This study was designed to examine brain activation within the VLPFC-subcortical mood circuit during a Go/No-Go task in patients with BD. We expected that patients in a mixed episode would exhibit greater behavioral deficits and neurophysiological abnormalities relative to healthy and psychiatric comparison groups.
Consistent with previous signal-detection findings in acute BD, both patient groups were less able to discriminate targets from non-targets relative to the healthy group (Fleck et al., 2005
; Strakowski et al., 2010
). In partial support of the behavioral prediction, the mixed group had difficulty inhibiting prepotent motor responses, resulting in a marginally higher commission error rate than the healthy group. However, the mood state specificity of this effect is questionable considering the null patient group follow-up comparison.
Voxel-wise analysis of the full sample showed general correspondence with ROIs in the a priori
defined VLPFC-subcortical network, at least unilaterally, confirming this network’s role in motor impulsivity. The pattern of decreased straital and increased frontal lobe and cerebellar activation is consistent with a brain circuit thought to represent the affective response to Go/No-Go error processing (Stevens et al., 2008). Parietal lobe activation outside the VLPFC-subcortical network per se
may represent a complimentary posterior attention system (Posner and Peterson, 1990
) previously demonstrated in fMRI studies of attention in healthy (Adler et al., 2001
), euthymic (Strakowski et al., 2004
) and manic (Fleck et al., in press
) participants alike.
In voxel-wise comparisons, the mixed group overactivated the VLPFC-subcortical network relative to healthy and patient comparison groups. Regions of increased activation included amygdala and OFC (BP-M>HC), and VLPFC, thalamus and cerebellum (BP-M>BP-D). Impulsivity in primary mania has been previously associated with blunted rather than increased VLPFC activation, but this is in the context of normal Go/No-Go accuracy (Altshuler et al., 2005
; Mazzola-Pomietto et al., 2009
). The present finding of greater VLPFC and OFC activation in mixed mania may suggest a connection between response non-suppression (motor impulsivity) and failure constraining primary emotional brain centers (especially amygdala, OFC, and VLPFC). Over-activation of right amygdala in the ROI analysis provides additional support for this interpretation, but it is still speculative considering the lack of group activation differences within inferior frontal lobe ROIs. Functional connectivity studies are necessary to determine the temporal relationship between amygdala and frontal lobe activation to specify whether frontal activation actually constrains amygdala or is simply a cortical representation of limbic activation.
These results should be interpreted in light of certain study limitations. Foremost, the sample size was modest and may provide insufficient statistical power to detect certain effects. It is generally accepted that group sizes <10 are suboptimal in fMRI studies (Friston et al, 1999
). Additionally, the majority of participants with BD were receiving medications, potentially impacting the findings. The small number of unmedicated patient participants limited meaningful sub-analysis however. Finally, although our intent was to match the patient subgroups on depressive symptom severity, mean MADRS differences necessitated statistical control instead.
To our knowledge this is the first fMRI study examining neurophysiological functioning in mixed episode BD. Higher commission error rates may suggest increased vulnerability to impulsivity during mixed episodes. Moreover, the distinct pattern of greater brain activation in mixed mania may indicate a connection between behavioral impulsivity and a failure of neurophysiological “inhibition,” particularly in the right amygdala. Taken together, these results provide preliminary evidence for functional abnormalities within a VLPFC-subcortical emotional network during impulsive motor responding in mixed mania. Functional brain variations during motor impulsivity in mixed episodes, even in relation to depressed episodes, might serve as proxy state markers of risk taking behaviors.