Researchers have identified a neurochemical signature that sets Parkinson’s disease apart from essential tremor — two of the most common movement disorders, but each linked to distinct changes in the brain.
In a new study in Nature Communications, scientists from the Fralin Biomedical Research Institute at VTC and the Virginia Tech College of Science identified unique chemical signaling patterns of two key neurotransmitters — dopamine and serotonin — that distinguish these two disorders.
“This study builds on decades of work,” said Read Montague, a scientist at the Fralin Biomedical Research Institute and a co-senior author, who with colleagues developed the multi-faceted technologies and the theoretical constructs for the work over their 15 years at the research institute.
“From adapting behavioral game theory into something that functions like a medical test, to refining machine learning models that can see brain chemistry in real time — we’ve always aimed to translate insights into something clinically useful,” said Montague, who directs the Center for Human Neuroscience Research at the institute. “This study takes a clear step in that direction.”
The researchers focused on a brain region involved in decision-making and reward processing – the caudate of the striatum.
Using a machine learning-enhanced electrochemical technique during deep brain stimulation (DBS) surgery on essential tremor and Parkinson’s patients, the team measured fast fluctuations as patients played a game involving fair and unfair offers — a task designed to understand decision-making and brain chemistry.
In an early study to emerge from this work in 2018 in Neuropsychopharmacology, researchers revealed the first-ever recordings of simultaneous sub-second fluctuations of dopamine and serotonin during active decision-making in a conscious human subject.
The early breakthrough laid the groundwork for the latest.
“The data had been collected as long as eight years ago by Montague and his team at the research institute and their collaborators at Wake Forest University, but we came back at it with better tools and a fresh perspective — and finally saw what was there all along,” said William “Matt” Howe, assistant professor with the School of Neuroscience in the Virginia Tech College of Science and co-senior author.
The rise and fall of neurochemicals
During DBS surgeries in 2017 and 2018, Wake Forest University neurosurgeons Adrian Laxton and Stephen Tatter helped perform the recordings using carbon fiber electrodes in Parkinson’s disease and essential tremor patients while they played a game where they accept or reject offers.
The research protocol was carried during a part of the surgery where the neurosurgeons already monitor brain activity in real time to precisely locate a small target area of the brain for electrical stimulation to treat the symptoms of the disorders.
Now, in the Nature Communications study, researchers applied a computational model to track how those patients formed and adjusted their expectations during the game, revealing signature chemical signaling patterns tied to each disorder.
In people with essential tremor, monetary offers that violated their expectations during the game triggered a seesaw pattern — dopamine levels rose, while serotonin dropped. This oppositional response — with one neurotransmitter rising as the other fell — mirrored patterns seen in earlier studies of brain activity during decision-making.
In the latest findings, this reciprocal neurochemical signaling was absent in patients with Parkinson’s disease.
It’s known that dopamine-producing neurons die in Parkinson’s disease, so researchers expected dopamine to be the clearest chemical difference in the brain.
But when they looked closely — using refined tools and a model of how people formed expectations — it was not dopamine that best distinguished Parkinson’s from essential tremor. Instead, it was serotonin, a different neurotransmitter that has not been as prominent in theories of Parkinson’s disease, opening a new view and potentially powerful scientific and clinical insight into this disease.
“What surprised us was how much serotonin stood out,” Howe said. “It wasn’t just that dopamine was disrupted. It was that the normal back-and-forth between dopamine and serotonin was gone. There’s neither the serotonin dip nor the dopamine rise. It’s not just one system being disrupted — it’s the lack of that dynamic interaction that turned out to be the clearest difference between Parkinson’s and essential tremor.”
Learning by doing
The computational model followed a form of machine learning known as reinforcement learning, which gradually improved its ability to detect patterns as it processed more data from past experiments. Earlier work from Montague and his colleague, Terry Lohrenz, established the importance of this process at the level of neurons and behavior, setting the groundwork for this new series of experiments and analyses.
Co-first authors Alec Hartle, a School of Neuroscience doctoral student in Howe’s lab, and Paul Sands, a research assistant professor in Montague’s lab, reframed the task using an “ideal observer model” — a statistical tool that considers rewards and outcomes and simulates the best performance for a specified task.
Hartle did experiments in mice to inform the approach, which helped Sands refine and apply the statistical model to extract new insights from human patient decision-making behavior.
“What they added was a computational model of what the subjects expected would happen,” Howe said. “When we reframed the data that way, we were able to reveal a difference in how the brain responded in these two patient groups.”
Researchers saw that certain prediction errors — mismatches between what the research subjects expected and what they received — evoked changes in serotonin activity that were strong indicators of which disease the patient had.
Parkinson’s disease affects about 1 million people in the United States and more than 10 million globally, according to the Parkinson’s Foundation. Essential tremor is even more common, affecting an estimated 7 million Americans, based on research by Columbia University scientists.
“It’s very powerful to link moment-to-moment changes in internal beliefs — here what a person expects from others — to measurable chemical signals in the brain,” said Dan Bang, an associate professor at the Center of Functionally Integrative Neuroscience at Aarhus University in Denmark, adjunct associate professor at the Fralin Biomedical Research Institute, and one of the study authors. “This opens a new window into how deeply human cognitive processes, like social evaluation, are shaped by disease.”
A continuing source of insight
The Nature Communications study draws on foundational theories of dopamine signaling — including work Montague helped shape nearly 30 years ago — and uses a parameter rooted in models his lab has been refining for decades to extract the dopamine and serotonin signals.
The collaboration with Wake Forest was seeded by Kenneth Kishida, a co-first author on the original study who collected the original dataset while working with Montague as a postdoctoral associate at the Fralin Biomedical Research Institute before joining the faculty at Wake Forest University, where today he is the Boswell Presidential Chair of Neuroscience and Society.
“It’s exciting to see that effort applied in a way that might help diagnose or stratify real clinical populations.” said Montague, who is also the director of the Center for Human Neuroscience Research and the Human Neuroimaging Laboratory of the Fralin Biomedical Research Institute and a professor in the Virginia Tech College of Science.
The project also reflects years of iterative refinement and cross-disciplinary teamwork.
“These models improve over time as they’re trained on more data,” said Seth Batten, a co-author on the study. “The version we used in this study was far more refined than what we had early on. But just as important was the collaborative approach — bringing in new people with different expertise allowed us to see patterns we hadn’t recognized before.”
While the findings offer new insight into how Parkinson’s disease and essential tremor differ at the chemical level, the researchers see this as just the beginning.
“That’s what I’m proudest of — the collaboration,” Howe said. “The data had long been collected, and it took people with different backgrounds coming together to make sense of it. This study tells a compelling story, but the story doesn’t end here.”
The study was funded by the National Institutes of Health, the Lundbeck Foundation, the Fralin Biomedical Research Institute and the Red Gates Foundation.
Additional co-authors on the study include:
Leonardo Barbosa and Jason White, Fralin Biomedical Research Institute at VTC;
Arian Sohrabi and Rebecca L. Calafiore, Wake Forest University School of Medicine;
Alexandra G. DiFeliceantonio, Fralin Biomedical Research Institute and Virginia Tech Department of Human Nutrition, Foods, and Exercise;
Mark R. Witcher, Carilion Clinic and Virginia Tech Carilion School of Medicine. END