Summary: Although emotions can influence our behavior, they can have serious consequences for mental health if they persist for very long or arrive at the wrong moment. In a location research, researchers mapped brain-wide exercise habits triggered by an annoying but safe stimulus—eye puffs—in both humans and animals.
A quick initial response followed by a slower, continual sign that was related to emotional processing was discovered. This slower period, which ketamine was shown to suppress, may govern how emotions form, and dysfunctions in its timing does lead to neurological disorders.
Important Information:
- A quick original sign is followed by a protracted phase of brain-wide integration in emotional responses.
- Ketamine Insight: The antidepressant morphine carefully reduced this slower period, softening personal effects without blocking sensation.
- Evolutionary Conservation: Nearly identical brain activity was observed in humans and mice, demonstrating a deeply conserved emotional circuit between mammals.
Source: Stanford
We don’t always understand our emotions, but we couldn’t lead normal lives without them. They guide us through life, guiding our choices and choices. But if they’re inappropriate or stick around for too long, they can cause trouble.
Despite their best efforts, neuroscientists and psychiatrists are unable to learn nearly enough about the brain activity that drives our emotions, how they affect us, and how they can make us ill.
Investigators at Stanford University have now mapped the brainwide neuronal processing that underlies the emotional response triggered by a mildly unpleasant sensory experience in a study that is scheduled to be published on May 29 in Science.
Features of this brain activity turn out to be shared by humans and mice— and, by extension, every mammal in between. ( Your pet might already be explaining this to you. )
The findings could help unveil some of the driving forces behind numerous neuropsychiatric disorders, which are characterized in large part by troublesome emotional manifestations.
” Emotional states are fundamental to psychiatry”, said , Karl Deisseroth, MD, PhD, professor of bioengineering and of psychiatry and behavioral sciences, who led a collaborative team effort spanning Stanford Medicine’s hospital and laboratory facilities. The study’s senior co-authors include; Carolyn Rodriguez, MD, PhD, professor of psychiatry and behavioral sciences; Vivek Buch, MD, assistant professor of neurosurgery; and Paul Nuyujukian, MD, PhD, assistant professor of bioengineering and of neurosurgery.
The lead co-authors of the study are postdoctoral scholars Isaac Kauvar, PhD, and Ethan Richman, PhD, and MD/PhD student Tony Liu.
The study was a part of Stanford Medicine’s multidisciplinary collaboration, Human Neural Circuitry, which was founded and led by Deisseroth and was intended to learn the fundamental rules governing the inner workings of the human brain in both health and disease.
The HNC program develops and brings together, in an inpatient medical setting, state-of-the-art methods for synchronous and ultraprecise measurement and perturbation of both human behavior and brain activity.
In this study, Deisseroth and his colleagues focused primarily on responses to negative sensory experiences. However, he speculates that the brain-wide activity pattern his team observed also applies to positive experiences. ( His group is exploring those, too. )
Bringing it all together
” The mammalian lineage has made a huge evolutionary commitment to large brain size, with all its attendant costs and benefits”, said Deisseroth, who is the D. H. Chen Professor and a Howard Hughes Medical Institute investigator.
Even a mouse’s brain ( which is large compared with same-sized non-mammals ) contains nearly 100 million neurons, a human brain, almost 90 , billion  , — about 1, 000 times as many.
Deisseroth said,” A bigger brain means a richer, more complex mental life.”
” But there are real constraints once you scale up. Because the human brain is so large, it takes some time for those rich and complex signals to converge and be properly integrated before they fully spread throughout the brain.
” 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. If that doesn’t happen, wrong decisions will be made and wrong actions taken.”
Emotions may represent states that combine a lot of information to create long-lasting patterns of behavior, but Deisseroth said that in order to do that, widely dispersed brain structures may require persistent communication between themselves.
” Tuning the time scale of this communication could be an important aspect of typical brain function,” Richman added.
This would be comparable to the sustain pedal on a piano, which increases the duration of briefly played notes. ” Either overly shortened or overly prolonged stability of such brainwide communication patterns could contribute to neuropsychiatric disorders characterized by emotional dysfunction.
What might those emotion-enabling patterns of activity be? Finding out which observed signals are the most crucial is a challenge because human brain activity is so complex.
Deisseroth is , renowned for developing optogenetics, a sophisticated and now widespread method using a targeted light-activated protein together with pulses of light to induce select nerve cells, or groups of them, to fire or go silent at the flip of a switch. However, the new study, which used briefly hospitalized human patients, did not use optogenetics.
Instead, the Stanford team used a clever evolutionary trick. To determine how emotion emerges in response to experience, the researchers carried out brainwide screens of neural activity in both mice and humans — two species that emerged from the same ancestor some 70 million years ago — to search for activity patterns present in both species that could be induced by the same emotion-generating stimulus, measurable in the same way, synchronized with the same high-speed behaviors and blocked by the same interventions.
According to Kauvar,” This approach allowed us to concentrate our study on the fundamental ideas that mice and humans shared.”
If, over that vast amount of evolutionary time, a particular brain-activity pattern (ultimately determined by genes governing brain structure and function ) doesn’t help survival and reproduction, it will be lost, Deisseroth said, while” if a brain dynamical principle is conserved over that time, you’d better believe it could be important.”
Puff, blink, and squint
First the reflex, then the emotional response: You burn your hand on a stove, reflexively pull it away, then feel the pain spreading and curse. The sound of a gunshot — or a similar noise — on a dark street in a strange neighborhood late at night elicits a reflexive ducking response, then a sense of fear and caution.
There are far too many examples of emotion coming from an unpleasant sensory input. But those instances are typically tough to measure and often both difficult and dangerous to stage. The triggering stimulus for experiments must be reproducible, accessible, and safe, and in this case, applicable to people and mice.
For this study, the method of choice was a tool employed in every eye doctor’s office. Deisseroth’s team took advantage of the device an ophthalmologist uses to deliver little puffs of air to check the pressure in their patients ‘ eyes. Although it’s not painful, it can still be a little unpleasant.
Here, employing this aversive but medically safe stimulus permitted precision in timing, duration and intensity of the stimulus. The researchers were able to track each subject’s brainwave response to each puff by making sure they knew when each puff started and when it stopped.
The scientists administered multiple series of precisely timed” eye puffs” to participants, who, asked how they felt about the puffs, described them as” annoying,”” unpleasant “and” uncomfortable,” though certainly not painful. Repeated rapid-fire eye puffs produced an increasing feeling of annoyance that outlasted the eye puff series.
Deisseroth noted that that bummed-out state of mind can be adaptive. Any repeated series of negative events is important to the brain, to be considered in guiding future behavior.”
Deisseroth and his associates recruited a group of Stanford Hospital patients who had had electrodes surgically inserted deep into their brains to enable teams of neurologists and neurosurgeons to locate each patient’s unique focus, the hyperexcitable point of origin from which seizures would spread across otherwise healthy brain tissue, in order to capture brainwide activity at high resolution.
While all those electrodes had been implanted in patients ‘ brains for purely clinical reasons, it provided a serendipitous avenue for experiments that would otherwise be difficult or impossible to perform.
” These patients typically spend about a week in a hospital bed with limited mobility, during recording from these implanted intracranial electrodes, while the treatment team waits for spontaneous seizures to occur,” Liu said.
These patients were more than willing to volunteer for and take part in the investigators ‘ innovative study over a long period of time.
Subjects ‘ visible responses to randomly timed eye puffs were found to be quite consistent. The subjects briefly reflexively blinked as a result of each puff. In the seconds following each puff, subjects also exhibited additional eye squinting or rapid additional blinks.
This additional post-puff eye closure was a natural response to an unpleasant stimulus ( since they could not predict the timing of the next puff ). It also provided precise quantifiable insight into emotion-triggered behaviors right away following a sensory stimulus.
All the while, the experimenters tracked subjects ‘ brainwide activity. They observed a strong but brief-lived spike of activity broadcasting “news” of the eye puff throughout the brain in the first roughly 200 milliseconds of the pattern.
This was followed over the next 700 milliseconds or so by 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 pattern — which, Deisseroth noted, was discoverable thanks to the simultaneous electrical recording and behavioral technology of the team — displayed the interesting property of yielding an extended window of time for brainwide communication, which could be related to emotion.  ,
Since the core idea of the study was to search for shared principles among humans and mice, the scientists carried out the same experiment in parallel in mice. The team’s findings reveal remarkably that mice and mice have a very similar two-phase brain activity pattern.
Moreover, delivering a series of eight eye puffs in rapid succession to mice induced accumulating second-phase brain activity and put the mice into a generalized negative emotional state, as further evidenced by their persistently reduced willingness to engage in reward-seeking behavior. ( Such persistence and generalizability are classic hallmarks of emotion. )
With the squint, gone.
The researchers then used a medication, chosen to be suitable for use in both humans and mice, to further test for the importance of this persistent activity pattern. Ketamine, which is frequently used in high doses in anesthesia, is FDA-approved for use at lower doses as an antidepressant. Even at these lower doses, ketamine is known to cause a phenomenon called dissociation, in which typical emotional responses to stimuli are reduced or absent.
” 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 said.
It seems as though it is occurring to some or another person. ” This dissociative effect of ketamine wears off within an hour or so, he said.
The researchers carefully crafted their research protocol so they could safely administer a single dose of ketamine to electrode-implanted human subjects in the hospital, and with fully informed consent, found that in fact the negative emotion caused by the repeated puffs of air ( as the patients described ) was significantly lowered.
An important part of the clinical study was the ability to directly ask participants about their experiences, Liu said.
” The air puff… felt entertaining, “one participant said”. ” It sounded like little whispers on my eyes,” another said.
Consistent with this loss of their subjective sense of annoyance, the human subjects also did not show self-protective behavior — they kept their eyes open between puffs even though they were fully aware of the puffs and continued to have robust reflexive blinks. In the mice, it was interesting to see that the same selective behavior was present ( preserving the reflexive blink while preventing self-protection with prolonged eye protection ).
The team carried out a final set of definitive measurements to test their core hypothesis. If the persistent second phase of brain activity were important in the emotional response, this slower phase would be predicted to be selectively reduced by ketamine in both species, thereby effectively speeding up the brain’s response. The initial fast burst of brainwide activity was completely unaffected by ketamine in both humans and mice, according to the team’s findings.
But when the scientists measured the speed at which the slower, second phase of post-eye-puff brain activity subsided, they found that ketamine sped up this decay, effectively sharpening the brain’s response and restricting the puff-induced activity to a brief window of time ( analogous to releasing a piano’s sustain pedal to terminate the note ).
This all points to the strong correlation between emotional state and that persistent second phase of brain activity, according to Kauvar.  ,
If speeding-up of brain activity prevents formation of emotional states, this acceleration due to ketamine should also be detectable even in the eye puff’s absence. The team discovered that the” intrinsic time scale”, a measure of the period of time over which brain-activity patterns were correlated, was accelerated by ketamine even without the eye puff, as predicted. In both species, intrinsic time scale rapidly recovered to its normal duration after the ketamine wore off.
Finally, the team discovered that ketamine also reversely reversibly decreased synchrony across the brain in both species.
” 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,” Deisseroth said.
A science of emotion based on timing?
When pushed beyond a typical range, either in the slowed or sped-up direction, these tunable, measurable timing characteristics may provide insights into how to categorize, quantify, and perhaps even treat neuropsychiatric disorders.
” Far too-brisk decay of that integrative brain activity ( as ketamine causes ) could generally prevent coordination of information flowing in from diverse regions of the brain,” Deisseroth said.
This might lead to a situation where the right hand figuratively is incapable of comprehending what the left hand is doing.
” People with schizophrenia report perceptions of alien, as opposed to self-generated, control over their actions,” Deisseroth said.
On the other hand, if a brain disorder causes the second wave of brain activity to decay too slowly or to accumulate excessive strength ( perhaps due to differences in brain wiring or gene expression, or even related to personal experiences ), this could result in hyperstabilized brain states and, consequently, persistent or untimely emotions or intrusive thoughts like those experienced by people with post-traumatic stress disorder, obsessive-compulsive disorder, depression or eating disorders.
Depending on the specific circuits that represent this altered persistence, different symptoms ( and different disorders ) might show up.
Distinct from emotion in health and disease, this same quality of signal persistence could powerfully influence the fundamental speed of information processing, another property that varies substantially in the human population.
People with autism spectrum disorder are frequently cited as having trouble coping with rapid bursts of information, which is a skill needed for language and social-information processing, according to Deisseroth.
Could a hyperstabilized brain state be responsible for difficulty in following rapidly changing input?
” These are fascinating possibilities, which we are now exploring,” Deisseroth said”. What an impartial brainwide screen can reveal is amazing, especially with the right technology and over the course of millions of years of evolution. ”  ,
The Office of Technology Licensing at Stanford University has filed a patent for the study’s intellectual property.
Researchers from the Veterans Affairs Palo Alto Health Care System and Weill Cornell Medicine contributed to the work.
Funding: The study was funded by National Institutes of Health ( grants P50DA042012, R01MH105461, R01MH133553 and R01NS095985 ), the AE Foundation and anonymous donors.
About this news about neuroscience and emotion research
Author: Bruce Goldman
Source: Stanford
Contact: Bruce Goldman – Stanford
Image: The image is credited to Neuroscience News
Original Research: Private access.
” Conserved brain-wide emergence of emotional response from sensory experience in humans and mice” by Karl Deisseroth et al. Science
Abstract
Conserved brain-wide emergence of emotional response from sensory experience in humans and mice
INTRODUCTION
Emotional states are central to the human condition in health and disease, yet the neural processes by which emotions emerge from experience remain mysterious. In mammals, long-lasting emotional responses may help to integrate internal and external information spread across the brain and help to guide contextually appropriate behaviors.
We hypothesized that common structural and functional constraints on sensory integration into emotional states in the mammalian lineage could yield conserved dynamical principles governing the establishment and maintenance of emotional responses.
RATIONALE
We first created unbiased brain-wide activity screens spanning widely divergent mammalian species in order to identify broadly conserved patterns of neural activity. Specifically, we explored when, where, and how emotional states emerge, using high-speed, invasive, and global methods in human and mouse subjects carrying out the same task.
While recognizing and leveraging the value of obtaining verbal descriptions of subjective emotional experience from human subjects for this question, we also explicitly bridged human and mouse systems with temporally precise affective behavioral measures, clinically compatible pharmacological interventions, and deep brain-spanning intracranial electrophysiological readouts, designed to be similarly carried out in parallel in both human and mouse subjects, to investigate conserved principles underlying the emergence of lasting emotional states from brief sensory input.
RESULTS
We discovered that air puffs directed at human or mouse corneal subjects cause both fast/reflexive and sustained/affective eye closure behaviors, which both species exhibit negative valence, persistence, generalization, and ablation caused by the dissociative agent ketamine.
We performed a brain-wide neural activity screen of this temporally precise behavioral response, using intracranial stereo-electroencephalography (iEEG ) in humans and multiprobe Neuropixels single-unit electrophysiology in mice.
This brain-wide screen revealed a biphasic process where emotionally sensitive sensory signals are quickly broadcast throughout the mammalian brain and are immediately followed by a slower, widely distributed, persistent signal.
We discovered that the persistent signal could be selectively and similarly blocked by ketamine while preserving the fast sensory broadcast in both species, and that emergence of a behaviorally defined emotional state could be selectively blocked by this intervention.
We found that the accumulation and decay pattern of persistent population neural activity was consistent with first-order system dynamics, and that the dose-dependent pharmacological impact on the emotional response could be well-modeled by varying a single decay timescale parameter, with emotion-blunting dissociative drugs accelerating the decay.
We furthermore discovered that ketamine reduced brain-wide population coupling in networks with puff-triggered persistent activity and increased the intrinsic timescale of baseline spontaneous activity in both humans and mice.
Control experiments in mice with a neutral auditory stimulus ( while operating on faster timescales than emotionally salient stimuli ) revealed that the pharmacological effect of sharpening response dynamics and reducing capacity to maintain persistent information across the brain was generalizable, highlighting the importance of signal persistence in the establishment of brain-wide responses.
CONCLUSION
We discover that in a conserved pattern spanning divergent species, mammalian emotional states are incorporated from sensory experiences through persistent activity dynamics that can be shaped by a global and tunable intrinsic timescale, similar to the action of a piano sustain pedal. Functioning as a distributed neural context, adaptive emotional states appear to depend upon brain-wide mechanisms of signal persistence in specific networks.
Furthermore, consistent with our measurements of intrinsic timescale modulation by clinically relevant intervention, aspects of the etiology and treatment of certain neuropsychiatric disorders may be governed by altered stability of brain states linked to maladaptively fast or slow intrinsic timescales.
