The Brain's Sustain Pedal: How We Make Feelings

If your brain's activity patterns are hyper-stabilized you might experience challenges seen in autism spectrum disorders. The tempo of the brain, it seems, is fundamental to everything.

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We live in a world obsessed with quick fixes and instant gratification, yet our brains operate on a completely different timeline—one that Stanford researchers have just begun to decode. Their latest findings, published in Science this May, reveal something profound about the architecture of human emotion that should fundamentally change how we think about mental health, consciousness, and even our daily lives.

The study centers on something deceptively simple: what happens in your brain when you get a puff of air blown in your eye. It's mildly unpleasant—think of that moment at the eye doctor's office when you instinctively flinch. But what Stanford's team discovered goes far beyond that reflexive blink. They found that our brains don't just register the puff and move on. Instead, they enter a sustained state of processing that lasts nearly a full second—an eternity in brain time.

This isn't just academic curiosity. The researchers identified a two-phase pattern that appears to be fundamental to how we experience emotion. Phase one is the immediate alert: "Something happened." It's quick, broadcast widely across the brain, and over in 200 milliseconds. But phase two is where things get interesting—and where the implications become profound.

Phase two lasts much longer, around 700 milliseconds, and it's focused in specific emotional circuits. The researchers believe this sustained activity is what transforms a momentary sensation into a lasting feeling. It's the brain's equivalent of a piano's sustain pedal, letting the emotional "notes" ring out and blend together to create our subjective experience.

Here's where it gets unsettling: when they gave participants ketamine at low doses—the same doses used to treat depression—this sustain pedal got dramatically shortened. People still felt the puff, still blinked reflexively, but the emotional sting was gone. One person described it as "little whispers on my eyeballs." Another found it "almost entertaining."

This reveals something crucial about how ketamine works as an antidepressant, but it also exposes a more troubling truth about our understanding of consciousness and emotion. If a single drug can so precisely alter the timing of our emotional processing, what does that say about the reliability of our inner experiences? Are our feelings as solid and meaningful as we believe, or are they just patterns of electrical activity that can be chemically adjusted like the volume on a radio?

The researchers tested the same protocols in mice and found identical patterns. Across 70 million years of evolution, from tiny mouse brains with 100 million neurons to our massive 90-billion-neuron networks, this fundamental timing mechanism has remained conserved. That suggests it's not just important—it's essential for survival.

But here's what should really concern us: the study suggests that when this timing goes wrong, it might underlie some of our most challenging mental health conditions. Too fast, and you might experience the disconnection and loss of control reported in schizophrenia. Too slow or too persistent, and you could be looking at the intrusive thoughts of OCD, the emotional dysregulation of PTSD, or the rumination patterns of depression.

The implications extend beyond mental health into basic cognitive function. If your brain's activity patterns are hyper-stabilized—stuck in loops that won't fade—you might struggle to process rapid speech or complex social cues, challenges sometimes seen in autism spectrum disorders. The tempo of the brain, it seems, is fundamental to everything.

This research arrives at a moment when our collective mental health is under unprecedented strain. We're living in an era of constant stimulation, rapid-fire information processing, and chronic stress. Our brains evolved to handle brief threats followed by recovery periods, but modern life often resembles that repeated air puff experiment—constant mild stressors that our emotional circuits have to process without adequate time to reset.

The study mentions that factors affecting our brain rhythms and connectivity might be more important than we realize. This includes things we often take for granted: quality sleep, mindfulness practices, and perhaps most importantly, giving ourselves enough time and space to process complex information without constant interruption.

This isn't just about individual wellness—it's about how we structure society. If the brain's timing mechanisms are so crucial for healthy emotional processing, what are we doing to our collective mental health with always-on connectivity, constant notifications, and the expectation of immediate responses to every digital ping?

The researchers caution that much more work needs to be done before these findings translate into treatments. But they've opened a window into something fundamental about human consciousness that we're only beginning to understand. The brain doesn't just react to the world—it creates sustained states that become our reality. These states can be measured, manipulated, and potentially healed.

What's perhaps most remarkable is how this cutting-edge neuroscience research validates ancient wisdom about the importance of contemplative practices. When meditation teachers talk about observing thoughts and emotions without attachment, they're essentially describing the ability to let phase two activity decay naturally rather than getting caught in loops of rumination or reactivity.

The Stanford study gives us a scientific framework for understanding why practices that slow us down—meditation, deep breathing, even just taking a pause before reacting—might be more neurologically important than we realized. They're not just feel-good activities; they're maintenance protocols for the fundamental timing mechanisms that create our inner lives.

As we navigate an increasingly complex world, this research suggests we need to pay more attention to the tempo of our mental lives. The brain's sustain pedal isn't just a interesting quirk of neurobiology—it's the mechanism through which momentary experiences become lasting memories, fleeting sensations become persistent moods, and brief encounters shape who we become.

The question isn't whether we can control these patterns—ketamine proves we can. The question is whether we'll use this knowledge wisely, to create lives and societies that support the healthy timing our brains need to function well. Because in the end, the rhythm of our thoughts isn't just personal—it's the foundation of everything we think and feel and do.

References:

Sustained in the brain: How lasting emotions arise from brief stimuli, in humans and mice

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STUDY MATERIALS

1. Briefing Document

I. Executive Summary

This study, conducted by Stanford Medicine investigators, unveils a conserved brain-wide neuronal processing pattern underlying emotional responses to mildly unpleasant sensory experiences in both humans and mice. The research identifies a two-phase brain activity pattern, with a critical "second phase" of sustained communication across widely separated brain structures linked to the formation and persistence of emotion. Critically, this second phase is found to be tunable, and its perturbation by ketamine (an antidepressant known to cause dissociation) directly impacts emotional processing. These findings provide significant insights into the fundamental mechanisms of emotion, how they guide behavior, and offer a novel framework for understanding and potentially treating neuropsychiatric disorders characterized by emotional dysfunction, such as PTSD, OCD, depression, and schizophrenia.

II. Main Themes and Most Important Ideas/Facts

1. Emotions as Fundamental Guides for Life and Their Role in Neuropsychiatric Disorders:

• Emotions are essential for normal life, guiding decisions and actions.

• Inappropriate or prolonged emotions can lead to "trouble" and are central to numerous neuropsychiatric disorders.

• Neuroscientists and psychiatrists currently lack sufficient understanding of the brain activity underlying emotions.

• "Emotional states are fundamental to psychiatry,” said Karl Deisseroth.

1. Conserved Brain Activity Patterns Underlying Emotion in Mammals:

• The study mapped brain-wide neuronal processing for emotional responses triggered by mildly unpleasant sensory experiences.

• Features of this brain activity are "shared by humans and mice — and, by extension, every mammal in between." This conservation over vast evolutionary time suggests the fundamental importance of these principles.

• The research leveraged an "evolutionary trick" by studying two species (humans and mice) that emerged from the same ancestor to identify shared, fundamental principles.

• "If a brain dynamical principle is conserved over that time, you’d better believe it could be important,” Deisseroth emphasized.

1. The "Two-Phase" Brain Activity Pattern for Emotion Integration:

• The study utilized repeated "eye puffs" (aversive but safe stimuli) to elicit emotional responses in both humans and mice.

• A distinct "two-phase pattern" of brain activity was observed:

• Phase 1 (approx. 200 milliseconds): A "strong but short-lived spike of activity broadcasting 'news' of the eye puff throughout the brain." This is a rapid, reflexive response.

• Phase 2 (next 700 milliseconds or so): A "separate, longer-lasting phase of puff-triggered brain activity more specifically localized to a subset of specific circuits across the brain associated with emotion."

• This second phase provides an "extended window of time for brainwide communication, which could be related to emotion."

• This pattern was remarkably similar in both human and mouse subjects.

• "Emotions may represent states that integrate a great deal of information to guide lasting patterns of behavior, but may need a window of time with persistent communication among widely separated brain structures to accomplish that integration," Deisseroth stated.

1. The Role of Brain Size and Information Integration:

• The mammalian lineage has made a "huge evolutionary commitment to large brain size."

• "A bigger brain means a richer, more complex mental life," but also presents "real constraints once you scale up."

• The human brain's size means it "takes some time for those rich and complex signals to fully propagate throughout the brain, converge and be properly integrated."

• Accurate decision-making requires integrating multiple streams of sensory data, goals, spatial position, and physiological needs simultaneously.

• Failure in this integration leads to "wrong decisions will be made and wrong actions taken."

• The concept of a "sustain pedal" for a piano is used as an analogy: "Tuning the time scale of this communication could be an important aspect of typical brain function,” Richman added. "This would be akin to the action of a piano’s sustain pedal, which extends the duration of briefly played notes.”

1. Ketamine's Dissociative Effect and Its Impact on Emotional Brain Activity:

• Ketamine, an FDA-approved antidepressant at lower doses, is known to cause dissociation, reducing or absenting typical emotional responses.

• "Ketamine recipients are fully aware of sensory experience, but they often don’t have typical emotions about that experience, even if the sensation would normally be unpleasant,” Deisseroth explained. “It’s as if it’s happening to someone or something else.”

• In both humans and mice, ketamine "greatly inhibited" the negative emotion caused by repeated eye puffs, as reported by patients (e.g., "The air puff . . . felt entertaining," "It felt like little whispers on my eyeballs").

• Behaviorally, ketamine preserved reflexive blinks but blocked the "self-protective behavior" of prolonged eye closure between puffs in both species.

• Crucially, ketamine selectively affected the brain activity: The initial fast burst (Phase 1) was unaffected, but ketamine "sped up this decay" of the slower, second phase of post-eye-puff brain activity. This effectively "sharpened the brain’s response and restricting the puff-induced activity to a brief window of time."

• "This all points to that persistent second phase of brain activity as being strongly linked to emotional state,” Kauvar concluded.

• Ketamine also "reversibly reduced synchrony across the brain" in both species, suggesting that "Dissociative medication may render the stabilizing phase of brain activity so ephemeral that information can’t be properly integrated across the brain, including to build an emotional state.”

1. Implications for Neuropsychiatric Disorders: A "Science of Emotion Based on Timing":

• The "tunable, measurable timing properties" of this brain activity could provide clues for categorizing, quantifying, and treating neuropsychiatric disorders.

• Too-brisk decay of integrative brain activity (like with ketamine): Could prevent coordination of information across brain regions, leading to a disconnect. This might relate to conditions like schizophrenia, where individuals report "perceptions of alien, as opposed to self-generated, control over their actions.”

• Too-slow decay or excessive strength of the second wave: Could lead to "hyperstabilized brain states and, consequently, persistent or untimely emotions or intrusive thoughts." This framework could apply to conditions such as post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), depression, or eating disorders.

• Impact on fundamental speed of information processing: This signal persistence could also influence information processing speed, which varies in the population. For instance, "People with autism spectrum disorder are often known to have trouble keeping up with high-speed bursts of information, an ability required for language and social-information processing.” A hyperstabilized brain state might be responsible for difficulty in following rapidly changing input.

• Deisseroth stated, "These are fascinating possibilities, which we are now exploring."

III. Methodology Highlights

• Human Neural Circuitry (HNC) Program: A multidisciplinary collaboration led by Deisseroth at Stanford Medicine's hospital and laboratory facilities, designed for synchronous and ultraprecise measurement and perturbation of human behavior and brain activity in an inpatient medical setting.

• In-patient Human Subjects: Patients with frequent seizures unresponsive to medication, who had electrodes surgically inserted deep into their brains for clinical seizure localization. This provided a "serendipitous avenue for experiments that would otherwise be difficult or impossible to perform," as these patients were willing to volunteer during their hospital stay.

• Aversive but Safe Stimulus: Precisely timed "eye puffs" delivered using an ophthalmologist's device. This allowed for exact control of timing, duration, and intensity, and was applicable to both humans and mice.

• Cross-Species Comparison: The "same experiment" was carried out in parallel in mice to identify conserved brain activity patterns.

• Behavioral Measurement: Quantifiable behavioral responses (e.g., reflexive blinks, post-puff squinting/additional blinks) were tracked alongside brain activity. In mice, reward-seeking behavior was used as an indicator of negative emotional state.

• Pharmacological Intervention: Ketamine was used as a probe to manipulate emotional responses and observe its effects on the identified brain activity patterns in both species.

• Advanced Measurement: Simultaneous electrical recording and behavioral technology enabled the discovery of the two-phase brain activity pattern.

IV. Broader Implications

• This research represents a significant step towards a more precise and mechanistic understanding of how emotions are formed and sustained in the brain.

• The identification of a "tunable" time scale for brain-wide communication opens new avenues for diagnosing and treating neuropsychiatric disorders. By quantifying and potentially manipulating the "speed" of brain activity decay, novel therapeutic targets might be identified.

• The conserved principles found across humans and mice underscore the fundamental biological basis of emotion and provide powerful translational tools for future research.

V. Future Directions

The team is actively exploring:

• Whether the observed brainwide activity pattern generalizes to positive experiences.

• The fascinating possibilities of how altered timing properties of brain activity could lead to diverse neuropsychiatric symptoms and disorders like schizophrenia, PTSD, OCD, depression, eating disorders, and autism spectrum disorder.

2. Quiz & Answer Key

Quiz

1. What is the central question Stanford Medicine investigators aimed to answer regarding emotions in their study? Why is understanding this important for neuroscientists and psychiatrists?

2. Describe the two-phase pattern of brain activity observed in response to the unpleasant stimulus. Include the approximate timings and what each phase is thought to represent.

3. Why was the "eye puff" chosen as the sensory stimulus for this study? What characteristics made it suitable for both human and mouse experiments?

4. How did the researchers measure the emotional response in human subjects, beyond just brain activity? What behavioral observations were made, and how did they change with repeated stimuli?

5. What was the key finding regarding the similarity of brain activity patterns between humans and mice? Why is this evolutionary conservation significant?

6. Explain the purpose of using ketamine in the study. What specific effect does ketamine have on emotional responses, and how does this relate to its dissociative properties?

7. How did ketamine affect the two-phase brain activity pattern? Specifically, which phase was influenced, and how was its timing altered?

8. According to Karl Deisseroth, how might a "too-brisk decay" of integrative brain activity, similar to what ketamine causes, manifest in neuropsychiatric disorders? Provide an example.

9. Conversely, what could be the consequence if the "second wave" of brain activity decays too slowly or accumulates excessive strength? Name two neuropsychiatric disorders that might involve such a mechanism.

10. Beyond emotional disorders, how might altered signal persistence (hyperstabilized brain states) relate to information processing difficulties, as suggested by Deisseroth? What specific group of individuals is mentioned in this context?

Answer Key

1. Stanford Medicine investigators aimed to map the brainwide neuronal processing that underlies the emotional response triggered by a mildly unpleasant sensory experience. This understanding is crucial because emotions steer daily life, but if inappropriate or prolonged, they can cause trouble and are central to many neuropsychiatric disorders.

2. The two-phase pattern consists of an initial, strong but short-lived spike of activity (roughly 200 milliseconds) broadcasting the stimulus's "news" throughout the brain. This is followed by a separate, longer-lasting phase (next 700 milliseconds or so) of activity more localized to specific emotion-associated circuits, providing an extended window for brainwide communication.

3. The "eye puff" was chosen because it is safe, reproducible, and easy to deliver, and applicable to both humans and mice. While unpleasant, it is not painful, allowing for precise control over timing, duration, and intensity, which was critical for tracking the brain's response.

4. Beyond brain activity, researchers measured human subjects' self-reported feelings, described as "annoying," "unpleasant," and "uncomfortable." Behaviorally, subjects exhibited a reflexive blink immediately after each puff, followed by additional eye squinting or rapid blinks in the seconds after, indicating a self-protective response to the unpleasant stimulus. Repeated puffs led to an increasing feeling of annoyance that outlasted the puff series.

5. The key finding was the observation of a very similar two-phase pattern of brain activity in both humans and mice in response to the eye puffs. This evolutionary conservation is significant because if a brain dynamical principle is preserved over vast evolutionary time (70 million years since common ancestor), it suggests it is fundamentally important for survival and reproduction.

6. Ketamine was used to test the importance of the persistent second phase of brain activity in emotional responses. Ketamine is known to cause dissociation, where individuals are aware of sensory experiences but do not have typical emotional responses to them, effectively reducing or abolishing the negative emotion caused by the repeated puffs.

7. Ketamine selectively affected the slower, second phase of post-eye-puff brain activity. It sped up the decay of this phase, effectively sharpening the brain's response and restricting the puff-induced activity to a brief window of time. The initial fast burst of brainwide activity was completely unaffected.

8. According to Deisseroth, a "too-brisk decay" of integrative brain activity could prevent coordination of information flowing from diverse brain regions, leading to a disconnect. This might manifest as perceptions of alien control over one's actions, as reported by people with schizophrenia.

9. If the second wave of brain activity decays too slowly or accumulates excessive strength, it could result in hyperstabilized brain states. This could lead to persistent or untimely emotions or intrusive thoughts, characteristic of neuropsychiatric disorders such as Post-Traumatic Stress Disorder (PTSD), Obsessive-Compulsive Disorder (OCD), depression, or eating disorders.

10. Deisseroth suggests that hyperstabilized brain states, or altered signal persistence, could powerfully influence the fundamental speed of information processing. This might explain why people with autism spectrum disorder often have trouble keeping up with high-speed bursts of information, which is required for language and social-information processing.

3. Essay Questions

1. Analyze the role of the two distinct phases of brain activity identified in the study. How do these phases interact to produce a lasting emotional state from a brief stimulus, and what insights does this provide into the brain's integrative processes for emotion?

2. Evaluate the methods employed in this study, particularly the use of eye puffs as a stimulus and the recruitment of electrode-implanted human patients. Discuss the advantages and limitations of these approaches for investigating human emotions and brain function.

3. Explain how the effects of ketamine on both behavior and brain activity provided crucial evidence for the study's core hypothesis regarding the link between persistent brain activity and emotional states. What specific observations were key to demonstrating this link?

4. Beyond the direct findings on emotion, elaborate on the potential implications of this research for understanding and treating neuropsychiatric disorders. Discuss how the concept of "tunable, measurable timing properties" of brain activity could offer new avenues for diagnosis, classification, and intervention across different conditions.

4. Glossary of Key Terms

• Brainwide Neuronal Processing: The comprehensive activity and communication across multiple regions and networks of the brain.

• Conserved (Evolutionary): A biological feature, such as a gene, protein, or brain activity pattern, that has remained largely unchanged throughout evolution across different species, suggesting its fundamental importance.

• Dissociation (Ketamine-induced): A mental state characterized by a sense of detachment from one's body, surroundings, or emotional experience, often caused by certain drugs like ketamine.

• Emotional State: A prolonged and generalized feeling or mood that influences behavior and perception, arising from internal or external stimuli.

• Human Neural Circuitry (HNC) Program: A multidisciplinary research collaboration at Stanford Medicine focused on understanding the principles of human brain function in health and disease, often involving inpatient medical settings.

• Hyperstabilized Brain State: A hypothetical condition where brain activity patterns persist for too long or accumulate excessive strength, potentially leading to prolonged or intrusive emotional states or thoughts.

• Intrinsic Time Scale: A measure of the duration over which brain activity patterns remain correlated or stable, reflecting the inherent speed of information processing within a brain region or network.

• Ketamine: A medication used at high doses for anesthesia and at lower doses as an antidepressant, known for its dissociative effects where emotional responses to stimuli are reduced or absent.

• Neuropsychiatric Disorders: A broad category of medical conditions that involve both neurological and psychiatric symptoms, often characterized by problematic emotional manifestations (e.g., depression, PTSD, schizophrenia).

• Non-contact Tonometry Equipment: A device used by ophthalmologists to measure intraocular pressure by delivering a brief puff of air to the eye.

• Optogenetics: A sophisticated research technique (developed by Karl Deisseroth, though not used in this study) that uses light-activated proteins to control the activity of specific neurons, allowing researchers to turn them on or off with light pulses.

• Persistent Brain Activity: Brain activity that continues for a noticeable duration after the initial stimulus has ceased, often contributing to the maintenance of a cognitive or emotional state.

• Reflexive Blink: An involuntary, rapid closure of the eyelid in response to a sudden stimulus, such as a puff of air or a loud noise.

• Sustain Pedal Analogy: Used to describe the effect of the persistent second phase of brain activity, akin to a piano's sustain pedal extending the duration of briefly played notes, allowing for prolonged brain communication.

• Synchrony (Brain): The coordinated or simultaneous activity of different brain regions or neural populations, indicating effective communication and integration of information.

5. Timeline of Main Events

• March 1, 2023: Stanford Medicine researchers publish findings on how a racing heart drives anxiety behavior in mice, using optogenetics to control heart rate.

• March 28, 2024: Publication of an article featuring bipolar disorder expert Po Wang, highlighting Stanford Medicine's long-standing research and clinical attention to the condition.

• April 12, 2024: A Stanford Medicine-led study is published, identifying two key brain systems central to psychosis, linking them to difficulties in filtering information and predicting events.

• Prior to May 29, 2025 (Ongoing): The Human Neural Circuitry (HNC) research program, founded and led by Karl Deisseroth, is actively conducting multidisciplinary inpatient research at Stanford Medicine to understand human brain function and dysfunction, particularly related to neuropsychiatric disorders. This includes developing and utilizing state-of-the-art methods for synchronous and ultraprecise measurement and perturbation of human behavior and brain activity.

• Prior to May 29, 2025 (Ongoing): The specific study detailed in the source is conducted. This involves recruiting patients at Stanford Hospital with surgically implanted intracranial electrodes (for seizure monitoring), who volunteer for the research. The study also involves parallel experiments conducted on mice.

• Study Methodology: Researchers administer precisely timed "eye puffs" (using non-contact tonometry equipment, similar to what's used in eye doctor's offices) to both human participants and mice.

• Observation Phase 1 (Initial Response): Brainwide activity is tracked, revealing a distinctive two-phase pattern. The first phase, lasting approximately 200 milliseconds, shows a strong, short-lived spike of activity broadcasting the sensory input throughout the brain. This is accompanied by immediate reflexive blinks in both species.

• Observation Phase 2 (Emotional Response): This is followed by a longer-lasting second phase of brain activity, lasting about 700 milliseconds, more specifically localized to emotion-associated circuits. In humans, this phase is linked to feelings of annoyance and additional eye squinting/blinks. In mice, it is linked to accumulating negative emotional states and reduced reward-seeking behavior.

• Intervention Phase: Ketamine (at low, antidepressant-approved doses) is administered to both human participants (with informed consent) and mice.

• Ketamine's Effects on Emotion & Behavior: Ketamine greatly inhibits the negative emotional response to repeated eye puffs in humans, who describe the experience as "entertaining" or "whispers." It also blocks self-protective behaviors (like prolonged eye closure) in both humans and mice, while preserving reflexive blinks.

• Ketamine's Effects on Brain Activity: Ketamine does not affect the initial fast burst of brainwide activity. However, it significantly speeds up the decay of the slower, second phase of post-eye-puff brain activity, effectively "sharpening" the brain's response and restricting the puff-induced activity to a brief window. It also reduces synchrony across the brain in both species.

• "Intrinsic Time Scale" Measurement: The study finds that ketamine accelerates the brain's "intrinsic time scale" (the time over which brain-activity patterns are correlated) even in the absence of the eye puff. This effect is reversible after ketamine wears off.

• May 29, 2025: The detailed study, "How lasting emotions arise from brief stimuli, in humans and mice," is published in Science.

• May 29, 2025: An article about the study is published by Stanford Medicine, highlighting the findings and their implications for understanding emotions and neuropsychiatric disorders.

• Ongoing (Post-publication): Researchers, particularly Karl Deisseroth and his team, continue to explore the observed brainwide activity pattern in relation to positive experiences and delve into the "fascinating possibilities" of how tunable timing properties of brain activity could lead to new ways of categorizing, quantifying, and treating neuropsychiatric disorders like schizophrenia, PTSD, OCD, depression, eating disorders, and autism spectrum disorder.

• Ongoing (Post-publication): Stanford University’s Office of Technology Licensing files a patent for intellectual property associated with the study.

Cast of Characters

• Karl Deisseroth, MD, PhD:Bio: Professor of Bioengineering and of Psychiatry and Behavioral Sciences at Stanford Medicine. He is the D. H. Chen Professor and a Howard Hughes Medical Institute investigator. He led the collaborative team effort for the study and is a senior co-author. Deisseroth is renowned for developing optogenetics, although this specific study did not utilize it. He founded and leads Stanford Medicine’s Human Neural Circuitry research program.

• Carolyn Rodriguez, MD, PhD:Bio: Professor of Psychiatry and Behavioral Sciences at Stanford Medicine. She is a senior co-author of the study.

• Vivek Buch, MD:Bio: Assistant Professor of Neurosurgery at Stanford Medicine. He is a senior co-author of the study.

• Paul Nuyujukian, MD, PhD:Bio: Assistant Professor of Bioengineering and of Neurosurgery and a Wu Tsai Neurosciences Institute faculty scholar at Stanford Medicine. He is a senior co-author of the study.

• Isaac Kauvar, PhD:Bio: Postdoctoral scholar and lead co-author of the study. He is also an interdisciplinary postdoctoral scholar at the Wu Tsai Neurosciences Institute.

• Ethan Richman, PhD:Bio: Postdoctoral scholar and lead co-author of the study.

• Tony Liu:Bio: MD/PhD student and lead co-author of the study.

• Bruce Goldman:Bio: Senior science writer in the Office of Communications at Stanford Medicine. He is the media contact for the study's press release.

• Po Wang:Bio: Bipolar disorder expert at Stanford Medicine, mentioned in a related article about bipolar disorder research. (Specific role in the main study is not detailed).

6. FAQ

What was the main objective of the Stanford Medicine study on emotions?

The primary objective of the Stanford Medicine study was to map the brainwide neuronal processing underlying emotional responses, particularly those triggered by mildly unpleasant sensory experiences. The researchers aimed to understand how emotions arise from brief stimuli and how this process might relate to neuropsychiatric disorders. A key approach was to identify brain activity patterns conserved across humans and mice, assuming that such conserved patterns would be evolutionarily significant.

How did the researchers trigger emotional responses in the study participants?

The researchers used a common ophthalmological tool that delivers precisely timed, non-painful air puffs to the eye. While not painful, participants described these puffs as "annoying," "unpleasant," and "uncomfortable." Repeated rapid-fire eye puffs produced an increasing feeling of annoyance that outlasted the stimulus itself, demonstrating the lasting nature of the emotional response. This method was chosen because it was safe, reproducible, easy to deliver, and applicable to both humans and mice.

What distinctive two-phase pattern of brain activity did the study observe?

The study observed a distinctive two-phase pattern of brain activity in response to the eye puffs. The first phase, lasting approximately 200 milliseconds, was a strong but short-lived spike of activity broadcasting "news" of the eye puff throughout the brain. This was followed by a second, longer-lasting phase, spanning about 700 milliseconds, which was more specifically localized to a subset of circuits across the brain associated with emotion. This second phase, displaying an extended window for brainwide communication, was strongly linked to the emotional state.

How did the study confirm the link between the second phase of brain activity and emotional states?

To confirm this link, the researchers used ketamine, a medication known to reduce typical emotional responses. They found that in both human and mouse subjects, ketamine selectively inhibited the negative emotion caused by repeated air puffs. Crucially, ketamine did not affect the initial fast burst of brain activity but significantly sped up the decay of the slower, second phase of post-eye-puff brain activity. This acceleration effectively sharpened the brain’s response and restricted the puff-induced activity to a brief window, analogous to releasing a piano's sustain pedal. This demonstrated that the persistent second phase of brain activity is strongly linked to emotional state.

Why did the researchers study both humans and mice?

The core idea of the study was to identify "shared principles" of emotional processing that have been conserved over millions of years of evolution. By conducting the same experiment in parallel in mice, the scientists could focus on key principles that were present in both species. This comparative approach is valuable because if a brain dynamical principle is conserved over vast evolutionary time, it is likely to be fundamentally important. The remarkable similarity in the two-phase brain activity pattern observed in both humans and mice supported this approach.

How might the findings of this study contribute to understanding neuropsychiatric disorders?

The study suggests that alterations in the "time scale" of brainwide communication, particularly the persistence of the second phase of brain activity, could offer clues about neuropsychiatric disorders. If this integrative brain activity decays too briskly (as with ketamine), it could prevent proper information coordination, potentially leading to symptoms like those reported by people with schizophrenia (perceptions of alien control). Conversely, if this brain activity decays too slowly or accumulates excessive strength, it could result in "hyperstabilized brain states" and persistent or untimely emotions or intrusive thoughts, similar to those experienced in PTSD, OCD, depression, or eating disorders.

What is the significance of the "intrinsic time scale" mentioned in the study?

The "intrinsic time scale" refers to the natural duration over which brain-activity patterns are correlated, even in the absence of an external stimulus. The study found that ketamine, which reduces negative emotions, also accelerated this intrinsic time scale in both humans and and mice. This suggests that the speed at which the brain processes and integrates information, an inherent property of brain function, is linked to emotional states and could be a measurable factor in health and disease.

What new technology or methods were crucial for this study's success?

A key to the study's success was the Human Neural Circuitry (HNC) research program at Stanford Medicine, which enabled synchronous and ultraprecise measurement and perturbation of human behavior and brain activity in an inpatient medical setting. This involved recruiting patients with surgically implanted intracranial electrodes (for seizure monitoring), which provided a unique opportunity to record brainwide activity at high resolution. This combined with precise timing, duration, and intensity control of the air puff stimulus, and parallel experiments in mice, allowed for unprecedented insights into the dynamics of emotion. Notably, the study did not use optogenetics, a technology often associated with leading researcher Karl Deisseroth, but relied on existing clinical setups and comparative neuroscience.

7. Table of Contents

Introduction to Heliox Deep Dive ................. 0:00
Welcome and podcast overview, setting the stage for exploring emotion formation

The Fundamental Mystery of Emotion ............... 1:15
Why understanding brain-based emotions has been such a challenge for neuroscience

The Stanford Study Overview ...................... 3:30
Introduction to the May 2025 Science publication from Carl Deisseroth's group

Evolutionary Conservation & Research Strategy .... 5:45
How comparing human and mouse brains reveals fundamental principles

The Experimental Design .......................... 8:20
Air puff methodology, clinical electrode patients, and behavioral measurements

The Two-Phase Brain Activity Pattern ............ 12:10
Discovery of distinct fast and slow phases of emotional processing

Phase One: The Alert Signal ..................... 14:30
200-millisecond broadcast of initial sensory information

Phase Two: Sustained Emotional Processing ....... 16:45
700-millisecond focused activity in emotional circuits

Accumulation Effects in Repeated Exposure ....... 19:20
How persistent stimulation builds negative emotional states

The Ketamine Experiment ......................... 22:15
Testing causation vs correlation using low-dose ketamine

Human Responses Under Ketamine .................. 25:40
"Little whispers on my eyeballs" - transformed emotional experience

Brain Activity Changes with Ketamine ............ 28:30
Shortened phase two activity and the "sustain pedal" effect

Implications for Neuropsychiatric Disorders .... 32:45
Too fast, too slow - timing disruptions in mental health conditions

Beyond Emotion: Processing Speed Effects ........ 37:20
Connections to autism spectrum disorders and information processing

Modern Life and Brain Timing .................... 40:15
Sleep, mindfulness, and giving the brain time to process

Conclusion and Future Directions ................ 43:30
Wrapping up key insights and implications for understanding consciousness

Heliox Closing & Frameworks ..................... 46:00
Boundary dissolution, adaptive complexity, embodied knowledge, quantum uncertainty

8. Index

A
Air puff methodology, 8:20, 22:15
Autism spectrum disorders, 37:20

B
Brain activity patterns, 12:10, 28:30
Brain timing mechanisms, 32:45, 40:15

C
Carl Deisseroth, 3:30
Conservation across species, 5:45

D
Dissociation effects, 25:40

E
Electrode implantation, 8:20
Emotional circuits, 16:45
Emotional processing, 12:10, 16:45
Evolution, 5:45

F
FDA approval, 22:15

H
Human brain complexity, 5:45
Hyper-stabilized states, 32:45

I
Information processing, 37:20
Intrinsic time scale, 28:30

K
Ketamine experiment, 22:15
Ketamine effects, 25:40, 28:30

M
Mental health implications, 32:45
Mindfulness, 40:15
Mouse brain studies, 5:45, 19:20

N
Neuroplasticity, 40:15
Neuropsychiatric disorders, 32:45

O
OCD implications, 32:45

P
Phase one activity, 14:30
Phase two activity, 16:45, 28:30
PTSD implications, 32:45

R
Repeated exposure effects, 19:20

S
Schizophrenia implications, 32:45
Science journal publication, 3:30
Sleep importance, 40:15
Stanford Medicine, 3:30, 8:20
Sustain pedal analogy, 28:30

T
Two-phase pattern, 12:10

9. Post-Episode Fact Check

Based on my search and analysis of the content, I can verify several key facts about this podcast episode:

VERIFIED FACTS:

• Stanford researchers did publish research on brain activity patterns related to emotional responses, with findings about "intrinsic time scale" being affected by ketamine StanfordNews

• The study involved both humans and mice, showing shared persistent brain-activity patterns in response to adverse sensory experience Sustained in the brain: How lasting emotions arise from brief stimuli, in humans and mice

• The research found two phases of brain activity after air puff stimulation, with ketamine affecting the sustained second phase while leaving reflexive responses intact To get from experience to emotion, the brain hits 'sustain'

• Stanford Medicine does conduct ketamine research with 0.5mg/kg dosing under clinical supervision Our Clinical Studies | Depression Research Clinic | Stanford Medicine

PARTIALLY VERIFIED:

• The May 29, 2025 publication date in Science could not be independently verified through my search, though Stanford research on this topic is confirmed

• Carl Deisseroth's specific involvement as lead researcher was mentioned in the podcast but not confirmed in search results

SCIENTIFICALLY PLAUSIBLE:

• The two-phase brain response pattern described aligns with known neuroscience principles

• Ketamine's effects on dissociation and emotional processing are well-documented

• The evolutionary conservation argument between humans and mice is scientifically sound

• The methodology described (air puff stimulation, electrode recordings) represents standard neuroscience research practices

AREAS REQUIRING CAUTION:

• Some specific technical details about timing (200ms vs 700ms phases) could not be independently verified

• The direct quotes from study participants ("little whispers on my eyeballs") were not found in available sources

• Some connections to specific psychiatric disorders are presented as hypothetical implications rather than established findings

OVERALL ASSESSMENT: The podcast content appears to be based on legitimate scientific research from Stanford, with the core findings about brain activity patterns and ketamine effects being factually supported. However, some specific details and quotes may be paraphrased or interpreted rather than directly verified from the original research publication.

10. Image (3000 x 3000 pixels)