The goal of the present study was to examine amygdala-OFC FC to emotional faces in BD and HC. Our main finding, in support of our first hypothesis, was that BD showed abnormal amygdala-OFC FC to sad and happy faces. All BD showed significantly greater right amygdala-OFC FC than HC to all faces in the sad experiment. Although both depressed and remitted female BD showed significantly greater right amygdala-OFC FC than female HC to these faces, only depressed female BD showed significantly greater left amygdala-OFC FC than female HC to these faces. The BD showed significantly reduced amyg-dala-OFC FC over both hemispheres, compared with HC, to intense happy faces that was evident in depressed but not remitted female BD versus female HC, in support of our second hypothesis.
Our finding of significantly greater right amygdala-OFC FC to all faces in the sad experiment in BD versus HC is consistent with previous data implicating abnormal right frontal cortical activity in mood-disordered and anxiety-prone individuals (49
) and greater right OFC activity to sad versus neutral distractors in manic BD versus HC (51
We recently highlighted a role of ventrolateral prefrontal cortex in voluntary emotion regulatory subprocesses, including attentional control and reappraisal that might be mediated via OFC (18
). In depressed and remitted individuals with unipolar depression, previous reports indicate positive relationships between activity in right ventrolateral prefrontal cortex during sad mood induction and depression severity in depressed individuals (52
) and between increased regional cerebral blood flow in this region and depressive ruminations (53
). We can speculate that our finding of greater right amygdala-OFC FC in all BD, compared with HC, to all faces in the sad experiment might be associated with abnormal “over-appraisal” of these faces, which might reflect a predisposition to negative ruminations in depressed and remitted BD (54
Depressed but not remitted female BD showed significantly greater left amygdala-OFC FC, compared with female HC, to all faces in the sad experiment. This finding is consistent with previous studies showing significantly greater left OFC activity to negative emotional faces (55
) and significantly greater left amygdala activity to sad faces (56
) in depressed BD versus HC. All BD versus HC and depressed female BD versus female HC showed reduced amygdala-OFC FC over both hemispheres to intense happy faces, consistent with our previous finding of significantly reduced left “top-down” OFC-amygdala and right “bottom-up” amygdala-OFC effective connectivity to happy faces in depressed BD versus HC (33
). Abnormally elevated right amygdala-OFC FC to sad faces that we observed in both remitted and depressed BD might represent a predisposition to depression in BD, abnormally elevated amygdala-OFC FC to sad faces, and abnormally reduced amygdala-OFC FC to happy faces, a state marker of depression in BD. These findings are in contrast to the abnormally elevated inverse left but not right OFC-amygdala effective connectivity to happy faces (33
), which we recently reported in unipolar depressed adults; this suggests that, unlike unipolar depression, bipolar depression is associated with abnormal amygdala-OFC FC (and effective connectivity) to emotional stimuli in both hemispheres.
Left-sided prefrontal cortical dysfunction was previously associated with proneness to hypomania (57
). We found no significant group × laterality interaction in the happy experiment but only a group × emotion interaction. It is possible that our study was not powered to detect a three-way interaction between group × intensity laterality. We were therefore unable to determine whether the significantly reduced amygdala-OFC FC in depressed BD versus HC was more evident in the left than in the right hemisphere. This can be a focus of future studies.
Only in HC did one nonlinear cubic relationship between left amygdala-OFC FC to sad faces and left UF FA meet our stringent significance threshold after controlling for multiple tests. A previous report indicated a positive linear relationship between pericingulate gyral-amygdala FC and UF FA in BD during happy and fearful facial expression processing but did not examine left and right FC–FA relationships separately in either BD or HC and did not include a sad face emotion labeling task condition (31
). Direct comparison of these previous data and our present data are therefore difficult. Further studies are needed to elucidate nonlinear amygdala-OFC FC–FA relationships in BD and HC.
Although both HC and BD were more accurate on happy than on sad emotion labeling, BD were less accurate than HC on happy but not sad labeling. Here, BD showed a trend for mislabeling intense happy faces as neutral more than HC, which in turn might relate to the significantly decreased amygdala-OFC FC to intense happy faces in BD (driven by depressed BD) versus HC. These relationships need further exploration in future studies. Our findings from exploratory analyses suggest normalizing effects of aging and greater age of illness onset upon amygdala-OFC FC to faces in the sad but not happy experiment in BD but did not survive correction for multiple tests.
There were no differential patterns of between-group differences for all BD versus HC in right amygdala-OFC FC and for depressed female BD versus female HC in left amygdala-OFC FC, for the different facial emotion intensities in the sad experiment. This might reflect a tendency in BD for all faces in the sad experiment to be processed as negative emotional displays. In contrast, our finding of reduced amygdala-OFC FC in the happy experiment in depressed female BD was restricted to intense happy faces, suggesting that processing of intense but not mild happy or neutral faces was associated with abnormally reduced amygdala-OFC FC in this BD subgroup.
There are limitations to the study. Our findings should be replicated in future studies of BD. Our analyses of depressed and remitted BD subgroups versus HC were restricted to women only because of different gender ratios across BD subgroups. Future studies could include similar gender ratios across BD subgroups and HC. We recruited medicated BD adults, as in most neuroimaging studies of BD (18
). Although depressed female BD had significantly greater left amygdala-OFC FC than female HC to all faces in the sad experiment, antidepressant medications were associated with reduced and not greater left amygdala-OFC FC to mild sad faces in all BD, and there was no significant difference in the proportion of individuals taking versus not taking antidepressant medications in depressed and remitted female BD. These findings suggest that antidepressants were associated with a normalization of abnormal amygdala-OFC FC to sad faces rather than being a potential confounding factor upon these neuroimaging measures in BD. Although we covaried for age in our main analyses, future studies could match age across BD and HC. Future studies could also employ more difficult paradigms including larger numbers of events for each stimulus to allow examination of between-group differences in FC to correct and incorrect behavioral responses and measures of electrodermal activity to examine emotional responses to different emotional stimuli in BD and HC. Although we showed no significant relationships between amygdala-OFC FC and lifetime comorbid substance abuse/dependence, it is possible that other related lifestyle factors in BD (e.g., disrupted sleep) might have impacted amygdala-OFC FC.
We show that abnormally elevated right amygdala-OFC FC to sad stimuli might reflect a predisposition to depression in BD, whereas abnormally elevated left amygdala-OFC FC to sad stimuli, together with abnormally reduced amygdala-OFC FC to intense happy stimuli, might represent a state marker of depression in BD. This pattern of abnormal amygdala-OFC FC might be specific to bipolar rather than shared with unipolar depression. In BD, abnormal FC measures might normalize with antidepressant and anxiolytic medication and aging. The nature of nonlinear relationships between amygdala-OFC FC and FA during emotion labeling in HC and BD requires further study. Future studies can determine the extent to which this pattern of abnormal amygdala-OFC FC to emotional stimuli represents a vulnerability marker of BD in individuals at future risk of BD.