Human Neural Circuitry program seeks to investigate deepest mysteries of brain function, dysfunction

From his vantage point as a psychiatrist working in the emergency room, Karl Deisseroth used his 2021 book, Projections: A Story of Human Emotions, to describe things he couldn’t yet fully explain to the public as a scientist.

What autism, eating disorders, borderline personality disorder and schizoaffective disorder look and feel like up close — in exquisitely discomforting detail. Or how the frantic fragmentation of mania and psychosis, the hallmarks of bipolar disorder and schizophrenia, can seemingly scatter all semblance of rational thought.

Making mysterious neuropsychiatric maladies relatable, with honesty and empathy, even if few answers exist, was the driver of Deisseroth’s literary debut. Privy to the raw realities that too few see up close, his vision was to share how it feels to suffer in silence because of stigma, the need for personal privacy and the field’s still evolving base of knowledge.

“Most people have no idea that level of suffering even exists,” said Deisseroth, MD, PhD, the D. H. Chen Professor and a professor of bioengineering and of psychiatry and behavioral sciences.

With an eye for detail, a gift for language and a research scientist’s inquisitiveness, Deisseroth put that suffering into powerful words. Now, he’s decided, it’s time to take greater steps toward action. In late November he pulled the curtain back on his latest endeavor, a unique Stanford Medicine collaboration years in the making that was spawned by key research he and collaborating neuroscience innovators unearthed just before the COVID-19 pandemic.

He named it the Human Neural Circuitry research program, and with its technological firepower and a team of Stanford Medicine biomedical scientists equally committed to discovery, Deisseroth hopes to push the limits of understanding, inquiry and treatment for the most baffling mysteries of the mind.

How are the brain, human awareness and emotions interconnected? What’s happening at the cellular level when brains react differently to certain stimuli? What differentiates function from dysfunction? Those are the types of questions he seeks to answer by taking our comprehension of human brain function down to the level of neurons within circuits. There, he believes, is where the deepest answers lie.

“Our ultimate goal is to understand the inner world of human beings, as it is experienced in health and disease,” he said. “And we’re putting together the physical space, the workflow and a first-in-the-world technology network that we think we can begin to make it possible.”

On a recent sunny morning, Deisseroth stood in the HNC’s central hub, a spacious fifth-floor corner patient suite at Stanford Hospital, gazing out the window at Hoover Tower and the Stanford University campus. The man famous for pioneering optogenetics, who has spent his career hunting for novel entry points into understanding brain function, has a hard time hiding his passion for this latest inquiry into the human brain — and explaining the heretofore inexplicable.

“The brain is such a powerful contributor to both the highest and the lowest points of the human experience, yet it’s so poorly understood,” he said. “The HNC program will help bring psychiatry out of the shadows and into public consideration where it belongs — and we expect to make discoveries in this very room that will help that important process.”

‘An opportunity for creativity’

The space, located on the same floor as the hospital’s epilepsy monitoring unit, was previously used clinically for recording with intracranial electrodes, to help neurosurgeons and neurologists decipher which seizure-causing tissue to remove.

“This inpatient floor is set up for medical care of patients who have just had brain surgery and have electrodes implanted deep in their brain,” Deisseroth said. “It’s state-of-the-art medicine, but also an amazing source of real-time data from the brain of a human being.”

In the past, much of the available data, both digital and biological, has not been fully used. Even cells that remained on a freshly removed electrode “would simply be discarded.” So, just down the hall, Deisseroth and his team (including one of his lab members, Sam Vesuna, MD, PhD, a resident in psychiatry) are creating a small bio lab where those cells can be immediately analyzed and the data scanned for clues — with patient consent, safety and privacy at the forefront, Deisseroth emphasizes.

HNC’s unique real-time data-collection capabilities allow for the highest level of research science to be conducted with patients, from inside and outside Stanford Health Care, who have conditions ranging from epilepsy to obsessive compulsive disorder to depression and other neuropsychiatric disorders. The investigations are conducted by a team of neurosurgeons, neurologists, anesthesiologists and psychiatrists, collectively working both with the individual patient and with vast streams of data, potentially bringing team science to new levels.

“Karl has assembled an interdisciplinary team spanning many dimensions of expertise surrounding brain circuit dynamics — from foundational basic science to clinical trials to bioengineering and electrical engineering,” said Carolyn Rodriguez, MD, PhD, a professor of psychiatry and behavioral sciences who plans to further the understanding of OCD at the HNC. “There is a fearlessness in his paradigm-shifting approach. And the HNC space provides an opportunity for creativity, to do things differently.”

The HNC network also connects more than a dozen rooms across Stanford Health Care and Stanford Medicine Children’s Health, meaning discovery will be far from limited to a single room.

Deisseroth, a Howard Hughes Medical Institute investigator, sees combining a high-tech laboratory and a fully equipped patient setting as imperative to ramping up understanding of the body’s least-understood organ. “What you really want is a safe, comfortable environment for state-of-the-art medical care where you can simultaneously glean next-generation information streams,” he said.

Ultimately, he believes, the “magic” of discovery comes from humans working with humans — together seeking important new clues, and then sharing those discoveries with the world.

“The treatments will come in time, but true success will come from the community we build,” he said. “And from the new levels of empathy and understanding we can help create here.”

Seeking the next ‘game changer’

In a 2015 profile, The New Yorker called the even-keeled Deisseroth “unusually easygoing for someone who developed a transformative neuroscience technology before he was 40.”

Now 52, Deisseroth began his work on optogenetics in 2004 as a 33-year-old faculty member building his laboratory across the departments of bioengineering and psychiatry from the very beginning. His name emerges in Nobel Prize discussion each September because of his pioneering work developing methods to turn on or off individual types of neurons with light, using genes from algae and archaebacteria. It’s a quest that continues to lead to new discoveries and new therapies around the globe.

Though Deisseroth prefers to eschew talk of awards — and he has won plenty — many of those who follow closely the Nobel Prize still consider his feting a matter of when rather than if. “Every year I expect to hear his name among the winners because I sincerely believe he deserves it,” said Robert Malenka, MD, PhD, currently on leave from his role as the Nancy Friend Pritzker Professor in Psychiatry and the Behavioral Sciences, a mentor of Deisseroth’s from his earliest days at Stanford Medicine.

With optogenetics, and later his unique solution to 3D mapping the brain, Deisseroth created novel research tools that have laid the foundation for understanding brain function and dysfunction. Now he has the space to test theories and gather important data with actual human patients seeking relief from conditions that cause suffering. It’s a full-circle moment.

“It’s the next step in his journey,” said Deisseroth’s wife, Michelle Monje, MD, PhD, professor of neurology, the Milan Gambhir Professor of Pediatric Oncology and a Howard Hughes Medical Institute Investigator. “He developed a way to address his very incisive questions, at a time when there were no suitable techniques available. So, Karl being Karl, he invented them.

“Now he’s able to take the next step and really study circuit-level aspects of human cognition and emotions — all with the goal of healing and comforting. He is compelled and moved by psychiatric diseases.”

Like her husband, Monje is a scientist of the highest caliber and curiosity, seeking out mysterious causes of great suffering that arise in the brain. So, despite their shared life journey — and shared parenthood of five kids ranging in age from 7 to 27 — her opinion of his latest endeavor is notable.

“Because of the deep level of neuroscientific understanding he brings to psychiatric disease,” she said, “I truly believe Karl is going to transform mental health care.”

Deisseroth looks at HNC as a synergistic extension of the work he began with Projections and continued with experimentations, primarily on mice but extending to human beings as well, on how dissociation causes changes in awareness. He knows this could easily become his most important achievement in terms of immediate human impact — and he’s not alone.

Rodriguez is one of his close HNC collaborators. As an expert in clinical trials that seek out novel therapeutics, she knows firsthand the importance of translating animal study findings to human studies. She said this HNC approach has the potential to be a “game changer” in neuropsychiatric discovery.

“To be able to study the human brain, and human behavior, in this type of setting, with this technology, with this array of specialists generating tools and insights — it could really accelerate discovery and improve the lives of patients,” said Rodriguez, director of the Translational Therapeutics Lab.

It’s a sentiment echoed by another key HNC collaborator, Paul Nuyujukian, MD, PhD, an assistant professor of bioengineering and of neurosurgery who shares Deisseroth’s belief that the first-of-a-kind data collection speeds they have enabled will key novel discoveries in the HNC.

“The problem with treating brain diseases has been that we have no way of measuring them,” Nuyujukian said. “This fundamentally changes that because we’ve built the framework to support that measurement.”

The need for speed

That change begins with data flow. No expense has been spared for the outlay of fiber-optic and copper cable needed to conduct massive streams of data quickly and securely across all the HNC-wired rooms. As he references this first-in-the-world high-speed inpatient information network, the cavalcade of terabyte power brings the light of discovery to Deisseroth’s face.

“It goes from this room to a server farm across campus in Forsythe Hall,” he said. “Closed-loop time from here in the patient’s head to Forsythe and back: less than half a millisecond.”

The treatments will come in time, but true success will come from the community we build.

While most human brains can’t readily picture how fast that is, Nuyujukian confirms the firepower of the network is where the magic of unearthing the most unexplained cognitive phenomena exists.

“The bandwidth of this clinical research network, in hundreds of gigabtyes-per-second, is astonishing,” he said. “I’m pretty sure this is by far the fastest dedicated research network in a clinical setting ever constructed. It will allow us to tease out what a region of the brain is actually doing in a manner that can’t be measured any other way.

“With the HNC program, we will understand what happens in the minds of people when they are initiating actions, making decisions, recalling memories and experiencing emotions — at a scale never before measured.”

Deisseroth says the first studies, now ongoing, involve dissociation using intravenous ketamine; then they’ll look at OCD and other psychiatric diseases, including depression and phobias, and other altered human states beyond dissociation. “Then we’ll see where the science takes us,” he said. Unlike the animal-subject laboratory setting, where observations are the only available data points, the ability to get first-person feedback from patients will be a major paradigm shift.

“Careful work with animal subjects has done a lot for the world and will continue to do so, but there’s nothing like the real-time verbal feedback we can get from humans,” he said.

‘No turning away’

It was by accident, Deisseroth’s decision to focus on psychiatry.

He was headed toward neurosurgery late in his residency at Stanford Medicine. But during his mandatory psychiatry phase, a single episode with a patient exhibiting the full-blown effects of schizoaffective order — “a destructive storm of emotion and broken reality that combines the major symptoms of depression, mania and psychosis,” as he wrote in his book — changed his course.

“Nobody could give answers to the simplest questions regarding what this disease really was in a physical sense, or why this person was the one suffering, or how such a strange and terrible state had come to be part of the human experience,” he wrote. “Being human, we try to find explanations, even when the quest seems hopeless. And for me, after that moment, there was no turning back — and the more I learned, no turning away.”

So here he remains, deep into his journey for explanation, and Monje could not be less surprised. She was still a medical student and Deisseroth an intern when they met, looking after patients in the neurology ward — many with dire prognoses.

“These were people very sick with neurological diseases and it was so evident how much he cared, how much he wanted to be there, connect and be present with them,” she said. “He very intuitively knows how to show compassion and empathy and read emotional states.”

Deisseroth thinks about the patient he wrote about in the Projections prologue. The same way it drove him to change his mind, he wants that kind of suffering to change the perspective of a society underinformed and lacking full insight into the true nature of serious mental illness.

“If people saw someone with schizoaffective disorder, they would be absolutely stunned — that level of suffering is not usually seen,” he said. “People don’t reveal their illness to the community as much with psychiatry as they do with other diseases. It’s not as simple as a broken bone on an X-ray.”

But perhaps it could be, if only we knew more about the epidemiology and could share that with the world, Deisseroth reasons. His book was a verbally stunning first step in communicating the dire need of psychiatric suffering. With the Human Neural Circuity research program, Deisseroth intends to show it beyond the evocative use of words on a written page.

“Despite the best intentions, our society doesn’t fully appreciate how severe psychiatric illnesses are or how common they are,” he said. “There are a lot of people suffering in mysterious ways, and we should all want that to change. The first step is understanding.”