Reduced coupling between global brain activity and cerebrospinal fluid flow in middle-aged and older adults with chronic insomnia: enhancement by low-frequency rTMS

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.