Abstract Study Objectives Whether cerebrospinal fluid (CSF)–dynamics–related glymphatic alterations occur in middle-aged and older adults with chronic insomnia (CI) remains unknown. We therefore examined global and network-level blood oxygenation level–dependent (BOLD)–CSF coupling in this population and assessed the effects of low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) during standardized hypnotic tapering. Methods This two-stage study included a cross-sectional comparison and a randomized, double-blind, parallel-group, sham-controlled trial. In Stage 1, 43 CI patients and 40 matched healthy controls completed sleep assessments and resting-state functional magnetic resonance imaging to quantify global and network-level BOLD–CSF coupling. In Stage 2, 26 CI patients were randomized (1:1) to receive 4 weeks of active or sham LF-rTMS during hypnotic tapering. Sleep was assessed at baseline, 2 weeks, 4 weeks, and 12 months. Neuroimaging was acquired at baseline and 4 weeks. Results CI patients showed significantly reduced global BOLD–CSF coupling, particularly in frontoparietal network (FPN) and default mode network (DMN). Global and FPN coupling correlated with sleep quality. In the randomized trial, LF-rTMS produced greater improvements in sleep at 4 weeks than sham resulted in fewer participants resuming hypnotics at 12 months. LF-rTMS increased global and DMN BOLD–CSF coupling, and these changes were associated with improvements in sleep. Conclusions Middle-aged and older adults with chronic insomnia exhibit reduced global BOLD–CSF coupling, indicating alterations in CSF dynamics that may relate to glymphatic function. LF-rTMS improved insomnia symptoms and modulated this coupling, indicating therapeutic potential for chronic insomnia. Trial Registration: ChiCTR2100049455. Clinical Trial Information This trial is registered with the Chinese Clinical Trial Registry (ChiCTR; ChiCTR2100049455), titled “Application of neurodegenerative techniques for insomnia and cognitive impairment in the elderly,” with the registry record available at: https://www.chictr.org.cn/bin/project/edit?pid=130047. Statement of Significance This study demonstrates that middle-aged and older adults with chronic insomnia show reduced global blood oxygenation level–dependent (gBOLD)–cerebrospinal fluid (CSF) coupling, indicating alterations in CSF–related dynamics that may reflect glymphatic-relevant processes at the cortical functional level. These alterations were most pronounced in high-order brain networks and were associated with poorer sleep quality. Low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) applied to the right dorsolateral prefrontal cortex modulated gBOLD–CSF coupling and improved sleep symptoms, with benefits maintained at 12 months. These findings suggest that disrupted CSF-dynamics coupling may be a functional marker associated with chronic insomnia in later adulthood and support LF-rTMS as a feasible non-pharmacological approach for long-term management, potentially enabling targeted modulation of CSF-dynamics–related processes.
Lu et al. (2026) studied this question.