Preliminary evidence for persistent abnormalities in amygdala volumes in adolescents and young adults with bipolar disorder

OBJECTIVES: Abnormalities in volumes of the amygdala have been reported previously in adolescents and adults with bipolar disorder (BD). Several studies have reported reduced volumes in adolescents with BD; however, both decreases and increases in volumes have been reported in adults with BD. Understanding of potential developmental contributions to these disturbances in morphology of the amygdala has been limited by the absence of longitudinal data in persons with BD. Here we use a within-subject longitudinal design to investigate whether amygdala volume abnormalities persist in adolescents and young adults with BD over a time interval of approximately 2 years. METHODS: Participants included 18 adolescents and young adults: 10 participants with BD I and 8 healthy comparison participants. Amygdala volumes were measured on high-resolution magnetic resonance imaging scans acquired twice for each subject over intervals of approximately 2 years. Amygdala volumes were the dependent measures in a mixed-model statistical analysis to compare amygdala volumes between groups over time while covarying for total brain volume. RESULTS: Amygdala volumes were significantly smaller in adolescents and young adults with BD compared with healthy participants (p = 0.018). The effect of time was not significant. CONCLUSIONS: Although the sample size is modest, this study provides preliminary evidence to support the presence of decreased amygdala volumes in adolescents and young adults with BD that persist during this developmental epoch.     

Diffusion-weighted magnetic resonance imaging of white matter in bipolar disorder: a pilot study

OBJECTIVE: Diffusion-weighted magnetic resonance imaging (MRI) has shown increased sensitivity in detecting brain white matter disease compared to traditional T2-weighted MRI. Diffusion-weighted imaging (DWI) can quantitatively assess the microstructural integrity of white matter using the average apparent diffusion coefficient (ADC(av)), a measure of the extent to which water molecules move freely within tissue. On the basis of numerous studies suggesting white matter disease in bipolar patients, particularly patients with more severe illness, this study aimed to test the utility of DWI in assessing the white matter integrity of bipolar patients with severe illness. METHODS: The existing MRI scans of eight bipolar patients and eight age-matched controls with neurological illness were examined retrospectively. ADC(av) values for pixels within white matter regions of interest (ROIs) were calculated and used to plot ADC(av) frequency histograms for each ROI. Mean ADC(av) values for the two groups were then compared by ANCOVA. RESULTS: The bipolar mean ADC(av) (0.855 +/- 0.051 x 10(-3) mm2/s) for combined white matter ROIs significantly exceeded that of controls (0.799 +/- 0.046 x 10(-3) mm2/s), while covarying for age (F = 4.47, df = 3, p = 0.025). CONCLUSIONS: This is the first report of an elevated ADC(av) in the white matter of a group of patients with bipolar disorder. In this group of patients with severe illness, increased white matter ADC(av) suggests microstructural changes consistent with decreased white matter integrity. DWI may be an additional, useful tool to assess white matter abnormalities in bipolar disorder.     

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.     

Review of functional magnetic resonance imaging studies comparing bipolar disorder and schizophrenia

Whalley HC, Papmeyer M, Sprooten E, Lawrie SM, Sussmann JE, McIntosh AM. Review of functional magnetic resonance imaging studies comparing bipolar disorder and schizophrenia.
Bipolar Disord 2012: 14: 411–431. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective: Although bipolar disorder (BD) and schizophrenia (SCZ) have a number of clinical features and certain susceptibility genes in common, they are considered separate disorders, and it is unclear which aspects of pathophysiology are specific to each condition. Here, we examine the functional magnetic resonance imaging (fMRI) literature to determine the evidence for diagnosis‐specific patterns of brain activation in the two patient groups. Method: A systematic search was performed to identify fMRI studies directly comparing BD and SCZ to examine evidence for diagnosis‐specific activation patterns. Studies were categorized into (i) those investigating emotion, reward, or memory, (ii) those describing executive function or language tasks, and (iii) those looking at the resting state or default mode networks. Studies reporting estimates of sensitivity and specificity of classification are also summarized, followed by studies reporting associations with symptom severity measures. Results: In total, 21 studies were identified including patients (n = 729) and healthy subjects (n = 465). Relative over‐activation in the medial temporal lobe and associated structures was found in BD versus SCZ in tasks involving emotion or memory. Evidence of differences between the disorders in prefrontal regions was less consistent. Accuracy values for assignment of diagnosis were generally lower in BD than in SCZ. Few studies reported significant symptom associations; however, these generally implicated limbic regions in association with manic symptoms. Conclusions: Although there are a limited number of studies and a cautious approach is warranted, activation differences were found in the medial temporal lobe and associated limbic regions, suggesting the presence of differences in the neurobiological substrates of SCZ and BD. Future studies examining symptom dimensions, risk‐associated genes, and the effects of medication will aid clarification of the mechanisms behind these differences.     

Meta-analysis of magnetic resonance imaging studies of the corpus callosum in bipolar disorder

Objective: The corpus callosum (CC) plays a pivotal role in inter‐hemispheric transfer and integration of information and is a relatively understudied structure in bipolar disorder (BD). Magnetic resonance imaging (MRI) studies have reported callosal abnormalities in this condition but findings have been inconsistent. Structural changes affecting the CC may underlie functional abnormalities in BD and could contribute to, or explain the pathophysiology of, the condition. Method: A systematic review was carried out to identify, appraise and summarize MRI studies which compared callosal areas in BD with an unrelated control group. The findings were then synthesized using random effects meta‐analysis. Consideration was given to a number of variables to explain heterogeneity. Results: Five case–control studies were identified. Bipolar patients showed reduced callosal areas in comparison with healthy volunteers with no evidence of heterogeneity or publication bias. Conclusion: Findings from this study indicate that callosal areas are reduced in BD and suggest that a failure to integrate information across the hemispheres may contribute to the pathophysiology of the disorder. Further research is necessary to clarify the underlying cellular changes leading to these morphometric differences.     

Regional brain changes in bipolar I depression: a functional magnetic resonance imaging study

Objective:  To investigate neural activity in prefrontal cortex and amygdala during bipolar depression.
Methods:  Eleven bipolar I depressed and 17 normal subjects underwent functional magnetic resonance imaging (fMRI) while performing a task known to activate prefrontal cortex and amygdala. Whole brain activation patterns were determined using statistical parametric mapping (SPM) when subjects matched faces displaying neutral or negative affect (match condition) or matched a geometric form (control condition). Contrasts for each group for the match versus control conditions were used in a second-level random effects analysis.
Results:  Random effects between-group analysis revealed significant attenuation in right and left orbitofrontal cortex (BA47) and right dorsolateral prefrontal cortex (DLPFC) (BA9) in bipolar depressed subjects. Additionally, random effects analysis showed a significantly increased activation in left lateral orbitofrontal cortex (BA10) in the bipolar depressed versus control subjects. Within-group contrasts demonstrated significant amygdala activation in the controls and no significant amygdala activation in the bipolar depressed subjects. The amygdala between-group difference, however, was not significant.
Conclusions:  Bipolar depression is associated with attenuated bilateral orbitofrontal (BA47) activation, attenuated right DLPFC (BA9) activation and heightened left orbitofrontal (BA10) activation. BA47 attenuation has also been reported in mania and may thus represent a trait feature of the disorder. Increased left prefrontal (BA10) activation may be a state marker to bipolar depression. Our findings suggest dissociation between mood-dependent and disease-dependent functional brain abnormalities in bipolar disorder.     

White matter hyperintensity detected by magnetic resonance imaging and lithium response in bipolar disorder: a preliminary observation

The possible relationship between deep white matter hyperintensity (WMHI) lesions detected by magnetic resonance imaging and response to lithium was examined in 16 patients with bipolar disorder who had been under maintenance treatment with lithium for more than 1 year. Bipolar patients who had higher scores of WMHI responded significantly better to lithium (r = 0.57, P < 0.05) than did those who had lower scores. This preliminary result suggests that the presence of WMHI may be associated with a better response to lithium.     

Gray matter,white matter,brain, and intracranial volumes in first‐episode bipolar disorder: a meta‐analysis of magnetic resonance imaging studies

Objectives: To perform a comprehensive quantitative analysis of the existing magnetic resonance imaging (MRI) studies of the brain conducted on patients with first‐episode bipolar disorder (BD). Methods: A systematic search was performed of MRI studies that reported quantitative measurements of brain volumes of first‐episode bipolar patients and healthy controls. Four meta‐analyses were performed for four cerebral regions. Results: Significant overall effect sizes were demonstrated, with a reduction detected in patients with BD for total intracranial and white matter volumes, but not for gray matter and whole brain volumes. Conclusions: The available MRI literature indicates that specific structural brain abnormalities are already present in first‐episode bipolar patients. These do not overlap with those emerging from previous meta‐analyses performed in patients with chronic BD. These findings support the hypothesis of different patterns of changes in brain morphology over the time course of bipolar disorder.     

Meta-analysis of magnetic resonance imaging brain morphometry studies in bipolar disorder.

BACKGROUND: Several studies assessing volumetric measurements of regional brain structure in bipolar disorder have been published in recent years, but their results have been inconsistent. Our aim was to complete a meta-analysis of regional morphometry in bipolar disorder as assessed using magnetic resonance imaging (MRI). METHODS: We conducted a systematic literature search of MRI studies of bipolar disorder and identified studies which reported volume measurements in a selected number of regions. Twenty-six studies comprising volumetric measurements on up to 404 independent patients with bipolar disorder were included. A meta-analysis was carried out comparing the volumes of regions in bipolar disorder to comparison subjects using a random effects model. RESULTS: Patients with bipolar disorder had enlargement of the right lateral ventricle, but no other regional volumetric deviations which reached significance. Strong heterogeneity existed for several regions, including the third ventricle, left subgenual prefrontal cortex, bilateral amygdala and thalamus. CONCLUSIONS: Regional volume of most structures we studied is preserved in bipolar disorder as a whole, which was significantly associated only with right-sided ventricular enlargement. However the extensive heterogeneity detected indicates the need for further studies to establish if consistent regional brain volume deviation exists in bipolar disorder or in specific clinical subsets of the illness.     

A preliminary functional magnetic resonance imaging study of prefrontal-amygdalar activation changes in adolescents with bipolar depression treated with lamotrigine

Objectives:  Hypotheses regarding mood dysregulation in bipolar disorder (BD) have centered on limbic overactivity with relative prefrontal underactivity during mood episodes. Therefore, we hypothesized that adolescents with bipolar depression successfully treated with lamotrigine would show decreases in amygdalar activation, and increases in prefrontal activation.
Methods:  Eight adolescents with BD underwent functional magnetic resonance imaging (fMRI) at baseline and after eight weeks of lamotrigine treatment. Blocks of negatively and neutrally valenced emotional pictures were presented during scanning, and subjects were asked to rate how each picture made them feel. Activation in bilateral amygdalae and dorsolateral prefrontal cortices (DLPFC) for negative minus neutral pictures was correlated with Children's Depression Rating Scale (CDRS) scores.
Results:  Mean (SD) CDRS scores decreased significantly, from 53.0 (10.6) at baseline to 26.3 (5.3) at Week 8. This clinical improvement was correlated with decreased right amygdalar activation ( r  = 0.91, p = 0.002). At Week 8, but not baseline, CDRS score was positively correlated with bilateral amygdalar activation ( r  = 0.85, p = 0.007). DLPFC activation was not correlated with change in CDRS score.
Conclusions:  These preliminary results indicate that adolescents with BD treated with lamotrigine demonstrated less amygdalar activation when viewing negative stimuli as depressive symptoms improved. Larger controlled studies are needed to confirm these findings.     

A prospective study of bipolar disorder in children and adolescents from India

Bipolar disorder in adults is known to run an episodic course. However, little information exists on the long-term naturalistic course of bipolar disorder in juvenile populations. The present study was undertaken with the objectives of (i) documenting the rates of recovery and relapse, (ii) identifying the predictors of recovery and relapse and (iii) assessing the rates of comorbid conditions. A total of 30 subjects with onset of bipolar illness (according to DSM-III-R criteria) in childhood and adolescence were assessed systematically at baseline and 4 to 5 years later. All 30 subjects (100%) had recovered from their index episodes and none had exhibited chronicity. Twenty of the 30 subjects (67%) had relapsed, with most relapses occurring within 2 years of recovery from index episodes. No predictors of recovery and relapse could be identified. Conduct disorder was the only comorbid diagnosis in two subjects (7%). The main implication of our study, in view of the high rates of relapse in the crucial developmental phase of a young individual, is that long-term maintenance medication should be considered in juvenile bipolar patients, even if it is a first episode.     

Cortical magnetic resonance imaging findings in familial pediatric bipolar disorder.

BACKGROUND: Morphometric magnetic resonance imaging (MRI) studies of pediatric bipolar disorder (BD) have not reported on gray matter volumes but have reported increased lateral ventricular size and presence of white matter hyperintensities (WMH). We studied gray matter volume, ventricular-to-brain ratios (VBR), and number of WMH in patients with familial, pediatric BD compared with control subjects. METHODS: Twenty subjects with BD (aged 14.6 +/- 2.8 years; 4 female) according to the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia, each with a parent with BD, and 20 age-, gender-, and intelligence quotient-matched healthy control subjects (aged 14.1 +/- 2.8 years; 4 female) were scanned at 3 T. Most subjects were taking psychotropic medications. A high-resolution T1-weighted spoiled gradient echo three-dimensional MRI sequence was analyzed by BrainImage for volumetric measurements, and T2-weighted images were read by a neuroradiologist to determine presence of WMH. RESULTS: After covarying for age and total brain volume, there were no significant differences between subjects with BD and control subjects in volume of cerebral (p = .09) or prefrontal gray matter (p = .34). Subjects with BD did not have elevated numbers of WMH or greater VBR when compared with control subjects. CONCLUSIONS: Children and adolescents with familial BD do not seem to have decreased cerebral grey matter or increased numbers of WMH, dissimilar to findings in adults with BD. Gray matter decreases and development of WMH might be later sequelae of BD or unique to adult-onset BD.     

Neuronal pathology in the hippocampal area of patients with bipolar disorder: a study with proton magnetic resonance spectroscopic imaging.

BACKGROUND: The brain regions involved in the pathophysiology of bipolar disorder have not been definitively determined. Previous studies have suggested possible involvement of the hippocampus and of prefrontal regions. Proton magnetic resonance spectroscopic imaging ((1)H-MRSI) allows measurement of N-acetylaspartate (NAA, marker of neuronal integrity), choline-containing compounds (CHO), and creatine+phosphocreatine (CRE) in multiple brain regions. The objective of this study was to assess possible NAA reductions in hippocampus and prefrontal regions in patients with bipolar disorder. METHODS: We studied 17 patients with bipolar disorder and 17 age- and gender-matched healthy subjects on a 1.5-T nuclear magnetic resonance (NMR) machine. With (1)H-MRSI we measured ratios of areas under the metabolite peaks of the proton spectra (i.e., NAA/CRE, NAA/CHO, CHO/CRE) for multiple cortical and subcortical regions. RESULTS: Patients showed significant reductions of NAA/CRE bilaterally in the hippocampus. There were no significant changes in CHO/CRE or in NAA ratios in any other area sampled. CONCLUSIONS: This study shows that patients with bipolar disorder have a regional reduction of NAA relative signals, suggesting neuronal damage or malfunction of the hippocampus. As suggested by other studies, neuronal pathology in the hippocampus may be involved in the pathophysiology of bipolar disorder and in susceptibility to psychosis.     

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.     

Brain development after intrauterine exposure to lithium: A magnetic resonance imaging study in school-age children

Objective

Lithium is often continued during pregnancy to reduce the risk of perinatal mood episodes for women with bipolar disorder. However, little is known about the effect of intrauterine lithium exposure on brain development. The aim of this study was to investigate brain structure in children after intrauterine exposure to lithium.

Methods

Participants were offspring, aged 8–14 years, of women with a diagnosis of bipolar spectrum disorder. In total, 63 children participated in the study: 30 with and 33 without intrauterine exposure to lithium. Global brain volume outcomes and white matter integrity were assessed using structural MRI and diffusion tensor imaging, respectively. Primary outcomes were total brain, cortical and subcortical gray matter, cortical white matter, lateral ventricles, cerebellum, hippocampus and amygdala volumes, cortical thickness, cortical surface area and global fractional anisotropy, and mean diffusivity. To assess how our data compared to the general population, global brain volumes were compared to data from the Generation R study (N = 3243).

Results

In our primary analyses, we found no statistically significant associations between intrauterine exposure to lithium and structural brain measures. There was a non-significant trend toward reduced subcortical gray matter volume. Compared to the general population, lithium-exposed children showed reduced subcortical gray and cortical white matter volumes.

Conclusion

We found no differences in brain structure between lithium-exposed and non-lithium-exposed children aged 8–14 years following correction for multiple testing. While a rare population to study, future and likely multi-site studies with larger datasets are required to validate and extend these initial findings.     

Attention-deficit hyperactivity disorder -- bipolar comorbidity in children and adolescents

OBJECTIVE: A substantial portion of juvenile bipolar disorder (BD) has a comorbid attention-deficit hyperactivity disorder (ADHD). The aim of our study was to analyze the cross-sectional and longitudinal implications of such comorbidity in children and adolescents with BD. METHODS: Ninety-eight refereed patients (mean age 13.7 +/- 3.0 years) with a diagnosis of BD by the Schedule for Affective Disorders and Schizophrenia for School-Age Children, Present and Lifetime version (K-SADS-PL) were followed for 6 months. RESULTS: Thirty-seven BD patients (37.8%) presented a lifetime diagnosis of comorbid ADHD. The mean age of onset of ADHD was 3.7 +/- 1.1 years, and the mean age of onset of BD was 10.0 +/- 3.2 years. Bipolar subjects with comorbid ADHD were predominantly male, younger, and had an earlier onset of BD (8.1 +/- 2.8 versus 11.1 +/- 2.9 years). Bipolar-ADHD patients presented more frequently a chronic rather than an episodic course of BD, with an irritable rather than an elated mood. They showed higher rates of oppositional defiant disorder/conduct disorder, lower rates of panic disorder, and less frequently received antidepressant medications. Finally, ADHD comorbidity was associated with a greater psychosocial impairment. CONCLUSIONS: ADHD comorbidity is frequent in juvenile BD and can influence age of onset, phenomenology, comorbidity, and course of BD. A timely diagnosis should improve our efforts regarding the outcome of these subjects.     

White matter lesions in euthymic patients with bipolar disorder

Objective: We aimed to quantify both load and regional distributions of hyperintensities on magnetic resonance imaging (MRI) in prospectively verified euthymic bipolar patients and matched controls. Method: Cerebral hyperintensities on T2, proton density and fluid‐attenuated inversion recovery (FLAIR) MRI were compared between 48 bipolar and 47 control subjects using semi‐quantitative rating scales. Results: Bipolar subjects had more severe frontal deep white matter lesions (DWML). Hyperintensity load was independent of age in bipolar patients but increased with age in controls. Global prevalence and severity of hyperintensities did not differ between groups. Exploratory analysis showed DWML in excess in the left hemisphere in bipolar subjects but not in controls. Conclusion: Findings are consistent with clinical, particularly some neurocognitive, features of bipolar disorder and implicate fronto‐subcortical circuits in its neurobiology. They more probably reflect a trait abnormality or illness scar rather than a mood state‐dependent finding. Processes other than ageing and vascular factors may underlie their development.     

Anterior cingulate subregion volumes and executive function in bipolar disorder

OBJECTIVE: Although research findings suggest a relationship between the function of anterior cingulate cortex (ACC) and both cognitive ability and the pathophysiology of bipolar disorder (BPD), few studies have examined cognitive correlates of specific ACC subregion volumes in BPD. Therefore, the primary aim of this study was to examine the relationship between magnetic resonance imaging (MRI)-derived gray and white matter volumes of ACC subregions (caudal, rostral, and subgenual) and performance on tests of executive function in 27 patients with BPD and 22 healthy subjects. METHODS: 1.5T MRI and neuropsychological assessment were conducted with all participants. RESULTS: MANCOVA revealed statistically significant group differences in performance on executive function measures. However, no group differences were observed in any of the ACC white matter or gray matter regions of interest. Multiple regression analyses revealed that rostral and subgenual gray matter each interacted significantly with group in predicting performance on the Wisconsin Card Sorting Test. In addition, a significant interaction was observed between group and both rostral gray and white matter in predicting performance on the Trail Making Test. CONCLUSIONS: The results of this preliminary study support the extant literature that suggests that patients with BPD perform more poorly than healthy subjects on tests of executive function. Furthermore, the relationship between ACC subregion volumes and cognitive test performance was found to differ between patients with BPD and healthy subjects, despite comparable ACC volumes in the two groups.