There are several questions that remain unanswered, however, regarding amygdala dysfunction in BD and MDD depression. First, it is unclear whether abnormal amygdala activity to emotional facial expressions is a persistent marker of BD during both remission and depression or whether abnormal amygdala activity to these stimuli is a state marker of depression, common to or differentiating BD and MDD depression. Earlier studies suggested elevated amygdala activity to happy and fearful facial expressions in remitted, depressed, and hypomanic BD adults (9). Later studies did not, however, demonstrate abnormal amygdala activity to either negative (fearful, disgust, sad) or positive (happy) emotional facial expressions in remitted or stabilized BD adults (BDr) (10–13). Similarly, recent studies reported no abnormality in amygdala activity to fearful, angry, or sad facial expressions in depressed BD adults (BDd) (14,15). In depressed adults with MDD, studies reported abnormally elevated amygdala activity to masked, covertly presented fear, happy, and neutral facial expressions (16–18); increased amygdala blood flow at rest (19); and pretreatment abnormalities in capacity of amygdala activity, the response elicited by the difference between baseline and all facial trials taken together, to sad and neutral emotional expressions (20). Other studies, however, reported no increases in amygdala activity to happy, sad, or fearful facial expressions, even in a subliminal condition, in depressed adults with recurrent MDD (21–24). Major depressive disorder might, therefore, be characterized by abnormally increased baseline amygdala activity, resulting in no further increase in activity to emotional stimuli versus baseline.

These discrepant findings regarding amygdala activity to facial expressions in BDr, BDd, and MDD patients likely result from the employment of different paradigms and different neuroimaging measures across the aforementioned studies. No studies directly compared amygdala activity in BDd, BDr, and MDD depressed individuals, however. Such a study would be particularly important to understanding likely pathophysiologic processes that might differentiate BD from recurrent MDD depression.

Second, it is unclear whether abnormally elevated amygdala activity occurs predominantly to negative or to positive emotional facial expressions in BD and recurrent MDD. Although previous studies reported abnormally elevated amygdala activity to both positive and negative emotional facial expressions in BDr patients (21) and in remitted, depressed, and hypomanic adults with BD (9), studies in depressed adults with recurrent MDD reported abnormally elevated amygdala activity mainly to negative emotional facial expressions (16,17,20). Some findings suggest abnormally elevated amygdala activity to positive emotional facial expressions in depressed adults with MDD, however (16).

Additionally, although studies in healthy adults reported amygdala activity to neutral faces (25–28) and one study in youth with BD reported that neutral faces assessed as hostile were associated with abnormally elevated amygdala activity relative to healthy youth (29), there have been no studies in adults with mood disorders that focused on examination of amygdala activity to neutral faces. Although we previously showed increasing magnitude of striatal activity to facial expressions of increasing intensity of sadness in depressed individuals with MDD (22), few studies in BD and recurrent MDD patients examined amygdala activity to different mild and intensely emotional facial expressions.

We therefore first aimed to examine the extent to which abnormally elevated amygdala activity to emotional facial expressions was one of the following three possibilities: 1) a persistent marker of BD during remission and depression, 2) a state marker of depression in both BD and recurrent MDD, or 3) a specific marker of depression in either BD or recurrent MDD. We secondly aimed to examine whether abnormally elevated amygdala activity occurred mainly to negative or to positive emotional facial expressions in each disorder. Our third aim was to examine the extent to which abnormally elevated amygdala activity would be elicited by emotional facial expressions other than those displaying prototypical emotion: mild intense and neutral facial expressions. Extant data did not allow us to make specific hypotheses related to these aims, because no study has yet directly compared amygdala activity to facial expressions of different intensities of emotional facial expressions in BDr, BDd, and depressed individuals with recurrent MDD. We recruited BDr, BDd, and depressed MDD individuals and a group of age-and gender ratio-matched healthy control participants (HC). We employed a well-validated facial expression processing paradigm involving displays of negative (fear, sad) and positive (happy) facial expressions as important signals of socially relevant emotions of social approval (happy), external threat (fear), and internal distress (sad) of both prototypical (intense) and mild intensities of each emotion, together with neutral expressions.

Our finding of a bipolar depression-specific pattern of abnormally elevated amygdala activity is interesting, given the inconsistent findings in the literature regarding amygdala activity in BDr, BDd, and depressed adults with recurrent MDD (9,10,12,14,16,17,20–22,33). There are several points to highlight in these previous studies, however. First, no previous study directly compared amygdala activity to different emotional facial expressions in BDd, BDr, and depressed adults with recurrent MDD. Second, the discrepancy of these findings might relate to the use of different paradigms and different neuroimaging measures across the studies. Third, although previous studies of depressed individuals with recurrent MDD reported elevated amygdala activity mainly to negative emotional facial expressions (16,17,20), there are points to consider about these studies. In two of these studies (16,17), facial expressions were presented covertly in a backward masking paradigm; furthermore, elevated left amygdala activity was observed to happy, fearful, and neutral masked facial expressions in one of these studies (16). The backward masking procedure might have made these emotional facial expressions appear more ambiguous and potentially threatening, which might in turn have contributed to the elevated amygdala activity observed in depressed recurrent MDD relative to healthy individuals in this previous study. In another study, greater capacity of amygdala activity to sad facial expressions was demonstrated in depressed individuals with recurrent MDD (20), but the extent to which this relates to greater magnitude of amygdala activity to negative emotional expressions remains unclear. Additional studies reported relationships between pretreatment amygdala activity to emotional facial expressions and symptom improvement after treatment (34) and depression symptom severity (22) but did not show abnormally elevated amygdala activity to these facial expressions in depressed MDD adults relative to HC. Furthermore, we previously showed elevated ventral striatal but not elevated amygdala activity to sad facial expressions in depressed individuals with recurrent MDD (22). These previous findings, together with the present findings of abnormally elevated amygdala activity in BDd but not BDr patients or depressed individuals with recurrent MDD, therefore suggest that abnormally elevated amygdala activity might represent a pathophysiological process specific to BD but not recurrent MDD depression.

The use of an overt emotion labeling task in the present study might have contributed to our findings of abnormally elevated amygdala activity only in BDd patients and not in depressed recurrent MDD individuals or BDr patients. Previous reports indicate that, unlike implicit emotion processing such as gender labeling, explicit emotion labeling of facial expressions is not consistently associated with robust amygdala activity in HC, because it might be dependent on explicit appraisal and reappraisal processes supported by lateral prefrontal cortex rather than the amygdala (35). Our finding of elevated amygdala activity in BDd patients in the present study might therefore reflect aberrant amygdala–lateral prefrontal cortical functional coupling during appraisal of emotion in BDd patients but not depressed individuals with recurrent MDD or BDr that could be examined in future studies with functional connectivity analyses. It is also possible that, with larger numbers of participants, we would have been able to demonstrate significant increases in amygdala activity in depressed individuals with recurrent MDD and BDr relative to HC during the sad- or other emotion-experiments. The effect sizes in the significant post hoc pairwise between-group comparisons for the sad experiment (Cohen’s d = 1.02 – d = 1.97) are similar to the effect sizes in previous between-group comparisons of amygdala activity (e.g., Lawrence et al. [21]), suggesting that our study was powered to detect significant between group differences in amygdala activity during each emotion experiment consistent with previous findings.

Regarding our second aim, we found a negative-emotion–specific pattern of abnormally elevated amygdala activity in BDd patients to all faces in the sad experiment relative to other groups. This finding is consistent with previous cognitive theories of depression proposing a negative emotion attentional bias in depression in general and in particular to self-relevant negative emotional material (36), such as mood-congruent, sad facial expressions in the present study. Our findings suggest, however, that the negative emotional attentional bias in BD and recurrent MDD depression might be associated with different pathophsysiologic processes in the two disorders. In further support of the latter point, we recently demonstrated that recurrent MDD depression is associated with a top-down, negative connectivity between orbital medial prefrontal cortex (OMPFC) and amygdala to positive (happy) facial expressions, suggesting an “inhibition” of amygdala activity to positive emotional facial expressions in recurrent MDD depression, whereas BD depression is associated with a disconnectivity between OMPFC and amygdala to happy faces (37). We also previously demonstrated an attentional bias away from labeling facial expressions mild happy rather than a bias toward labeling facial expressions as sad in recurrent MDD depression (38). These, together with the present findings, therefore suggest that recurrent MDD depression might be characterized more by an inhibitory response to positive emotional facial expressions that might lead to an attentional bias away from these stimuli rather than by attentional bias toward negative emotional facial expressions. By contrast, our previous and present findings in BDd patients of OMPFC–amygdala disconnectivity to happy faces and elevated amygdala activity to mood-congruent sad facial expressions suggest that BD depression might be characterized by an attentional bias to negative, mood-congruent expressions rather than an attentional bias away from happy faces.

The BDd patients showed, with regard to our third aim, elevated amygdala activity to neutral and mild rather than intense sad facial expressions relative to BDr and depressed individuals with recurrent MDD. Mild emotional and neutral facial expressions are often perceived as more ambiguous and potentially threatening than intense facial expressions (38,39) and might elicit amygdala activity because of the proposed role of this structure in processing ambiguity and potential threat (40). Although BDd patients accurately labeled facial expressions in the sad and fear experiments, abnormally elevated amygdala activity to mild sad and neutral facial expressions might therefore suggest abnormal perception of potential threat in these faces in BDd patients, consistent with previous observations of abnormally elevated amygdala activity to neutral facial expressions appraised as hostile in BD youth (29). Employment of subjective ratings of threat and hostility during facial expression emotion labeling in future studies in BD could help clarify this.

The laterality of our amygdala findings in BDd patients is interesting. Previous studies report sustained response of the left rather than right amygdala during fearful facial expression processing in HC (41,42), whereas studies that manipulated displays of facial expressions to prevent subjective awareness of these stimuli, most frequently through a backward masking procedure, reported right-sided lateralization of amygdala activity (43). In our analyses, we fitted a hemodynamic response function to the presentation of each facial stimulus that models sustained rather than initial transient activity to all stimuli of a given emotion intensity in each experiment. Our finding of a between-group difference in left- rather than right-sided amygdala activity during facial emotion labeling therefore supports a more sustained and evaluative response of the left than right amygdala during emotion processing.

Although there was no significant effect of group on emotion labeling in the sad experiment, all participants demonstrated a minimum of 54% and a maximum of 82% accuracy rather than nearer to 100% accuracy on labeling emotional faces. This was likely due to the known difficulty in accurately labeling mild emotional facial expressions from the facial expression series employed in our study (44). Previous studies in MDD depressed individuals indicated facial emotional expression labeling impairments in MDD and BD depressed individuals (45–47). The more difficult nature of the facial expression-labeling task we used might have masked any between-group difference on task performance, because all individuals had some difficulty with emotion face labeling.

Our exploratory analyses indicated few significant relationships between left amygdala activity to facial expressions in the sad experiment and clinical variables. The BDd patients with longer illness duration and higher medication load had lower amygdala activity to intense sad but not mild sad or neutral facial expressions. Previous findings in MDD indicate a reduction in amygdala capacity and activity after antidepressant treatment (20,34), which parallel our finding in medicated BDd patients in the present study. It is therefore possible that the combined effects of psychotropic medication and longer illness duration might have contributed to normalization of elevated left amygdala activity, at least to intense sad facial expressions, in BDd patients. The possible perception of the more ambiguous mild sad and neutral facial expressions as potentially threatening by BDd patients might have accounted for the absence of effects of illness duration and medication upon left amygdala activity to these stimuli. Greater left amygdala activity in BDr patients was associated with more accurate emotion labeling of all facial expressions, especially the more ambiguous mild sad facial expressions. The BDr patients taking antidepressant medication also showed greater left amygdala activity to the more ambiguous mild sad and neutral facial expressions although did not differ from HC on magnitude of left amygdala activity to these expressions. Together, these findings might suggest that, in BDr patients, greater left amygdala activity during emotion labeling of mild sad and neutral facial expressions—which in turn is more significant in BDr patients potentially more vulnerable to depression (i.e., BDr patients taking vs. BDr patients not taking antidepressant medication)—might represent a persistent, attentional bias to sad faces associated with more accurate sad emotion labeling that represents a vulnerability marker to depression in BDr patients. Depressed individuals with recurrent MDD showed a positive correlation between left amygdala activity and age at scan and with age of MDD onset, suggesting that older individuals with later age of illness onset had a pattern of left amygdala activity more similar to BDd patients.

There were limitations to the present study. We did not include a group of euthymic individuals with a history of recurrent MDD and therefore did not examine whether amygdala activity to emotional facial expressions differentiated remitted and depressed phases of recurrent MDD. Future studies could therefore compare depressed with recovered individuals with a history of MDD. We deliberately focused examination on the amygdala in this first study comparing BDd, BDr, and depressed individuals with recurrent MDD, but clearly other neural regions are implicated in emotion processing (6). Many patients were medicated, especially depressed patients, because of the need for medication in these severely depressed individuals. We showed normalizing rather than confounding effects of medication upon amygdala activity in BDd patients, however, suggesting that medication was unlikely to have contributed to the elevated left amygdala activity in the sad experiment in BDd patients. There were relatively small numbers of men in each group, and we did not obtain accurate information regarding the amount of current or past use of nicotine in study participants. Greater numbers of men and tobacco-using histories could be included in future studies of BDr, BDd, and MDD depressed individuals.

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