In the operating room, a hidden difference came into focus. During deep brain stimulation surgeries at Wake Forest in 2017 and 2018, surgeons recorded rapid brain-chemical changes while patients played a simple fairness game. When Virginia Tech and Fralin Biomedical Research Institute researchers reanalyzed the data years later, they found that serotonin, not just dopamine, provided the clearest way to tell Parkinson’s disease apart from essential tremor.
Their report was published September 2, 2025, in Nature Communications.
The moment the signals diverged
The team focused on the caudate, a decision making hub deep in the brain. During clinically indicated electrode mapping for deep brain stimulation, patients with essential tremor or Parkinson’s disease viewed monetary offers and chose to accept or reject them. Some offers were designed to surprise, providing a way to probe how the brain handles unexpected outcomes. With carbon fiber microelectrodes and advanced analysis, the researchers tracked sub-second changes in dopamine, noradrenaline, and serotonin.
In essential tremor, positive surprises produced a seesaw pattern: dopamine rose while serotonin fell. That classic interplay was missing in Parkinson’s. Dopamine responses were blunted, and, more strikingly, the serotonin dip to positive surprises was absent. The loss of that chemical back-and-forth turned out to be the clearest divider between the two diseases.
“It wasn’t just that dopamine was disrupted. It was that the normal back-and-forth between dopamine and serotonin was gone.”
From behavior to a chemical boundary
The group used a computational model that estimated what each patient expected from the game and then compared those expectations to the offers they received. By tying brain chemistry to these “prediction errors,” they found that serotonin responses alone could separate Parkinson’s and essential tremor patients with high accuracy. Statistical tests confirmed the split even after accounting for electrode position, antidepressant use, or Parkinson’s clinical features.
Noradrenaline played little role. The small sample—12 patients with Parkinson’s and 6 with essential tremor—is typical for intraoperative human studies. Larger groups will be needed to refine the findings, but the serotonin signal stood out clearly.
Why serotonin, and why the caudate
Parkinson’s disease is best known for the death of dopamine-producing neurons, yet serotonin has long been implicated in both motor and non-motor symptoms. The new work shows that, at least in the caudate during decision making, serotonin provides the sharpest signal of disease. That shift matters for how scientists think about cognition in Parkinson’s, from social decision making to mood.
“This opens a new window into how deeply human cognitive processes, like social evaluation, are shaped by disease.”
What this could change in the clinic
Right now, doctors distinguish Parkinson’s disease and essential tremor mainly by symptoms, sometimes with dopamine brain scans. A fast, chemical signature seen during surgery could one day complement these tools. The method here is experimental and not a diagnostic test, but it suggests a path toward better patient stratification, customized stimulation settings, or new ways to track non-motor symptoms.
The study builds on earlier work that recorded the first simultaneous dopamine and serotonin fluctuations in a conscious human during decision making. Over the years, improved models and hardware made it possible to revisit the old data with fresh eyes. The result: serotonin, long a supporting actor in Parkinson’s research, steps into the lead role.
Context and sources
Parkinson’s affects about 1 million people in the United States and more than 10 million globally. Essential tremor is even more common, with estimates of roughly 7 million Americans. For background on Parkinson’s see the U.S. National Institute of Neurological Disorders and Stroke overview. For essential tremor, see the NINDS fact sheet.
Attribution and sample: Virginia Tech, Fralin Biomedical Research Institute at VTC, and Wake Forest University School of Medicine. n = 12 Parkinson’s disease patients, n = 6 essential tremor patients, all undergoing clinically indicated DBS with intraoperative electrochemistry in the caudate.
Links
Journal + DOI: Nature Communications. DOI: 10.1038/s41467-025-63079-w
Explainer: What is the caudate serotonin signal telling us?
Prediction errors are the brain’s way of learning from surprises. When something turns out better than expected, dopamine typically rises. Serotonin often moves in the opposite direction, signaling caution or aversion. In essential tremor patients, that classic pattern held: dopamine up, serotonin down. In Parkinson’s patients, it did not. The absence of serotonin changes, together with muted dopamine signals, provided a clean way to separate the two conditions. Because the caudate links reward, movement, and social evaluation, its chemistry offers a compact readout of brain function. The finding does not replace diagnosis, but it sharpens our picture of how Parkinson’s disrupts fast neurochemical coordination that supports decision making.
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