Relationship between amygdala responses to masked faces and mood state and treatment in major depressive disorder

Abstract

Context: Major depressive disorder (MDD) is associated with behavioral and neurophysiological evidence of mood-congruent processing biases toward explicitly presented, emotionally valenced stimuli. However, few studies have investigated such biases toward implicitly presented stimuli.

Objective: To investigate differential amygdala responses to sad, happy, and neutral faces presented below the level of explicit conscious awareness using a backward masking task in unmedicated participants with MDD and healthy controls (HCs).

Design: Initial cross-sectional design followed by a longitudinal treatment trial using functional magnetic resonance imaging.

Setting: Psychiatric outpatient clinic at the National Institute of Mental Health.

Participants: We studied 22 unmedicated, currently depressed people with MDD (dMDD), 16 unmedicated individuals with MDD in full remission (rMDD), and 25 HCs.

Intervention: Ten dMDD participants underwent 8 weeks of antidepressant treatment with the selective serotonin reuptake inhibitor sertraline hydrochloride.

Main outcome measures: Amygdala region-of-interest and whole-brain analyses evaluated the hemodynamic response during exposure to masked sad vs masked happy faces, to masked sad vs neutral faces, and to masked happy vs neutral faces.

Results: The dMDD participants showed greater amygdala responses than HCs to masked sad faces, whereas HCs showed greater amygdala responses to masked happy faces. The bias toward sad faces also was evident in rMDD participants relative to HCs and did not differ between dMDD and rMDD participants. This processing bias reversed toward the normative pattern in dMDD participants after sertraline treatment.

Conclusions: Emotional-processing biases occur in amygdala responses to sad faces presented below the level of conscious awareness in dMDD or rMDD individuals and to happy faces in HCs. By influencing the salience of social stimuli, mood-congruent processing biases in the amygdala may contribute to dysfunction in conscious perceptions and social interactions in MDD. Our data suggest, however, that the negative bias resolves and a positive bias develops in patients with MDD during selective serotonin reuptake inhibitor treatment.

Conflict of interest statement

All of the authors on this manuscript report no competing interests. The antidepressant drug, sertraline, used in the treatment portion of these experiments, was provided by the National Institutes of Health (NIH), Division of Intramural Research Program (DIRP), NIH Clinical Center.

Figures

Figure 1. Design of the backward masking task

Two faces were shown as part of each trial presentation. Examples of the masked face event types (SN, HN, and NN) are shown with “Neutral Face” placeholders to indicate the presentation of a neutral face. Closed mouth images were used to reduce nonspecific differences in the stimulus features across stimulus types. SN= masked-sad face followed by an unmasked-neutral face; HN= masked-happy face followed by an unmasked-neutral face; NN= masked-neutral face followed by an unmasked-neutral face; ISI= interstimulus interval

Figure 2. Neuroimaging results for experiments 1 and 2

(a) Voxels in bilateral amygdala showing differences in the hemodynamic response to SN-HN between dMDD and HC subjects, shown on a coronal slice located 1 mm posterior to the anterior commissure. (b) Coordinates of peak T-values for the difference in the amygdala response to SN-HN for dMDD versus HC that correspond to the stereotaxic array of Talairach and Tournoux (1988) as the distance in mm from the origin (anterior commissure), with positive × indicating right, positive y indicating anterior and positive z indicating dorsal. Cluster size= contiguous voxels (pbeta-weights are shown for specified contrasts in dMDD versus HC subjects for loci identified (see b) in left (c,d) and right amygdala (e). Location in left amygdala (f,g) showing a diagnosis x task condition interaction. Contrast beta-weights are shown for specified contrasts (h,i,j) in HC, rMDD and dMDD from the locus identified in the ANOVA. SN-HN= masked-sad versus masked-happy faces; SN-NN= masked-sad versus masked-neutral faces; HN-NN= masked-happy versus masked-neutral faces

Figure 3. Relationship between depression severity and amygdala response to HN-NN

Correlation between depression severity (HAM-D score) in currently depressed subjects (n=22) and the beta-weight value at the peak voxel response to HN-NN in the right amygdala (26, −1, −12) (r=−0.48, p<0.05).

Figure 4. Neuroimaging results for experiment 3

Areas in the amygdala (a,b,c) where the hemodynamic response to masked-sad (SN-NN) and masked-happy (HN-NN) differed in MDD patients following sertraline treatment versus the pre-treatment baseline. Beta-weights are shown for specified contrasts, for identified loci (see a). Location in right amygdala (d,e) showing a time × group interaction. Beta-weights are shown for the specified contrasts as obtained during the two scanning time points for the healthy control and MDD groups.