Although patients with bipolar disorder (BD) have historically been characterized as returning to baseline function between affective episodes, it is increasingly apparent that this view is somewhat inaccurate. Euthymic BD patients, although clinically in remission, often continue to be functionally compromised. Some studies point to a significant degree of psychosocial dysfunction even when patients are euthymic.[3, 4] Other reports have emphasized the impact of cognitive dysfunction on psychosocial functioning in BD patients.[5, 6] In addition, psychosocial functioning seems to be more strongly associated with cognitive impairment than most other clinical variables. Verbal fluency is an aspect of higher executive function, a spectrum of cognitive processes that are essential to control and regulate lower-level processing and goal-directed behavior. A recent meta-analysis of cognitive deficits in euthymic BD patients found a small impairment in phonetic fluency.
Neuroimaging techniques, such as functional magnetic resonance imaging (fMRI), are now widely used to study BD. Studies of executive functioning in BD patients have included working memory tasks, continuous performance tasks, Stroop and language tasks. Some functional neuroimaging studies found blunted activation of the prefrontal cortex (PFC) during cognitive tasks in BD patients.[11, 12] Other studies did not find hypoactivation but reported enhanced or unchanged activation.[13, 14] Although there has been variability of results depending on the clinical state of the patients and the task design, the PFC has been consistently involved. Psychosocial functioning is a sophisticated construct that encompasses interactions and activities in personal, occupational, and recreational contexts. The biological underpinnings of psychosocial impairment are unclear. Few studies have specifically examined psychosocial functioning using brain activation and neuropsychological tasks.
The present study analyzed the association between psychosocial functioning and brain activation during higher cognitive functions in euthymic BD patients. We hypothesized that euthymic BD patients would exhibit different cortical activation during a verbal fluency task, but not during lower motor or sensory tasks, compared to healthy controls. More specifically, euthymic BD patients would have a more extended pattern of brain activation compared to the controls to achieve similar behavioral performance, reflecting insufficient processing in the anterior cingulate cortex (ACC) and left lateral PFC, which have been consistently reported to be activated during verbal fluency tasks. In addition, psychosocial functioning, known to be impaired in BD even during remission, was hypothesized to be associated with ACC and left lateral PFC activation during the task.
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The principal findings of this study are twofold. First, euthymic BD patients had greater activation in the bilateral precuneus compared to the controls, with similar behavioral performance during the verbal fluency task. There were no significant differences in patterns of brain activation between the two groups for the visual task and the simple motor task. Second, activation of both the left ACC and the left lateral PFC were significantly positively correlated with GAF score in the euthymic BD participants. There was no significant group difference, however, in the activations of the regions with which GAF score was correlated. This suggests that changes in the activation of these regions are associated with the current general functioning of BD patients, but are not the trait abnormality of BD. To our knowledge, this is the first study to show a clear relationship between functional brain activation and GAF in daily life in euthymic BD patients.
Although the cross-sectional nature of the present study precludes definitive conclusions about a causal relationship, the present findings suggest that the poorer general psychosocial functioning found in euthymic BD patients may be attributable to attenuation of ACC and left lateral PFC activation during the higher cognitive task. Consistent with the present results at the behavioral level, verbal fluency has been reported to be a predictor of psychosocial functioning in BD patients. Difficulty in retrieving verbal information may represent a serious problem for BD patients in their occupational functioning as well as in their interpersonal relationships. The ACC has been considered a key cortical area during the processing of cognitively demanding information. It has been shown to be associated with a number of functions including response selection, inhibition, vocalization and attention. In contrast, the lateral PFC has been related to working memory, cognitive-set shifting, and planning. Preceding neuroimaging studies have found alterations in the ACC–dorsolateral PFC system in both unipolar depressed and BD patients, putatively reflecting an abnormal interplay of monitoring and executive neurocognitive functions.
One contradictory finding in the present study is that we failed to find a difference in the offline verbal fluency performance between the two groups, even though there was significant activation in the precuneus in euthymic BD patients compared to healthy controls. One explanation of this finding may be that the BD patients were able to produce similar numbers of words by activating more brain regions other than the usually activated areas such as the ACC, left lateral PFC, and cerebellum. This suggests that the patients used an alternative neural strategy to process verbal information to improve their performance. The present findings are in agreement with other studies that have found greater activation in different regions during cognitive tasks in patients with BD.[28, 29] The precuneus has traditionally received little attention, mainly because of its hidden location and the virtual absence of focal lesion studies. Recent functional imaging findings in healthy individuals, however, suggest that the precuneus is a multimodal association area that is involved in episodic memory retrieval. It has been suggested that the prefrontal regions drive memory retrieval and that successful retrieval prompts the reactivation of engrams stored in the precuneus. In the present study, BD patients had hyperactivation in the dorsoposterior portion of the precuneus near the parieto-occipital fissure during the verbal fluency task. This portion is functionally connected to adjacent visual cortical regions, and related to visual and spatial attention. Therefore, the present results suggest that the BD patients required greater attention resources to perform the same task, possibly because of an inefficiency of the neural systems supporting verbal fluency performance. Interestingly, a considerable number of previous studies have indicated the differential recruitment of the precuneus between BD patients and controls, during various cognitive tasks. Greater activation in the precuneus of euthymic BD patients compared to controls during the verbal fluency task corroborates a previous study suggesting that BD patients have reduced deactivation in the precuneus, in comparison to healthy controls. Significantly, studies using tasks other than the verbal fluency task have also suggested the diminished, or absent activity in the precuneus, as compared to healthy controls.[33, 34] Although there is a lack of consistency in the direction of the effects observed across tasks, possibly because of differences in samples, imaging tasks, and analysis protocols among others, a study using voxel-based morphometry has also suggested that the precuneus is affected in BD. It is suggested that the role of the precuneus in BD is an important issue for future investigation.
Several limitations must be considered when interpreting the present study. First, the overall number of participants is relatively small, which limits the generalizability of the study findings. The patient sample, however, consisted of well-diagnosed, stable individuals with chronic BD, and the sample size provided enough power to detect between-group differences. This sample size limitation is particularly true for correlation analysis, although the results for all participants are similar to those for BD patients. Nonetheless, this study provides some hypotheses for future research with larger samples. Second, the patients receiving medications were being treated with a variety of drug combinations, so that specific medication effects could not be determined given the number of patients available. Medications, however, may alter brain activation in regions that are associated with cognitive tasks, so the study of specific drug effects on cognition (and corresponding brain activation) in a larger patient sample is warranted. Third, the task performance data were obtained in an offline condition, but not in an online condition, because of the risk of verbal movement confounding the data. All participants, however, performed the same task using different phonemic characters outside of the scanner, although there is no guarantee that the task performance at each session was the same. Fourth, the present paradigm had no sufficient baseline prior to the active block. This means that we cannot exclude the possibility that the early MRI data may include unstable magnetization. But we demonstrated that the activations on the WFT corresponded with the findings of previous studies. The effect of unstable magnetization seems to be small.
In conclusion, patients with euthymic BD had significant positive correlations between psychosocial functioning and activations in the ACC and the left lateral PFC during a verbal fluency task. Thus, the hidden cognitive disturbance, detected only on functional brain imaging with neuropsychological tests, is always present in BD, even though bipolar patients exhibit minimal affective symptoms during periods of euthymia. These results suggest that the precuneus may be sensitive to the impact of BD, and are also indicative of an association between the general functioning of euthymic BD patients and the function of the ACC and the lateral PFC. Further studies of brain activity using neuropsychological tasks as probes for psychosocial functioning in BD and other neuropsychiatric disorders are warranted.