Studies by an international research team have revealed how the neurotransmitters dopamine and serotonin, signaling at sub-second speed in the human brain, appear to integrate and shape how people perceive the world and take action based on their perceptions. The observations, claimed to be the first-of-their-kind in the human brain, indicate that dopamine and serotonin have far more expansive roles in the human nervous system than had previously been known.

The study results also demonstrate that researchers can continually and simultaneously measure the activity of both dopamine and serotonin—whose receptor and uptake sites are therapeutic targets for disorders ranging from depression to Parkinson’s disease—in the human brain. Reported in Neuron, the findings could help scientists understand more about the expanded role that the dopamine and serotonin systems play in perception and decision making—and their roles in human health—and so provide important insights into psychiatric and neurological disorders.

“An enormous number of people throughout the world are taking pharmaceutical compounds to perturb the dopamine and serotonin transmitter systems to change their behavior and mental health,” said senior study author P. Read Montague, PhD, a professor and director of the Center for Human Neuroscience Research and the Human Neuroimaging Laboratory at the Fralin Biomedical Research Institute at Virginia Tech Carilion. “For the first time, moment-to-moment activity in these systems has been measured and determined to be involved in perception and cognitive capacities. These neurotransmitters are simultaneously acting and integrating activity across vastly different time and space scales than anyone expected.”

P. Read Montague, PhD, a professor and director at the Center for Human Neuroscience Research at Virginia Tech’s Fralin Biomedical Research Institute, said dopamine and serotonin are at work at sub-second speeds to shape how people perceive the world and take action based on their perception. [Virginia Tech]
Montague, who is an honorary professor at the Wellcome Center for Human Neuroimaging at University College London and a professor of physics at the Virginia Tech College of Science, and colleagues reported on their studies in a paper titled, “Sub-second Dopamine and Serotonin Signaling in Human Striatum during Perception Decision-Making.”

Dopamine and serotonin are neuromodulators that have traditionally been linked to reward processing, effectively, how good or how bad people perceive an outcome to be after taking an action. “Every choice that someone executes involves taking in information, interpreting that information, and making decisions about what they perceived,” said Kenneth Kishida, PhD, a corresponding author of the study and an assistant professor of physiology and pharmacology, and neurosurgery, at Wake Forest School of Medicine. “There’s a whole host of psychiatric conditions and neurological disorders where that process is altered in the patients, and dopamine and serotonin are prime suspects.”

Recent research in animals has also indicated that dopamine and serotonin “… are also involved in sensory inference and decisions based on such inference,” the researchers wrote. However, they noted, “… our understanding of these systems has been impeded by a lack of chemically specific methods for studying neuromodulation in humans at fast timescale.”

The researchers have now solved this problem, through the use of an electrochemical method known as fast scan cyclic voltammetry, which employs a small carbon fiber microelectrode that has low voltages ramped across it, to enable real-time detection of dopamine and serotonin activity. In the study, the team recorded fluctuations in dopamine and serotonin using specially designed electrodes, in five patients who were undergoing deep brain stimulation electrode implantation surgery to treat essential tremor or Parkinson’s disease. Patients were awake during surgery, playing a computer game designed to quantify aspects of thought and behavior while the measurements were taken. On each round of the game, each participant briefly viewed a cloud of dots and was asked to judge the direction they were moving.

Virginia Tech researchers along with scientists at the Fralin Biomedical Research Institute Center for Human Neuroscience Research construct carbon fiber microelectrodes for real-time detection of dopamine and serotonin activity in human patients. [Virginia Tech]
The task was designed by corresponding author Dan Bang, PhD, a Sir Henry Wellcome postdoctoral fellow, and Steve Fleming, PhD, a Sir Henry Dale/Royal Society Fellow, both at the Wellcome Center for Human Neuroimaging at University College London. Montague had approached colleagues Bang and Fleming at University College London to tailor a test for patients to perform during surgery that could reveal sub-second dopamine and serotonin signaling in real-time inference about the external world—separate from their often-reported roles in reward-related processes.

“I said I have this new method to measure dopamine and serotonin, but I need you to help with the task,” Montague explained. “Using fast scan cyclic voltammetry adapted for use in neurosurgical patients, we measured for the first time sub-second changes in dopamine and serotonin delivery to human striatum during a visual perceptual decision task—a commonly used laboratory system for studying cognition in humans and non-human primates,” the authors noted.

The results indicated that dopamine and serotonin were involved in simple perceptual decisions, outside of the traditional context of reward and loss. “Our results reveal that subsecond dopamine and serotonin signaling in human striatum participates in real-time inference about the external world—beyond their often-reported roles in reward-related processes,” the authors noted. “By augmenting the standard random dot motion paradigm, we were able to separate the uncertainty about a sensory stimulus from the difficulty associated with a decision about this stimulus.” And while the studies were carried out in patients who were diagnosed with Parkinson’s disease or essential tremor, the team suggested that there are several reasons why the results are “ … likely to generalize to the healthy brain.”

Bang further commented: “These neuromodulators play a much broader role in supporting human behavior and thought, and in particular they are involved in how we process the outside world. For example, if you move through a room and the lights are off, you move differently because you’re uncertain about where objects are. Our work suggests these neuromodulators—serotonin in particular—are playing a role in signaling how uncertain we are about the outside environment.”

The relative size of a microelectrode used to make recordings of dopamine and serotonin activity during deep brain stimulation procedures. [Virginia Tech]
As the researchers concluded, “Overall, our study opens the door to a deeper understanding of neuromodulatory systems that have remained poorly understood due to a lack of chemically specific methods for fast neuromodulator measurement in humans … These first-of-their-kind observations in the human brain reveal a role for sub-second dopamine and serotonin signaling in non-reward-based aspects of cognition and action.”

Montague and Kishida, along with Terry Lohrenz, PhD, a research assistant professor, and Jason White, PhD, a senior research associate, now both at the Fralin Biomedical Research Institute, started working on a new statistical approach to identify dopamine and serotonin signals while still at the Baylor College of Medicine in Houston, Texas. “Ken rose to the challenge of doing fast neurochemistry in human beings during active cognition,” Montague said. “A lot of other good groups of scientists were not able to do it. Aside from the computation of enormous amounts of data, there are complicated issues to solve, including great, fundamental algorithmic tasks.”

Until recently, only slow methodologies such as PET scanning could measure the impact of neurotransmitters, but they were nowhere near the frequency or volume of the second-to-second measurements of fast scan cyclic voltammetry. The measurements in the new study were taken at the Wake Forest Baptist Medical Center, and involved neurosurgical teams led by Adrian W. Laxton, MD, and Stephen B. Tatter, MD, PhD. “The enthusiasm the neurosurgeons have for this research is derived from the same reasons that drove them to be doctors—first and foremost, they want to do the best for their patients, and they have a real passion for understanding how the brain works to improve patient outcomes,” said Kishida, who oversaw the data collection in the operating room during the surgeries. “Both are collaborative scientists along with Charles Branch, the chair of the neurosurgery department at Wake Forest, who has been an amazing advocate for this work.”

Likewise, Montague said, “You can’t do it without the surgeons being real, shoulder-to-shoulder partners, and certainly not without the people who let you make recordings from their brains while they are having electrodes implanted to alleviate the symptoms of a neurological disorder … The research really took a lot of hard work and an integrated constellation of people to obtain these results.”

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