, particularly in verbal fluency (p = 0.006) and recognition memory (p = 0.025), compared to sham stimulation. Significant ReHo changes were observed in the superior frontal gyrus (SFG) and superior temporal gyrus (STG) exclusively in the multi-site group (p < 0.05). Additionally, multi-site tACS induced broader functional connectivity alterations in the default mode network (DMN), executive control network (ECN), and left frontoparietal network (FPN). Correlations were found between the Reho changes in SFG and STG and the score changes of immediate memory (r = 0.367, p = 0.039) and language naming (r = 0.371, p = 0.037), respectively. Functional connectivity changes in the right inferior parietal lobe were also significantly correlated with the score changes of language naming (r = -0.374, p = 0.035). Moreover, more functional connectivity changes between the prefrontal gyrus stimulation site and the salience network and DMN were also detected in the multi-site group relative to the single-site group. CONCLUSIONS: Multi-site tACS is more effective than single-site tACS in enhancing cognitive functions and modulating cognition-related brain networks in MCI patients. These superior neuromodulatory effects of multi-site tACS may be attributed to its capacity to modulate functional networks across the prefrontal gyrus more extensively.