These data demonstrate that negative emotional processing biases occur automatically, below conscious awareness, in unmedicated-depressed MDD subjects. Both unmedicated-depressed and unmedicated-remitted MDD subjects showed greater amygdala activity than controls when processing masked-sad
versus masked-happy faces. Depressed MDD subjects also responded faster than HC subjects to masked-sad faces, despite being unaware of the masked face (). In contrast, healthy subjects showed larger responses in the amygdala and faster behavioral responses to masked-happy
faces relative to masked-sad or neutral faces, consistent with other evidence that healthy humans show a processing bias toward positively valenced stimuli15,33–34
This non-conscious processing of emotional stimuli is consistent with evidence that the amygdala contains cells that are tuned selectively to specific stimulus characteristics, facilitating early detection of biologically salient information35
. The coordinates for the emotional processing biases found herein () appear to implicate specifically the lateral nucleus of the amygdala31
, which receives monosynaptic projections both from the sensory cortices that allow conscious or explicit stimulus perception and from the subcortical structures that support rapid, non-conscious assessment of stimulus features13–14
. The rapid response system facilitates detection of and behavioral adaptation to stimuli that are novel, threatening, rewarding or socially significant36–42
. The exploratory whole brain analysis (eTable 3
) implicated hippocampus and thalamus in the extended anatomical network that, together with the amygdala, responds to non-conscious stimuli. Projections from the hippocampus to amygdala provide input during emotional processing about the environmental context43
, while the thalamus plays a role in gating the transmission of sensory information to other brain regions based upon the anticipated salience of this information within the behavioral context44
. Non-conscious emotional mood-congruent processing biases in the amygdala of MDD subjects may negatively influence their conscious perceptions of experiential stimuli and impact social interactions.
The comparison of hemodynamic responses to unmasked-sad versus unmasked-happy faces showed the specificity of our amygdala results to masked stimuli, as we found no difference across groups in the amygdala response to explicitly presented emotional faces. This suggests using backward masking confers an advantage in identifying emotional processing biases involving the amygdala in MDD.
The emotional processing abnormalities found in unmedicated-depressed MDD subjects extended to unmedicated-remitted MDD subjects, suggesting that MDD is associated with a trait-like bias toward processing negative stimuli independently of current mood state. Nevertheless, while rMDD cases met criteria for full remission, they showed an elevation of trait anxiety ratings and negative thought patterns (). These symptom clusters appear endophenotypic in individuals who develop MDD45
and conceivably relate to the persistent emotional processing bias observed herein. This finding is suggestive of an “illness-congruent” processing bias in remitted subjects that may serve as a biomarker for the vulnerability to depressive relapse and recurrence within MDD.
This pattern of amygdala activity reversed during treatment, however, as the response bias to masked-sad faces disappeared (), while a bias to masked-happy faces developed in MDD individuals receiving treatment (). Previous studies reported that the amygdala response to unmasked
attenuated during treatment, whereas our study was the first to identify a reciprocal increase in amygdala activity in response to masked-happy faces together with a concomitant decrease in amygdala activity in response to masked-sad faces associated with treatment. These findings thus provide the first evidence of a non-conscious negative processing bias toward sad faces in unmedicated patients with MDD that resolves, while a positive processing bias emerges, during treatment.
Our results appear compatible with the hypothesis48
that antidepressant drugs exert their primary therapeutic mechanism by normalizing the negative bias on information processing. This hypothesis was based partly on evidence that in healthy humans
short-term administration of citalopram enhanced the amygdala response to happy faces49
and in depressed subjects
acute administration of reboxetine enhanced the behavioral
responses to positively valenced stimuli.50
Longitudinal studies are needed to assess whether the ability of antidepressant drugs to reduce relapse vulnerability and improve clinical outcomes relates directly to the attenuation of the automatic amygdala response to negative stimuli.
Notably, Suslow et al (2009) reported that MDD patients who both were antidepressant-medicated and persistently depressed showed hemodynamic responses in right amygdala that were exaggerated to masked-sad faces and blunted to masked-happy faces. Although this study did not include an unmedicated sample for comparison, when their data are considered together with ours, the combined results suggest that the decrement in right amygdala responses to masked-sad faces we found () during pharmacotherapy may depend upon treatment effectiveness. Nine of the 10 cases we studied post-treatment showed good clinical responses, so we could not compare neurophysiological effects between responders and non-responders.
The importance of laterality effects also is raised by these data, although neither study addressed laterality effects specifically. Suslow et al. (2009) observed evidence of emotional processing biases in the right--but not in the left--amygdala in medicated-depressed MDD subjects. Our study, the first to examine the responses to masked-happy or sad stimuli in the amygdala of unmedicated-depressed MDD subjects and also the first to examine this phenomenon in unmedicated-remitted MDD subjects, additionally found these emotional processing biases exist in both subject groups in the left amygdala. Moreover in our longitudinal study the “normal” positive processing bias that emerged post-treatment was significant only in the left amygdala, while the attenuation of the negative processing bias was significant on the right ().
Some researchers have suggested emotional processing biases are limited to late or controlled information processing in MDD51–53
. In contrast, our data suggest these biases are also evident at an automatic or early processing level. Studies that have suggested processing biases in depression are limited to late or controlled processing employed behavioral assessments of attention and memory for anxiety-related or socially threatening stimuli, or sad words. Depressed patients exhibit a specific bias toward sad stimuli, but have not consistently shown processing biases to socially or physically threatening stimuli54
. In this study, the bias was for sad words shown for 500–1000ms. However, an implicit emotional processing bias was not found toward briefly presented sad words shown for 14ms53
. Verbal stimuli may require longer processing times to detect their emotional salience. Given the biological salience of faces, face stimuli can be processed rapidly, within the time frame needed for backward masking techniques14
. Also, the effects of antidepressant medication were not controlled in these studies. Antidepressant treatment has been shown decrease negative emotional information processing in depressed patients so it is plausible that previous studies were unable to detect a processing bias earlier during information processing due to confounding medication effects.
Several limitations of our study merit comment. First, we did not address the generalizability of these findings to other mood disorders or to other antidepressant drug classes. Second, the rMDD and dMDD samples were not the same subjects studied in distinct illness phases, and the rMDD sample had fewer subjects with comorbid anxiety disorders than the dMDD sample. Longitudinal component of this study did not include a placebo arm, so causal evidence for a pharmacotherapeutic effect could not be established by the results.
In summary, our findings provide behavioral and neurophysiological support for an emotional processing bias in depression to negatively-valenced stimuli presented below conscious awareness that persists independently of the current mood-state. Developmental studies are needed to explore whether this processing bias constitutes a potential endophenotype in MDD and to characterize its relationship to the emergence of depressive episodes.