A causal account of the neural origins of mental fatigue

Successful goal-directed behavior often requires the exertion of effortful cognitive control processes, but it remains unclear why engaging in cognitive control is experienced as effortful and induces fatigue. Here, we tested the hypothesis that sustained activation in the dorsolateral prefrontal cortex (DLPFC)—a neural substrate of cognitive control—causally induces motivational fatigue via the accumulation of prefrontal glutamate metabolites. For this purpose, we combined brain stimulation with spectroscopy imaging to assess how increasing DLPFC excitability during an effortful mental task changes the motivation for mental effort and glutamate concentrations. We found that stimulating the DLPFC during mental effort exertion improved mental performance at the cost of increased posteffort motivational fatigue, suggesting a causal role of DLPFC activation for inducing fatigue. On the neural level, DLPFC activation during effortful cognition also increased prefrontal concentrations of glutamate, which statistically explained the fatigue-induced lower motivation for mental effort. A corresponding analysis of combined glutamate–glutamine (Glx) concentrations revealed converging effects. Together, these findings provide causal evidence that enhanced DLPFC activation contributes to fatigue via neurochemical changes, supporting neuro-metabolic accounts of fatigue and offering new insights into why demanding cognitive tasks are perceived as effortful.