Interstitial Ion Regulation in Cognitive Fatigability and Delayed Recovery: A Hypothesis-Driven Critical Review

Cognitive fatigability is the time-dependent destabilization of cognitive performance under sustained demand and is distinct from subjective fatigue. Neurophysiological effects may persist after demand. To link performance instability during demand with delayed recovery, this non-systematic, hypothesis-driven Review focuses on the extracellular milieu, which reflects and shapes neural activity. This Review operationally defines the interstitial ionic state as extracellular K+, Ca2+, Mg2+, pH, and extracellular space volume. Neurons, glia, and the vasculature generate this state; astrocytes couple neuromodulatory input to K+ and glutamate transport, metabolism, and water movement. Astrocyte involvement should be assessed through transport and extracellular variables rather than Ca2+ alone. This Review proposes that sustained cognitive demand constrains maintenance of this milieu during information processing and reconfiguration afterward. Delayed recovery may reflect incomplete reconfiguration of the milieu or incomplete recovery of neuronal and astrocytic responsiveness. Within the literature examined, no direct test of this integrated hypothesis under ordinary sustained cognitive demand was identified. The hypothesis predicts that recovery trajectories will outperform single post-demand measurements in forecasting renewed-demand performance and that recovery-phase manipulation of ion regulation or cellular responsiveness will alter fatigability. Brain fatigue may partly reflect reduced capacity to maintain and flexibly reconfigure the extracellular milieu across brain states.