AUTHOR=Yuan Xiao , Tu Zhilan , Li Renren , Pan Chenxi , Ma Jing , Liu Meng , Yang Dan , Yang Hualan , Li Fangyun , Bie Zhi , Ku Yixuan , Li Yunxia 

TITLE=Cross-frequency neuromodulation: leveraging theta-gamma coupling for cognitive rehabilitation in MCI patients

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=Volume 17 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2025.1541126

DOI=10.3389/fnagi.2025.1541126

ISSN=1663-4365

ABSTRACT=BackgroundTheta-gamma coupling (TGC) plays a critical role in working memory (WM) processing, yet it is often dysregulated in mild cognitive impairment (MCI). While gamma activity is known to support cognitive functions, excessive gamma activity in MCI may impair WM. This study investigates how repetitive transcranial magnetic stimulation (rTMS) modulates gamma activity by regulating TGC to enhance WM in MCI patients.ObjectivesThis study aims to explore the effects of rTMS on WM by targeting TGC and reducing occipital gamma activity under varying WM loads.MethodsWe recruited 34 participants, including 20 MCI patients and 14 healthy elderly controls (HC), from Shanghai Tongji Hospital. All participants received a 1 week intervention of 10 Hz rTMS targeting the left dorsolateral prefrontal cortex (DLPFC). Gamma power and TGC were measured using electroencephalography (EEG), and WM performance (accuracy, capacity, reaction time) was assessed through a visual WM paradigm.ResultsThe rTMS intervention significantly reduced gamma power in left occipital region, correlating with improved WM performance (enhanced accuracy, capacity, and faster reaction time). Changes in TGC between left frontal theta and occipital gamma oscillations were significantly associated with WM performance, indicating a neurocognitive link.ConclusionThis study highlights rTMS as a non-invasive tool for enhancing WM by modulating TGC and reducing gamma power. These findings suggest a promising strategy for improving cognitive function in MCI, with significant clinical implications for cognitive optimization and therapeutic interventions.