A possible chemical explanation for why we give up on tough tasks

by Paul Arnold, Medical Xpress

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edited by Lisa Lock, reviewed by Robert Egan

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When we engage our brains in a mentally taxing task, we eventually reach a point where we hit a wall or run on empty. Even when the rewards of finishing are obvious, we often find ourselves simply stopping. Exactly why this happens has long remained a mystery. We can easily point to tiredness or lack of motivation, but what is driving this disengagement at a biological level?

That is precisely what a team of scientists led by Hongmei Xia at Ludwig-Maximilians-Universität München in Germany set out to answer in experiments involving 31 healthy volunteers.

What happens when the brain works harder?

Each participant took part in a demanding 20-minute memory test on two separate days. During one session, they received electrical stimulation designed to increase activity in part of their prefrontal cortex. During the other, they received a fake version that delivered a brief initial tingle to make it feel like the real thing.

The test was designed to induce mental fatigue. To measure its effects, researchers asked participants, both before and after the test, whether they would be willing to complete additional memory tasks. They could choose between easier ones for smaller cash rewards and harder ones for more money.

The research team also measured brain chemistry before and after the tests using magnetic resonance spectroscopy. They were paying particular attention to glutamate because previous research has linked this brain chemical to mental exhaustion.

The scans confirmed a clear pattern, as the research team details in a paper published in the Proceedings of the National Academy of Sciences.

The chemical cost of mental work

Active stimulation increased the excitability of the dorsolateral prefrontal cortex (DLPFC). This was associated with significantly higher glutamate levels after the test compared to the control. While this increased brain activity initially boosted memory task performance, there was a downside. Volunteers became less likely to choose high-effort tasks after the test, even when this hard work paid more.

"Yet, this performance benefit from enhanced DLPFC excitability came at the cost of a subsequently reduced willingness to select high-effort options, indicating increased motivational fatigue," wrote the scientists.

The study suggests a possible biochemical cause for the reduced motivation associated with mental fatigue. If this turns out to be a driving mechanism, it could form the basis of new medical interventions when exhaustion becomes severe or chronic.

"Prefrontal glutamatergic metabolism may thus serve as a potential biomarker as well as treatment target for pathological fatigue."

Written for you by our author Paul Arnold, edited by Lisa Lock, and fact-checked and reviewed by Robert Egan—this article is the result of careful human work. We rely on readers like you to keep independent science journalism alive. If this reporting matters to you, please consider a donation (especially monthly). You'll get an ad-free account as a thank-you.

Publication details

Hongmei Xia et al., A causal account of the neural origins of mental fatigue, Proceedings of the National Academy of Sciences (2026). DOI: 10.1073/pnas.2534136123

Journal information: Proceedings of the National Academy of Sciences

Key medical concepts

Mental FatigueGlutamatesDorsolateral Prefrontal CortexElectric StimulationMagnetic Resonance Spectroscopy

Clinical categories

NeurologyPsychology & Mental health Who's behind this story?

Paul Arnold

BSc Biology from University of London. BBC documentary producer with world travel experience. Freelances from southern Spain. Full profile →

Lisa Lock

BA art history, MA material culture. Former museum editor, paramedic, and transplant coordinator. Editing for Science X since 2021. Full profile →

Robert Egan

Bachelor's in mathematical biology, Master's in creative writing. Well-traveled with unique perspectives on science and language. Full profile →

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