Anxiety can be created by the body, according to a recent study with mice that may have significant implications for humans.

The research, published in the journal Nature, demonstrated that artificially raising a mouse's heart rate leads to anxious behavior in the rodent.

Scientists have long known that emotional states influence our bodily physiologically. But whether or not an increased heart rate might induce anxiety, or fear itself, has remained unclear.

"This paper addresses a long-standing question that has inspired us in the lab, dating back at least to [American philosopher and psychologist] William James," Karl Deisseroth, an author of the Nature study at Stanford University, told Newsweek. "In 1884, James posited that bodily changes represent emotion, and that the brain's perception and experience of these changes is the emotion, in a fundamental way."

"As a psychiatry doctor in training 20 years ago, I was intrigued by epidemiology linking primary cardiac disorders with panic attacks," he said. "But there was no way of proving a causal link arising from cardiac abnormalities, since there was no way of specifically and directly controlling cardiac function in real time in behaving animals."

Illustration of the heart and brain
An artist's illustration of the human heart and brain. "This work reinforces the notion that autonomically controlled organs like the heart also transmit information about their state to the brain, which integrates this information with other sources to influence emotion," one academic concluded.

Previously, the available pharmacological and electrical interventions couldn't be shown to have specific direct action on the heart muscle cells themselves.

"It took my lab's development over 20 years of optogenetics—a way of controlling specific cells with light––and in particular a fast and non-invasive form of optogenetics that we developed over the past three years to enable these experiments," said Deisseroth, who is affiliated with Stanford's Department of Bioengineering, as well as the college's Department of Psychiatry and Behavioral Sciences.

The researchers developed a non-invasive optogenetic pacemaker that enabled them to precisely control the cardiac rhythms of lab mice and make their hearts beat faster—up to 900 beats per minute. For context, a normal resting heart rate for a mouse usually hovers around 600 beats per minute.

"We found that directly pacing the heart at higher rates caused increases in anxiety-related symptoms, especially in potentially risky environments," Deisseroth said. "This effect was mediated by communication from heart muscle-cell activity to the insular cortex in the brain."

The Nature study demonstrates that cells outside the brain play an important role in setting emotional states.

"This could be a general principle, since many emotions are felt in the body—not just anxiety and fear and rage, but also positive emotions relating to reward and social bonding," Deisseroth said.

The results of the study show that the insular cortex is the main area of the brain involved in the processes described, "concluding that both brain and body are mutually involved in the origins of emotional states," Dr. Antonio Giordano, president of the Philadelphia-based Sbarro Health Research Organization, who was not involved in the Nature paper, told Newsweek.

The issue of the relationship between largely unconscious processes regulated by the autonomic nervous system—for example, the heartbeat, the gastrointestinal tract, etcetera—and emotions has been an area of debate going back to James's theory.

Sometimes referred to as the James-Lange theory, this idea posited that emotional sensations are the sum of the autonomic sensations that an activity arouses, Clifford Saper, a professor of neurology and neuroscience at Harvard Medical School, who was also not involved in the Nature paper, told Newsweek.

"Under this theory when you see a bear, you are afraid," Saper said. "But the feeling of fear is produced by the cerebral cortex seeing something threatening, setting off changes in heart rate, blood pressure, breathing, etcetera, in response to seeing a bear, and that the 'feeling' you get is the sum of the sensations produced by the autonomic response."

"This paper studies the way that the brain reacts to a stressful stimulus, showing that the brain sensation of the changes in heart rate augment the emotional response—although may not be the sole cause of it. It is a well done study by a very strong group of scientists."

Deisseroth said it is "quite likely" that the study's findings could be applicable to humans as well, even though these animals are not perfect model.

"The same basic circuitry is present in both species, and human epidemiology—the source of my initial psychiatric inspiration—strongly correlates primary cardiac disorders and anxiety symptoms, including panic attacks," Deisseroth said.

Vasanth Vedantham, a professor of medicine at the University of California, San Francisco, who was not involved in the Nature study, told Newsweek that the paper's authors used "innovative" methods and that the main finding is generally "well-supported" by the data.

"The result itself is not necessarily surprising and fits with current thinking about the relevance of bodily states to determination of the state of arousal—what is important is that the methods used can be generalized and will allow for a deeper exploration of the mechanistic pathways in the heart and nervous system that are involved in this processing," he said.

"Thus, this work creatively circumvents experimental obstacles in this field and will open a new path to developing a detailed understanding of how bodily states influence the mind and its emotional states."

The study provides some experimental support for the notion that the relationship between emotional states and the body involves a two-way flow of information, according to Vedantham.

"We are familiar with the notion that information taken in via sensory organs—vision, hearing, touch, etcetera—is processed and interpreted in the brain to influence our emotional states. This work reinforces the notion that autonomically controlled organs like the heart also transmit information about their state to the brain, which integrates this information with other sources to influence emotion—so the brain combines 'external perception' with 'internal perception,'" he said.

"Importantly, the brain also influences the function of these organs so there is the potential for feedback. Thus, when we try to understand the factors that influence emotional states such as anxiety, we need to take account of this potential for feedback and it might be that altering the state of a bodily organ could have important effects on mood and that dysfunction of a bodily organ can directly affect mood through these pathways."

Vedantham also said the findings of the study could be broadly applicable to humans. This is because autonomic control of the heart rate and interoceptive processes are likely to be similar among mammals.

"Since our access to the emotional states of non-human animals is limited for obvious reasons, the term 'anxiety-like state' is used to describe the mouse behavior and is not likely to capture the precise ways we use the term 'anxiety' with respect to human subjective emotional states," he said. "But the main principle that bodily states influence arousal and emotion is likely to apply to humans."

Several white mice eating
A file photo of white mice. Anxiety can be created by the body, a recent study in mice has suggested.

There are certain scenarios where the findings that the researchers uncovered might apply in real-life situations, according to the experts.

"Many natural settings cause elevated heart rates, and some are positive (as with exercise) but others are negative (as with running to catch a train, or anxiety-related situations)," Deisseroth said. "The elevated heart rate in the negative contexts likely contributes to the negative emotions of anxiety."

For example, running to catch a train would increase your heart rate, blood pressure, and respiration—and these, in turn, might increase your anxiety, Saper said.

"In the real world, our ancestors needed this boost to get away from a threat such as a bear, or fight off an attacker," Saper said. "In the modern world, these responses can be less adaptive, because the challenges we face are often cognitive, rather than physical."

One might also imagine a scenario involving public speaking—in which an initial bout of anxiety increases the heart rate. This then creates a feedback loop that amplifies anxiety even further.

"One can imagine that establishing such a 'positive feedback loop' could allow for the brain and body of an animal to rapidly and coordinately respond to a sudden threat. But the same system can produce or amplify anxiety and distress to even mild perceived threats under some circumstances," Vedantham said.

"These concepts may partly explain why some patients with arrhythmias can experience profound anxiety and distress even when the arrhythmias are not severe enough to compromise the pumping function of the heart. Indeed, there is a family of disorders known as 'dysautonomias' that may well involve abnormal function of the systems described in this paper, although future work will be required to test that theory."

In theory, the ideas outlined in the Nature study could have implications for medicine and the treatment of certain mental health disorders, according to Deisseroth.

"Many people have elevated heart rates due to medical complications, and therefore directly reducing heart rate may be considered as a treatment goal if patients also have anxiety symptoms," he said.

"Most current anxiety treatments directly act on the brain but have brain-related side effects as a result, including sedation and addiction. But directly reducing heart rate is possible with safe current medications, and with cognitive therapies that focus on regulating and controlling bodily responses including breathing rate."

Gary Small, a professor of psychiatry and behavioral health at Hackensack University Medical Center who was also not involved in the Nature paper, told Newsweek the results supported the long-held clinical observation that physical symptoms of anxiety can induce emotional and behavioral anxiety responses

"These results support the use of anxiety interventions aimed at controlling physical symptoms—for example, palpitations and shortness of breath—associated with anxiety states," Small said. "Also, educating people about both the physical and psychological symptoms of anxiety will help them recognize and treat their symptoms earlier."

"Clearly, a rapid heart rate does exacerbate anxiety symptoms," he said. "If people prone to anxiety recognize the physical symptoms early, they can take steps to alleviate them and reduce their emotional anxiety. They can then slow their heart rate through meditation, relaxation exercises, or vagal maneuvers—i.e., actions that stimulate the parasympathetic nervous system by activating the vagus nerve—like coughing, bearing down as if having a bowel movement or putting an ice pack on their face."

The methods used in the study could have a wide range of potential applications for human medicine, according to Giordano.

"The goal could be the evaluation of the interactions between the physiological system in the development of several diseases and the exploration of new targets of therapy," he said.

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