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Original Investigation |

Increased Prefrontal Cortex Activity During Negative Emotion Regulation as a Predictor of Depression Symptom Severity Trajectory Over 6 Months

Aaron S. Heller, MS1,2,3; Tom Johnstone, PhD4; Michael J. Peterson, MD, PhD5; Gregory G. Kolden, PhD3,5; Ned H. Kalin, MD3,5,6,7; Richard J. Davidson, PhD1,2,3,5,8
[+] Author Affiliations
1Laboratory for Affective Neuroscience, University of Wisconsin, Madison
2Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin, Madison
3Department of Psychology, University of Wisconsin, Madison
4Centre for Integrative Neuroscience and Neurodynamics, Department of Psychology, University of Reading, Reading, England
5Department of Psychiatry, University of Wisconsin, Madison
6Lane Neuroimaging Laboratory, University of Wisconsin, Madison
7Health Emotions Research Institute, University of Wisconsin, Madison
8Center for Investigating Healthy Minds, University of Wisconsin, Madison
JAMA Psychiatry. 2013;70(11):1181-1189. doi:10.1001/jamapsychiatry.2013.2430.
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Importance  Emotion regulation is critically disrupted in depression, and the use of paradigms that tap into these processes may uncover essential changes in neurobiology during treatment. In addition, because neuroimaging outcome studies of depression commonly use only baseline and end-point data—which are more prone to week-to-week noise in symptomatology—we sought to use all data points over the course of a 6-month trial.

Objective  To examine changes in neurobiology resulting from successful treatment.

Design, Setting, and Participants  Double-blind trial examining changes in the neural circuits involved in emotion regulation resulting from 1 of 2 antidepressant treatments during a 6-month trial. Twenty-one patients with major depressive disorder and without other Axis I or Axis II diagnoses were scanned before treatment and 2 and 6 months into treatment at the university’s functional magnetic resonance imaging facility.

Interventions  Venlafaxine hydrochloride extended release (with doses of up to 300 mg) or fluoxetine hydrochloride (with doses of up to 80 mg).

Main Outcomes and Measures  Neural activity, as measured using functional magnetic resonance imaging during performance of an emotion regulation paradigm, as well as regular assessments of symptom severity using the Hamilton Depression Rating Scale. For use of all data points, slope trajectories were calculated for rate of change in depression severity and for rate of change in neural engagement.

Results  The depressed individuals who showed the steepest decrease in depression severity over the 6-month period were the same individuals who showed the most rapid increases in activity in Brodmann area 10 and the right dorsolateral prefrontal cortex activity when regulating negative affect over the same time frame. This relationship was more robust when using only the baseline and end-point data.

Conclusions and Relevance  Changes in prefrontal cortex engagement when regulating negative affect correlate with changes in depression severity over 6 months. These results are buttressed by calculating these statistics, which are more reliable and robust to week-to-week variation than are difference scores.

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Figure 1.
Schematic of the Emotion Regulation Paradigm

This is an example trial in which a positive image was presented. Four seconds into image presentation, participants received an auditory prompt instructing them to “enhance,” “suppress,” or “attend” to their affect. ITI indicates intertrial interval.

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Figure 2.
Trajectories of Hamilton Depression Rating Scale (HDRS) Scores Over Time for 21 Patients With Major Depressive Disorder
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Figure 3.
Correlation Between Treatment-Related BOLD Signal Changes During Regulation of Negative Effect and HDRS Trajectory

The changes in Brodmann area 10 (BA 10 [A]) and the right dorsolateral prefrontal cortex (RDPFC [B]) during negative emotion regulation demonstrated significant associations with the changes in the Hamilton Depression Rating Scale (HDRS). The functional magnetic resonance imaging scans, along with their y coordinates (insets), are shown on the left. BOLD indicates blood oxygenation level–dependent; L, left.

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