In this study, we examined fMRI regional brain activation during a response inhibition task in first-episode manic bipolar patients and demographically similar healthy subjects. Significant differences between groups were observed in regional brain activation, despite no differences in task performance. The lack of differences in task performance failed to support our initial prediction of greater impulsive responding in the manic patients. Specifically, both groups exhibited relatively poor rates of response to targets (about 50% correct hits) with correspondingly high rates of successful ‘stops’ (i.e., low rates of false hits). This pattern of responses suggests two likely behavioral strategies. The first is that subjects excessively delayed responses to targets in order to avoid failing ‘stops,’ resulting in high rates of missed targets. Supporting this interpretation is the observation that the response times were slightly longer than the presentation interval, suggesting that subjects in both groups were delaying the response until the possibility of the target changing had passed. Alternatively, subjects may have inconsistently attended to the task, thereby increasing rates of non-response to targets, which would also decrease the rates of false hits during ‘stops.’ Our task design does not allow us to determine whether one of these behavioral strategies predominated in either group. Moreover, subjects were not questioned regarding the cognitive strategy they used when completing this task. These possibilities become relevant when interpreting fMRI data.
The pattern of regional activation in healthy subjects suggested active response inhibition, consistent with the first of the paradigms discussed in the previous paragraph. Namely, activation in regions of the cingulate (BA 24, 32, 23), insula, thalamus, inferior frontal gyrus and precuneus is consistent with previous studies of similar response inhibition tasks15–19
We also observed relative deactivation within the posterior cingulate; this may reflect that the posterior cingulate is more activated during search for targets (i.e., when viewing the series of non-targets), than during response inhibition, as has been suggested in other studies.18
The activation pattern observed in healthy subjects is consistent with an activation of response inhibition networks and an active response inhibition behavioral strategy during this task.
In contrast, the bipolar subjects exhibited limited activation in cingulate, inferior frontal gyrus, and thalamus. Like the healthy subjects, the patients exhibited similar patterns of decreased activation in regions of the posterior cingulate (BA 29) and left middle temporal gyrus (BA 39). Unlike the healthy subjects, the bipolar patients also exhibited activation in middle frontal gyrus (BA 10), although the difference between groups in this region did not meet a priori
statistical significance. Since task performance was similar to healthy subjects, several possibilities are suggested by the differences in activation patterns. First, as noted previously, the differences in activation may reflect a different underlying reason for the relatively low rate of target hits; namely, rather than choosing a conservative strategy as suggested by the healthy subjects (i.e., delayed response to prevent false hits during ‘stops’), the similar task performance in the patients may have resulted from poorer attention to the task. The lack of cingulate activation supports this notion. On the other hand, the similar reaction times and measures of bias (B″) suggest that the two groups were approaching the task similarly vis-à-vis their behavioral response strategy. Bias represents factors other than the ability to discriminate targets from non-targets during the CPT that affect performance. These factors include motivation, fatigue or tendencies toward either more liberal or conservative task performance. The recruitment of BA 10 by the patients suggests instead that patients may have used a compensatory neural strategy to manage the demands of this task, even while using a similar behavioral strategy (i.e., delaying target response in order to maximize ‘stops’). This brain region has been associated with decision making, affective modulation, and conflict resolution, and may be activated as tasks become more difficult.22, 23
Alternatively, medication effects may account for some of the differences between bipolar and healthy subjects. The patients who had not received medication demonstrated greater activation in brain areas that have been associated with affect modulation, namely amygdala and insula,6
than patients who had received medications, even though they had only received treatment for a few days. The patients who received medications showed increased activation in posterior attentional areas. In previous work in unmedicated euthymic patients, we suggested that activation of posterior attentional areas compensates for interference of cognitive networks by over-activated mood networks.6
Therefore, the increased activation noted here, even after only a few days of medication, may be an early marker toward clinical improvement. Notably, in this secondary analysis between medicated and unmedicated patients there were no differences in activation in brain regions that differed between healthy and bipolar subjects in the primary analysis. Nonetheless, the possibility that medication-related effects might have indirectly contributed to differences between bipolar and healthy subjects cannot be excluded.
Several limitations to this study should be considered when interpreting results. Additional cognitive tasks (e.g., an attentional task such as a continuous performance taske.g.7
) may have helped to better differentiate the underlying reasons for similar task performance with different brain activation patterns. Related to this limitation, the task selected did not differentiate between healthy and manic subjects. An alternative design, or additional or more difficult tasks, might have better identified specific behavioral deficits related to response inhibition in bipolar disorder, which would then be reflected in brain activation patterns. Specifically, this task appeared to be less cognitively demanding than those used in other studiese.g.3
. On the other hand, the lack of task performance differences controls for this potential confound when interpreting differences in fMRI activation patterns. An alternative approach would be to use a Logan stop-signal task,28
which dynamically adjusts the stop-signal based on individual subject response times. Doing so would control for inhibition success across groups; however, in this study, no differences in successful stop rates were observed. Another limitation was that the number of subjects was relatively small, particularly for sub-analyses (i.e., patients on and off of medication). Consequently, these secondary analyses in particular should be interpreted cautiously and additional differences between groups may have been observed with larger numbers of subjects. In the absence of larger numbers of subjects, specific medication effects could not be delineated. Nonetheless, the preliminary contrasts suggest that medication exposure does not explain differences observed between the bipolar and healthy subjects. The bipolar subjects were more likely to have histories of co-occurring psychiatric disorders. However, the numbers of subjects with each precluded meaningful analyses. Similarly, many of the patients exhibited psychotic symptoms as is common during mania. Whether some differences could be ascribed to specific symptoms or co-occurring syndromes cannot be discounted; larger samples might be able to address these possibilities. Balancing these limitations is the unique, early course patient sample scanned while manic and while using a well-defined response inhibition task. Future studies incorporating additional cognitive tasks with this patient population may extend this work to clarify the functional neuroanatomy of response inhibition in bipolar disorder, in general, and mania, specifically.