A preliminary longitudinal fMRI study of frontal-subcortical circuits in bipolar disorder using a paced motor activation paradigm

BACKGROUND: Compelling evidence suggests abnormal functioning of frontal-subcortical (FSC) circuits in bipolar disorder, but it is unknown whether these are state or trait abnormalities. Longitudinal functional neuroimaging studies may help clarify this issue. However, studies to date have not determined which activation paradigms may be most useful for this purpose. A paced motor task has the potential to be more reliable than cognitive or emotional activation paradigms. METHODS: To evaluate the utility of a paced motor activation task as a longitudinal probe of FSC function, we conducted fMRI scans of 10 subjects with bipolar I disorder when euthymic. We compared activation patterns to the same subjects who had been previously scanned during an episode of depression. RESULTS: The paced motor task resulted in activation in the bilateral striatum which was consistent across mood states as well as greater activation among the subjects when euthymic in the right anterior cingulate and medial frontal gyrus. LIMITATIONS: The study sample was small (10 subjects) which limits generalizability of findings. CONCLUSIONS: To our knowledge, this is the first longitudinal study of bipolar illness utilizing a paced motor task. These findings suggest that a paced motor task is useful as a longitudinal probe of both state and trait function in bipolar disorder. Further, this study provides preliminary evidence that striatal functional abnormalities may represent a trait characteristic.     

A pilot study of positive mood induction in euthymic bipolar subjects compared with healthy controls

BACKGROUND: Demonstrating differences between euthymic bipolar subjects and healthy controls in response to positive (happy) mood induction may help elucidate how mania evolves. This pilot study evaluates the Go task in a reward paradigm as a method for inducing a happy mood state and compares the response of euthymic bipolar subjects and healthy controls. METHOD: The Sense of Hyperpositive Self Scale, the Tellegen positive and negative adjectives, the Global-Local task and a visual analogue scale for measuring positive affect were administered to 15 euthymic bipolar subjects and 19 age-and-sex-matched healthy control subjects before and after they had performed the Go task in a reward paradigm. RESULTS: Significant differences were found between subjects and controls on several measures at each time-point but there were no differences across the groups across time except for the visual analogue scales, where subjects had a more sustained duration in self-reported happiness compared with controls. CONCLUSIONS: This pilot study has shown that a positive affect can be induced in bipolar subjects and controls which can be demonstrated by changes in scores on several tasks. However, only the visual analogue scales showed a significant difference between cases and controls over time. Such tests may prove valuable in furthering understanding about the evolution of manic mood states.     

Decreased activation of the anterior cingulate in bipolar patients: an fMRI study

BACKGROUND: Previous neuroimaging investigations of patients with bipolar disorder have reported abnormalities of the frontal subcortical network. The role of the anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex (DLPFC) in bipolar disorder are not clear, although both regions have been shown to be components of a neural network which plays a critical role in the completion of tasks requiring self-monitoring and inhibition, functions often noted to be altered in bipolar patients. fMRI studies have helped clarify the role of specific subdivisions of the ACC and the DLPFC during the performance of cognitive challenges, including the Stroop color word test. To date, studies that have examined ACC function in bipolar patients have not differentiated subregions within this area, nor have they examined changes in these subregions in relation with DLPFC activation. METHODS: To help clarify the specific roles of these regions in bipolar patients, we examined stable patients and control subjects during performance of the Stroop test using BOLD fMRI techniques. We hypothesized that bipolar patients would demonstrate reduced activation of two subdivisions of the ACC (AAA and VOA), as well as altered activation of the DLPFC, during the interference condition. RESULTS: Results indicate that relative to controls, bipolar patients demonstrated significantly reduced signal intensity within the right AAA subdivision (p=0.011), which accompanied an increase in the DLPFC (p=0.049) during the task. LIMITATIONS: The study sample was somewhat small (11 patients, 10 controls) which limits the generalizability of the study findings, however, the patient sample consisted of well-diagnosed, stable, chronic individuals with bipolar disorder and the sample size provided enough power to detect between-group differences. CONCLUSIONS: These findings suggest differential processing strategies of bipolar patients and support the theory of altered frontal systems in these patients during the performance of cognitive tasks.     

Behavioural and neurocognitive responses to sad facial affect are attenuated in patients with mania

BACKGROUND: The processing of facial emotion involves a distributed network of limbic and paralimbic brain structures. Many of these regions are also implicated in the pathophysiology of mood disorders. Behavioural data indicate that depressed subjects show a state-related positive recognition bias for faces displaying negative emotions. There are sparse data to suggest there may be an analogous, state-related negative recognition bias for negative emotions in mania. We used functional magnetic resonance imaging (fMRI) to investigate the behavioural and neurocognitive correlates of happy and sad facial affect recognition in patients with mania. METHOD: Functional MRI and an explicit facial affect recognition task were used in a case-control design to measure brain activation and associated behavioural response to variable intensity of sad and happy facial expressions in 10 patients with bipolar I mania and 12 healthy comparison subjects. RESULTS: The patients with mania had attenuated subjective rating of the intensity of sad facial expressions, and associated attenuation of activation in the subgenual anterior cingulate and bilateral amygdala, with increased activation in the posterior cingulate and posterior insula. No behavioural or neurocognitive abnormalities were found in response to presentation of happy facial expressions. CONCLUSIONS: Patients with mania showed a specific, mood-congruent, negative bias in sad facial affect recognition, which was associated with an abnormal profile of brain activation in paralimbic regions implicated in affect recognition and mood disorders. Functional imaging of facial emotion recognition may be a useful probe of cortical and subcortical abnormalities in mood disorders.     

Differential frontal activation in schizophrenia and bipolar illness during verbal fluency

INTRODUCTION: The precise nature of frontal lobe dysfunction in schizophrenia remains unclear. We have previously demonstrated, using fMRI, a task-specific attenuation of frontal activation in schizophrenic patients. By using an identical methodology in matched bipolar subjects, we sought to determine whether this finding is specific to schizophrenia or a correlate of psychosis in general. METHOD: Five dextral male bipolar patients and matching groups of schizophrenic subjects and controls were studied using fMRI. Echoplanar images were acquired while subjects performed two paced tasks: covert verbal fluency and a semantic decision task. Generic brain activation maps were constructed from individual images by sinusoidal regression analysis. Between-group differences in the mean power of experimental response were identified on a voxel-wise basis by an analysis of variance (ANOVA). RESULTS: The bipolar patients showed extensive prefrontal activation during verbal fluency which was significantly greater than in controls. There was no difference in the prefrontal BOLD response during the semantic decision task. CONCLUSIONS: These data indicate that bipolar patients show a strikingly different pattern of frontal responses compared to those with schizophrenia and provide further evidence that abnormal frontal activation in psychotic disorders is more apparent during verbal fluency than semantic decision.     

Regional brain responses to pleasant and unpleasant IAPS pictures: different networks

Purpose: The purpose of this study was to investigate the brain circuitry involved in the processing of both positive and negative emotions in normal healthy subjects. Method: we have recruited 15 healthy volunteers (9 males and 6 females, age range 30-60). In this block-design fMRI study, we compared the blood oxygen level dependant (BOLD) signal change as response to pleasant and unpleasant IAPS pictures, each compared to a neutral condition. Results: Pleasant pictures versus neutral condition contrast demonstrated significant activation (p(FDRcorrected) <0.05) in bilateral pre-frontal cortex (PFC), anterior and posterior cingulate gyri and temporal lobe. Unpleasant pictures relative to neutral condition exhibit significant activation (p(FDRcorrected) <0.05) in amygdala, hippocampus, parahippocampal gyri, temporal lobe, visual cortex, fusiform gyri, PFC and anterior cingulate gyrus. Conclusion: Amygdala is mainly involved in the processing of negative emotions. Although an overlap in regions involved in the processing of pleasant and unpleasant IAPS pictures exists, the neural network for each is unique.     

Trait impulsivity in patients with mood disorders

BACKGROUND: Impulsivity is a key component of the manic behavior of bipolar disorder and is reported to occur in bipolar patients as a stable characteristic, i.e. a trait. Nevertheless, impulsivity has not been widely studied in depressed bipolar patients. We assessed impulsivity in depressed and euthymic bipolar and unipolar patients and healthy controls. We hypothesized that bipolar subjects would have higher levels of trait impulsivity than the comparison groups. METHODS: Twenty-four depressed bipolar, 24 depressed unipolar, 12 euthymic bipolar, and 10 euthymic unipolar patients, as well as 51 healthy subjects were evaluated with the Barratt Impulsiveness Scale (BIS). Analysis of covariance with age and sex as covariates was used to compare mean group differences. RESULTS: Depressed bipolar, euthymic bipolar, and depressed unipolar patients did not differ, and showed greater impulsivity than healthy controls on all of the BIS scales. Euthymic unipolar patients scored higher than healthy controls only on motor impulsivity. LIMITATIONS: Higher number of past substance abusers in the bipolar groups, and no control for anxiety and personality disorders, as well as small sample sizes, limit the reach of this study. CONCLUSIONS: This study replicates prior findings of stable trait impulsivity in bipolar disorder patients, and extends them, confirming that this trait can be demonstrated in depressed patients, as well as manic and euthymic ones. Trait impulsivity may be the result of repeated mood episodes or be present prior to their onset, either way it would influence the clinical presentation of bipolar disorder.     

Functional MRI correlates of the recall of unresolved life events in borderline personality disorder

BACKGROUND: Patients with borderline personality disorder (BPD) frequently report unresolved life events but it is still poorly understood, how these experiences are represented in the brain. Using functional magnetic resonance imaging (fMRI), the present study aimed at investigating the neural correlates of the recall of unresolved life events in patients with BPD and healthy controls. METHOD: Twenty female BPD patients and 21 healthy control subjects underwent fMRI. During measurement subjects recalled unresolved and resolved negative life events. Individual cue words were used to stimulate autobiographical memory. After scanning, subjects rated their emotional states during the recall of both types of memories. RESULTS: When contrasting unresolved and resolved life events, patients showed significant bilateral activation of frontotemporal areas including the insula, amygdala, and the anterior cingulate cortex, the left posterior cingulate cortex, right occipital cortex, the bilateral cerebellum and the midbrain. In healthy subjects, no differential brain activation was related to these conditions. The 2 x 2 factorial analysis (DeltaBPD - Deltacontrols) revealed similar results with bilateral activation of the frontal cortex including parts of the insula and of the orbitofrontal cortex, temporal activation including the amygdala, activation of the right occipital cortex, and parts of the cerebellum. Patients but not controls reported higher levels of anxiety and helplessness during the unresolved versus resolved memory condition. CONCLUSIONS: The activation of both, the amygdala and prefrontal areas, might reflect an increased effortful but insufficient attempt to control intensive emotions during the recall of unresolved life events in patients with BPD.     

Neural mechanisms of cognitive reappraisal in remitted major depressive disorder

Background

Down-regulation of negative emotions by cognitive strategies relies on prefrontal cortical modulation of limbic brain regions, and impaired frontolimbic functioning during cognitive reappraisal has been observed in affective disorders. However, no study to date has examined cognitive reappraisal in unmedicated euthymic individuals with a history of major depressive disorder relative to symptom-matched controls. Given that a history of depression is a critical risk factor for future depressive episodes, investigating the neural mechanisms of emotion regulation in remitted major depressive disorder (rMDD) may yield novel insights into depression risk.

Method

We assessed 37 individuals (18 rMDD, 19 controls) with functional magnetic resonance imaging (fMRI) during a task requiring cognitive reappraisal of sad images.

Results

Both groups demonstrated decreased self-reported negative affect after cognitive reappraisal and no group differences in the effects of cognitive reappraisal on mood were evident. Functional MRI results indicated greater paracingulate gyrus (rostral anterior cingulate cortex, Brodmann area 32) activation and decreased right midfrontal gyrus (Brodmann area 6) activation during the reappraisal of sad images.

Limitations

Trial-by-trial ratings of pre-regulation affect were not collected, limiting the interpretation of post-regulation negative affect scores.

Conclusions

Results suggest that activation of rostral anterior cingulate cortex, a region linked to the prediction of antidepressant treatment response, and of the right midfrontal gyrus, a region involved in cognitive control in the context of cognitive reappraisal, may represent endophenotypic markers of future depression risk. Future prospective studies will be needed to validate the predictive utility of these neural markers.     

Effects of an antidepressant on neural correlates of emotional processing in patients with major depression

We measured brain activation in patients with major depressive disorder when exposed to emotional pictures before and after antidepressant treatment. The participants included 18 first-episode unmedicated patients with current major depressive disorder and 18 age- and gender-matched control subjects. All subjects performed an emotional task during functional magnetic resonance imaging scanning at baseline and after 8 weeks of fluoxetine treatment. Unmedicated depressed patients showed lower accuracy rates (0.53 ± 0.26) than did subjects in the control group (0.71 ± 0.18) while viewing positive pictures. During exposure to positive stimuli, decreased activations were seen in the right insula (BA13) and left anterior cingulate cortex (BA32) in patients after antidepressant treatment. After antidepressant treatment, patients exhibited greater activation in the right middle frontal gyrus (BA8,9) in response to negative stimuli. Our results suggest that the prefrontal cortex, anterior cingulate cortex and insula may play key roles as biological markers for treatment response and as predictors of therapeutic success.     

Functional MRI of visuospatial working memory in schizotypal personality disorder: a region-of-interest analysis

BACKGROUND: Functional MRI studies have begun to identify neural networks implicated in visuo-spatial working memory in healthy volunteers and patients with schizophrenia. The study of schizotypal personality disorder (SPD) provides regional analysis in unmedicated patients in the schizophrenia spectrum. METHOD: Unmedicated patients with SPD by DSM-IV criteria and normal controls were assessed with fMRI while performing a visuo-spatial working-memory task. It required the subjects to retain the location of three dots located on the circumference of an imaginary circle and then respond to a query display in which one dot was presented and the subject required to press a button to indicate whether the probe dot location was previously displayed. Subject groups did not differ significantly in spatial memory scores. The exact Talairach and Tournoux coordinates of brain areas previously reported to show activation with spatial memory tasks were assessed. RESULTS: The majority of these locations showed BOLD response activation significantly less in patients during the memory retention period, including the left ventral prefrontal cortex, superior frontal gyrus, intraparietal cortex and posterior inferior gyrus. Regions in the right middle prefrontal and prestriate cortex showed greater activation at a trend level for patients with SPD than for normal controls. In addition, we replicated the findings of increased activation with the task in healthy volunteers in the premotor areas, ventral prefrontal cortex and parietal cortex. CONCLUSIONS: SPD patients show decreased activation compared to healthy volunteers in key frontal regions and we also provided a partial replication of findings reported in healthy subjects.     

音乐刺激激活人脑情感系统的fMRI研究

目的：利用fMRI技术，对音乐欣赏相关脑功能区进行定位，并初步探讨音乐情感反应和音乐治疗的可能神经机制。方法：采用组块设计模式，对30名非音乐专业志愿者进行被动聆听音阶、轻音乐和恐怖音乐（各3段）实验。应用SPM99软件对实验结果进行组分析，获得平均激活图。结果：轻音乐和恐怖音乐可激活大脑与情感加工相关的脑区．前者主要包括双侧前额皮层外侧部（左侧为著）、左侧眶额皮层、扣带回前部、左侧岛叶前部、右侧丘脑和左侧豆状核；后者主要包括双侧前额皮层外侧部（右侧为著）、双侧眶额皮层、双侧额内回和扣带回前部和双侧杏仁复合体，结论：音乐可有效激活人脑与情感加工相关脑区；大脑对喜悦和恐惧情感具有不同（或部分交叉）的神经加工网络．其中．轻音乐引起的正性情感加工可能是音乐治疗的部分神经基础。     

5-HT, prefrontal function and aging: fMRI of inhibition and acute tryptophan depletion

Age-related declines in prefrontal functions and age-related declines in prefrontal serotonin (5-HT) are documented. The effect of 5-HT on prefrontal cortex (PFC) is also documented; however, no one has examined the effect of experimental 5-HT modulation on PFC in healthy older adults. We investigated the effect of 5-HT on brain functioning in 10 women over 55 (mean=63.0+/-5.3 years) during cognitive interference inhibition (Simon task) using fMRI and acute tryptophan depletion (ATD). ATD did not affect task performance; it did affect brain function. During sham/no depletion, participants activated brain regions associated with the Simon (e.g., left inferior PFC). During ATD, there was no prefrontal but alternative posterior brain activation. ATD relative to sham reduced activity in left inferior PFC, anterior cingulate and basal ganglia but increased activity within neocerebellum and parietal lobe. In older adults, ATD modulates task-relevant brain activation for cognitive interference inhibition and is associated with an anterior-to-posterior activation shift. Maintaining successful Simon performance during ATD is achieved by increasing cerebellar and parietal contributions to compensate for decreased fronto-cingulo-striatal involvement.     

Backward masking task performance in stable, euthymic out-patients with bipolar disorder.

BACKGROUND: Several studies have suggested that visual backward masking (VBM) impairment is present in patients with bipolar disorder, but the clinical features, such as current symptoms, treatment status and past burden of illness that may contribute to the impairment have not been well described. This study examined well-characterized euthymic patients on two VBM tasks to ascertain the extent of VBM impairment in this group and the clinical correlates of this impairment. METHOD: Twenty-eight euthymic patients with a DSM-IV diagnosis of bipolar disorder were matched by age, sex and IQ with 28 non-psychiatric control subjects. Both groups completed two VBM tasks; one required subjects to locate the target stimulus, one required identification of the target stimulus. Reaction times and error rates across a range of target-mask inter-stimulus intervals were assessed. RESULTS: Patients were significantly slower and had more errors on both VBM tasks. There was a significant relation between reaction times on the identification task and past burden of illness, particularly past number of depressions. There was no discernible impact of treatment status on reaction time or performance, including no difference in lithium-treated versus not treated subjects. CONCLUSIONS: These results are consistent with previous reports of neuropsychological deficits in euthymic bipolar disorder patients. The potential benefit to employing tasks such as VBM is that it may provide a method for relating clinical variables such as illness burden with known neural pathways in order to elucidate better the pathophysiology leading to impaired cognitive performance in patients with bipolar disorder.     

Increased left prefrontal activation in patients with unipolar depression: an event-related, parametric, performance-controlled fMRI study

BACKGROUND: Executive deficits associated with frontal lobe dysfunction are prominent in depression. We applied a newly developed WM task to investigate the neural correlates of executive processes with functional magnetic resonance imaging (fMRI) at comparable performance levels analyzing correct trials only. METHODS: We studied 12 partially remitted, medicated inpatients meeting DSM-IV criteria for major depressive disorder and 17 healthy controls. We used a parametric version of a delayed match-to-sample WM task requiring manipulation of verbal material during a delay period in an event-related fMRI design. RESULTS: Depressed patients were generally slower and load-dependently less accurate than healthy controls. Patients showed significantly more activation of left dorsolateral prefrontal cortex with highest cognitive load. Additionally, they showed higher activation in ventromedial prefrontal cortex during the control condition. LIMITATIONS: The fact that patients were taking different antidepressant drugs could limit the explanatory power of the present results. CONCLUSIONS: Increased lateral prefrontal activation despite comparably successful performance - when only correct trials were analyzed - in patients with depression can be interpreted as evidence for compensatory recruitment of prefrontal cortical resources.     

Neural basis of the emotional Stroop interference effect in major depression

BACKGROUND: A mood-congruent sensitivity towards negative stimuli has been associated with development and maintenance of major depressive disorder (MDD). The emotional Stroop task assesses interference effects arising from the conflict of emotional expressions consistent with disorder-specific self-schemata and cognitive colour-naming instructions. Functional neuroimaging studies of the emotional Stroop effect advocate a critical involvement of the anterior cingulate cortex (ACC) during these processes. METHOD: Subjects were 17 medication-free individuals with unipolar MDD in an acute depressive episode (mean age 39 years), and 17 age-, gender- and IQ-matched healthy volunteers. In an emotional Stroop task, sad and neutral words were presented in various colours, and subjects were required to name the colour of words whilst undergoing functional magnetic resonance imaging (fMRI). Overt verbal responses were acquired with a clustered fMRI acquisition sequence. RESULTS: Individuals with depression showed greater increases in response time from neutral to sad words relative to controls. fMRI data showed a significant engagement of left rostral ACC (BA 32) and right precuneus during sad words in patients relative to controls. Additionally, rostral ACC activation was positively correlated with latencies of negative words in MDD patients. Healthy controls did not have any regions of increased activation compared to MDD patients. CONCLUSIONS: These findings provide evidence for a behavioural and neural emotional Stroop effect in MDD and highlight the importance of the ACC during monitoring of conflicting cognitive processes and mood-congruent processing in depression.     

Failure to deactivate in the prefrontal cortex in schizophrenia: dysfunction of the default mode network?

BACKGROUND: Functional imaging studies using working memory tasks have documented both prefrontal cortex (PFC) hypo- and hyperactivation in schizophrenia. However, these studies have often failed to consider the potential role of task-related deactivation. METHOD: Thirty-two patients with chronic schizophrenia and 32 age- and sex-matched normal controls underwent functional magnetic resonance imaging (fMRI) scanning while performing baseline, 1-back and 2-back versions of the n-back task. Linear models were used to obtain maps of activations and deactivations in the groups. RESULTS: The controls showed activation in the expected frontal regions. There were also clusters of deactivation, particularly in the anterior cingulate/ventromedial PFC and the posterior cingulate cortex/precuneus. Compared to the controls, the schizophrenic patients showed reduced activation in the right dorsolateral prefrontal cortex (DLPFC) and other frontal areas. There was also an area in the anterior cingulate/ventromedial PFC where the patients showed apparently greater activation than the controls. This represented a failure of deactivation in the schizophrenic patients. Failure to activate was a function of the patients' impaired performance on the n-back task, whereas the failure to deactivate was less performance dependent. CONCLUSIONS: Patients with schizophrenia show both failure to activate and failure to deactivate during performance of a working memory task. The area of failure of deactivation is in the anterior prefrontal/anterior cingulate cortex and corresponds to one of the two midline components of the 'default mode network' implicated in functions related to maintaining one's sense of self.     

Developmental changes in the functional brain responses of adolescents to images of high and low-calorie foods

We examined cerebral responses to visually presented food images in children and adolescents. Eight healthy normal-weight females (ages 9-15) underwent functional magnetic resonance imaging (fMRI) while viewing photographs of high- and low-calorie foods and dining utensils. In general, food images yielded significant activation within the inferior orbitofrontal cortex, hippocampus, and fusiform gyri. High calorie food images activated the left hippocampus and subgenual cingulate, and age correlated positively with activity within the orbitofrontal cortex but negatively with activity within the anterior cingulate gyrus. Low-calorie foods activated the fusiform gyrus and demonstrated age-related increases in the left superior temporal gyrus and anterior cingulate. Utensils activated the fusiform gyrus and showed age-related increases in the prefrontal cortex. Data were also compared statistically to a sample of adults exposed to the same stimulus conditions. Findings support a developmental model of adolescent maturation whereby age-related changes in cerebral functioning develop from lower-order sensory processing toward higher-order processing of stimuli via prefrontal cortical systems involved in reward anticipation, self-monitoring, and behavioral inhibition.     

Sex differences in prefrontal cortical brain activity during fMRI of auditory verbal working memory

Functional imaging studies of sex effects in working memory (WMEM) are few, despite significant normal sex differences in brain regions implicated in WMEM. This functional MRI (fMRI) study tested for sex effects in an auditory verbal WMEM task in prefrontal, parietal, cingulate, and insula regions. Fourteen healthy, right-handed community subjects were comparable between the sexes, including on WMEM performance. Per statistical parametric mapping, women exhibited greater signal intensity changes in middle, inferior, and orbital prefrontal cortices than men (corrected for multiple comparisons). A test of mixed-sex groups, comparable on performance, showed no significant differences in the hypothesized regions, providing evidence for discriminant validity for significant sex differences. The findings suggest that combining men and women in fMRI studies of cognition may obscure or bias results.     

An MRI study of subgenual prefrontal cortex in patients with familial and non-familial bipolar I disorder

BACKGROUND: Over the past few years there has been an interest in the use of magnetic resonance imaging (MRI) to study specific brain regions in bipolar disorder. The present study compared the grey matter volume in the subgenual prefrontal cortex in patients with familial and non-familial bipolar disorder and normal control subjects. METHODS: MRI brain scans were performed on 12 patients with bipolar I disorder including six patients with a positive family history of bipolar disorder as well as eight control subjects. RESULTS: There was a significant reduction in the grey matter volume in the right subgenual prefrontal cortex, but not in the left subgenual prefrontal cortex. A family history x sex interaction with right prefrontal cortex volume was also observed as a trend. For females, a positive family history was associated with reduced right prefrontal cortex volumes; for males, a positive family history was associated with increased right prefrontal cortex volumes. LIMITATIONS: Small sample size, reduced statistical power. CONCLUSION: These data add to the emerging literature on structural changes in the subgenual prefrontal cortex in bipolar disorder, especially in patients with a positive family history.