Mapping the cortical architecture of sleep deprivation: insights from fMRI, neurotransmission, and metabolic activity

• A sleep deprivation–related cortical dysfunction map was identified using meta-analytic seeds and lesion network mapping. • This dysfunction map was associated with working-memory decline and showed altered cortex–subcortex directional influence following acute sleep deprivation. • This dysfunction map was associated with alterations in neural activity, the distributions of nine neurotransmitter receptors, and four metabolites. Sleep deprivation (SD) produces profound cognitive deficits, yet its integrative effects on large-scale cortical organization, metabolic alterations, and cognitive function remain unclear. Based on meta-analytic seeds, lesion network mapping was applied to connectome data from 1000 healthy individuals to generate an SD-related cortical weight map (SD-CWM). Thirty participants then completed a 24-hour acute SD protocol, during which resting-state and memory-task-evoked brain activities, untargeted metabolomics, and memory performance were measured under both rested wakefulness (RW) and SD. (1) After SD, alterations in both resting-state and task-evoked activities within the SD-CWM were associated with memory performance decline, with resting-state changes showing stronger associations. (2) The SD-CWM was predominantly localized to the occipital cortex and encompassed the visual and ventral attention networks, showing spatial correspondence with nine neurotransmitter receptors that also tracked individual differences in resting-state changes. (3) Granger causality analysis indicated cortex–subcortex directional influences between the SD-CWM and subcortical nuclei under RW, whereas SD exhibited a shift toward subcortex–cortex patterns, centered on the caudal temporal thalamus. (4) Four metabolites were associated with resting-state changes within the SD-CWM, with cortical activity alterations showing stronger associations with metabolic variation than subcortical activity. This study identifies an SD-related cortical map and characterizes its functional, directional, and metabolic associations, offering a systems-level perspective on the neural vulnerability underlying cognitive impairment after sleep loss.