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Background <p>Insomnia disorder with comorbid anxiety is a prevalent clinical challenge. Although transcranial direct current stimulation (tDCS) is a promising noninvasive neuromodulatory approach, its effects on glymphatic-related neurovascular-cerebrospinal fluid (CSF) coupling in insomnia remain unclear. This study investigated the effects of tDCS on global blood oxygen level-dependent (gBOLD)-CSF coupling using resting-state functional magnetic resonance imaging (rs-fMRI) in patients with insomnia disorder and comorbid anxiety.</p> Methods <p>We conducted a 2-week, double-blind, randomized, sham-controlled trial. Patients with insomnia disorder and comorbid anxiety were randomized to receive either active or sham tDCS. The intervention consisted of 14 consecutive daily 20-min sessions delivered at 1.1&#xa0;mA, targeting the left forehead and right dorsolateral prefrontal cortex. Healthy controls were frequency-matched to the overall patient cohort by age and sex. The Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), 14-item Hamilton Anxiety Rating Scale (HAMA-14), 17-item Hamilton Depression Rating Scale, Epworth Sleepiness Scale, 20-item Multidimensional Fatigue Inventory, polysomnography (PSG), and rs-fMRI were assessed at baseline, and patients were reassessed after treatment. The primary outcome was the post-intervention between-group difference in gBOLD-CSF coupling; clinical scales and PSG parameters were secondary outcomes.</p> Results <p>Sixty patients with insomnia disorder and comorbid anxiety and 30 healthy controls completed baseline assessments. Compared with healthy controls, patients showed significantly lower gBOLD-CSF coupling (<i>P</i> &lt; 0.001, <i>P</i><sub>FDR</sub> = 0.002). Coupling strength was negatively correlated with ISI, PSQI, HAMA-14 scores, and arousal index, and positively correlated with NREM stage 3 (N3) sleep duration in patients. Multivariate regression identified N3 sleep duration as an independent predictor of gBOLD-CSF coupling (<i>β</i> = 0.328, <i>P</i> = 0.005, <i>P</i><sub>FDR</sub> = 0.040). After therapy, the active tDCS group showed a greater increase in gBOLD-CSF coupling than the sham tDCS group (effect size: 0.035, 95% CI: 0.011 to 0.058; <i>P</i><sub>interaction</sub> = 0.005, <i>P</i><sub>FDR</sub> = 0.014). Adverse events were mild and comparable between groups.</p> Conclusions <p>Patients with insomnia disorder and comorbid anxiety showed reduced gBOLD-CSF coupling during wakeful rs-fMRI, which was associated with subjective sleep quality, insomnia severity, anxiety level, arousal index, and N3 sleep duration. Active tDCS enhanced gBOLD-CSF coupling compared with sham stimulation, suggesting that its therapeutic effects may involve modulation of neurovascular-CSF dynamics alongside improvements in sleep and anxiety symptoms.</p> Clinical trial registration <p>ClinicalTrials.gov ID NCT07340268, retrospectively registered on January, 13, 2026.</p>

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Transcranial direct current stimulation improves reduced global BOLD-CSF coupling in patients with insomnia disorder and comorbid anxiety: a resting-state functional MRI study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月17日

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  • Yanan Zhang,
  • Qingqing Sun,
  • Xiaotong Zhang,
  • Wanru Li,
  • Yaru Wang,
  • Lijia Cai,
  • Zan Wang

摘要

Background

Insomnia disorder with comorbid anxiety is a prevalent clinical challenge. Although transcranial direct current stimulation (tDCS) is a promising noninvasive neuromodulatory approach, its effects on glymphatic-related neurovascular-cerebrospinal fluid (CSF) coupling in insomnia remain unclear. This study investigated the effects of tDCS on global blood oxygen level-dependent (gBOLD)-CSF coupling using resting-state functional magnetic resonance imaging (rs-fMRI) in patients with insomnia disorder and comorbid anxiety.

Methods

We conducted a 2-week, double-blind, randomized, sham-controlled trial. Patients with insomnia disorder and comorbid anxiety were randomized to receive either active or sham tDCS. The intervention consisted of 14 consecutive daily 20-min sessions delivered at 1.1 mA, targeting the left forehead and right dorsolateral prefrontal cortex. Healthy controls were frequency-matched to the overall patient cohort by age and sex. The Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), 14-item Hamilton Anxiety Rating Scale (HAMA-14), 17-item Hamilton Depression Rating Scale, Epworth Sleepiness Scale, 20-item Multidimensional Fatigue Inventory, polysomnography (PSG), and rs-fMRI were assessed at baseline, and patients were reassessed after treatment. The primary outcome was the post-intervention between-group difference in gBOLD-CSF coupling; clinical scales and PSG parameters were secondary outcomes.

Results

Sixty patients with insomnia disorder and comorbid anxiety and 30 healthy controls completed baseline assessments. Compared with healthy controls, patients showed significantly lower gBOLD-CSF coupling (P < 0.001, PFDR = 0.002). Coupling strength was negatively correlated with ISI, PSQI, HAMA-14 scores, and arousal index, and positively correlated with NREM stage 3 (N3) sleep duration in patients. Multivariate regression identified N3 sleep duration as an independent predictor of gBOLD-CSF coupling (β = 0.328, P = 0.005, PFDR = 0.040). After therapy, the active tDCS group showed a greater increase in gBOLD-CSF coupling than the sham tDCS group (effect size: 0.035, 95% CI: 0.011 to 0.058; Pinteraction = 0.005, PFDR = 0.014). Adverse events were mild and comparable between groups.

Conclusions

Patients with insomnia disorder and comorbid anxiety showed reduced gBOLD-CSF coupling during wakeful rs-fMRI, which was associated with subjective sleep quality, insomnia severity, anxiety level, arousal index, and N3 sleep duration. Active tDCS enhanced gBOLD-CSF coupling compared with sham stimulation, suggesting that its therapeutic effects may involve modulation of neurovascular-CSF dynamics alongside improvements in sleep and anxiety symptoms.

Clinical trial registration

ClinicalTrials.gov ID NCT07340268, retrospectively registered on January, 13, 2026.