E. Serap Monkul

Patterns of memory impairment in bipolar disorder and unipolar major depression

Unipolar and bipolar depression are known to exert detrimental effects on learning and memory processes. However, few comparisons have been undertaken between bipolar and unipolar patients with comparable illness histories, and predictors of impairment are not well understood. Adult outpatients with unipolar major depressive illness (UP, n = 30) and bipolar disorder (BP, n = 30), group-matched for illness duration and severity of depressive symptomatology (16% clinically remitted, 42% partially remitted, 42% depressed), and 30 demographically matched controls completed measures of general cognitive functioning and declarative memory. Despite comparable general intellectual abilities, BP and UP patients exhibited significant memory deficits relative to healthy controls. A similar deficit profile was observed in both patient groups, involving poorer verbal recall and recognition. Impairments were not secondary to strategic processing deficits or rapid forgetting. Although depression severity was not associated with neurocognitive performance, number of hospitalizations and family history of mood disorder significantly affected memory function in BP, but not UP, patients. Results suggest qualitatively similar patterns of memory impairment in BP and UP patients, consistent with a primary encoding deficit. These impairments do not appear to be secondary to clinical state, but rather suggest a similar underlying pathophysiology involving medial temporal dysfunction.

Conceptualizing impulsivity and risk taking in bipolar disorder: Importance of history of alcohol abuse

BACKGROUND Elevated levels of impulsivity and increased risk taking are thought to be core features of both bipolar disorder (BD) and addictive disorders. Given the high rates of comorbid alcohol abuse in BD, alcohol addiction may exacerbate impulsive behavior and risk-taking propensity in BD. Here we examine multiple dimensions of impulsivity and risk taking, using cognitive tasks and self-report measures, in BD patients with and without a history of alcohol abuse. METHODS Thirty-one BD subjects with a prior history of alcohol abuse or dependence (BD-A), 24 BD subjects with no history of alcohol abuse/dependence (BD-N), and 25 healthy control subjects (HC) were assessed with the Barratt Impulsiveness Scale (BIS) and the computerized Balloon Analogue Risk Task (BART). RESULTS Both BD groups scored significantly higher than controls on the BIS. In contrast, only the BD-A group showed impaired performance on the BART. BD-A subjects popped significantly more balloons than the BD-N and HC groups. In addition, subjects in the BD-A group failed to adjust their performance after popping balloons. Severity of mood symptomatology was not associated with performance on either task. DISCUSSION The current study supports a primary role of prior alcohol abuse in risk-taking propensity among patients with bipolar disorder. In addition, findings suggest that impulsivity and risky behavior, as operationalized by self-report and experimental cognitive probes, respectively, are separable constructs that tap distinct aspects of the bipolar phenotype.

Amygdala hyperactivation in untreated depressed individuals

The amygdala participates in the detection and control of affective states, and has been proposed to be a site of dysfunction in affective disorders. To assess amygdala processing in individuals with unipolar depression, we applied a functional MRI (fMRI) paradigm previously shown to be sensitive to amygdala function. Fourteen individuals with untreated DSM-IV major depression and 15 healthy subjects were studied using fMRI with a standardized emotion face recognition task. Voxel-level data sets were subjected to a multiple-regression analysis, and functionally defined regions of interest (ROI), including bilateral amygdala, were analyzed with MANOVA. Pearson correlation coefficients between amygdala activation and HAM-D score also were performed. While both depressed and healthy groups showed increased amygdala activity when viewing emotive faces compared to geometric shapes, patients with unipolar depression showed relatively more activity than healthy subjects, particularly on the left. Positive Pearson correlations between amygdala activation and HAM-D score were found for both left and right ROIs in the patient group. This study provides in vivo imaging evidence to support the hypothesis of abnormal amygdala functioning in depressed individuals.

Abnormal left superior temporal gyrus volumes in children and adolescents with bipolar disorder: a magnetic resonance imaging study

Abnormalities in left superior temporal gyrus (STG) have been reported in adult bipolar patients. However, it is not known whether such abnormalities are already present early in the course of this illness. Magnetic resonance imaging (MRI) morphometric analysis of STG was performed in 16 DSM-IV children and adolescents with bipolar disorder (mean age+/-SD 15.5+/-3.4 years) and 21 healthy controls (mean age+/-SD 16.9+/-3.8 years). Subjects underwent a 3D spoiled gradient recalled acquisition MRI examination. Using analysis of covariance with age, gender and intra-cranial brain volume as covariates, we found significantly smaller left total STG volumes in bipolar patients (12.5+/-1.5 cm(3)) compared with healthy controls (13.6+/-2.5 cm(3)) (F=4.45, d.f.=1, 32, P=0.04). This difference was accounted for by significantly smaller left and right STG white matter volumes in bipolar patients. Decreased white matter connections may be the core of abnormalities in STG, which is an important region for speech, language and communication, and could possibly underlie neurocognitive deficits present in bipolar patients.

Fronto-limbic circuitry in euthymic bipolar disorder: Evidence for prefrontal hyperactivation

Functional magnetic resonance imaging (fMRI) studies of bipolar disorder have revealed fronto-limbic abnormalities in patients during manic and depressive episodes. However, relatively few studies have examined neural activity during euthymia, leaving unanswered questions concerning the impact of mood state on activity in these brain regions. In the present study, we examined 15 remitted bipolar type I patients and 16 demographically matched healthy comparison subjects during performance on an affective face-matching task previously shown to elicit amygdala hyperactivation and prefrontal hypoactivation in manic relative to healthy subjects. In our euthymic sample, amygdala activation did not differ from controls. However, bipolar patients showed hyperactivation in inferior prefrontal cortical regions compared with controls, a finding that contrasts with the hypoactivation previously reported in this region in manic patients. Given the reciprocal relationship between the prefrontal cortex and limbic structures, we propose state-related amygdala activity, similar to that of healthy controls, may be associated with prefrontal hyperactivation when bipolar patients are asymptomatic.

Prefrontal gray matter increases in healthy individuals after lithium treatment: A voxel-based morphometry study

The objective of this study was to test the hypothesis that 4 weeks of lithium administration would be associated with changes in brain gray and white matter volumes in healthy individuals. Thirteen right-handed healthy volunteers (6 females, mean age=25.9+/-10.0 years) were studied. 3D SPGR MRIs (TR=25 ms, TE=5 ms, slice-thickness=1.5 mm) were acquired using a 1.5 T GE Signa Imaging System, at baseline and after 4 weeks of lithium administration at therapeutically relevant doses. Optimized voxel-based morphometry (VBM) analyses were conducted. Left and right dorsolateral prefrontal cortex and left anterior cingulate gray matter volumes increased significantly following lithium administration. Total white matter volume was increased, whereas total brain volume and total gray matter volume were not significantly changed following 4 weeks of lithium. Lithium treatment resulted in prefrontal regional gray matter volume increases in healthy volunteers, as well as increases in total white matter volume. Whether these changes are mediated by neurotrophic/neuroprotective or osmotic effects remains unknown.

Temperament and character traits in major depressive disorder: influence of mood state and recurrence of episodes.

Background: The objective of this study was to compare personality traits between major depressive disorder (MDD) patients and healthy comparison subjects (HC) and examine if personality traits in patients are associated with specific clinical characteristics of the disorder. Methods: Sixty MDD patients (45 depressed, 15 remitted) were compared to 60 HC using the Temperament and Character Inventory. Analysis of covariance, with age and gender as covariates, was used to compare the mean Temperament and Character Inventory scores among the subject groups. Results: Depressed MDD patients scored significantly higher than HC on novelty seeking, harm avoidance, and self‐transcendence and lower on reward dependence, self‐directedness, and cooperativeness. Remitted MDD patients scored significantly lower than HC only on self‐directedness. Comorbidity with anxiety disorder had a main effect only on harm avoidance. Harm avoidance was positively correlated with depression intensity and with number of episodes. Self‐directedness had an inverse correlation with depression intensity. Conclusions: MDD patients present a different personality profile from HC, and these differences are influenced by mood state and comorbid anxiety disorders. When considering patients who have been in remission for some time, the differences pertain to few personality dimensions. Cumulated number of depressive episodes may result in increased harm avoidance. Depression and Anxiety, 2009.

Anterior genu corpus callosum and impulsivity in suicidal patients with bipolar disorder

Suicidality is a life-threatening symptom in patients with bipolar disorder (BD). Impulsivity and mood instability are associated with suicidality in mood disorders. Evidence suggests that gray and white matter abnormalities are linked with impulsivity in mood disorders, but little is known about the association between corpus callosum (CC) and impulsivity in BD. We examined the relationship between CC areas, impulsivity and suicidality in BD patients. We studied 10 female BD patients with a history of suicide attempt (mean+/-SD age 36.2+/-10.1 years), 10 female BD patients without suicide attempt history (44.2+/-12.5 years) and 27 female healthy subjects (36.9+/-13.8 years). Impulsivity was evaluated by the Barratt Impulsivity Scale (BIS). We traced MR images to measure the areas of the CC genu, anterior body, posterior body, isthmus and splenium. The genu was divided into anterior, middle and posterior regions. The suicidal and non-suicidal BD patients had significantly higher BIS total, attention and non-planning scores than the healthy subjects (ps<0.01), and the suicidal BD patients had significantly higher BIS motor scores than the non-suicidal BD and healthy subjects (ps<0.01). There were no significant differences among the three groups on any regional CC areas, although the suicidal BD patients had the smallest areas. The suicidal BD patients showed a significant inverse correlation between anterior genu area and the BIS total (r=-0.75, p=0.04), motor (r=-0.79, p=0.02) and non-planning scores (r=-0.79, p=0.02). These correlations were not found in the non-suicidal BD patients or healthy subjects. The results suggest that the anterior medial frontal region may be involved in the pathophysiology of impulsive and suicidal behaviors in BD.

MRI Study of the Cerebellum in Young Bipolar Patients

Prior studies demonstrate structural abnormalities of cerebellar vermis in adult bipolar patients. Cerebella of 16 young bipolar patients (mean age+/-S.D.=15.5+/-3.4) and 21 healthy controls (mean age+/-S.D.=16.9+/-3.8) were examined using magnetic resonance imaging. The volumes of right, left and total cerebellum, vermis, and areas of vermal regions V1 (lobules I-V), V2 (lobules VI-VII), and V3 (lobules VIII-X) were measured. Analysis of covariance, with age, gender, and intra-cranial brain volume as covariates, revealed no significant differences in cerebellum or vermis measures between patients and controls; however, there was a trend to smaller vermis V2 areas in patients (p=0.06). The number of previous affective episodes and vermis area V2 were inversely correlated (partial correlation coefficient=-0.97, P=0.001) in the male bipolar patient group. Our results are preliminary, but consistent with the findings from studies in adult bipolar patients suggesting the involvement of structural changes in cerebellar vermis in the pathophysiology of bipolar disorder.

Abnormal resting state corticolimbic blood flow in depressed unmedicated patients with major depression: A 15O-H 2O PET study

We investigated the differences in the resting state corticolimbic blood flow between 20 unmedicated depressed patients and 21 healthy comparisons. Resting state cerebral blood flow (CBF) was measured with H215O PET. Anatomical MRI scans were performed on an Elscint 1.9 T Prestige system for PET‐MRI coregistration. Significant changes in cerebral blood flow indicating neural activity were detected using an ROI‐free image subtraction strategy. In addition, the resting blood flow in patients was correlated with the severity of depression as measured by HAM‐D scores. Depressed patients showed decreases in blood flow in right anterior cingulate (Brodmann areas 24 and 32) and increased blood flow in left and right posterior cingulate (Brodmann areas 23, 29, 30), left parahippocampal gyrus (Brodmann area 36), and right caudate compared with healthy volunteers. The severity of depression was inversely correlated with the left middle and inferior frontal gyri (Brodmann areas 9 and 47) and right medial frontal gyrus (Brodmann area 10) and right anterior cingulate (Brodmann areas 24, 32) blood flow, and directly correlated with the right thalamus blood flow. These findings support previous reports of abnormalities in the resting state blood flow in the limbic‐frontal structures in depressed patients compared to healthy volunteers. Hum Brain Mapp, 2012.