Enhancement of glymphatic function and cognition in chronic insomnia using low-frequency rTMS

Abstract Study Objectives Low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) is a promising treatment for chronic insomnia, however; its effectiveness in improving cognitive and glymphatic clearance functions remains unclear. We aimed to investigate the effects of chronic insomnia on glymphatic clearance function and effectiveness of LF-rTMS on chronic insomnia. Methods Thirty-two patients with chronic insomnia and 40 healthy controls underwent baseline assessments of clinical measures and glymphatic functions using diffusion tensor imaging analysis along the perivascular space (DTI-ALPS). Thereafter, 22 patients underwent 10 sessions of LF-rTMS over 2 consecutive weeks, sleep assessments at week 2 and months 1, 2, and 3, and DTI-ALPS and cognitive-related assessments at week 2 and month 3. Results Compared to healthy controls, patients showed significant differences in the Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Montreal Cognitive Assessment scale (MoCA), digit symbol substitution test (DSST), color trails test (CTT), Digital Span (DST), Stroop tests, and DTI-ALPS index (all p<0.05). After LF-rTMS, patients showed a significant decrease in PSQI and ISI scores from week 2 onwards, and significant improvement in MoCA, DSST, DST, CTT-B tests, and DTI-ALPS index by month 3 (all p<0.05). Furthermore, the increase in DTI-ALPS index was significantly associated with improvements in PSQI, ISI, MoCA and DST-Backward at month 3 (r=0.579, 0.558, 0.836 and 0.642, respectively, and p=0.038, 0.047, <0.001 and 0.018, respectively). Conclusions This study provided preliminary evidence for LF-rTMS’ valuable effects on glymphatic clearance and cognitive function in patients with chronic insomnia, which supports LF-rTMS’ clinical application in those population.