Neurophysiological effects of multiple mood episodes in bipolar disorder.

OBJECTIVES: Bipolar disorder is marked by progressive symptomatic changes, which have been linked with episode-related structural findings-particularly in the prefrontal cortex. However, few studies have examined neurofunctional and neurochemical effects of disease burden. In this study, we compared first- and multi-episode bipolar individuals. We hypothesized that the latter would demonstrate evidence of neurophysiological differences consistent with a model of progressive functional degradation of these networks. METHODS: First- and multi-episode manic bipolar subjects participated in functional magnetic resonance imaging (fMRI) including a continuous performance task with emotional distractors, and in single-voxel (1 H) magnetic resonance spectroscopy (MRS). A priori fMRI regions-of-interest (ROI) included structures comprising prefrontal-striatal-amygdala networks; (1 H)MRS voxels were placed within bilateral ventrolateral prefrontal (VLPFC) and anterior cingulate cortex (ACC). Both ROI and voxel-based brain activation in response to emotional stimuli, and neurochemical concentrations derived from (1 H)MRS were compared across bipolar groups. RESULTS: Multi-episode bipolar subjects showed relatively lower regional activation across prefrontal-striatal-amygdala networks, including bilateral VLPFC, orbitofrontal cortex, ACC, putamen, caudate, and amygdala. Exploratory whole-brain, voxel-based analysis suggested additional areas of lower activation extending into Brodmann area 22, posterior parietal regions, and right thalamus. Glutamate and N-acetylaspartate (NAA) concentrations were also relatively lower in the ACC of multi-episode subjects. CONCLUSIONS: Disease burden, exemplified by multiple affective episodes is associated with evidence of widespread decrements in affective network activity. Lower ACC NAA concentration is similarly consistent with a model of progressive functional deficits. These findings support the functional significance of previously observed progressive structural changes throughout these regions.

Cardiometabolic risks and omega-3 index in recent-onset bipolar I disorder.

OBJECTIVES: The aims of the present study were to characterize cardiometabolic risk factors in a cohort of bipolar disorder patients with limited exposure to psychotropic medications, and to evaluate their associations with mood symptoms and omega-3 polyunsaturated fatty acid (PUFA) blood levels. METHODS: Cardiometabolic risk assessments were compared in individuals with bipolar I disorder experiencing a first manic or mixed episode or an early depressive episode (n=117) and healthy subjects (n=56). Patients were medication free at assessment and had no or limited exposure to mood-stabilizer or antipsychotic medications prior to the current admission. Associations among cardiometabolic parameters and Clinical Global Impression-Severity scale (CGI-S), manic (Young Mania Rating Scale [YMRS]), and depressive (Hamilton Depression Rating Scale [HDRS]) symptom ratings were evaluated within the bipolar group. RESULTS: Following adjustment for demographic variables (i.e., age, gender, and parental education), significantly higher fasting triglyceride levels were observed in the bipolar group compared to the healthy group (121.7 mg/dL vs 87.0 mg/dL; P<.01). There were no clear trends for other metabolic indicators, including blood pressure, body mass index, and fasting glucose. Nineteen percent of the bipolar group and 6% of the healthy group met the criteria for metabolic syndrome (P=.23). The omega-3 index was lower in the bipolar group (3.4% vs 3.9%; P<.01). Within the bipolar group, no associations were found between the cardiometabolic parameters and CGI-S, YMRS, and HDRS symptom ratings. CONCLUSIONS: Recent-onset medication-free bipolar disorder is associated with higher triglyceride levels. These findings are suggestive of early metabolic dysregulation prior to long-term psychotropic medication exposure. Lower omega-3 PUFA levels in individuals with bipolar I disorder represent a potential therapeutic target for additional investigation.

Age-dependent decreases of high energy phosphates in cerebral gray matter of patients with bipolar I disorder: a preliminary phosphorus-31 magnetic resonance spectroscopic imaging study.

OBJECTIVES: To identify abnormalities in high energy phosphate cerebral metabolism in euthymic bipolar disorder. METHODS: Phosphorus-31 magnetic resonance spectroscopic imaging ((31)P MRSI) data were acquired from the entire brain of 9 euthymic adults with bipolar disorder and 13 healthy adults. Estimates of phosphocreatine (PCr) and adenosine triphosphate (ATP) in homogeneous gray and white matter were obtained by tissue regression analysis. RESULTS: Analyses of covariance revealed the effect of age to be significantly different between bipolar and healthy groups for concentrations of PCr (p=0.0018) and ATP (p=0.013) in gray matter. These metabolites were negatively correlated with age in gray matter in bipolar subjects while PCr was positively correlated with age in gray matter of healthy subjects. Additionally, age-corrected concentrations of PCr in gray matter were significantly elevated in bipolar subjects (p=0.0048). LIMITATIONS: Given that this cross-sectional study possessed a small sample and potentially confounding effects of medication status, we recommend a larger, longitudinal study to more robustly study relationships between bioenergetic impairment and duration of disease. CONCLUSIONS: Our results suggest bioenergetic impairment related to mitochondrial function may be progressive in multi-episode bipolar subjects as they age.

Docosahexaenoic acid supplementation increases prefrontal cortex activation during sustained attention in healthy boys: a placebo-controlled, dose-ranging, functional magnetic resonance imaging study.

BACKGROUND: Emerging evidence suggests that docosahexaenoic acid (DHA, 22:6n-3), the principal omega-3 (n-3) fatty acid in brain gray matter, positively regulates cortical metabolic function and cognitive development. However, the effects of DHA supplementation on functional cortical activity in human subjects are unknown. OBJECTIVE: The objective was to determine the effects of DHA supplementation on functional cortical activity during sustained attention in human subjects. DESIGN: Healthy boys aged 8-10 y (n = 33) were randomly assigned to receive placebo or 1 of 2 doses of DHA (400 or 1200 mg/d) for 8 wk. Relative changes in cortical activation patterns during sustained attention at baseline and endpoint were determined by functional magnetic resonance imaging. RESULTS: At 8 wk, erythrocyte membrane DHA composition increased significantly from baseline in subjects who received low-dose (by 47%) or high-dose (by 70%) DHA but not in those who received placebo (-11%). During sustained attention, both DHA dose groups had significantly greater changes from baseline in activation of the dorsolateral prefrontal cortex than did the placebo group, and the low-dose and high-dose DHA groups had greater decreases in the occipital cortex and cerebellar cortex, respectively. Relative to low-dose DHA, high-dose DHA resulted in greater decreases in activation of bilateral cerebellum. The erythrocyte DHA composition was positively correlated with dorsolateral prefrontal cortex activation and was inversely correlated with reaction time, at baseline and endpoint. CONCLUSION: Dietary DHA intake and associated elevations in erythrocyte DHA composition are associated with alterations in functional activity in cortical attention networks during sustained attention in healthy boys. This trial was registered at clinicaltrials.gov as NCT00662142.

The functional neuroanatomy of bipolar disorder.

In this manuscript, research articles using functional magnetic resonance imaging (fMRI) to study adult patients with bipolar disorder were reviewed. The findings from these studies identify altered brain activation in five regions in cortico-limbic pathways responsible for emotional regulation: portions of the prefrontal cortex; anterior cingulate cortex; amygdala; thalamus; and striatum. The most consistent findings were overactivation of amygdala, striatum, and thalamus. Findings in prefrontal cortex were less consistent, but most studies also showed increased activation in ventrolateral and dorsolateral prefrontal cortical areas. Excessive activation in brain regions associated with emotional regulation may contribute to the affective symptoms of bipolar disorder. However, there are several important limitations in this body of research. Even when similar tasks were used, brain activation was often discrepant among studies. Most fMRI studies examined small samples (ten or fewer bipolar subjects) limiting statistical power. Additionally, most studies were confounded by patients taking psychotropic medications. Nonetheless, from this work an anterior limbic over-activation model of bipolar disorder is emerging.

Neuroanatomical characterization of child offspring of bipolar parents.

OBJECTIVE: To examine structural differences in selected anterior limbic brain regions between at-risk children of parents with bipolar I disorder and children with healthy parents. We hypothesized that at-risk (AR) children would exhibit abnormalities in brain regions that are involved in mood regulation. METHOD: Children (8-12 years old) of parents with bipolar I disorder (AR children, n = 21) and of parents without any DSM-IV Axis I disorder (healthy controls, n = 24) were evaluated using diagnostic assessments and brain magnetic resonance imaging. Morphometric analyses were used to examine group differences in the prefrontal cortical, thalamic, striatal, and amygdalar volumes. RESULTS: Nine (43%) of the AR children met DSM-IV-TR criteria for a nonbipolar mood disorder at the time of assessment. AR and healthy control children did not demonstrate statistically significant differences across regions of interest (Wilks lambda =.86, F4,39 = 1.64, p = .18; effect size, f = 0.19). Post hoc analyses of covariance showed the largest relative effect size was contributed by the prefrontal cortex (f = 0.26). CONCLUSIONS: Eight- to 12-year-old children with a familial risk for mania do not exhibit any statistically significant volumetric differences in the prefrontal cortex, thalamus, striatum, or amygdala as compared with age-matched children of parents without any psychopathology. Longitudinal studies examining whether structural changes over time may be associated with vulnerability for developing subsequent bipolar disorder are needed to clarify the underlying pathophysiology of this disorder.

Voxel-based study of structural changes in first-episode patients with bipolar disorder.

BACKGROUND: Although morphometric studies of bipolar disorder (BD) suggest that neurofunctional abnormalities reflect underlying structural changes, it remains unclear whether abnormalities are present at illness onset or reflect disease progression. Previous voxel-based morphometry (VBM) findings suggest that ventrolateral prefrontal cortex (VLPFC) changes develop over time, whereas morphologic abnormalities elsewhere in the anterior limbic network (ALN) are present early in BD. In this study, we used VBM to explore structural brain changes in first-episode bipolar patients. METHODS: First-episode bipolar (n = 33) and healthy (n = 33) subjects underwent magnetic resonance imaging. Images were normalized and compared on a voxel-by-voxel basis. RESULTS: Bipolar subjects showed no change in VLPFC density or volume. We observed increased volume in left thalamus and fusiform and cerebellum bilaterally; increased gray matter density in anterior cingulate and posterior parietal structures; and increased gray matter volume and density in middle/superior temporal and posterior cingulate gyri. No areas of decreased volume or density were observed. CONCLUSIONS: These data indicate that structural changes are absent from VLPFC early in the course of BD. Morphologic abnormalities are present in other portions of the ALN and in structures previously observed to mediate neurofunctional changes in BD, suggesting that dysfunctional neuronal proliferation or pruning may occur in bipolar patients.

First episode schizophrenia-related psychosis and substance use disorders: acute response to olanzapine and haloperidol.

BACKGROUND: Co-occurring substance use disorders, mostly involving alcohol, cannabis or cocaine, occur commonly in patients with schizophrenia and are associated with increased morbidity and mortality. Available but limited data suggest that substance use disorders (especially cannabis use disorders) may also be common in first-episode patients and appear linked to a poor outcome in these patients. Strategies to curtail substance use form an important dimension of the treatment program for both first-episode and chronic patients. We report on rates of co-occurring substance use disorders in patients within their first episode of schizophrenia-related psychosis from a multicenter, international treatment trial of olanzapine vs. haloperidol. METHODS: The study involved 262 patients (of 263 who were randomized and who returned for a post-randomization evaluation) within their first episode of psychosis (schizophrenia, schizoaffective disorder or schizophreniform disorder) recruited from 14 academic medical centers in North America and Western Europe. Patients with a history of substance dependence within 1 month prior to entry were excluded. RESULTS: Of this sample, 97 (37%) had a lifetime diagnosis of substance use disorder (SUD); of these 74 (28% of the total) had a lifetime cannabis use disorder (CUD) and 54 (21%) had a lifetime diagnosis of alcohol use disorder (AUD). Patients with SUD were more likely to be men. Those with CUD had a lower age of onset than those without. Patients with SUD had more positive symptoms and fewer negative symptoms than those without SUD, and they had a longer duration of untreated psychosis. The 12-week response data indicated that 27% of patients with SUD were responders compared to 35% of those without SUD. Patients with AUD were less likely to respond to olanzapine than those without AUD. DISCUSSION: These data suggest that first-episode patients are quite likely to have comorbid substance use disorders, and that the presence of these disorders may negatively influence response to antipsychotic medications, both typical and atypical antipsychotics, over the first 12 weeks of treatment.

Magnetic resonance imaging analysis of amygdala and other subcortical brain regions in adolescents with bipolar disorder.

OBJECTIVES: Few studies have examined the abnormalities that underlie the neuroanatomy of bipolar disorder in youth. The aim of this study was to evaluate brain regions that are thought to modulate mood utilizing quantitative analyses of thin-slice magnetic resonance imaging (MRI) scans of adolescents with bipolar disorder. We hypothesized that adolescents with bipolar disorder would exhibit abnormalities in brain regions that are involved in the regulation of mood including the amygdala, globus pallidus, caudate, putamen, and thalamus. METHODS: Bipolar adolescents (n = 23) and healthy subjects (n = 20) matched for age, race, sex, socioeconomic status, IQ, education and Tanner stage, were evaluated using the Washington University at St Louis Kiddie-Schedule for Affective Disorders and Schizophrenia (WASH-U K-SADS). Contiguous 1 mm axial T1-weighted MRI slices were obtained using a GE 1.5 T MR scanner. Regions of interest (ROI) included total cerebral volume, amygdala, globus pallidus, caudate, putamen, and thalamus. RESULTS: Total cerebral volume was smaller in bipolar adolescents than in healthy adolescents. A MANCOVA revealed a significant group difference in overall ROI volumes after adjusting for total cerebral volume. Specifically, adolescents with bipolar disorder exhibited smaller amygdala and enlarged putamen compared with healthy subjects. CONCLUSIONS: Our findings indicate that adolescents with bipolar disorder exhibit abnormalities in some of the brain regions that are thought to be involved in the regulation of mood. Additional structural and functional neuroimaging investigations of children, adolescents, and adults with bipolar disorder are necessary to clarify the role of these brain regions in the neurophysiology of adolescent bipolar disorder.

Proton magnetic resonance spectroscopy of the frontal lobe and cerebellar vermis in children with a mood disorder and a familial risk for bipolar disorders.

OBJECTIVE: Few studies have examined the neurochemical abnormalities that might be associated with pediatric bipolar disorder. The aim of this study was to use magnetic resonance spectroscopy to evaluate several brain regions implicated in bipolar disorder in children with a mood disorder and a familial risk for bipolar disorder. We hypothesized that these children would exhibit neurochemical differences compared with healthy children of parents without a psychiatric disorder. Specifically, decreased N-acetylaspartate (NAA) and creatine and phosphocreatine (Cr) of the prefrontal cortex and cerebellar vermis would reflect impairments in neuronal function and cellular metabolism, and elevated myo-inositol (mI) would reflect impaired phosphoinositide metabolism, potentially representing early markers of neurophysiologic changes that might underlie the development of bipolar disorder. METHODS: Children with a mood disorder and at least one parent with bipolar disorder (n = 9) and healthy children (n = 10) group matched for age (8-12 years), race, sex, education, and Tanner stage were evaluated using the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia. Proton magnetic resonance spectroscopy was acquired using 8-cc volumes within the frontal cortex, frontal white matter, and the cerebellar vermis. Metabolite ratios (NAA/Cr, cholines (Cho)/Cr, mI/Cr, NAA/Cho, NAA/mI, and Cho/mI) and concentrations (NAA, Cr, Cho, and mI) were calculated and compared between groups. RESULTS: The trend in concentration levels of NAA and Cr was approximately 8% lower for children with a mood disorder than healthy children within the cerebellar vermis. The frontal cortex in children with a mood disorder revealed elevated mI concentration levels, approximately 16% increased, compared with healthy children. CONCLUSIONS: Similar to findings in adults with bipolar disorders, neurochemical abnormalities within the frontal cortex and the cerebellar vermis were present in this preliminary comparison of children with a mood disorder and a familial risk for bipolar disorder. Larger sample sizes are needed to replicate these findings.

Ventricular and periventricular structural volumes in first- versus multiple-episode bipolar disorder.

OBJECTIVE: Ventriculomegaly has been reported in bipolar disorder, although whether it occurs at illness onset or progresses during the course of the disorder is unknown. In addition, it is unknown whether ventriculomegaly in bipolar disorder reflects acquired volume loss or underdevelopment of periventricular structures. METHOD: Magnetic resonance imaging was used to measure the volumes of the lateral and third ventricles and periventricular structures (caudate, putamen, thalamus, hippocampus). Patients with DSM-IV bipolar disorder, 18 who were having a first episode and 17 with multiple episodes, were compared with 32 healthy subjects. RESULTS: The lateral ventricles were significantly larger in the patients with multiple-episode bipolar disorder than in the first-episode patients or the healthy subjects, even after periventricular and total cerebral volumes were taken into account. Having larger lateral ventricles was associated with a higher number of prior manic episodes. The multiple-episode patients had a smaller total cerebral volume than the healthy subjects but not the first-episode patients. The putamen was significantly larger in the first-episode patients (and nearly so in the multiple-episode patients) than in the healthy subjects, although there was no difference between patient groups. CONCLUSIONS: Lateral ventriculomegaly was greater in bipolar disorder patients who had had repeated manic episodes, but it does not appear to be secondary to small critical periventricular structures. A larger than normal striatum, which has been reported in previous studies, was observed in first-episode patients. These results support the importance of prospectively studying neuroanatomic changes in bipolar disorder.

Frontal lobe differences in bipolar disorder as determined by proton MR spectroscopy.

OBJECTIVES: Proton magnetic resonance spectroscopy (MRS) provides insight into neurochemical processes. Imaging and postmortem studies have implicated abnormalities of structure and function within the frontal lobe. Patients with bipolar disorder having a manic or mixed episode were hypothesized to demonstrate metabolic abnormalities within the frontal lobe. METHODS: Seventeen patients with bipolar disorder type I (ages 16-35 years, mean 22 +/- 7.3 years) hospitalized for a manic (n = 9) or mixed (n = 8) episode and 21 healthy subjects (ages 16-35 years, mean 21.7 +/- 5.2 years) were evaluated with proton MRS. The gray matter medially and white matter laterally within the frontal lobe were sampled. Metabolite concentrations were calculated for each voxel, corrected for cerebral spinal fluid (CSF) contributions to the voxel, and compared between study populations. RESULTS: Patients demonstrated with multivariate analyses of variance (MANOVA) a significant overall difference in gray matter metabolite concentrations compared with healthy subjects. The largest effect sizes for group differences were found with reductions of N-acetyl aspartate (NAA) and Choline (Cho) concentrations (f = 0.41 and 0.37, respectively). A significant group difference with MANOVA in white matter metabolite concentrations was also observed with the largest effect size at f = 0.44 for elevation of the composite amino acid (AA) concentration. CONCLUSIONS: A reduction of NAA within the gray matter of patients suggests neuronal dysfunction. Altered phospholipid metabolism suggestive of a trend toward decreased volume is implicated with a reduction of Cho concentrations. Within white matter, composite concentrations of AAs were elevated in patients indicating altered neurotransmission.