Reduced glymphatic clearance is linked to language impairments in patients with post-stroke aphasia

Post-stroke aphasia (PSA) is characterized by persistent language impairment, but its underlying physiological mechanisms remain unclear. Glymphatic dysfunction has been implicated in post-stroke pathophysiology, but its role in PSA remains unclear. The cingulo-opercular network (CON) is a key network implicated in language recovery after stroke. Using blood-oxygen-level-dependent (BOLD) and cerebrospinal fluid (CSF) coupling as a putative non-invasive marker of glymphatic function, we examined global and CON-specific alterations in patients with PSA and their associations with language impairment and treatment-related recovery. We enrolled 79 patients with PSA and 72 healthy controls (HCs). Among the patients, 20 underwent transcranial electrical stimulation (TES) targeting key CON nodes. Global and CON-specific BOLD-CSF coupling were quantified. Language function was assessed using the Western Aphasia Battery (WAB) and the Aphasia Battery of Chinese (ABC). We compared BOLD-CSF coupling between groups and examined its associations with language performance and intervention-related changes. Compared with HCs, patients with PSA showed significantly reduced BOLD-CSF coupling at both the global level and within the CON (all p < 0.05). CON-specific coupling was positively associated with AQ ( r = 0.27, p = 0.022), comprehension ( r = 0.28, p = 0.018) and fluency ( r = 0.23, p = 0.048), and showed a trend-level positive association with naming ( r = 0.22, p = 0.056). After TES, the treated patients showed concurrent improvements in language performance and BOLD-CSF coupling. Increases in CON-specific coupling were positively associated with naming recovery ( r = 0.59, p = 0.006), and this association remained significant after adjustment for covariates ( r = 0.53, p = 0.041). AQ recovery was also associated with increased CON-specific coupling ( r = 0.47, p = 0.034), with a trend-level association after adjustment ( r = 0.51, p = 0.053). Patients with PSA showed altered BOLD-CSF coupling, particularly within the CON, and these alterations were associated with language impairment and treatment-related recovery. These findings provide preliminary evidence that CON-specific glymphatic dysfunction may be relevant to PSA and support further investigation of the CON as a potential therapeutic target for aphasia rehabilitation. Trial Registration NCT05502822, NCT07700537.