Global nonequilibrium cortical dynamics tie mid-level pupil-linked arousal to optimal task performance in humans

Ongoing fluctuations in brain state, largely driven by neuromodulators of arousal, shape how sensory inputs are processed and decisions are made. Here, we combined pharmacological manipulations and pupillary proxies of arousal to examine how global cortical state dynamics relate to perceptual sensitivity. We applied the thermodynamics-inspired INSIDEOUT framework to electroencephalography (EEG) recordings from two visual discrimination tasks performed under placebo, atomoxetine (noradrenergic enhancer), and donepezil (cholinergic enhancer) challenges. INSIDEOUT quantifies the strength of functional hierarchies within the brain via the computation of temporal irreversibility in neural activity. Trial-wise global irreversibility increased linearly with pupil-indexed arousal and exhibited a nonlinear inverted-U relationship with perceptual sensitivity, while showing no differences across drug conditions. A nonlinear mediation analysis revealed that temporal irreversibility can account for a significant portion of the association between pupil-linked arousal and perceptual sensitivity. At lower arousal, increases in prestimulus irreversibility improved perceptual accuracy, whereas at higher arousal, pre- and poststimulus irreversibility had different effects. These results bridge intrinsic whole-brain dynamics with perceptual decision-making, demonstrating that neuromodulator-linked arousal tunes cortical states and, in turn, perceptual performance. More broadly, the results shed new light on how arousal may reconfigure neural global dynamics.