Computational neuroscientist P. Read Montague Jr. poses an unassuming question filled with hidden complications: “When you’re deciding whether to turn left or right, or to eat the chocolate cake or the carrots, what’s happening in your brain?”
This simple question masks a complex web of brain activity. Underlying our decisions and behavior — the ‘‘software’’ — are hidden biological processes that make up the ‘‘hardware’’ of the brain.
Understanding these processes is key to unraveling not just the roots of human behavior, but also the core elements of medical issues such as depression, obsessive-compulsive disorder, and neurological disorders like Parkinson’s disease.
“It might seem like we are desperately trying to get inside people’s heads,” said Montague, director of the Center for Human Neuroscience Research and the Human Neuroimaging Laboratory at the Fralin Biomedical Research Institute at VTC, “but we aim to understand why people do things that simply can’t be gleaned from observing their behavior. We want to measure it.”
To that end, Montague’s team employs non-invasive techniques to study human brain activity, such as functional MRI (fMRI), electroencephalography (EEG), voltammetry, and Optically Pumped Magnetometry to “listen” to the brain as it processes thoughts and emotions.
Along the way, he is redefining our understanding of how we think, feel, and perceive the world.
Opening the Black Box
It was a pivotal moment in science.
Montague, with colleagues from Wake Forest Baptist Medical Center, University College London, and the University of Oxford, tracked for the first time in history the neurotransmitters dopamine and serotonin at work at high speeds to influence human perception and decision-making.
The observations were made in five patients who were undergoing deep brain stimulation electrode implantation surgery to treat essential tremor or Parkinson’s disease. The patients were playing a computer game designed to quantify aspects of thought and behavior while surgeons and scientists measured electrical activity to detect dopamine activity.
“This was the first time anyone has been able to do this in humans,” Montague said, talking about the groundbreaking findings that appeared in a study published on Oct. 12, 2020, in the journal Neuron.
The work attracted attention from leading experts in the field.
“Brain circuits depend on both electrical and chemical signaling and, for the most part, up until now, understanding those circuits during behavior, especially in larger organisms and humans, has focused on the electrical part of the equation,” said Wael Asaad, the director of functional and epilepsy neurosurgery at Rhode Island Hospital and a professor of neurosurgery, neuroscience, and the Sidney A. Fox and Dorothea Doctors Fox professor of ophthalmology and visual science at Brown University, who was not involved in the research.
“This work is a great example of the power and importance of studying how specific neurotransmitters contribute to interesting, complex social behaviors, and should inspire more work into the neurochemical correlates of cognition and behavior more broadly,” Asaad said.
The surgical procedures took place at the Wake Forest University School of Medicine.
“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,” Montague said.
Neural Mechanisms, Revealed
Until Montague and colleagues cracked the code, seeing this neural clockwork in action was impossible. Historically, insights into the human mind relied heavily on examinations of animal models, which fell far short of the mark.
The scientists zeroed in by using an electrochemical method called “fast scan cyclic voltammetry,” which employs small carbon fiber microelectrodes that have low voltages ramped across it.
Voltammetry’s use in rodents and other laboratory models have yielded deep insights into brain function for about 30 years, but there was no clear path to use the techniques in humans because they require electrodes to be inserted into the brain.
Montague’s game-changing idea emerged when he saw the opportunities presented by common surgical procedures like Deep Brain Stimulation, where surgeons implant wires in the brain for medical purposes.
To piggyback on clinical efforts, Montague designed electrodes to record neurochemical activity in the brain, specifically targeting neurotransmitters involved in decision-making and other cognitive processes.
Specific substances, such as neurotransmitters, undergo chemical reactions at electrodes, enabling real-time detection of dopamine and serotonin activity.
The Insights Keep Coming
In a study published in Current Biology on Oct. 23, 2023, Montague and his international team revealed insights into the brain’s noradrenaline system, a long-standing target for medications addressing attention-deficit/hyperactivity disorder, depression, and anxiety.
Perhaps even more crucial was the innovative methodology they developed to record real-time chemical activity. Rather than using specially designed electrodes in Parkinson’s patients, they employed standard clinical electrodes typically used for epilepsy monitoring.
“For the first time, we have measured the moment-to-moment activity of these systems, revealing their involvement in perception and cognitive capacities,” Montague said. “These neurotransmitters are simultaneously acting and integrating activity across vastly different time and space scales than anyone expected.”
More recently, in a discovery published Feb. 26 in Nature Human Behavior, the curtains were pulled back on dopamine and serotonin’s sophisticated interplay in social behavior.
In a study involving Parkinson’s patients during awake brain surgery, dopamine levels increased significantly when participants interacted with human players, leading to greater sensitivity to social fairness. This suggests dopamine heightens responses to perceived injustice.
Conversely, serotonin was found to track the immediate economic value of offers without being influenced by social dynamics. This supports serotonin’s role in mood regulation and impulse control.
“This work is changing the entire field of neuroscience and our ability to query the human mind and brain — with a technology that was just not even imagined not many years ago,” said neuroscientist Michael Friedlander, executive director of the Fralin Biomedical Research Institute at VTC and Virginia Tech vice president for health sciences and technology. “There is an enormous number of people in the world who suffer from a variety of psychiatric conditions, and, in many cases, the pharmacological solutions do not work very well. This effort adds real precision and quantitation to understand those problems. One thing I think we can be sure of is that this work is going to be extremely important in the future for developing treatments of heretofore intractable conditions.”
Notably, Montague theoretically proved that dopamine processes were associated with decision-making nearly 30 years before the most recent study was published.
Collaborating with Peter Dayan, today the director at the Max Planck Institute for Biological Cybernetics in Tübingen, Germany, and Terrence Sejnowski, now the Francis Crick Professor at the Salk Institute for Biological Studies, Montague co-authored a groundbreaking theoretical proof on dopamine system activity published in the Journal of Neuroscience in 1996.
Back then, the scientific community was uncertain how to interpret the findings. Fast forward to 2022, and Montague was invited to present this work at a Nobel symposium at the Karolinska Institute in Stockholm.
Sometimes good ideas take time to catch on.
A Quiet Place
The room looks like a vault, with thick walls and a door that closes with a handwheel, like you would expect on a submarine.
Other than that, there’s not much to write home about. It’s just a white room inside of a nondescript building on Virginia Tech’s Health Sciences and Technology campus in Roanoke. Few people would guess it’s one of only a handful of places on the planet to go to escape the Earth’s magnetic field.
Inside this room, geomagnetic fields are eliminated. Interference from cell phones, automobile traffic, computers, power lines, wall outlets, even the Earth’s core — cannot get inside.
The facility is constructed from mu-metal, a nickel-iron alloy that absorbs and redirects magnetic fields.
It’s a quiet place, where scientists can hear brains think.
With the background noise removed, the magnetic fields produced by neurons firing in the brain — which are a billion times weaker than Earth’s — can be accurately measured, offering a window into the brain’s hidden workings.
Welcome to the Fralin Biomedical Research Institute’s Human Magnetometry Laboratory.
Miniature Mobile MRIs
OPM-MEG, short for Optically Pumped Magnetometry Magnetoencephalography, is a non-invasive neuroimaging technique used to measure the magnetic fields produced by neurons’ miniscule electrical activity in the brain.
OPM devices are lightweight, wearable headsets that measure brain activity while allowing research volunteers to move freely and interact.
Picture miniature MRI machines, completely mobile, and not confined to expensive, cumbersome MRI tables. And picture them at work in a room that is completely free from magnetic interference.
The shift from stationary MRI machines to wearable OPM is like going from desktop computers to smartphones. Just as smartphones made computing portable and accessible anywhere, OPM frees brain-imaging from confining setups, allowing researchers to study natural movement and real-world interactions.
For Montague, who was among the neuroscience leaders to pioneer the concept of hyperscanning — the technique of recording the brain activity of two or more people as they interact — OPM is yet another way to see into not just one person’s brain, but the brains of two people in a social situation.
Resembling hats with wires, the headsets utilize quantum sensor chips to detect the strength and location of magnetic fields produced by the brain. They are custom-made by Montague and his team at the Fralin Biomedical Research Institute.
“We’re thrilled to get people out of MRI machines and into a natural setting where we can study social interactions, motion, and human behavior with fewer limitations,” said Montague, who is also a professor in the Department of Physics at the Virginia Tech College of Science and in the Department of Psychiatry and Behavioral Medicine at the Virginia Tech Carilion School of Medicine. “We’ve never been able to make such sensitive magnetic measurements, and now we’re applying this transformative technology to the study of social interactions.”
The technology will allow Virginia Tech researchers to be among the first in the world to study the brain activity underlying social interactions during face-to-face, upright exchanges.
For example, the laboratory is helping adapt OPM-MEG for use with infants and their mothers during natural interactions.
Unlike traditional methods, this quiet, non-invasive imaging allows for accurate measurements while babies move, helping researchers understand how infants’ brains develop in real-life situations and identify signs of health issues, while also collecting the first-ever brain activity data from infants and mothers together.
Ultimately, researchers are working to optimize OPM technology and establish best practices, establishing Virginia Tech as the first in the world to study the brain activity underlying social interactions during face-to-face, upright exchanges.
With each step forward, Montague and colleagues are revealing the hidden neural circuits shaping our health and daily choices.
As Montague had expected, lots more than meets the eye goes on inside people’s heads when they decide to turn right or left, or to eat the cake or the carrots.
