Daily shifts in brain activity may help us measure fatigue

Your brain doesn’t move through the day quietly. It reshuffles its command centers, lights up new networks, and resets them all again during sleep.

Now, scientists have captured that process in unprecedented detail, creating whole-brain maps that track the rise and fall of activity across the 24-hour cycle – and offering a new path toward decoding fatigue itself.

Researchers at the University of Michigan mapped these shifting patterns by tracking when different regions of the mouse brain light up across the day, down to individual cells.

Using whole-brain imaging and new computational tools, the researchers followed how neurons and networks switch on as animals wake, stay active, and sleep.

“We’re seeing profound changes in the brain over the course of the day as we stay awake, and they seem to be corrected as we go to sleep,” said study senior author Daniel Forger.

Brain fatigue is hard to gauge

Fatigue remains notoriously slippery. People misjudge it, and the stakes can be high for pilots, surgeons, and others.

“We’re actually terrible judges of our own fatigue. It’s based on our subjective tiredness,” Forger said. “Our hope is that we can develop ‘signatures’ that will tell us if people are particularly fatigued, and whether they can do their jobs safely.”

The study, published in PLOS Biology, outlines a path toward those signatures by showing how brain-wide activity reorganizes over time and with sleep.

A whole-brain daily snapshot

The project stitched together expertise across three countries. In Japan and Switzerland, collaborators built an experimental pipeline centered on light sheet microscopy. This technique produces high-resolution 3D images of intact brains.

They engineered mice so that neurons active at specific times would glow, letting the team capture when and where cells had fired across the entire brain.

Meanwhile, the Michigan group designed mathematical and computational workflows to align, integrate, and interpret the massive datasets, turning static 3D snapshots into a coherent chronology of daily neural dynamics.

Daily shifts in brain control

The resulting maps revealed a striking pattern. In general, activity first ramps up in deeper, subcortical structures when the animals wake.

As the nocturnal mice progress through their active period, hubs of activity shift outward to the cortex, the brain’s outer mantle.

Co-author Konstantinos Kompotis uses a city analogy: “The brain doesn’t just change how active it is throughout the day or during a specific behavior,” he said.

“It actually reorganizes which networks or communicating regions are in charge, much like a city’s roads serve different traffic networks at different times.”

That temporal brain choreography (what’s central, what’s peripheral, and when) could underpin the subjective feeling of fatigue and its relief through sleep.

Finding the brain’s fatigue clues

The study draws its strength from two things: it delivers a brain-wide, single-cell view of activity, and it uses a standardized approach that researchers can repeat across conditions.

That opens the door to developing biomarkers for tiredness grounded in network organization rather than self-report.

Forger sees broader horizons too. “This study doesn’t touch on that,” he said when asked about mental health.

“But I do think the activity we saw in different regions is going to be important for understanding certain psychiatric disorders.” When daily reorganization becomes blunted, exaggerated, or mistimed, it can leave a signature linked to mood, cognition, or attention.

Engineering a whole-brain atlas

The experimental side engineered activity-dependent fluorescent tagging so active neurons “mark” themselves during predefined windows. Light sheet microscopes then scanned the whole brain rapidly, capturing millions of labeled cells in situ.

On the analysis side, the team built alignment and inference tools that fuse these images with existing mouse brain atlases, quantify region-by-region activation, and infer network-level flow across the day.

Co-author Guanhua Sun emphasized that the team designed the core analytics to be adaptable. “The mathematics behind this problem are actually quite simple,” he said.

The harder part, he noted, is respecting biology – combining new and archival data in ways consistent with known neuroanatomy and physiology.

Applying the approach to humans

Although you cannot clear and image a living human brain the way you can a mouse, the computational framework can translate to human modalities.

“The way we detect human brain activity is more coarse-grained than what we see in our study,” Sun said. “But the method we introduced in this paper can be modified in a way that applies to human data.

“You could also adapt it for other animal models, for example, that are being used to study Alzheimer’s and Parkinson’s. I would say it’s quite transferable.”

That means researchers can analyze EEG, PET, or MRI data with the same logic to find daily patterns and spot deviations that flag risky fatigue.

Why collaboration mattered

The Human Frontier Science Program helped seed and sustain the collaboration among teams from the University of Michigan, the University of Zurich, and RIKEN.

“We know from studies over the last 20 or 30 years, how to decipher how one aspect – a gene or a type of neuron, for instance – can contribute to behavior,” Kompotis said.

“But we also know that whatever governs our behavior, it’s not just one gene or one neuron or one structure within the brain. It’s everything and how it connects and interacts at a given time.”

Bringing those pieces together – genetic tagging, 3D microscopy, and scalable analytics – made a genuinely global view possible.

Next steps in brain fatigue mapping

Kompotis has already begun working with industry partners to test how therapies and drug candidates reshape these daily activation maps. The results could help refine dosing schedules or flag off-target effects on sleep–wake regulation.

For fatigue, the immediate agenda is to define robust, generalizable signatures in mice, then validate analogous metrics in humans using clinical data.

If successful, the payoff could range from evidence-based duty scheduling to personalized countermeasures that help restore healthy daily brain rhythms.

The human story behind the study

The authors dedicate the paper to Steven Brown, a senior co-author and chronobiology leader at the University of Zurich. He died in a plane crash during the project.

“We learned how important one person can be in scientific research, be it in brainstorming or in bridging ideas and concepts. Steve was a core element of this collaboration,” Kompotis said. “It is yet another reason for us to be very proud of this story.”

The researchers traced how the brain shifts control throughout the day. They also showed how sleep rebuilds those patterns. The result is a foundation for something both practical and profound – an objective language for fatigue drawn from the brain’s own choreography.

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