Gray matter abnormalities as brain structural vulnerability factors for bipolar disorder: A review of neuroimaging studies of individuals at high genetic risk for bipolar disorder.

OBJECTIVE: Cortical and subcortical gray matter abnormalities have been reported in individuals at high genetic risk for bipolar disorder, but the findings are inconsistent. The aim of this study was to review the available literature to identify common findings that could represent brain structural vulnerability factors for bipolar disorder and to discuss challenges for the advancement of the field. METHOD: A systematic search was conducted using the PubMed database to identify all original articles investigating cortical or subcortical gray matter abnormalities in first-degree relatives of bipolar disorder patients. RESULTS: Very few findings were replicated, with the exception of larger insular cortex volumes in adult first-degree relatives and larger right inferior frontal gyrus in offspring of probands with bipolar disorder, both when compared with healthy controls. Isolated findings included decreased gray matter density in the left thalamus, decreased gray matter volumes in the left hippocampus and parahippocampal gyrus, and thicker right hippocampus in unaffected first-degree relatives. Genetic liability for bipolar disorder was associated with gray matter volumes in regions of the anterior cingulate cortex, ventral striatum, medial frontal gyrus, right precentral gyrus, right insular cortex, and medial orbital gyrus. Some studies found no evidence for gray matter abnormalities in first-degree relatives of bipolar disorder patients. CONCLUSIONS: Possible reasons for the discrepancies of findings across studies include small samples sizes, small effect size of susceptibility genes, the phenotypic heterogeneity of bipolar disorder, and the possible confounding effect of other Axis I psychopathologies among the relatives of patients. Future multisite, prospective, large studies with more homogeneous samples would be a key strategy to advance the field. The ultimate benefit would be an understanding of how to use brain imaging tools to identify individuals at increased risk for bipolar disorder and develop preventive strategies for that population.

Trait impulsivity is increased in bipolar disorder patients with comorbid alcohol use disorders.

BACKGROUND: Up to 60% of bipolar disorder (BD) patients develop alcohol use disorders (AUD) at some point in their lives. The causes of this highly prevalent comorbidity are unknown. High trait impulsivity characterizes both isolated BD and AUD and may be a link to explain the association between BD and AUD. In this study, our aims were to investigate whether BD patients with comorbid AUD would present higher trait impulsivity levels compared to BD patients without comorbid AUD, and whether trait impulsivity levels differ within subgroups of BD according to the subcategory of AUD (abuse vs. dependence, alcoholism alone vs. alcoholism plus drug use disorders). SAMPLING AND METHODS: Forty-seven outpatients with BD with comorbid AUD (alcoholic BD group) were compared to 66 outpatients with BD alone (nonalcoholic BD group) and to 90 healthy controls (HC). BD and AUD diagnoses were obtained using the Structured Clinical Interview for DSM-IV diagnoses. Impulsivity was assessed using the Barratt Impulsiveness Scale (BIS-11), a self-report instrument that measures trait impulsivity in three domains: nonplanning, attentional and motor. RESULTS: Alcoholic BD patients scored significantly higher than nonalcoholic BD and HC on the total and on each subscale BIS scores. Within the alcoholic BD patients, alcohol abusers and alcohol dependents did not statistically differ from each other on the BIS-11 scores. BD patients with AUD plus drug use disorders presented statistically higher nonplanning impulsivity than BD patients with AUD alone. CONCLUSIONS: This was a cross-sectional study and causal inferences about the relationship between impulsivity and the comorbidity phenomenon cannot be made. Increased impulsivity may be a trait marker for the co-occurrence between BD and AUD, and mediate some severe manifestations of this comorbidity.

Major depressive disorder severity and the frequency of painful physical symptoms: a pooled analysis of observational studies.

OBJECTIVE: This retrospective post-hoc analysis of observational studies assesses the frequency of painful physical symptoms (PPS) in patients with major depressive disorder (MDD) of varied severity as may be seen in clinical practice. METHODS: Observational studies of MDD that collected a clinician-reported measure of depression severity and included assessment of PPS were screened for this individual patient-level analysis. Six observational studies were included that enrolled outpatients with a diagnosis of MDD (assessed using the 17-item Hamilton depression scale, Hospital Anxiety and Depression Scale-Depression, or Inventory of Depressive Symptomatology). Measures of PPS were based on the original study assessment (modified Somatic Symptom Inventory [SSI] and Visual Analogue Scale [VAS]). Patients were divided into analysis cohorts based on the presence or absence of PPS. To model PPS status, odds ratios were calculated from logistic regression for cross-sectional analysis (main analysis) and generalized linear mixed models for longitudinal models (exploratory longitudinal analysis). RESULTS: For the main analysis, four studies (N = 2943, 71.6% female, mean age 45.3 years) were identified. Of 2901 eligible patients, 61.7% were classified as having painful physical symptoms (PPS+). At study entry, 73.1% (957/1309) of patients in the severe category of depression, 56.8% (537/945) of those with moderate depression, and 45.6% (295/647) of those with mild depression were PPS+. The exploratory longitudinal analysis was performed using a subset (N = 2430) from the studies used in the main analysis plus two others (an additional 7984 patients, 6742 of which were modeled). The likelihood of patients that were PPS- at baseline later developing PPS was 5% to 13% greater for patients with increased depression severity (P < 0.001) and the likelihood of PPS+ patients later not having PPS was 9% to 17% less for patients with increased depression severity (P < 0.0001). CONCLUSIONS: Since this is a retrospective aggregate analysis of several observational studies, and due to missing data, care should be taken in the interpretation of these results. Despite the use of adjustment techniques, selection bias and unmeasured confounding may still be an issue for comparative analysis as not all variables were collected for all studies. For patients treated in typical care settings, PPS were associated with depression severity. However, patients with mild and moderate depression also exhibited PPS. Clinicians should be aware that PPS are present, and may warrant treatment, across depression severities.

Abnormal resting state corticolimbic blood flow in depressed unmedicated patients with major depression: a (15)O-H(2)O 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 H(2)(15)O 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.

Association between prior alcohol use disorders and decreased prefrontal gray matter volumes in bipolar I disorder patients.

Up to 50% of bipolar disorder (BD) patients present a lifetime diagnosis of alcohol use disorders (AUD). BD patients with comorbid AUD, even when in remission from the AUD, have a poorer outcome and functional impairment than patients with BD alone. The neurobiological abnormalities that potentially characterize this severe subgroup of BD patients are unknown. Our goal was to investigate gray matter (GM) volume abnormalities in BD I patients with comorbid AUD. Twenty-one BD-AUD patients, 21 BD-nonAUD BD patients, and 25 healthy controls (HC), matched by age, gender, and handedness were studied. The BD-AUD patients were in remission from AUD on average for 6.8 years. 3D SPGR MRIs (TR=25 ms, TE=5 ms, slice thickness=1.5 mm) were acquired from all subjects using a 1.5 T GE Signa Imaging System. We used an optimized voxel-based morphometry protocol to compare GM volumes among the groups. BD-AUD patients presented smaller GM volumes in the left medial frontal and the right anterior cingulate gyri compared to BD-nonAUD patients. BDnon-AUD patients did not present GM volume differences compared to HC. These findings provide evidence for an effect of comorbid AUD on regional brain structure of BD I patients and warrant further research on neurobiological aspects of this prevalent and severe comorbidity.

History of suffocation, state-trait anxiety, and anxiety sensitivity in predicting 35% carbon dioxide-induced panic.

The aim of this study was to examine the effects of history of suffocation, state-trait anxiety, and anxiety sensitivity on response to a 35% carbon dioxide (CO2) challenge in panic disorder patients, their healthy first-degree relatives and healthy comparisons. Thirty-two patients with panic disorder, 32 first-degree relatives, and 34 healthy volunteers underwent the 35% CO2 challenge. We assessed baseline anxiety with the Anxiety Sensitivity Index (ASI) and State-Trait Anxiety Inventory (STAI1), and panic symptoms with the Panic Symptom List (PSL III-R). A history of suffocation was associated with greater risk of CO2 reactivity in the combined sample. Patients had more anxiety sensitivity and state and trait anxiety than relatives and healthy comparisons; the difference between relatives and healthy comparisons was not significant. In female patients, trait anxiety predicted CO2-induced panic. Having a CO2-sensitive panic disorder patient as a first-degree relative did not predict CO2-induced panic in a healthy relative. History of suffocation may be an important predictor of CO2-induced panic. Trait anxiety may have a gender-specific relation to CO2 reactivity.

Fronto-temporal dysregulation in asymptomatic bipolar I patients: a paired associate functional MRI study.

Bipolar disorder is associated with persistent declarative memory disturbances, but the neural basis of these deficits is not well understood. We used fMRI to investigate brain activity during performance on a face-name paired associate task, which allows for the dissociation of encoding and recall-related memory processes. Fifteen clinically remitted bipolar I disorder patients and 24 demographically matched healthy comparison subjects were scanned during task performance. At the voxel level, bipolar patients showed reduced cortical activation, relative to controls, in multiple task-related brain regions during encoding. During recognition, bipolar patients under-activated left hippocampal and parahippocampal regions, despite adequate task performance. Region of interest analyses indicated that, during encoding, bipolar patients had greater bilateral dorsolateral prefrontal (DLPFC) activity than healthy subjects. In contrast, during recognition patients showed hypo-activation relative to controls in the right, but not the left, DLPFC. Although hippocampal activity did not differ between groups during encoding, bipolar patients failed to activate hippocampal regions to the same extent as healthy subjects during recognition. Finally, while better task performance was associated with recognition-related hippocampal activity in healthy subjects, bipolar patients showed an inverse relationship between task performance and hippocampal activity. Remitted bipolar patients over-engaged dorsolateral prefrontal regions when learning face-name pairs, but relative hypoactivation in both prefrontal and medial temporal regions during recognition. These findings suggest a neural basis for the long-term memory deficits consistently observed in patients with bipolar disorder; further, as these patterns appear in symptomatically remitted patients, they are unlikely to be an artifact of mood symptoms.

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.

Bipolar disorder comorbid with alcoholism: a 1H magnetic resonance spectroscopy study.

Alcoholism is highly prevalent among bipolar disorder (BD) patients, and its presence is associated with a worse outcome and refractoriness to treatment of the mood disorder. The neurobiological underpinnings that characterize this comorbidity are unknown. We sought to investigate the neurochemical profile of the dorsolateral prefrontal cortex (DLPFC) of BD patients with comorbid alcoholism. A short-TE, single-voxel (1)H spectroscopy acquisition at 1.5T from the left DLFPC of 22 alcoholic BD patients, 26 non-alcoholic BD patients and 54 healthy comparison subjects (HC) were obtained. Absolute levels of N-acetyl aspartate, phosphocreatine plus creatine, choline-containing compounds, myo-inositol, glutamate plus glutamine (Glu+Gln) and glutamate were obtained using the water signal as an internal reference. Analysis of co-variance was used to compare metabolite levels among the three groups. In the primary comparison, non-alcoholic BD patients had higher glutamate concentrations compared to alcoholic BD patients. In secondary comparisons integrating interactions between gender and alcoholism, non-alcoholic BD patients presented significantly higher glutamate plus glutamine (Glu+Gln) than alcoholic BD patients and HC. These results appeared to be driven by differences in male subjects. Alcoholic BD patients with additional drug use disorders presented significantly lower myo-inositol than BD patients with alcoholism alone. The co-occurrence of BD and alcoholism may be characterized by neurochemical abnormalities related to the glutamatergic system and to the inositol second messenger system and/or in glial pathology. These abnormalities may be the neurochemical correlate of an increased risk to develop alcoholism in BD, or of a persistently worse clinical and functional status in BD patients in remission from alcoholism, supporting the clinical recommendation that efforts should be made to prevent or early diagnose and treat alcoholism in BD patients.

Anterior cingulate volumes associated with trait impulsivity in individuals with bipolar disorder.

OBJECTIVE: Impulsivity is associated with the clinical outcome and likelihood of risky behaviors among bipolar disorder (BD) patients. Our previous study showed an inverse relationship between impulsivity and orbitofrontal cortex (OFC) volume in healthy subjects. We hypothesized that BD patients would show an inverse relationship between impulsivity and volumes of the OFC, anterior cingulate cortex (ACC), medial prefrontal cortex, and amygdala, which have been implicated in the pathophysiology of BD. METHODS: Sixty-three BD patients were studied (mean +/- SD age = 38.2 +/- 11.5 years; 79% female). The Barratt Impulsiveness Scale (BIS), version 11A, was used to assess trait impulsivity. Images were processed using SPM2 and an optimized voxel-based morphometry protocol. We examined the correlations between BIS scores and the gray matter (GM) and white matter (WM) volumes of the prespecified regions. RESULTS: Left rostral ACC GM volume was inversely correlated with the BIS total score (t = 3.95, p(corrected) = 0.003) and the BIS motor score (t = 5.22, p(corrected) < 0.001). In contrast to our hypothesis, OFC volumes were not significantly associated with impulsivity in BD. No WM volume of any structure was significantly correlated with impulsivity. No statistical association between any clinical variable and the rostral ACC GM volumes reached significance. CONCLUSIONS: Based on our previous findings and the current results, impulsivity may have a different neural representation in BD and healthy subjects, and the ACC may be involved in the pathophysiology of abnormal impulsivity regulation in BD patients.

Fronto-temporal dysregulation in remitted bipolar patients: an fMRI delayed-non-match-to-sample (DNMS) study.

OBJECTIVES: Bipolar disorder is associated with working memory (WM) impairments that persist during periods of symptomatic remission. However, the neural underpinnings of these deficits are not well understood. METHODS: Fifteen clinically remitted bipolar patients and 15 demographically matched healthy controls underwent functional magnetic resonance imaging while performing a novel delayed-non-match-to-sample (DNMS) task. This nonverbal DNMS task involves two conditions, one requiring the organization of existing memory traces ('familiarity'), and one involving the formation of new memory traces ('novelty'). These processes are thought to differentially engage the prefrontal cortex and medial temporal lobe, respectively. RESULTS: Although behavioral performance did not differ between groups, bipolar patients and controls exhibited significantly different patterns of neural activity during task performance. Patients showed relative hyperactivation in the right prefrontal gyrus and relative hypoactivation in visual processing regions compared to healthy subjects across both task conditions. During the novelty condition, patients showed a pattern of hypoactivation relative to controls in medial temporal regions, with relative hyperactivation in the anterior cingulate. CONCLUSIONS: These findings suggest that disruption in fronto-temporal neural circuitry may underlie memory difficulties frequently observed in patients with bipolar disorder.

An MRI-based approach for the measurement of the dorsolateral prefrontal cortex in humans.

The dorsolateral prefrontal cortex (DLPFC) has been implicated in the pathophysiology of mental disorders. Previous region-of-interest MRI studies that attempted to delineate this region adopted various landmarks and measurement techniques, with inconsistent results. We developed a new region-of-interest measurement method to obtain morphometric data of this region from structural MRI scans, taking into account knowledge from cytoarchitectonic postmortem studies and the large inter-individual variability of this region. MRI scans of 10 subjects were obtained, and DLPFC tracing was performed in the coronal plane by two independent raters using the semi-automated software Brains2. The intra-class correlation coefficients between two independent raters were 0.94 for the left DLPFC and 0.93 for the right DLPFC. The mean +/- S.D. DLPFC volumes were 9.23 +/- 2.35 ml for the left hemisphere and 8.20 +/- 2.08 ml for the right hemisphere. Our proposed method has high inter-rater reliability and is easy to implement, permitting the standardized measurement of this region for clinical research applications

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.

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.

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.

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.

Temperament and character traits in patients with bipolar disorder and associations with comorbid alcoholism or anxiety disorders.

Temperament and character traits may determine differences in clinical presentations and outcome of bipolar disorder. We compared personality traits in bipolar patients and healthy individuals using the Temperament and Character Inventory (TCI) and sought to verify whether comorbidity with alcoholism or anxiety disorders is associated with specific personality traits. Seventy-three DSM-IV bipolar patients were compared to 63 healthy individuals using the TCI. In a second step, the bipolar sample was subgrouped according to the presence of psychiatric comorbidity (alcoholism, n=10; anxiety disorders; n=23; alcoholism plus anxiety disorders, n=21; no comorbidity, n=19). Bipolar patients scored statistically higher than the healthy individuals on novelty seeking, harm avoidance and self-transcendence and lower on self-directedness and cooperativeness. Bipolar patients with only comorbid alcoholism scored statistically lower than bipolar patients without any comorbidity on persistence. Bipolar patients with only comorbid anxiety disorders scored statistically higher on harm avoidance and lower on self-directedness than bipolar patients without any comorbidity. Limitations of this study include the cross-sectional design and the small sample size, specifically in the analysis of the subgroups. However, our results suggest that bipolar patients exhibit a different personality structure than healthy individuals and that presence of psychiatric comorbidity in bipolar disorder is associated with specific personality traits. These findings suggest that personality, at least to some extent, mediates the comorbidity phenomena in bipolar disorder.

Abnormal cellular energy and phospholipid metabolism in the left dorsolateral prefrontal cortex of medication-free individuals with bipolar disorder: an in vivo 1H MRS study.

OBJECTIVES: While the pathophysiology of bipolar disorder (BD) remains to be elucidated, postmortem and neuroimaging studies have suggested that abnormalities in the dorsolateral prefrontal cortex (DLPFC) are implicated. We compared the levels of specific brain chemicals of interest measured with proton magnetic resonance spectroscopy ((1)H MRS) in medication-free BD subjects and age- and gender-matched healthy controls. We hypothesized that BD subjects would present abnormal cellular metabolism within the DLPFC, as reflected by lower N-acetyl-aspartate (NAA) and creatine + phosphocreatine (Cr + PCr). METHODS: Thirty-two medication-free BD subjects (33.8 +/- 10.2 years) and 32 matched controls (33.8 +/- 9.0 years) underwent a short echo-time (TE = 30 ms) (1)H MRS. An 8-cm(3) single voxel was placed in the left DLPFC, and individual concentrations of NAA, Cr + PCr, choline-containing compounds (GPC + PC), myo-inositol, and glutamate were obtained, using the water signal as an internal reference. RESULTS: BD subjects had lower Cr + PCr [F((1,62)) = 5.85; p = 0.018; one-way analysis of variance (ANOVA)] and lower GPC + PC [F((1,62)) = 5.79; p = 0.019; one-way ANOVA] levels in the left DLPFC. No significant differences were observed for other brain metabolites. CONCLUSIONS: These findings provide further evidence that the pathophysiology of BD involves impairment in the DLPFC. Our findings can be interpreted as evidence for reduced cellular energy and phospholipid metabolism, consistent with the hypothesis of mitochondrial dysfunction in BD.

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.

A social cognitive approach to emotional intensity judgment deficits in schizophrenia.

Patients with schizophrenia are impaired in both emotion perception and contextual processing, however these two processes have not been thoroughly assessed simultaneously in adults with schizophrenia. This study examined the impact of social contextual information upon the perception of emotional intensity in schizophrenia. 30 clinically stable outpatients with schizophrenia and 30 demographically matched healthy subjects assessed the intensity of a single emotion (anger, disgust, happiness, sadness or fear) from images of people presented under two conditions (context-free and context embedded). During the first assessment, a single person (face and body) was presented without any background (e.g., contextual) scenery. The second assessment included the same person but with the original background of the image. Differences between the first and second ratings provided an index of the extent to which contextual information was used to judge emotional intensity. Without contextual cues, patients with schizophrenia viewed scenes as having greater disgust and anger than healthy subjects. Furthermore, patients were less impacted by contextual cues as evidenced by the minute changes in their assessments. These results suggest that patients with schizophrenia differ from healthy subjects in both their ability to rate emotional intensity and the influence of contextual adjustment upon such ratings.