GAD Patients Less Able to Regulate Response to Negative Emotions

Deborah Brauser

February 16, 2010

February 16, 2010 — Patients with generalized anxiety disorder (GAD) have abnormalities in the brain that may keep them from spontaneously processing negative emotions, a new imaging study suggests.

"[These] patients were completely unable to regulate emotional conflict and failed to engage the pregenual anterior cingulate in ways that would dampen amygdalar activity," the study authors, led by Amit Etkin, MD, PhD, Stanford University, Palo Alto, California, write.

In a statement, they note that this finding, as well as the "first solid demonstration that a psychiatric population has a deficit in a form of unconscious emotion regulation," has not been shown before.

"[This] may open up avenues for novel treatments, such as by targeting the medial prefrontal cortex," the investigators write.

"There's a suggestion from the clinical world from theory, going all the way back to Freud, that abnormality in unconscious emotion regulation is one of the core deficits," Dr. Etkin told Medscape Psychiatry.

"But there's never before been a brain-based investigation looking at that to try to understand what is going on in these subjects that leads them to be so intolerant and avoidant of emotion. This really leads to a new way of thinking about anxiety," he said.

This study was published online February 1 in the American Journal of Psychiatry.

Extreme Anxiety to Negative Stimuli

Patients with GAD often have extreme feelings of fear and uncertainty. "They experience anxiety and worry and respond excessively to emotionally negative stimuli, but it's never been clear really why," said Dr. Etkin.

Previous studies have suggested that adult GAD patients initially register negative stimuli in a largely normal way but have deficits in how they then control negative emotions.

"For the most part, however, past research hasn't examined unconscious emotion regulation," he said.

He noted that GAD also has not been as heavily studied as other disorders, such as posttraumatic stress disorder (PTSD) and social anxiety disorder, which have more obvious affecting stimuli "making it somewhat easier to study. With GAD, it can be any kind of emotional stimulus that patients find aversive."

The study included 17 patients with GAD (65% female; mean age, 31.5 years) and 24 healthy controls (75% female; mean age, 36.5 years). All underwent functional magnetic resonance imaging (fMRI) while they viewed photographs of people with happy or fearful facial expressions and the words "fear" or "happy" overlaid. To test both congruent and incongruent adaptation, these word labels did not always match the expressions.

In other words, all participants "performed an emotional conflict task that involved categorizing facial affect while ignoring overlaid affect label words," explain the study authors. "We hypothesized that [GAD] patients would show abnormalities in adapting to emotional conflict in our task."

In addition to undergoing the fMRI, all patients filled out the Spielberger State-Trait Anxiety Inventory, the Penn State Worry Questionnaire, the Beck Anxiety Inventory, the Beck Depression Inventory, and the Mood and Anxiety Symptoms Questionnaire.

Poor Adaptability

Results showed that both groups had similar reaction times when shown a series of congruent photographs. However, across-trial reaction time adjustment during incongruent trials was significantly different (P < .05).

Although the healthy controls effectively regulated emotional conflict from photograph to photograph, "even though they were unaware of having done so," the GAD patients could not.

This finding in the healthy volunteers was not a surprise to the authors. "We hypothesized that [these] participants would not be aware of the adaptation effect, and thus this process is carried at an implicit level," write the study authors.

In addition, "performance and brain activation [in all patients] were correlated with symptoms and could be used to accurately classify the 2 groups," they write.

The investigators also found that the most anxious patients had the greatest impairment in emotional conflict adaptation as shown by both their reaction times and dorsomedial prefrontal modulation.

"The most anxious patients had the hardest time and even went the opposite direction, where the more emotionally incongruent the stimuli, the worse they got," explained Dr. Etkin.

"[Our findings] suggest that the inability of patients to adapt to emotional conflict is an important aspect of the pathophysiology of [GAD] — and potentially of other psychiatric disorders — and thus merits continued, deeper study," summarized the study authors.

Dr. Etkin added that his team is now looking at how anxiety and depression are related to each other within this same task in order to develop specific and combined biomarkers for the disorders. Plus, they plan to also examine how "a faulty pregenual cingulated-amygdala circuit" could also be involved in PTSD.

"My hope is that taking this approach will really transform how we think about these disorders and not just how we treat them," he said.

More Implicit Deficits

"This is an exciting study and I was glad to see it come out," Douglas Mennin, PhD, director of the Yale Anxiety and Mood Services Clinic, Yale University, New Haven, Connecticut, told Medscape Psychiatry.

"For those of us who are doing this type of work, it's great to see this type of analysis because it's a challenging area," said Dr. Mennin, who was not involved with this study. "We've been interested in showing how people who worry a lot get very anxious and how their management of their emotions contributes to their worried state. One of the things we have said is that worry itself may be a poor way of trying to manage anxiety or emotion."

"What's exciting about this study is that it's showing some of these deficits more implicitly and also showing some important brain areas that may mediate some of these problems," he noted. "They found that the GAD patients had a tough time [after looking at the incongruent photographs] returning their mind to a normalized state. It threw them off longer and made it harder for them to get back on task, which was very interesting."

Dr. Mennin said that the suggestion of a unique deficit associated with people who chronically worry that are independent of depression might have implications for psychopharmacology. "However, I'm hesitant to speculate too much on treatment based on 1 finding."

"One thing I would caution clinicians to keep in find is that these deficits may be quite ingrained and not always amendable to conscious thought. I think the implicit nature of this suggests that we need to take what our patients tell us at more than just face value. Instead, we should identify their patterns of ways they respond to problems and examine that further," he concluded.

This study was funded by grants from the National Institute of Health and the residency research program of the Veterans Affairs–Palo Alto Health Care System. One of the study authors reported numerous financial relationships, listed in full in the original article. Dr. Mennin has disclosed no relevant financial relationships.

Am J Psychiatry. Published online February 1, 2010.

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