We detected disturbances in pACC-amygdala functional connectivity during the processing of faces depicting positive and negative emotions in BD. Moreover, we found an association between pACC-amygdala functional connectivity measurements and the structural integrity of ventrofrontal white matter, including the uncinate fasciculus where FA was also significantly decreased in the BD group. Taken together, these data provide some of the first evidence that abnormalities in the structural integrity of white matter may contribute to disruptions in the coordinated response of the pACC and amygdala to emotional stimuli in BD.
The pACC and amygdala are critical components of emotional processing circuitry and share extensive interconnections (1
). Evidence has suggested that the pACC activates local inhibitory circuits in the amydala, thereby regulating amygdala response (36
). The decrease in pACC-amygdala functional connectivity in BD could reflect a reduction in the pACC's inhibitory control over the amygdala. Disrupted structural integrity of white matter bundles that contain pACC-amygdala connections, as reported herein, might contribute to pACC-amygdala functional connectivity deficits. PACC structural abnormalities (6
) have also been reported in BD and may contribute to the circuitry dysfunction. Finally, abnormalities in a third structure with connectivity to both pACC and amygdala might play a role in the reduced functional connectivity between the regions. Therefore, further study of gray-white matter relationships and their associations to pACC-amygdala functional connectivity disruptions, and exploration of abnormalities in other regions with connectivity to pACC and amygdala, are required to advance understanding of the interconnections between the pACC and amygdala. Of note, results from conventional functional activation analyses show pACC activation decreases in the BD group compared to the HC group, during fearful and happy face processing (Supplementary Materials). No group differences were observed in amygdala activation. The absence of group differences in amygdala activation, despite the significant decreases in pACC-amygdala connectivity, is unclear. A possible explanation is that our imaging methods were more sensitive to detecting connectivity abnormalities than within-region amygdala abnormalities. Alternatively, connectivity abnormalities may have been especially prominent in this sample or factors such as medication might have blunted amygdala differences (4
). Other research groups that used similar functional connectivity methods to study disorders in which frontotemporal connectivity disturbances are implicated, such as schizophrenia, have similarly detected connectivity differences in the absence of activation differences within the connected brain regions (38
White matter fibers that course through the ventral prefrontal cortex, including the uncinate fasciculus, are thought to provide the structural framework for the functional connections between the pACC and amygdala (25
). We performed structural and functional connectivity measures in the same subjects, during the same scanning session, permitting examination of their relationship. Significant positive associations were identified between FA values in the region of the uncinate fasciculus and the correlation coefficients for functional coupling between the pACC and amygdala, suggesting that abnormalities in ventrofrontal white matter may contribute to disruptions in pACC-amygdala functional connectivity in BD. A recent DTI tractography study reported an increase in the number of fibers connecting the subgenual cingulate and amygdalo-hippocampal complex in BD (39
), providing a view of white matter abnormalities in BD complementary to that described herein. However, this study did not detect FA reductions in these fibers. Potential explanations for the divergent results between the two studies may include differences in the specific fibers studied due to the different imaging processing and analysis methodologies and differences in sample characteristics. Future work using complementary DTI imaging methods in a single study, and collaborative studies across imaging centers using comparable methods, could help resolve discrepant results.
The functional connectivity analyses revealed significant decreases in pACC-amygdala functional coupling in BD during the processing of fearful and happy faces, but not during processing of emotionally neutral faces. This is consistent with previous functional neuroimaging studies which showed engagement of this circuitry in response to both fearful and happy faces (40
) and the efficacy of emotionally-valenced faces as stimuli to study pACC-amygdala interactions in functional connectivity analyses (11
). Moreover, it supports the utility of this approach to probe abnormalities in pACC-amygdala functional connectivity in disorders of affective regulation.
Reduced functional coupling from pACC was also detected in the ventral caudate and nucleus accumbens, although these findings did not survive more stringent corrections for multiple comparisons. The ventral caudate and nucleus accumbens are interconnected with pACC and amygdala (25
) and are implicated in BD because of their role in motivated behaviors that are dysregulated in the disorder and findings of alterations in their shape, volumes and activation in BD (44
). In addition to ventrofrontal areas, regions in which the structural integrity of white matter were associated with pACC-amygdala coupling included fronto-thalamo-striatal projections and projections to posterior sensory regions that provide connections within a more widely distributed neural system. This suggests that disruptions in pACC-amygdala connectivity may be associated with abnormalities in the development of a more widely distributed neural system subserving emotional regulation (47
Participants with BD were in different mood states, and had variable histories of rapid-cycling, comorbidity and medication and substance exposure. While we did not detect significant main effects of these factors on pACC-amygdala functional connectivity or ventrofrontal FA, our ability to detect effects of these factors was potentially limited by inadequate power. We also performed our analyses with current tobacco use as a covariate, yielding equivalent results. Additional studies reporting reduced functional connectivity in manic participants (48
) as well as across acute mood states and euthymia (49
) suggest that functional connectivity disturbance may be a trait abnormality in BD. The majority of our BD participants reported symptom onset in adolescence/early adulthood. Interestingly, ACC receives a progressive and dramatic growth of fibers originating from the amygdala during adolescence/early adulthood (50
), a time period coinciding with this peak in the onset of BD, suggesting that further study in the development of the ACC-amygdala connectivity in adolescence/early adulthood in BD may help to elucidate a neurodevelopmental mechanism contributing to the disorder.