Emotions serve as the invisible navigators of the human experience. They steer our daily decisions, color our memories, and guide our social interactions, providing a necessary framework for navigating a complex world. Yet, for all their importance, emotions remain one of the most enigmatic frontiers of science. When they function correctly, they are seamless and adaptive; when they become inappropriate, excessive, or pathologically persistent, they become the foundation of neuropsychiatric suffering.
Despite decades of intensive research, the precise neural mechanisms that transform a sensory experience into a lasting emotional state have remained largely obscured. Psychiatrists and neuroscientists have long struggled to understand the specific brain activity that makes us "tick" during a moment of joy or "sick" during a period of clinical depression.
Now, a landmark study from Stanford Medicine, published May 29 in the journal Science, offers a significant breakthrough. A multidisciplinary team of investigators has successfully mapped the brainwide neuronal processing that underlies the emotional response triggered by unpleasant sensory experiences. Perhaps most strikingly, the study reveals that the fundamental features of this brain activity are shared between humans and mice—an evolutionary conservation that suggests these emotional blueprints have remained virtually unchanged for over 70 million years.
The findings do more than just satisfy scientific curiosity; they provide a potential roadmap for understanding the driving forces behind a wide array of neuropsychiatric disorders, many of which are defined by dysfunctional emotional manifestations.
"Emotional states are fundamental to psychiatry," said Karl Deisseroth, MD, PhD, a professor of bioengineering and of psychiatry and behavioral sciences at Stanford, who led the collaborative effort. The study drew upon the expertise of a diverse team, including senior co-authors Carolyn Rodriguez, MD, PhD; Vivek Buch, MD; and Paul Nuyujukian, MD, PhD, as well as lead co-authors Isaac Kauvar, PhD, Ethan Richman, PhD, and MD/PhD student Tony Liu.
The research was a flagship project of Stanford Medicine’s Human Neural Circuitry (HNC) research program. Founded and led by Deisseroth, the HNC program is designed to bridge the gap between laboratory discovery and clinical application, utilizing an inpatient medical setting to measure and perturb human brain activity with ultra-precise synchronization.
The Computational Cost of a Large Brain
To understand why emotions are processed the way they are, the researchers looked toward the history of mammalian evolution. The move toward larger, more complex brains was a massive evolutionary gamble, bringing with it both immense cognitive advantages and significant biological costs.
"The mammalian lineage has made a huge evolutionary commitment to large brain size, with all its attendant costs and benefits," explained Deisseroth, who is also the D. H. Chen Professor and a Howard Hughes Medical Institute investigator. While a mouse brain contains roughly 100 million neurons, the human brain contains nearly 90 billion. This thousand-fold increase in scale allows for a richer mental life, but it introduces a problem of physics: signal propagation.
In a brain as large as a human’s, complex signals take time to travel, converge, and integrate across distant regions. "Yet, to make accurate decisions, your brain has to pull together your multiple streams of sensory data, your goals, your position in space, your physiological needs and more—all at the same time," Deisseroth said. "If that doesn’t happen, wrong decisions will be made and wrong actions taken."
The team hypothesized that emotions act as a sort of integrative state, holding information in place long enough for the brain to coordinate a response. Deisseroth suggests that emotions may require a specific "window of time" where persistent communication occurs among widely separated brain structures.
Ethan Richman, one of the study’s lead authors, compared this mechanism to a musical instrument. "Tuning the time scale of this communication could be an important aspect of typical brain function," he said. "This would be akin to the action of a piano’s sustain pedal, which extends the duration of briefly played notes."
If the brain’s "sustain pedal" is held too long, or released too quickly, the result could be the emotional dysfunction seen in various psychiatric conditions.
An Evolutionary Shortcut
To find these elusive patterns of activity, the Stanford team employed a strategy rooted in evolutionary biology. Rather than trying to decode every signal in the incredibly complex human brain, they looked for patterns that were conserved across species. If a brain-activity pattern is present in both humans and mice—species that diverged from a common ancestor 70 million years ago—it is likely essential for survival.
"This approach allowed us to focus our study on the key principles that were shared between mice and humans," said lead co-author Isaac Kauvar.
The researchers sought activity patterns that met a strict set of criteria: they had to be induced by the same stimulus, measurable in the same way, synchronized with the same behaviors, and blocked by the same pharmacological interventions in both species.
The "Eye Puff" Experiment
To trigger a measurable emotional response, the researchers needed a stimulus that was safe, reproducible, and effective for both mice and humans. They found the answer in a common ophthalmological tool: the "eye puff" device used by eye doctors to check for glaucoma.
While a puff of air to the eye is not painful, it is inherently unpleasant. For the study, the team administered series of precisely timed puffs to participants. When asked to describe the experience, human subjects labeled the puffs as "annoying," "unpleasant," and "uncomfortable." Critically, repeated puffs led to a cumulative feeling of annoyance that lasted even after the stimulus stopped—a hallmark of an emotional state.
This state, while irritating, is adaptive. Deisseroth noted that any repeated negative event is information the brain must use to guide future behavior.
To record the brain activity during these events, the researchers worked with a unique cohort of patients at Stanford Hospital. These individuals suffered from medication-resistant epilepsy and had already undergone surgery to have electrodes implanted deep within their brains. These electrodes allow neurologists to locate the "focus" of a patient’s seizures, but they also provide a rare opportunity for scientists to observe human brain activity at high resolution.
"These patients typically spend about a week in a hospital bed with limited mobility… while the treatment team waits for spontaneous seizures to occur," said lead co-author Tony Liu. During these waiting periods, the patients volunteered to participate in the eye-puff study.
The Two-Phase Pattern
As the participants reacted to the air puffs, the researchers tracked their brain activity and physical responses. They observed a distinct two-phase neural pattern.
The first phase occurred within roughly 200 milliseconds of the puff. This was a sharp, short-lived spike of activity that functioned like a "news broadcast," alerting the entire brain to the sensory event. Immediately following this, the subjects would reflexively blink.
The second phase was more complex. Lasting for about 700 milliseconds, this longer phase was localized to specific emotion-related circuits across the brain. During this period, subjects exhibited "post-puff" eye squinting or rapid additional blinks—behaviors that were not reflexive but rather a self-protective, emotional response to an unpleasant situation.
When the team ran the same experiment on mice, they found the exact same two-phase pattern. Just like the humans, the mice showed a cumulative negative emotional state after repeated puffs, evidenced by a decreased interest in seeking rewards—a classic sign of a "bummed-out" state.
Dissociation and the Speed of Emotion
To prove that the second, slower phase of brain activity was the key to the emotional state, the team used a pharmacological intervention: ketamine.
In clinical settings, low doses of ketamine are known to cause dissociation. "Ketamine recipients are fully aware of sensory experience, but they often don’t have typical emotions about that experience," Deisseroth explained. "It’s as if it’s happening to someone or something else."
Under the influence of ketamine, the human participants reported that the air puffs no longer bothered them. One participant described the sensation as "entertaining," while another said it felt like "little whispers on my eyeballs."
The behavioral data backed up these subjective reports. While the reflexive first-phase blink remained intact, the self-protective second-phase squinting disappeared. The brain still received the "news" of the puff, but the emotional "sustain" was gone.
In both humans and mice, ketamine selectively accelerated the decay of the second phase of brain activity. It effectively "released the sustain pedal," preventing the brain from integrating the sensory information into a lasting emotional state. Furthermore, the team found that ketamine reduced overall brain synchrony and accelerated the brain’s "intrinsic time scale"—the rate at which activity patterns correlate—even when no stimulus was present.
A New Framework for Neuropsychiatry
The discovery that emotional states are tied to the timing and persistence of brainwide signals opens a new door for psychiatric medicine. Deisseroth suggests that many disorders could be categorized by how they affect these timing properties.
If the decay of integrative brain activity is too fast—as seen with ketamine—the brain may struggle to coordinate information, leading to the "alien" perceptions or lack of self-agency associated with schizophrenia.
Conversely, if the second wave of activity decays too slowly or becomes hyper-stabilized, it could result in the intrusive thoughts and persistent negative emotions characteristic of PTSD, obsessive-compulsive disorder, or clinical depression. In these cases, the brain’s "sustain pedal" may be stuck, keeping the individual trapped in a specific emotional state long after the triggering event has passed.
The researchers also see implications for autism spectrum disorder. "People with autism spectrum disorder are often known to have trouble keeping up with high-speed bursts of information," Deisseroth said. It is possible that a hyper-stabilized brain state makes it difficult for the brain to reset and follow rapidly changing social or linguistic inputs.
By shifting the focus from "where" things happen in the brain to "how long" they persist, the Stanford team has introduced a temporal dimension to our understanding of mental health.
"These are fascinating possibilities, which we are now exploring," Deisseroth said. "It’s amazing what an unbiased brainwide screen can reveal, especially with the right technology and across millions of years of evolution."
The research was supported by the National Institutes of Health, the AE Foundation, and private donors. Stanford University’s Office of Technology Licensing has filed a patent for intellectual property related to the study’s findings.
