The subjective nature of emotions makes them difficult to study. The high-resolution brain recording methods available for use in animal models can’t be used with people, but at the same time, researchers cannot ask an animal how it is feeling.
“That’s one of the biggest bottlenecks,” says Nicole Rust, professor of psychology at the University of Pennsylvania. “For that reason, emotion research has not been progressing at the same rapid clip as these other brain functions,” such as memory, vision and attention.
But a new cross-species paradigm breaks through the bottleneck, Rust says. An unpleasant sensory experience—puffs of air directed at the eye—elicits an emotional response characterized by activity patterns that linger in higher-order brain areas in both mice and people. The dissociative anesthetic ketamine blocks this activity but does not affect sensory responses to the eye puffs, according to the paper, published in May in the journal Science.
“It’s just a thrilling set of experiments to see a brain-wide pattern of activity that is altered in a state where we know that there is going to be a subjective alteration as well,” says lead investigator Karl Deisseroth, professor of bioengineering, psychiatry and behavioral sciences at Stanford University. “It’s one of those moments where you’re getting a first glimpse at a vast and complex landscape.”
The “setup and the scope are impressive,” but it’s not convincing that the lingering brain state is in fact driven by an emotion, says Ralph Adolphs, professor of psychology, neuroscience and biology at the California Institute of Technology, who was not involved in the study. Instead, the main benefit of the work, he says, “is that it gives us a protocol, an approach to study aspects of emotion” and related states across species, “which is incredibly difficult to set up.”
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he inspiration for the study came in 2019, Deisseroth says, when his team recorded the brain activity of a person with epilepsy while the person naturally entered a dissociative state, or a separation of emotion from sensory awareness, in the run-up to a seizure. The individual displayed slow oscillations in their retrosplenial cortex, similar to what ketamine induces in mice, the team reported in a resulting 2020 paper.
“It was an n of one—a very interesting n of one,” Deisseroth says. “But then the question was, ‘How can we systematize this?’ We’re not going to get that lucky again, or not likely to. And so we thought, ‘Well, let’s find a way to cause dissociation. Let’s find a way to cause this separation out of the emotional state from sensory awareness,’” and in a way that can be done in both mice and people. To do this, the team reasoned, they would first induce an emotional state in both species using the same stimulus and then separate it from the sensory response using ketamine.
The team selected eye puffs as their stimulus because it is safe, uncomfortable but not painful, and temporally precise, which makes it easier to synchronize with electrical recordings. The team recorded activity across the brain using single-unit Neuropixels probes in mice and surgically implanted electrodes in people with epilepsy who were in the hospital for seizure monitoring.
The eye puffs promptly elicited a reflexive sensory response: Both mice and people quickly blinked their eyes, and event-related potentials peppered most of the brain.
The puffs also evoked an affective response, during which both species closed their eyes for a prolonged period. The participants described the sensation as “annoying” and “very unpleasant.” The mice, after repeated eye puffs, drank less of a liquid reward—the nutritional shake Ensure. After the global, rapid sensory response, slower, reverberating patterns of brain activity unfolded across subsets of the brain, including the frontoparietal and limbic networks. The “persistent timescale” of the activity patterns may be what enables emotions to integrate information from different sources and create a state that guides behavior, Deisseroth says.
An infusion of ketamine abolished this affective state but did not dampen the sensory response: The eye closure stopped but the eye blink remained. Comments from the participants confirmed the distinction between the states. One person reported that after ketamine, the eye puff “was this thing happening to me, but I wasn’t really there paying attention to it.”
The brain dynamics changed in a parallel way. The ketamine did not alter the event potentials in the initial response yet quashed the prolonged activity patterns in the second phase.
This cross-species protocol is “really elegant” and “one of the most exciting parts of the study,” says Meryl Malezieux, a postdoctoral researcher in Nadine Gogolla’s lab at the Max Planck Institute of Psychiatry, who studies heart-brain interactions in emotions but was not involved with this particular study. “Even in basic science, what we do in rodents we want to translate to humans. It’s really hard to design a study—and to have the opportunity, actually—to be able to do something in humans and in rodents at the same time.”
Tracking activity across the entire brain for an extended period of time is also a fantastic approach, says Luiz Pessoa, professor of psychology at the University of Maryland, who was not associated with this research. “I really commend the authors for this,” he says, because the field needs to move beyond only looking at the brain through “snapshots in space and time.”
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et some emotion researchers say they aren’t convinced that the state Deisseroth and his colleagues recorded is in fact an emotion.
“There’s nothing possible you can do to say that a mouse is having an emotional state comparable to what a human is having,” says Joseph E. LeDoux, professor of neural science and psychology at New York University, who was not involved in the work. “The fact that a mouse behaviorally responds in a way that a human does, doesn’t mean that the human subjective experience is transferable to the mouse.”
That conundrum is “the whole reason we did this mouse-human bridging study,” Deisseroth says.
On the human side, it’s dubious that blowing puffs of air into someone’s eye is enough to cause an emotional response, Pessoa says. “It’s a very potent stimulus,” but it’s far removed from the complex emotional experiences that color people’s lives.
The investigators “know it was an emotional response—as much as anyone can know it’s an emotional response—because that’s how it was described by the humans experiencing it,” Deisseroth says. “These descriptions are how we work with emotion in the field of psychiatry.”
Additional experiments would bolster the argument that eye puffs can produce an emotion, Adolphs says. These include testing if other negative stimuli—such as an unpleasant image, sound or odor—elicit the same patterns in brain activity, and if conditioning can generate the same brain state without using the eye puffs.
Malezieux says she is convinced that the team captured an emotional state. “This dissociation, to me, shows that these are two separate states,” she explains, and “the second, longer-lasting state is the emotional component.” But she agrees that conditioning experiments would strengthen the findings, although there likely would be insufficient time to complete these experiments with the participants while they are in the hospital for seizure monitoring. Measurements of physiologic signals that change during an emotion, such as heart rate and respiration, would also be a helpful addition, she says, and it would be interesting to see if positive emotions have similar brain dynamics.
Ultimately, the debates surrounding the paper, and the questions the work raises, add to its value, Adolphs says. “If you’re uncomfortable saying that this really amounts to an emotion—as I am—it then forces you to say, ‘Okay, tell me what would be needed. What else do you want?’ And I think that’s really the most useful exercise for the whole field to come up with.”