The brain's sensitivity to different types of regret may affect mood disorders such as depression

Researchers at the Icahn School of Medicine at Mount Sinai have found that the way the brain processes complex regret emotions may be linked to an individual's ability to cope with stress and change
in mental illnesses such as depression.

The study, published Oct.
19 in Science Advances, shows that mice show sensitivity to two different types of regret, and that these different thought processes may originate from different parts of
the brain.
The team also found that a genetic marker that predisposes to maladaptive stress response traits and vulnerability to depression is associated with sensitivity to one regret, while healthy and stress-resistant animals are sensitive to
a second.

These new findings could have wide-ranging implications for multiple fields, including psychiatry, psychology, and behavioral economics, and could inform
the future design of targeted therapies for human mood disorders.

"Until now, little
was known about how the sensitivity to regret changes in people with mood disorders such as depression.
For example, is regret exaggerated? Do people over-reflect on past decisions? Or are those suffering from depression numb to this emotion? Is this adaptive or inadaptable? Are individuals unable to learn from their mistakes? Brian Sweis, M.
D.
, an instructor in the Department of Neuroscience and a resident at Mount Icahn Sinai Psychiatry, is also the study's senior author
.
"Until now, there has been no clear description of regret as a defining feature of
depression for people with depression.
"

Mount Sinai's study builds on previous research that rats and mice are able to deal with thoughts
like regret.
This study pushes the boundaries
of what can be captured in rodent models used for the study of mental illness.
The authors achieve this goal
by combining complex approaches in behavioral economics and chronic stress programs with viral gene therapy to study the neural and molecular basis of complex decision-making in animals.

This approach is based on the principles of neuroeconomics, which studies how the physical limits of the brain cause us to be biased
in making decisions.
This approach allows researchers to capture how complex choices a person has made in the past affect later decisions and, importantly, how the way individuals process or become aware of missed opportunities interacts with emotional states when influencing future choices—the basis of
regret.

The team trained the mice to perform a decision-making task called a "restaurant platoon," in which animals search a maze for their only source of food (see animation).

The rats were assigned a limited amount of time each day to invest in rewards of varying costs (a delay of 1 to 30 seconds chosen at random based on pitch) and subjective values (unique tastes associated with four different locations or "restaurants"
).
The rats will choose to enter or skip
based on the price and taste of the restaurant.
If rats accept a reward by entering a restaurant, they are asked to wait for the countdown to end to receive the reward before going to the next restaurant
.
According to the tastes of each restaurant, the rats showed a steady willingness to
wait.
Violating one's own decision-making strategy can be understood as the first step
in constructing a situation that may trigger regret.

One of the main findings is that there are two different types of regret, which are not general but related to different parts of the brain, depending on the exact nature
of the missed opportunity being processed.
Both types involve animals making mistakes
.
However, the first category of regret is defined as an "economic violation", in which the animal gives up a good opportunity and is harmed in subsequent trials (see summary chart).

Conversely, the second type of regret is defined as animals making poor choices and spending limited time on things they normally can't afford
.
Thus, the first type of regret is due to the individual's realization that they missed or missed a favorable opportunity, while the second type of regret is characterized by facing the decision, reducing the loss, and moving on
.
Although both types of regret involve reflection on the road not traveled and reflection on what could have happened, the first type of regret emphasizes choosing to give up on something good, while the second type of regret emphasizes the need to change one's mind
.
The study found that the impact of these errors on changing future decisions is biologically unique and uniquely correlated with
stress response characteristics.

"We found that stress-sensitive mice were highly sensitive to the first regret and not to the second, whereas healthy mice were not sensitive to the first regret and only to the second, which was more pronounced in the stress-resilient mice," explains
Dr.
Scott Russell, professor of neuroscience and psychiatry at Mount Iconay.
"These findings tell us that the way the brain handles errors is multifactorial and related to the ability to cope with stress, with one regret being part of a healthy emotional trait, while another may be part of
the disease process itself.
" Just like pain, some forms are healthy and adaptive, while others are pathological, and we found that not all forms of regret are the same, they stem from different circuits in the brain
.
”

According to Dr.
Swayth, who is currently training as a psychiatrist at Mount Sinai, the team's research could have a significant impact on clinical practice and could even inform
the way mental health providers interview patients with mood disorders.

"Prior to our study, professionals may not have thought of asking patients more specific questions in psychiatric evaluations, detailing and subdividing regrets in detail with the subtlety we outlined," Dr.
Sways said
.
"Based on cutting-edge scientific findings in neuroscience and computational psychiatry, our work may improve the way psychiatric interviews are conducted to better determine which thought processes should be strengthened and which should disappear
.
" Our research can help guide conversations between clinicians and patients, identify specific circuits that may lead to mood disorders, and develop treatments
accordingly.
”

Researchers at Mount Sinai School of Medicine also found that a gene known to regulate many of the brain's stress-sensitive responses — may independently influence two types of regret in different brain regions: the medial prefrontal cortex and nucleus accumbens
.

Dr.
Roman Durand-de Cattori, lead author of the study and a postdoctoral researcher at the Mount Sinai School of Medicine, said: "In both humans and mice, this gene promotes stress resistance in the medial prefrontal cortex of the brain, but the opposite in the nucleus accumbens
.
"

Until now, it wasn't clear, if anything, that molecular functions play a role
in more complex emotional processes.
By experimentally controlling the activity of molecules in these two brain regions, the team discovered a biological link and a potential molecular target to develop new therapies that alter certain aspects of regret in a way specific to brain regions to restore healthy emotional processing while improving the potentially unhealthy and pathological forms of
this complex emotion.

Dr Durand-de Cuttoli said: "Knowing that the subtypes of remorse treatment come from different brain regions has broad implications for understanding which brain circuits not only drive different choices, but also different ways of driving us to reflect on the past, and how more precise interventions targeting specific pathological emotional traits, whether through drug development or more invasive neuromodulation approaches, may be more effective in treating mood disorders
.
"