In executive function, specifically in response inhibition, numerous studies support the essential role for the inferior frontal cortex (IFC). Hypoactivation of the IFC during response-inhibition tasks has been found consistently in subjects with bipolar disorder during manic and euthymic states. The aim of this study was to examine whether reduced IFC activation also exists in unmedicated subjects with bipolar disorder during the depressed phase of the disorder. Participants comprised 19 medication-free bipolar II (BP II) depressed patients and 20 healthy control subjects who underwent functional magnetic resonance imaging (fMRI) while performing a Go/NoGo response-inhibition task. Whole-brain analyses were conducted to assess activation differences within and between groups. The BP II depressed group, compared with the control group, showed significantly reduced activation in right frontal regions, including the IFC (Brodmann's area (BA) 47), middle frontal gyrus (BA 10), as well as other frontal and temporal regions. IFC hypoactivation may be a persistent deficit in subjects with bipolar disorder in both acute mood states as well as euthymia, thus representing a trait feature of bipolar disorder.

BACKGROUND:Patterns of abnormal neural activation have been observed during working memory tasks in bipolar I depression, yet the neural changes associated with bipolar II depression have yet to be explored.METHOD:An n-back working memory task was administered during a 3T functional magnetic resonance imaging scan in age- and gender-matched groups of 19 unmedicated, bipolar II depressed subjects and 19 healthy comparison subjects. Whole-brain and region-of-interest analyses were performed to determine regions of differential activation across memory-load conditions (0-, 1- and 2-back).RESULTS:Accuracy for all subjects decreased with higher memory load, but there was no significant group × memory load interaction. Random-effects analyses of memory load indicated that subjects with bipolar II depression exhibited significantly less activation than healthy subjects in left hemispheric regions of the middle frontal gyrus [Brodmann area (BA) 11], superior frontal gyrus (BA 10), inferior parietal lobule (BA 40), middle temporal gyrus (BA 39) and bilateral occipital regions. There was no evidence of differential activation related to increasing memory load in the dorsolateral prefrontal or anterior cingulate cortex.CONCLUSIONS:Bipolar II depression is associated with hypoactivation of the left medio-frontal and parietal cortex during working memory performance. Our findings suggest that bipolar II depression is associated with disruption of the fronto-parietal circuit that is engaged in working memory tasks, which is a finding reported across bipolar subtypes and mood states.

Structural neuroimaging studies of the amygdala and hippocampus in bipolar disorder have been largely inconsistent. This may be due in part to differences in the proportion of subjects taking lithium or experiencing an acute mood state, as both factors have recently been shown to influence gray matter structure. To avoid these problems, we evaluated euthymic subjects not currently taking lithium. Thirty-two subjects with bipolar type I disorder and 32 healthy subjects were scanned using magnetic resonance imaging. Subcortical regions were manually traced, and converted to three-dimensional meshes to evaluate the main effect of bipolar illness on radial distance. Statistical analyses found no evidence for a main effect of bipolar illness in either region, although exploratory analyses found a significant age by diagnosis interaction in the right amygdala, as well as positive associations between radial distance of the left amygdala and both prior hospitalizations for mania and current medication status. These findings suggest that, when not treated with lithium or in an acute mood state, patients with bipolar disorder exhibit no structural abnormalities of the amygdala or hippocampus. Future studies, nevertheless, that further elucidate the impact of age, course of illness, and medication on amygdala structure in bipolar disorder are warranted.

Functional neuroimaging studies have implicated the involvement of the amygdala and ventrolateral prefrontal cortex (vlPFC) in the pathophysiology of bipolar disorder. Hyperactivity in the amygdala and hypoactivity in the vlPFC have been reported in manic bipolar patients scanned during the performance of an affective faces task. Whether this pattern of dysfunction persists during euthymia is unclear. Using functional magnetic resonance imaging (fMRI), 24 euthymic bipolar and 26 demographically matched healthy control subjects were scanned while performing an affective task paradigm involving the matching and labeling of emotional facial expressions. Neuroimaging results showed that, while amygdala activation did not differ significantly between groups, euthymic patients showed a significant decrease in activation of the right vlPFC (BA47) compared to healthy controls during emotion labeling. Additionally, significant decreases in activation of the right insula, putamen, thalamus and lingual gyrus were observed in euthymic bipolar relative to healthy control subjects during the emotion labeling condition. These data, taken in context with prior studies of bipolar mania using the same emotion recognition task, could suggest that amygdala dysfunction may be a state-related abnormality in bipolar disorder, whereas vlPFC dysfunction may represent a trait-related abnormality of the illness. Characterizing these patterns of activation is likely to help in understanding the neural changes related to the different mood states in bipolar disorder, as well as changes that represent more sustained abnormalities. Future studies that assess mood-state related changes in brain activation in longitudinal bipolar samples would be of interest.

OBJECTIVE Although several lines of evidence implicate gray matter abnormalities in the prefrontal cortex and anterior cingulate cortex in patients with bipolar disorder, findings have been largely inconsistent across studies. Differences in patients' medication status or mood state or the application of traditional volumetric methods that are insensitive to subtle neuroanatomical differences may have contributed to variations in findings. The authors used MRI in conjunction with cortical pattern matching methods to assess cortical thickness abnormalities in euthymic bipolar patients who were not receiving lithium treatment. METHOD Thirty-four lithium-free euthymic patients with bipolar I disorder and 31 healthy comparison subjects underwent MRI scanning. Data were processed to measure cortical gray matter thickness. Thickness maps were spatially normalized using cortical pattern matching and were analyzed to assess illness effects and associations with clinical variables. RESULTS Relative to healthy comparison subjects, euthymic bipolar patients had significantly thinner gray matter in the left and right prefrontal cortex (Brodmann's areas 11, 10, 8, and 44) and the left anterior cingulate cortex (Brodmann's areas 24/32). Thinning in these regions was more pronounced in patients with a history of psychosis. No areas of thicker cortex were detected in bipolar patients relative to healthy comparison subjects. CONCLUSIONS Using a technique that is highly sensitive to subtle neuroanatomical differences, significant regional cortical thinning was found in lithium-free euthymic patients with bipolar disorder.

Recent evidence suggests that putting feelings into words activates the prefrontal cortex (PFC) and suppresses the response of the amygdala, potentially helping to alleviate emotional distress. To further elucidate the relationship between brain structure and function in these regions, structural and functional magnetic resonance imaging (MRI) data were collected from a sample of 20 healthy human subjects. Structural MRI data were processed using cortical pattern-matching algorithms to produce spatially normalized maps of cortical thickness. During functional scanning, subjects cognitively assessed an emotional target face by choosing one of two linguistic labels (label emotion condition) or matched geometric forms (control condition). Manually prescribed regions of interest for the left amygdala were used to extract percentage signal change in this region occurring during the contrast of label emotion versus match forms. A correlation analysis between left amygdala activation and cortical thickness was then performed along each point of the cortical surface, resulting in a color-coded r value at each cortical point. Correlation analyses revealed that gray matter thickness in left ventromedial PFC was inversely correlated with task-related activation in the amygdala. These data add support to a general role of the ventromedial PFC in regulating activity of the amygdala.

Introduction: Bipolar (BP) disorder is a severe chronic mental illness characterized by dramatic mood swings between mania and depression. Several lines of evidence have implicated disruptions of prefrontal cortex and amygdala, known components of an emotion regulatory network. Recent data from our group have shown such a disruption occurs during an emotion identification task in bipolar mania (Foland et al., 2008). Here, we use the same task to examine (1) if amygdala hyper-responsivity persists during euthymia, and (2) whether amygdala hyper-responsivity is associated with a reduction in prefrontal cortical (PFC) gray matter thickness, given that the PFC directly suppresses amygdala output (Hariri et al., 2000).

INTRODUCTION: Several lines of evidence implicate abnormalities in the prefrontal cortex (PFC) in patients with bipolar (BP) disorder. Previous findings have varied however, perhaps because of the inclusion of patients treated with lithium, a medication that increases cortical gray matter volume (Moore et al., 2000; Lancet, 7:356). Past studies have also relied on traditional volumetric methods, which may be insensitive to subtle neuroanatomic changes. METHODS: 34 subjects with BP type I disorder (13f, 38.1±12.0yrs) and 32 healthy subjects (13f, 38.2±13.1yrs) were scanned on a 1.5T MRI scanner. 33% of patients were unmedicated and all were free from lithium. MRI data were processed to provide a measurement of cortical gray matter thickness (Thompson et al., 2004; NeuroImage, 23:S2-18), and cortical pattern matching methods were used to associate homologous brain regions across subjects (Thompson et al., 2000; Hum. Br. Mapp. 9:81-92). Spatially normalized thickness maps were analyzed to assess illness effects while controlling for age, sex and medication. Based on our a priori hypotheses regarding specific brain regions that might be affected in BP disorder, permutation testing was conducted in PFC and anterior cingulate subregions, defined by Brodmann areas (Rasser et al., 2005; NeuroImage, 26:941-51). Associations with clinical demographics were assessed using correlation analyses. RESULTS: Relative to healthy subjects, patients showed overall significant decreases in cortical thickness in both left (p=0.045) and right (p=0.006) hemispheres. Frontal lobe thinning in patients was localized to bilateral orbitofrontal (BA11, p<0.01), right ventrolateral (BA47, p=0.03), left superior frontal (BA10, p=0.049) and left anterior cingulate cortices (BA32, p=0.047). No areas of thicker cortex were found in patients relative to healthy subjects. Significant inverse associations were found within these regions with duration of illness, prior number of depressions and duration of time between illness onset and initiation of treatment with medication (p<0.05). DISCUSSION: This is the first brain mapping study to examine illness effects in a patient sample free from lithium, a medication that has significant confounding effects on gray matter. We found thinning in anterior cingulate cortex, and ventrolateral and ventromedial PFC, brain regions which are critical in the modulation of attention, motivation, and emotion. Inverse association between thickness in these regions and prior course of illness variables suggest cumulative thinning may occur as a result of this illness, and pharmacological treatment could protect against such thinning.