Study shows how the brain's sensitivity to regret can change in mood disorders

Study shows how the brain's sensitivity to regret can change in mood disorders

Researchers at the Icahn School of Medicine at Mount Sinai have found that the way the brain processes the complex feeling of regret may be linked to a person's ability to cope with stress and changes in psychiatric disorders such as depression.

The study, published Oct. 19 in Science Advances, shows that mice are sensitive to two different types of regret and that these different thought processes likely originate from different parts of the brain. The team also discovered that a genetic marker that predisposes to maladaptive stress response traits and susceptibility to depression was linked to sensitivity to one type of regret, whereas healthy and stress-resistant animals were instead sensitive to a second type of regret.

These new findings could have broad implications across multiple fields, including psychiatry, psychology, and behavioral economics, and could inform the future design of targeted therapies for mood disorders in humans.

Until now, little was known about how sensitivity to regret can change in mood disorders such as depression. For example, is regret excessive and do people ruminate excessively on past decisions, or are people with depression numb to the feeling? Is this adaptive or maladaptive and are individuals unable to learn from their mistakes? To date, there is no clear description of regret as a characteristic feature of the disorder for patients struggling with depression.”

Brian Sweis, MD, PhD, lecturer in the Department of Neuroscience and resident in the Department of Psychiatry at Icahn Mount Sinai and senior author of the study

Building on previous work showing that rats and mice are capable of processing regretful thoughts, the Mount Sinai study pushes the boundaries of what can be captured in rodent models used to study mental illness. The authors achieved this goal by combining sophisticated behavioral economics and chronic stress approaches with viral gene therapy to investigate the neural and molecular basis of complex decision-making in animals.

This methodology is based on principles of neuroeconomics, which examines how the brain's physical limitations lead to biases we have when making decisions. This approach allowed researchers to capture how complex decisions made in the past can impact subsequent decisions and, more importantly, how the way individuals process or realize missed opportunities can interact with affective states in influencing future decisions—the basis of regret.

The team trained mice on a decision-making task called “Restaurant Row,” in which the animals navigated a maze looking for their only source of food (see animation). The mice were allotted a limited amount of time each day to invest in rewards of varying costs (randomly selected delays of 1 to 30 seconds signaled by pitch) and subjective value (unique flavors tied to four different locations or “restaurants”). ). Mice chose to enter or leave each restaurant depending on the cost and taste offered. When mice accepted an offer by entering the restaurant, they had to wait a countdown to receive the reward before moving on to the next restaurant. Mice showed stable preferences regarding willingness to wait depending on the taste of the respective restaurant. Violating one's decision-making policy can be interpreted as a first step toward constructing a situation that could cause regret.

Key findings include the existence of two distinct types of regret that are not generic but rather are associated with different parts of the brain depending on the exact type of missed opportunity being processed. In both species, animals make mistakes. However, type one regret was defined as an “economic transgression” in which animals missed a good opportunity only to get burned on subsequent attempts (see summary figure). Conversely, Type 2 regrets were defined as decisions in which animals made the poor choice of investing their limited time in offerings that they normally could not afford. Type one regret is therefore about the individual's realization that he has missed or missed a good opportunity, while type two regret is characterized by the fact that he is faced with the decision to cut his losses and move on. Although both types of regret can involve reflecting on the path traveled and what might have been, type one regret emphasizes the decision to let go of something good, while type two regret emphasizes the need to change one's mind. This study found that the weight these errors have in changing future decisions varies biologically and is clearly related to stress response characteristics.

“We found that stress-prone mice were hypersensitive to type one regret and insensitive to type two regret, while healthy mice were conversely insensitive to type one regret and only sensitive to type two regret, which was even more pronounced in stress-resistant mice,” explains co-author Scott Russo, PhD, professor of neuroscience and psychiatry. Icahn Mount Sinai. "These results show us that the way the brain processes mistakes is multifactorial and related to the ability to cope with stress, and that one type of regret is part of a healthy set of emotional traits, while the other may be part of the disease process itself." . As with pain, some forms of which are healthy and adaptive while others are pathological, we have found that not all forms of regret are the same and originate in different circuits in the brain.”

According to Dr. Sweis, who is currently training to be a psychiatrist at Mount Sinai, said the team's research could have a significant impact on clinical practice, including by influencing the way mental health providers interview patients with mood disorders.

“Prior to our study, professionals may not have considered asking patients more specific questions during psychiatric assessments that detail and subcategorize their regrets with the level of sensitivity we describe,” says Dr. Sweis. "Our work could improve the way psychiatric interviews could be conducted to better identify which thought processes should be enhanced or eliminated, informed by cutting-edge scientific discoveries in neuroscience and computational psychiatry. Our research could help guide interviews between clinicians and patients toward identifying specific circuits that do this." can contribute to mood disorders and develop appropriate therapeutic approaches.”

The Mount Sinai researchers also discovered that a gene known to regulate many stress-sensitive responses in the brain - CREB - can independently influence the two types of regret in separate brain regions: the medial prefrontal cortex and the nucleus accumbens.

“In both humans and mice, this gene is known to promote stress resilience in the medial prefrontal cortex, while causing the opposite effect, namely susceptibility to stress, in the nucleus accumbens,” says Dr. Romain Durand-de Cuttoli, lead author of the study, a postdoctoral researcher at Mount Sinai.

Until now, it remained unclear what role CREB function plays in more complex emotional processes. By experimentally manipulating CREB activity in both brain regions, the team found a biological link and a potential molecular target for developing new therapies that could alter certain aspects of regret in brain region-specific ways to restore healthy emotional processing while improving potentially unhealthy and pathological forms of this complex emotion.

“Knowing that regret processing subtypes originate from different brain regions has profound implications for assessing which brain circuits drive not only different decisions, but also the different ways we reflect on our past,” says Dr. Durand-de Cuttoli, “and how more precise interventions, whether through drug development or more invasive neuromodulation approaches tailored to specific pathological emotional characteristics, can be targeted to treat mood disorders more effectively.”

Source:

Mount Sinai Health System

Reference:

Durand-de Cuttoli, R., et al. (2022) Certain forms of regret related to resilience versus stress vulnerability are regulated by region-specific CREB function in mice. Scientific advances. doi.org/10.1126/sciadv.add5579.

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