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February 9, 2018
Abnormalities in Reward Processing May Underlie Depression, Outbursts

Understanding how the brain processes rewards and threat might hold the key to treating depression and a childhood condition of severe and chronic irritability called disruptive mood dysregulation disorder (DMDD).

Depression is the leading cause of disability around the world, explained Dr. Argyris Stringaris, chief of the mood brain and development unit at NIMH, during a recent Clinical Center Grand Rounds lecture in Lipsett Amphitheater.

The incidence of depression increases in adolescence and young adulthood. He added, “It contributes to more disability than traffic accidents, self-harm, back pain and all sorts of common infectious diseases.”

Dr. Argyris Stringaris
Dr. Argyris Stringaris

Forty percent of patients with depression do not respond to standard treatments such as selective serotonin reuptake inhibitors or cognitive behavioral therapy, said Stringaris. Of those who do respond, 25-40 percent of patients will relapse within a year.

His lab is studying two areas of the brain responsible for reward processing: the ventral striatum and the anterior cingulate cortex. Stringaris hopes to identify the neural circuits responsible for reward processing, with the goal of developing a drug to target the pathway.

In healthy volunteers, a reward, such as a piece of chocolate, triggers the release of dopamine, a chemical messenger that brain and nerve cells use to communicate feelings of happiness or satiety. Dopamine levels are highest when a person must wait for something or is surprised by something positive. However, when a person knows a reward is coming, he or she “won’t be terribly surprised nor pleased and dopamine will not vary much.”

In several studies, Stringaris has observed there is less activity in the striatum of patients who are depressed compared to healthy volunteers. This change begins in adolescence. This suggests there might be a causal relationship between reward processing and depression.

In a clinical study, he’s discovered that one anti-depressant, lurasidone, can increase activity in the parts of the brain that control reward processing. Although the results are preliminary, Stringaris believes the drug can affect the network involved in dopamine release.

Dr. Argyris Stringaris
Dr. Melissa Brotman

Another condition, DMDD, is associated with abnormalities in reward and threat processing in children and adolescents, said Dr. Melissa Brotman, director of neuroscience and novel therapeutics in the section on mood dysregulation and neuroscience in NIMH’s Emotion and Development Branch.

She said DMDD is “characterized by severe recurrent temper outbursts. These occur, on average, at least 3 times per week and they are inconsistent with the situation or developmental level” of the child.

Children with the disorder are irritable—“an elevated proneness to anger relative to peers”—and cranky most of the day, nearly every day. The irritability is pervasive; they are irritable around their peers, teachers and parents. Those who have increased irritability are at increased risk of suicide, anxiety and unipolar depression.

“Irritability is associated with abnormalities in reward processing, specifically responses to frustrative non-reward,” she said. Possible treatments for DMDD include interpretation bias training and exposure-based cognitive behavioral therapy, commonly known as CBT.

Interpretation bias training helps children learn over time to not view ambiguous facial expressions as threatening. Youth who are irritable have trouble reading facial emotions.

Stringaris hopes to identify the neural circuits responsible for reward processing, with the goal of developing a drug to target the pathway.
Stringaris hopes to identify the neural circuits responsible for reward processing, with the goal of developing a drug to target the pathway.

PHOTOS: CHIA-CHI CHARLIE CHANG

In one experiment, Brotman asked children to look at photographs of an actor making a happy facial expression, an angry facial expression and then used a computer program to generate morphs with varying degrees of happiness and anger (i.e., ambiguous facial stimuli). Those with DMDD perceived the “ambiguous faces as more threatening.” In another study, she demonstrated that irritable youth “rate neutral faces as more hostile and fear-producing.”

Exposure-based cognitive behavioral therapy is widely used to treat anxiety disorders. In Brotman’s novel application, patients are exposed to something that makes them irritable or frustrated in an attempt to help them learn to tolerate their emotional response.

In one example, Brotman worked with a young girl who exhibited temper outbursts and irritability whenever she was asked to complete her household chore of sorting laundry. During each therapy session, the girl’s mother brought in clean laundry and gave it to Brotman to use in exposure exercises with the girl. Over the course of the treatment, the girl was able to sort the laundry with less and less anger. By the end, she was able to do her chore and move on to another task. Her ability to complete her household chore in session transferred to the home environment as well.

This approach, however, has only been tried in 10 cases. Currently, Brotman and her colleagues are expanding this work and exploring neural correlates using functional magnetic resonance imaging pre- and
post-CBT.

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