ORIGINAL RESEARCH article
Front. Aging Neurosci.
Sec. Neurocognitive Aging and Behavior
Volume 17 - 2025 | doi: 10.3389/fnagi.2025.1597311
This article is part of the Research TopicBrain stimulation for cognitive impairments in psychiatric and neurodegenerative disordersView all articles
The Glymphatic System as a Therapeutic Target: TMS-Induced Modulation in Older Adults
Provisionally accepted
- 1Brain Imaging and TMS Laboratory, University of Arizona, Tucson, United States
- 2Department of Biomedical Engineering, University of Arizona, Tucson, United States
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While repetitive transcranial magnetic stimulation (rTMS) is a promising neuromodulatory intervention for cognitive impairment, its effects on the glymphatic system remain unexplored in clinical populations. Deficient glymphatic clearance has emerged as a central feature of neurodegenerative disease, which can now be assessed with specialized diffusion magnetic resonance imaging techniques. This study examines changes in the diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index following theta-burst stimulation (TBS) in older adults with mild cognitive impairment (MCI). DTI-ALPS is an MRI-based measure that reflects the efficiency of the brain's glymphatic waste removal system, as it quantifies how easily water molecules move along the perivascular spaces where waste is cleared. Participants underwent ten consecutive days of continuous TBS, intermittent TBS, and sham TBS, with DTI-ALPS measurements acquired before and after each intervention. Our sham-controlled findings reveal the capacity for TBS interventions to modulate glymphatic function and highlight a significant APOE ε4 effect. Specifically, ε4 carriers exhibited a lower baseline DTI-ALPS index (p < 0.05, Cohen’s d = 0.610), suggesting reduced glymphatic function, which was selectively responsive to TBS interventions (p < 0.005, Cohen’s d = 1.71). Further, within this subgroup, TBS-induced increases in glymphatic function correlated with memory improvements (r = 0.42-0.46, p < .05). These results provide novel evidence that TBS can modulate glymphatic function in humans and raise interesting questions about the relevance of APOE status. Further research is needed to elucidate the mechanisms underlying these effects and their therapeutic implications.
Keywords: Transcranial Magnetic Stimulation, Mild Cognitive Impairment, Glymphatic system, APOE, DTI-ALPS
Received: 21 Mar 2025; Accepted: 07 Jul 2025.
Copyright: © 2025 Sundman, Liu, Chen and Chou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Ying-hui Chou, Brain Imaging and TMS Laboratory, University of Arizona, Tucson, United States
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