Using cortical matching methods in conjunction with tools for measuring gray matter thickness, we found significant thinning in bilateral prefrontal and left anterior cingulate cortices in euthymic bipolar subjects relative to healthy subjects. Within these regions, thinning was localized to specific subregions including bilateral orbital (Brodmann Area 11), left frontopolar (Brodmann Area 10), left dorsomedial (Brodmann Area 8), left ventrolateral prefrontal cortex (Brodmann Area 44), left anterior cingulate (Brodmann Area 24) and left pericingulate (Brodmann Area 32) cortices.
Only two studies, to our knowledge, have examined brain structure in recurrently ill adult subjects with bipolar disorder using cortical thickness methods in conjunction with MRI. Lyoo et al. (29
) reported thinning of prefrontal cortical gray matter in 25 bipolar subjects relative to 21 healthy subjects in left Brodmann Areas 46, 24 and 32 and right Brodmann Area 10. And, in a region of interest-driven study, Fornito et al. (6
) found thinning in left Brodmann Area 24 and right Brodmann Area 32 in 24 patients relative to 24 healthy subjects. In the current study, which used a larger sample of 34 patients and 31 healthy subjects, cortical pattern matching methods were used to allow a more precise mapping of thickness abnormalities in bipolar disorder (30
). These methods improve upon the traditional registration approaches by aligning corresponding anatomy across subjects using sulcal features, eliminating much of the confounding anatomical variance when pooling data across subjects, thereby making it easier to identify and localize subtle group differences in brain structure (19
). Using this highly sensitive technique, we replicated and extended the above prior study findings.
The current study has several unique strengths. First, unlike a majority of previous studies which have either not specified (32
), or included a number of patients who were receiving treatment with lithium at the time of scanning (4
), all subjects in our patient sample were free from current treatment with this medication. This aspect may be particularly important given recent evidence showing that lithium medication is associated with significant increases in cortical gray matter. Moore et al. (33
) observed total gray matter volume increased by 3%, on average, in bipolar subjects after 4 weeks of lithium treatment. Sassi et al. (16
) found larger total gray matter volume in lithium-treated bipolar subjects, compared to both untreated patients and healthy subjects. And Bearden et al. (14
) found prefrontal cortical gray matter density was greater in bipolar subjects treated with lithium relative to both healthy subjects and bipolar subjects not treated with this medication. Our group has also found lithium-associated gray matter enlargement of subcortical structures in bipolar subjects (15
). Use of lithium, therefore, may serve to explain why some prior structural neuroimaging studies of bipolar disorder have either failed to detect gray matter reductions in patients (11
), or found group differences in the opposite direction (i.e., gray matter increases in bipolar versus healthy subjects (7
A second strength of the current study is that all bipolar subjects in our patient sample were in the same mood state (euthymia) at the time of scanning. Although prior studies have not controlled for this factor, recent data from our group (17
) and others (8
) suggest that, it, too may in fact impact MRI results. Brooks et al. (17
) found, compared to euthymic bipolar subjects, that depressed bipolar subjects exhibited lower gray matter density in dorsal prefrontal cortices. Nery et al. (8
) also found gray matter reductions in the orbitofrontal cortex of depressed relative to euthymic bipolar patients. A similar pattern of gray matter volume reductions has been more recently found by our group in patients scanned longitudinally (in different mood states) as well (J.O. Brooks et al., unpublished 2010 data).
A third strength of our study is that all subjects in the current patient sample were diagnosed with bipolar I (not II) disorder. Whether bipolar subtype (I or II) is associated with distinct cortical abnormalities is not known, but could add to the heterogeneity in structural neuroimaging findings. Only one study, to our knowledge, has specifically examined the impact of subtype on brain structure. In this study, unmedicated patients with bipolar type I disorder were found to exhibit smaller volumes of the left amygdala compared to unmedicated patients with bipolar type II disorder (35
). This finding, as well as data from studies which show bipolar type I disorder to be associated with greater neuropsychological impairment (36
), a higher risk for psychosis, and more severe manias than bipolar type II disorder, suggests that bipolar subtype could be associated with distinct patterns of thinning in cortical gray matter. Studies that directly compare cortical gray matter in patients with bipolar type I versus bipolar type II disorder are needed, however, to more thoroughly examine this issue.
With these efforts to study a more homogenous bipolar population and to control for some known confounds, we found reduced thickness in the prefrontal and anterior cingulate cortices of patients with bipolar disorder. The etiology of this thinning remains to be further understood. One possibility is that reduced thickness in the prefrontal and anterior cingulate cortex of patients is the result of an underlying neurodegenerative process associated with possible toxic effects of mood episodes. In line with this, and consistent with prior studies (28
), we found significant widespread negative associations between cortical thickness and prior course of illness. Although it is tempting to speculate that decreased thickness in patients is causally associated with greater illness duration and a higher number of prior depressive episodes, because these variables were highly correlated with age, we, like prior studies (28
) could not disentangle these effects. Future studies that sample from bipolar patient groups that have a very narrow age range but a wide range in the number of prior depressive episodes or other course of illness measures are needed to tease apart these factors.
Another possibility is that reduced cortical thickness is present early in the course of the disorder, possibly prior to illness onset, and that such thinning might alter normal inhibitory cortico-limbic networks, resulting in an increased vulnerability to emotion dysregulation. Data to support this comes from studies finding gray matter abnormalities in the prefrontal cortex of unaffected relatives of individuals with bipolar and unipolar depressive disorder (38
). Whether these individuals with cortical thinning go on to develop the disorder is unclear, however, and longitudinal studies that more thoroughly explore the relation between cortical thinning and illness onset would be of interest.
Thinning of the prefrontal and anterior cingulate cortices could contribute to some of the behavioral changes that are observed in bipolar disorder. Lesion studies show focal damage to the orbitofrontal cortex leads to a diminished ability for individuals to properly gauge the positive or negative emotional consequences to their actions (40
), and damage to anterior cingulate cortex results in symptoms which include inattention and emotional instability (41
). At least one functional neuroimaging study, to our knowledge, has reported activation in both the orbitofrontal and anterior cingulate cortex in healthy subjects during the conscious regulation of negative emotional states (43
). This same study found activation in the orbitofrontal cortex was negatively correlated with that of the amygdala, suggesting an inhibitory connection between these regions. Other studies involving emotion regulatory paradigms, however, have found frontal activation (and corresponding negative correlations with amygdala activation) to be localized to the lateral portion of prefrontal cortex (e.g. Brodmann Area 47) (44
). Although thinning in this ventrolateral region was not observed in patients here, it is well established that robust structural connections run between the lateral (e.g. Brodmann Area 47) and medial (e.g. Brodmann Area 11) sectors of the orbitofrontal cortex, but that only the medial subdivision sends direct inhibitory projections to the amygdala (47
). The lateral sector of orbitofrontal cortex, therefore, may suppress amygdala output via intermediary projections from the medial orbitofrontal cortex. Given this, it is interesting that our group has observed increased activation of the amygdala and decreased activation of the lateral orbitofrontal cortex (44
), but thinning in the medial orbitofrontal cortex (shown here). The current study data could, therefore, provide a structural etiology for the functional abnormalities previously observed by our group. Additional studies examining the relation between brain structure and function in emotion regulatory circuits are currently underway in our laboratory.
With the exception of thinning in orbitofrontal cortex, which was bilateral, most of the thinning observed in patients of the present study was localized to the left hemisphere. This hemispheric pattern agrees with prior studies; of the four that have reported abnormal structure of the anterior cingulate (i.e., Brodmann Area 24/32), three (10
) found deficits in the left hemisphere only, one (6
) found deficits in bilateral anterior cingulate, and no studies found deficits that were restricted to the right hemisphere. The reason for this laterality is not known, although the concept of hemispheric lateralization of mood regulation is well-documented. Current models of emotional processing suggest that positive (or approach-related) emotions are lateralized toward the left hemisphere, whereas negative (or withdrawal-related) emotions are lateralized toward the right hemisphere (52
). Lesions to the left prefrontal cortex, for example, have been associated with an increased risk for depressive symptoms (53
In addition to the negative associations observed here between cortical thickness and illness duration and prior number of depressive episodes, there are two findings that require further investigation. First, thickness in left subgenual prefrontal cortex was positively associated with the number of prior of hospitalizations for mania, a finding that remained significant when age was controlled for in our statistical model. It is possible, given recent evidence suggesting that mood state may affect brain structure (8
), that the manic state itself, particularly when severe enough to require hospitalization, may have enduring hypertrophic effects on gray matter. Future studies, however, are needed to address this possibility. Second, a history of psychosis in patients was associated with significantly greater thinning in left ventrolateral prefrontal cortex (Brodmann Area 44), left dorsomedial prefrontal cortex (Brodmann Area 8) and left temporal pole (Brodmann Area 38). More pronounced thinning in these regions may suggest that psychotic and non-psychotic forms of bipolar disorder could be characterized by distinct patterns of gray matter abnormalities. This pattern of deficit is congruent with neurocognitive studies that show bipolar patients with a history of psychosis to be impaired on some prefrontal functions such as executive functioning and spatial working memory compared with bipolar patients without such a history (54
). Moreover, studies of patients with chronic schizophrenia (55
) and psychosis (57
) consistently show reductions in gray matter of the left dorsomedial region of prefrontal cortex (Brodmann Area 8). Cortical gray matter loss in this region, therefore, may be associated with psychosis in particular. Unlike patients with schizophrenia however, cortical gray matter in dorsolateral prefrontal cortex (e.g. Brodmann Area 46) was relatively spared in patients of the current study. Thus, although distinct and identifiable patterns of neuroanatomic pathology could potentially distinguish these two disorders, future studies are needed to more accurately address this possibility.
Our study has several limitations. First, many of our patients were taking other medications, of which the long- and short-term effects on brain structure are not known. Our comparisons of cortical thickness between medicated and unmedicated patients, however, showed no evidence for a significant effect of this factor. Second, some patients had reported taking lithium in the years prior to scanning, and prior exposure to this medication could have affected our results. As lithium increases gray matter volume (33
) however, it would be expected that any enduring hypertrophic effects of prior treatment with this medication would have produced group differences opposite to those observed here. Additionally, comparisons between patients who had and had not previously taken this medication indicate that prior lithium use itself was not a significant confounder.
In conclusion, using sensitive cortical pattern matching methods, in conjunction with tools developed by our group to measure cortical gray matter thickness, we found significant gray matter thinning in the prefrontal cortex and anterior cingulate cortex of a bipolar patient sample that was carefully recruited to control for the potential confounding effects of lithium status, mood state and diagnosis subtype. Thinning within these areas of the brain was localized to bilateral orbital (Brodmann Area 11), left frontopolar (Brodmann Area 10), left ventrolateral (Brodmann Area 44), left dorsomedial (Brodmann Area 8) and left anterior cingulate cortex cortices (Brodmann Area 24 and Brodmann Area 32), brain areas which are critical for the modulation of emotion, motivation, and attention. Studies that examine possible associations between cortical thinning and behavior, and the impact of structural alterations on neural circuit function are currently underway by our laboratory.