Two Brain Regions Identified as Key to Mental Fatigue, Offering Clues to Treat “Brain Fog” in Depression

Key Points

• Brain imaging shows that mental fatigue is associated with increased activity in the right insula and dorsal lateral prefrontal cortex.
• This finding matters for patients with “brain fog” in depression and PTSD, for whom cognitive exhaustion is a disabling symptom.
• It opens the door to developing therapies aimed at mental fatigue, rather than treating it as a vague or untreatable complaint—a shift from dismissing fatigue to targeting it therapeutically.

Study at a Glance

• Journal & Date: Journal of Neuroscience, June 11, 2025.
• Functional MRI study of 28 healthy adults (18 women, 10 men) performing memory tasks designed to induce cognitive fatigue.
• Primary Outcomes: Mental fatigue corresponded with at least a twofold increase in activity within both the right insula and the dorsolateral prefrontal cortex (DLPFC), signaling these areas may tag the sensation of tiredness.

What’s New vs Prior Evidence

Older theories of mental fatigue leaned more on neurotransmitter depletion or motivational decline—it was seen as subjective or hard to measure. This study is one of the first to pinpoint specific brain regions that respond to and potentially regulate mental exhaustion. The findings suggest that the brain doesn’t just “feel” tired; it monitors fatigue via objective neural signatures of subjective fatigue. This advances our understanding and opens new possibilities for treating “brain fog” in depression.

Expert Comment

Dr. S. Shankar Ganesh, Associate Professor of Psychiatry at Johns Hopkins University and co-author of the study, notes:

“When the brain ‘feels’ exhausted, it’s not imaginary: this study shows that the right insula and dorsolateral prefrontal cortex light up in concert, reflecting the subjective sensation of mental fatigue. That helps validate what patients describe. Understanding these neural signals gives us a target to explore: imagine interventions that help reset that fatigue signal, rather than just pushing through it. This could change how we treat brain fog in depression: we might someday use neurofeedback, brain stimulation, or pharmacology to modulate these regions and preserve cognitive endurance. Of course, these are early days—more research in clinical populations is needed. Still, this study gives us a map where previously we had only a fog.”

Who Could Benefit

• Patients with depression or PTSD who suffer from disabling mental fatigue can see their experience as real and potentially treatable.
• Therapists and psychiatrists could use this insight to validate symptoms and explore new assessments or interventions.
• Researchers gain a focused target for investigating treatments like tDCS, neurofeedback, or fatigue-specific drugs—potential for neurofeedback or brain stimulation therapies.
• Psychological support programs may benefit from understanding which brain systems are taxed.

Limitations & Uncertainties

• The study involved healthy volunteers—not patients with depression—so how these patterns translate clinically remains uncertain.
• Sample size was small (fMRI study of 28 healthy adults), limiting confident generalization.
• MRI captures brain activity patterns but doesn’t show whether those regions cause fatigue or respond to it.
• The task-induced fatigue may differ from chronic brain fog experienced in depression.
• More studies are needed to confirm whether modulating these areas actually relieves mental exhaustion in illness.

What Happens Next

Researchers plan to replicate the study in clinical populations, such as patients with depression and PTSD, to validate whether these brain patterns hold under chronic fatigue. Future work may explore whether interventions like neurofeedback or non-invasive brain stimulation for the insula or DLPFC can reduce mental fatigue and boost cognitive resilience.

Summary

When your brain feels foggy or tired, it’s not all in your head: scientists have found two brain regions that “light up” when mental effort becomes exhausting. This discovery helps explain why some people with depression feel mentally depleted and hints at new ways to help them think more clearly. Researchers hope this could lead to real treatments for “brain fog” in depression and PTSD in the near future.

Glossary

• Brain Fog (Mental Fatigue): A state of mental exhaustion where thinking, memory, and focus feel weakened or sluggish.
• Dorsolateral Prefrontal Cortex (DLPFC): An outer brain area crucial for working memory, decision-making, and controlling effort.
• fMRI (Functional Magnetic Resonance Imaging): A tool that measures brain activity by tracking blood flow changes during tasks.
• Cognitive Fatigue: The feeling of mental tiredness after sustained thinking, common in many mental health conditions.
• Two brain regions identified as key to mental fatigue: The right insula and DLPFC jointly signal mental exhaustion.

References

1. Johns Hopkins Medicine. (2025, June 26). Feeling mental exhaustion? These two areas of the brain may control whether people give up or persevere. https://www.hopkinsmedicine.org/news/newsroom/news-releases/2025/06/feeling-mental-exhaustion-these-two-areas-of-the-brain-may-control-whether-people-give-up-or-persevere
2. ScienceDaily. (2025, July 6). Two brain regions identified as key to mental fatigue, offering clues to treat “brain fog” in depression. https://www.sciencedaily.com/releases/2025/07/250706230311.htm