“We discovered that stress-susceptible mice were hypersensitive to type- one regret and insensitive to type-two regret'' (credit: Dr. Brian Sweis)
The brain’s sensitivity to different types of regret may impact mood disorders like depression.
By JUDY SIEGEL-ITZKOVICH Published: OCTOBER 20, 2022
Updated: OCTOBER 22, 2022
Researchers from New York’s Icahn School of Medicine at Mount Sinai Hospital found that the way the brain processes the complex emotion of regret may be linked to our ability to cope with stress and be changed in psychiatric disorders.
The study was just published in the American Association for the Advancement of Science’s open-access journal, Science Advances. Entitled “Distinct forms of regret linked to resilience versus susceptibility to stress are regulated by region-specific CREB function in mice,” it reveals that rodents show sensitivity to two distinct types of regret and that these different thought processes likely stem from different parts of the brain.
The team, headed by Dr. Brian Sweis, an instructor in the department of neuroscience and a resident in the department of psychiatry at Icahn Mount Sinai, was the senior author of the study.
What were the findings of the study?
The team found that a genetic marker that predisposes maladaptive stress response traits and vulnerability to depression was linked to sensitivity to one type of regret, while healthy and stress-resilient animals were instead sensitive to a second type of regret. These novel findings could have broad implications for multiple fields, including psychiatry, psychology and behavioral economics, and could affect the future design of targeted therapies for mood disorders in humans, said Sweis.
“Is regret exaggerated and do individuals hyper-ruminate on past decisions, or are those with depression numb to this emotion? Is this adaptive or maladaptive, and are individuals unable to learn from their mistakes? For patients struggling with depression, there has been no clear description of regret as a defining feature of the condition,” he added.
Building on previous work demonstrating that rats and mice are capable of processing regret-like thoughts, the Mount Sinai Hospital study pushes the boundaries of what can be captured in rodent models used for the study of mental illnesses. The authors reached this goal by combining sophisticated approaches in behavioral economics and chronic stress procedures with viral gene therapy to study the neural and molecular basis of complex decision-making in animals.
This methodology was built on principles of neuroeconomics, which is the study of how the physical limits of the brain give rise to biases we have when making decisions. This approach made it possible for the researchers to capture how complex choices made in one’s past can impact subsequent decisions and, importantly, how the way in which individuals process or realize missed opportunities is capable of interacting with affective states when influencing future choices – the basis of regret.
The team trained mice on a decision-making task termed “Restaurant Row” during which the rodents navigated a maze foraging for their sole source of food. Mice were given only a limited amount of time each day to invest in rewards of varying costs (delays randomly selected from one to 30 seconds signaled by the pitch of a tone) and subjective value (unique flavors tied to four separate locations or “restaurants”).
Mice chose to enter or skip each restaurant depending on the cost and flavor presented. If mice accepted an offer by entering the restaurant, they were tasked to wait out a countdown to earn the reward before moving on to the next one. They showed stable preferences of willingness to wait depending on each restaurant’s flavor. A violation in one’s own decision policy can be interpreted as the first step in constructing a situation that could invoke regret.
Two types of regret
Among the major findings: the existence of two distinct types of regret that are not generic but rather are connected to separate parts of the brain, depending on the exact nature of the missed opportunity being processed. Both types involve animals making mistakes.
But type-one regret was defined as an “economic violation” in which animals walked away from a good opportunity only to “get burned” on subsequent trials. Conversely, type-two regret was defined as decisions in which animals made poor choices to invest their limited time in offers they typically could not afford. Thus, the first type was framed by the rodents’ realization that they missed or passed up a favorable opportunity, while the second type was characterized by facing the decision to cut their losses and move on.
Although both types of regret could involve reflecting on the road not traveled and what could have been, type-one regret emphasizes the choice of having let something good disappear, while type-two regret involved having to change one’s mind. This study found that the weight these mistakes carry in altering future decisions are biologically distinct and uniquely linked to stress-response traits.
“These findings tell us that the way the brain processes mistakes is multifactorial and linked 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,” said co-author and neuroscience Prof. Scott Russo. “Like pain, some forms of which are healthy and adaptive while others are pathological, we found that not all forms of regret are the same and they derive from different circuits in the brain.”
"These findings tell us that the way the brain processes mistakes is multifactorial and linked 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.” Prof. Scott Russo.
Sweis, who is currently training as a psychiatrist at Mount Sinai, said the research could have a significant impact on clinical practice, even by informing the way in which mental-health providers interview patients with mood disorders. “Our research could help steer clinician-patient interviews toward discerning specific circuits that may be contributing to one’s mood disorders and develop therapeutic approaches accordingly,” he said.
The team also discovered that a gene known to regulate many stress-sensitive responses in the brain – CREB – may 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 conferring the opposite, vulnerability to stress, in the nucleus accumbens,” added Dr. Romain Durand-de Cuttoli, first author of the study and a postdoctoral researcher at the medical school. “Until now, it was not clear what role, if any, CREB function plays in more complex emotional processes.”
