This is the first study to examine EC between key neural regions in emotion regulatory neural systems in bipolar and major depression. We found that different patterns of abnormal left-sided top-down OMPFC-amygdala during happy emotion labeling distinguished bipolar and major depressed individuals(BD, MDD, respectively) from HC, while only BD differed from HC on right-sided bottom-up amygdala-OMPFC EC. MDD showed significantly greater negative left-sided top-down OMPFC-amygdala EC than HC, while BD showed significantly reduced positive left-sided top-down OMPFC-amygdala EC and greater negative right-sided bottom-up amygdala-OMPFC EC than HC.
The reduced left-sided top-down EC in the happy experiment in BD versus HC may reflect reduced regulation of left amygdala by OMPFC –i.e. a “disconnection” –during positive emotion processing. This parallels previous functional neuroimaging studies in BD reporting abnormally increased left-sided amygdala and striatal activity to happy faces(19
), and abnormally decreased left-sided OMPFC activity during emotion regulation(41
), that we previously highlighted(42
). This left-sided reduction in top-down OMPFC-amygdala EC, possibly reflecting reduced regulation of amygdala by OMPFC during positive emotion processing, may represent a predisposition to elevated mood and mania in BD. Conversely, MDD showed left-sided top-down negative
OMPFC-amygdala EC in the happy experiment. This may reflect increased inhibition of the left amygdala by left OMPFC to positive emotional stimuli that parallels previous functional neuroimaging findings in MDD of abnormally reduced left striatal activity to positive emotional stimuli(36
). The increased negative left-sided top-down OMPFC-amygdala EC to happy faces may therefore represent an “over-regulation” by OMPFC of the amygdala to these stimuli and a potential neural basis for the increased negative and reduced positive emotional attentional bias that is frequently observed in major depression(44
). Together, these findings suggest that different patterns of abnormal left-sided top-down OMPFC-amygdala EC during positive emotion processing may reflect different neural mechanisms in bipolar and major depression, and also support a role of the left hemisphere in positive emotion processing(32
Only BD differed from HC on right-sided bottom-up amygdala-OMPFC EC during the happy experiment: this was positive in HC and MDD but negative in BD, suggesting an inverse functional relationship between right amygdala and OMPFC during happy emotion processing in BD –i.e. less amygdala activity associated with greater OMPFC activity. This pattern of abnormal right amygdala-OMPFC EC during the happy experiment is difficult to explain in the context of the hemispheric specialization of emotion theory above, but does suggest aberrant forward connectivity between right amygdala and right OMPFC during emotion processing in bipolar more than major depression. This finding also suggests that bipolar depression may be associated with functional abnormalities in neural systems supporting emotion regulation in both
hemispheres, while major depression may be associated with a functional abnormalities predominantly within the left hemisphere, as has previously been observed in human lesion studies(45
), and is suggested by the loss of normal left-right asymmetry in resting frontal activity in EEG studies of depression(48
). The involvement of functional abnormalities in both hemispheres in bipolar depression parallels our previous observation of abnormalities in left and right amygdala-OMPFC white matter structure in bipolar disorder(22
BD and MDD showed reduced left-sided top-down OMPFC-amygdala EC in the sad experiment, but the overall between group differences did not survive correction for multiple tests. This pattern of reduced left-sided EC in the sad experiment in both BD and MDD relative to HC is also difficult to explain in the context of existing theories regarding hemispheric specialization for emotion processing. Previous studies in MDD have, however, shown increased FC after treatment with antidepressants between left-sided subcortical limbic and OMPFC regions specifically during processing of negative emotional stimuli(52
). This suggests that abnormally reduced left-sided OMPFC and subcortical limbic functional integration during negative emotion processing may be a state marker of depression in both BD and MDD, and that this may ameliorate with treatment in MDD.
Another interpretation of these EC asymmetry findings is that this might reflect sampling error and noise in making what is possibly a bilateral abnormality appears unilateral. While sampling error may differ between slices(i.e. along the transversal axis), there is, however, no evidence to suggest that it will also differ between homologous regions in the left and right hemispheres. Moreover, our asymmetry findings are consistent with previous reports of asymmetry in MDD, as we highlight above, as well as with our previous observation of asymmetric anatomical connectivity asymmetry in BD.
An alternative interpretation of our overall findings is that abnormal OMPFC-amygdala EC in BD and MDD might not be a specific correlate of labeling of emotional faces but a more general correlate of face processing. The regions included in the DCM model, however, are well known for their involvement in emotion processing and the task required participants to attend to the emotional valence of the stimuli; therefore it is most likely that our findings reflect the emotional component of the experiment.
There are limitations to this study. Almost all depressed individuals were medicated. This was necessary, given the need to recruit individuals in severe depressed episode with either well-established bipolar or recurrent major depression. We found no significant relationship between medication load and left-sided top-down OMPFC-amygdala EC in the happy experiment in BD, although there was a trend association between antipsychotics and this EC measure in BD, suggesting that these medications may have increased EC rather than contributing to our finding of abnormally decreased EC in BD. There was a significant positive correlation between left-sided top-down OMPFC-amygdala EC in the happy experiment and medication load in MDD, such that the greater the medication load, the less negative(i.e. less abnormal) the EC. The latter finding also indicates an ameliorative rather than confounding effect of medication upon this EC measure in MDD. When we further explored potential effects of different subclasses of medication, we found a significant increase in this EC measures EC only in MDD taking versus those not taking benzodiazepines. MDD also showed a negative association between medication load and right-sided bottom-up amygdala-OMPFC EC, but did not differ significantly form HC on this EC measure. Future studies could examine further the potential effects of psychotropic medication upon EC in BD and MDD populations.
Another limitation of this study was age range of 18 and 55 years, it is possible that some MDD may have not yet been beyond the age for possible development of bipolar disorder. Interestingly, however, MDD showed a significant negative relationship between age of illness onset and left-sided top-down OMPFC-amygdala EC during the happy experiment. MDD who developed depression at an older age and later in adolescence or adulthood, and who were therefore closer to being at the age beyond which it was less likely to develop bipolar disorder, were, in fact, more likely to show negative top-down OMPFC-amygdala EC in the happy experiment. This provides additional support for the pattern of negative left-sided top-down OMPFC-amygdala EC in the happy experiment being MDD-specific. When we restricted our analyses to females only, we observed a similar pattern of findings regarding abnormal EC in BD and MDD as demonstrated by the entire groups, indicating that differences in gender ratio between groups did not contribute to our main findings.
Distinguishing bipolar disorder from major depression disorder depression is currently a major challenge in clinical practice, with a correct diagnosis of BD in only 20% of BD within the first year of seeking treatment(5
), indicating a strong bias away from diagnosing bipolar disorder in patients presenting in depressed episode. We show that bipolar depression and major depression are associated with different patterns of abnormal functional integration between different regions in neural systems supporting emotion regulation, in both hemispheres during happy emotion processing. This finding in turn suggests that different pathophysiological mechanisms may underlie these two types of depression, and is a promising step forward toward identifying biological markers to distinguish between these different illnesses.