Mental fatigue and brain activation using prolonged task-based fMRI: a systematic review on time-on-task and sequential task paradigms

Mental fatigue (MF) has a significant impact on performance and decision-making in various contexts. It is considered a transient psychophysiological state characterized by impaired cognition and behavior across a range of dynamic contexts. This condition is related to changes in activity and connectivity across certain brain regions. Despite advances in understanding MF, the neural mechanisms remain unclear, necessitating further investigation. This systematic review synthesizes task-based fMRI evidence on MF during prolonged tasks, identifies convergent activation patterns and methodological gaps, and outlines possible future research. Following PRISMA, we searched PubMed, Web of Science, PsycINFO and Embase until November 6th, 2025. Eligible studies involved healthy participants, a mentally fatiguing task ≥ 30 min, and task-based BOLD fMRI acquired either on-task or in pre/post designs. Study characteristics and fMRI findings were extracted; risk of bias was appraised with NIH tools. Nine studies (n = 235) met the inclusion criteria. Across both designs an increase in MF was recurrently linked to higher activation in prefrontal and salience-related regions (DLPFC/VLPFC/DMPFC, ACC, insula) and the thalamus, while tendencies towards deactivation in posterior cortices (parieto-occipital/precuneus) were observed. Some studies also reported cerebellar effects. This review demonstrates the complexity of the neural correlates of MF and underscores the need for comprehensive research to understand its impact on brain functioning.