Dissociated glymphatic pathways mediates the neuronal hypometabolism on consciousness

• Prolonged DoC showed significant impairments in both glymphatic measures and cerebral glucose metabolism. • Prolonged DoC exhibit a disrupted correlation between BOLD-CSF coupling and DTI-ALPS. • BOLD-CSF coupling mediated the cortical glucose metabolism on consciousness, while DTI-ALPS mediated the subcortical glucose metabolism on consciousness. We examine whether glymphatic metrics play a mediating role between regional metabolic deficits and impaired consciousness. We find that compared to healthy controls, prolonged disorders of consciousness (pDoC) patients exhibited significant reduced blood oxygen level-dependent and cerebrospinal fluid signals (BOLD-CSF coupling), diffusion tensor imaging along the perivascular space (DTI-ALPS) index, and cerebral glucose metabolism, alongside a disrupted relationship between the two glymphatic metrics. Second, both BOLD-CSF coupling and DTI-ALPS index correlated positively with CRS-R scores (r=0.317-0.450, p<0.001). Cortical glucose metabolism was positively correlated with behavioral scores (r=0.365-0.414, p<0.01), whereas subcortical glucose metabolism showed non-significant negative correlation (r=-0.018–0.159, p>0.05). Last, we reveal BOLD-CSF coupling preferentially associated with cortical metabolism, and DTI-ALPS preferentially linked to subcortical metabolism on consciousness. This two-pathway glymphatic-metabolic framework provides a novel integrative mechanism for understanding impaired consciousness.