Reduced Coupling of Global Brain Activity and Cerebrospinal Fluid Flow in Individuals With Betel Quid Dependence

Millions of people worldwide are affected by betel quid dependence (BQD), a prevalent psychoactive substance-use disorder. To evaluate cerebral glymphatic dysfunction in BQD, this work used the coupling between global blood-oxygen-level-dependent (gBOLD) and cerebrospinal fluid (CSF) signals collected via resting-state functional MRI (rs-fMRI). Sixty-six participants (29 BQD individuals and 37 healthy controls) underwent rs-fMRI scanning. Cross-correlation analysis between cortical BOLD and CSF time series was carried out to compute the gBOLD-CSF coupling intensity. Group comparisons were performed via independent sample t-tests, and correlations with clinical features were assessed using exploratory Pearson's analysis. Bonferroni correction was applied to the five correlation analyses (BQDS, duration, daily consumption, HAMA-14 and HAMD-24). The corrected significance threshold was set at p < 0.01 (0.05/5). BQD individuals exhibited significantly reduced gBOLD-CSF coupling (t = -2.42, p = 0.019), and weaker coupling correlated with longer BQD duration (r = 0.4313, uncorrected p = 0.0195). After Bonferroni correction for multiple comparisons, the correlation between duration and gBOLD-CSF coupling (original p = 0.0195) did not reach the adjusted threshold. Chronic betel quid exposure may impair glymphatic function, reflecting disrupted brain-CSF interactions. The gBOLD-CSF coupling metric could be used as a noninvasive imaging biomarker to evaluate neurotoxic effects and glymphatic dysfunction in substance-use disorders.