Decreased N-acetylaspartate in children with familial bipolar disorder.

BACKGROUND: Relatively low levels of brain N-acetylaspartate, as measured by magnetic resonance spectroscopy, may indicate decreased neuronal density or viability. Dorsolateral prefrontal levels of N-acetylaspartate have been reported to be decreased in adults with bipolar disorder. We used proton magnetic resonance spectroscopy to investigate dorsolateral prefrontal N-acetylaspartate levels in children with familial bipolar disorder. METHODS: Subjects were 15 children and adolescents with bipolar disorder, who each had at least one parent with bipolar disorder, and 11 healthy controls. Mean age was 12.6 years for subjects and controls. Subjects were allowed to continue current medications. Proton magnetic resonance spectroscopy at 3-Tesla was used to study 8 cm(3) voxels placed in left and right dorsolateral prefrontal cortex. RESULTS: Bipolar subjects had lower N-acetylaspartate/Creatine ratios only in the right dorsolateral prefrontal cortex (p <.02). No differences in myoinositol or choline levels were found. CONCLUSIONS: Children and adolescents with bipolar disorder may have decreased dorsolateral prefrontal N-acetylaspartate, similar to adults with BD, indicating a common neuropathophysiology. Longitudinal studies of at-risk children before the onset and during the early course of bipolar disorder are needed to determine the role of prefrontal N-acetylaspartate as a possible risk marker and/or indication of early bipolar illness progression.     

Cortical gray matter deficit in patients with bipolar disorder

Background: cortical gray matter volume deficit and ventricular enlargement are well documented in schizophrenia, but their presence in bipolar disorder is less well established.

Methods: global cortical gray matter, white matter and sulcal CSF, as well as lateral and third ventricular volume measures, were derived from axial MRI brain images obtained on age-matched bipolar (n=9), schizophrenic (n=9), and control (n=16) subjects. All subjects were free of history of alcohol or other substance dependence.

Results: relative to controls, bipolar patients had widespread volume deficits of cortical gray matter but not of cortical white matter. Schizophrenic patients had an even more severe cortical gray matter deficit and greater sulcal and lateral ventricular enlargement than the bipolar patients.

Conclusions: this group of patients with bipolar disorder had a widespread deficit of cortical gray matter similar to, but less pronounced than, that observed in patients with schizophrenia.     

Cortical gray matter differences identified by structural magnetic resonance imaging in pediatric bipolar disorder

OBJECTIVE: Few magnetic resonance imaging (MRI) studies of bipolar disorder (BPD) have investigated the entire cerebral cortex. Cortical gray matter (GM) volume deficits have been reported in some studies of adults with BPD; this study assessed the presence of such deficits in children with BPD. METHODS: Thirty-two youths with DSM-IV BPD (mean age 11.2 +/- 2.8 years) and 15 healthy controls (HC) (11.2 +/- 3.0 years) had structured and clinical interviews, neurological examinations, neurocognitive testing, and MRI scanning on a 1.5 T GE Scanner. Image parcellation divided the neocortex into 48 gyral-based units per hemisphere, and these units were combined into frontal (FL), temporal (TL), parietal (PL), and occipital (OL) lobe volumes. Volumetric differences were examined using univariate linear regression models with alpha = 0.05. RESULTS: Relative to controls, the BPD youth had significantly smaller bilateral PL, and left TL. Analysis of PL and TL gyri showed significantly smaller volume in bilateral postcentral gyrus, and in left superior temporal and fusiform gyri, while the parahippocampal gyri were bilaterally increased in the BPD group. Although the FL overall did not differ between groups, an exploratory analysis showed that the right middle frontal gyrus was also significantly smaller in the BPD group. CONCLUSIONS: Children with BPD showed deficits in PL and TL cortical GM. Further analyses of the PL and TL found differences in areas involved in attentional control, facial recognition, and verbal and declarative memory. These cortical deficits may reflect early age of illness onset.     

Normal pituitary volumes in children and adolescents with bipolar disorder: a magnetic resonance imaging study

The volume of the pituitary gland in adults with bipolar disorder has previously been reported to be smaller than that of healthy controls. Such abnormalities would be consistent with the HPA dysfunction reported in this illness. We conducted a study of children and adolescents with bipolar disorder to determine whether size abnormalities in the pituitary gland are already present early in illness course. Magnetic resonance imaging (MRI) morphometric analysis of the pituitary gland was carried out 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 1.5 T MRI, with 3-D Spoiled Gradient Recalled (SPGR) acquisition. There was no statistically significant difference between pituitary gland volumes of bipolar patients compared to healthy controls (ANCOVA, age, gender, and ICV as covariates; F=1.77, df=1,32, P=.19). There was a statistically significant direct relationship between age and pituitary gland volume in both groups (r=.59, df=17, P=.007 for healthy controls; r=.61, df=12, P=.008 for bipolar patients). No evidence of size abnormalities in the pituitary gland was found in child and adolescent bipolar patients, contrary to reports involving adult bipolar patients. This suggests that anatomical abnormalities in this structure may develop later in illness course as a result of continued HPA dysfunction.     

Juvenile bipolar disorder

OBJECTIVE: Bipolar disorder in children and adolescents is less well studied than bipolar disorder in adults. This review addresses issues related to its underdiagnosis, precursors of bipolarity, comorbidity, natural course and treatment. METHOD: Literature from Medline and other searches, and earlier relevant articles including references from recent review articles on juvenile bipolarity were reviewed. RESULTS: Bipolar disorder in juveniles is underdiagnosed and misdiagnosed on various counts. Few recent studies have reported high rates of comorbid attention deficit and disruptive disorders, prompting some researchers to consider them as probable developmental precursors of juvenile bipolarity. There is also evidence to suggest that some juvenile depression could be pre-bipolar, and that certain temperamental predispositions are probable precursors to bipolarity. Limited data on the natural course and outcome suggest that juvenile bipolar disorder is a highly recurring illness as in adults, and that it is associated with significant functional impairment. The psychopharmacological treatment of juvenile bipolar disorder is remarkably understudied, and treatment is often based on studies of adults. CONCLUSION: There is a need for epidemiological studies of juvenile bipolar disorder. Similarly, there is an urgent need for the methodologically rigorous studies to establish the efficacy of various antimanic drugs. Finally, issues related to comorbidity and temperamental predispositions to juvenile bipolarity need greater clarity, as they may have important treatment and research implications.     

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.     

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.     

White matter abnormalities in bipolar disorder and schizophrenia detected using diffusion tensor magnetic resonance imaging

Objectives:  Strong qualitative and quantitative evidence exists of white matter abnormalities in both schizophrenia and bipolar disorder (BD). Diffusion tensor imaging (DTI) studies suggest altered connectivity in both disorders. We aim to address the diagnostic specificity of white matter abnormalities in these disorders.
Methods:  DTI was used to assess white matter integrity in clinically stable patients with familial BD (n = 42) and familial schizophrenia (n = 28), and in controls (n = 38). Differences in fractional anisotropy (FA) were measured using voxel-based morphometry and automated region of interest analysis.
Results:  Reduced FA was found in the anterior limb of the internal capsule (ALIC), anterior thalamic radiation (ATR), and in the region of the uncinate fasciculus in patients with BD and those with schizophrenia compared with controls. A direct comparison between patient groups found no significant differences in these regions. None of the findings were associated with psychotropic medication.
Conclusions:  Reduced integrity of the ALIC, uncinate fasciculus, and ATR regions is common to both schizophrenia and BD. These results imply an overlap in white matter pathology, possibly relating to risk factors common to both disorders.     

Comparing diagnostic checklists for pediatric bipolar disorder in academic and community mental health settings

OBJECTIVES: To compare six promising mania measures, the Parent Mood Disorder Questionnaire (P-MDQ), the Adolescent self-report MDQ, the 10-item short form of the Parent General Behavior Inventory (PGBI-SF10), the 28-item Adolescent General Behavior Inventory (AGBI), the Parent Young Mania Rating Scale (P-YMRS), and the adolescent YMRS, in a demographically diverse outpatient sample. METHODS: Participants were 262 outpatients (including 164 males and 131 African-Americans) presenting to either an academic medical center (n = 153) or a community mental health center (n = 109). Diagnoses were based on semi-structured interviews with the parent and then youth sequentially. RESULTS: Ninety youths (34%) met criteria for a bipolar spectrum disorder. Parent measures yielded Areas Under the Receiver Operating Curve (AUROC) values of 0.81 for the PGBI-SF10 to 0.66 for the P-YMRS. Adolescent report measures performed significantly less well, with AUROCs ranging from 0.65 to 0.50. There were no significant differences in the diagnostic performance of the measures across the sites or by racial groups, although the reliability of measures tended to be lower in the urban community mental health site. The PGBI-SF10 made a significant contribution to logistic regression models examining all combinations of the instruments. The P-MDQ added information in the younger age group, and no measure improved classification of bipolar cases after controlling for the PGBI-SF10 in the older age group. DISCUSSION: Results replicate previous findings that, in decreasing order of efficiency, the PGBI-SF10, P-MDQ, and P-YMRS significantly discriminate bipolar from non-bipolar cases in youths aged 5-18; and they appear robust in a demographically diverse community setting. Adolescent self-report measures are significantly less efficient, sometimes performing no better than chance at detecting bipolar cases.     

Rapid, continuous cycling and psychiatric co-morbidity in pediatric bipolar I disorder

Objectives: The primary purpose of this study was to describe the clinical presentation of bipolar I disorder (BP-I) as it occurs in children and adolescents and to assess whether the manifestations of BP-I were similar in both age groups.

Method: Ninety youths between the ages of 5 and 17 years meeting full diagnostic symptom criteria for BP-I were included in this study. The diagnosis of BP-I was established for these youths based on the results of a semi-structured diagnostic interview and a clinical assessment by a child and adolescent psychiatrist. The course of a subset of these youngsters' illnesses was assessed using the Life Charting Method (LCM). Data regarding the clinical presentation, longitudinal history, psychiatric co-morbidities and parental psychopathology were also obtained.

Results: The clinical presentation of BP-I was similar in children and adolescents. Youths meeting diagnostic criteria for BP-I developed an average of approximately 5.8 of the 7 symptoms of mania during periods of elevated or irritable mood. BP-I was found to be a cyclic disorder characterized by high rates of rapid cycling (50%) with almost no inter-episode recovery. Almost 75% of these subjects also met diagnostic symptom criteria for a disruptive behavior disorder. High rates of mood disorders were found in fathers.

Conclusions: These data suggest that the presentation of juvenile BP-I is a cyclic and valid clinical condition with manifestations on a continuum with the later-onset forms of this illness.     

Review of risperidone for the treatment of pediatric and adolescent bipolar disorder and schizophrenia

Risperidone is a commonly used medication for the treatment of bipolar disorder and schizophrenia in children and adolescents. It has been studied as a monotherapy treatment in early onset schizophrenia and as both monotherapy and combination therapy for pediatric bipolar disorder. Studies to date indicate that risperidone is an effective treatment for positive and negative symptoms of schizophrenia and mania symptoms of bipolar disorder. In young patient populations, side effects such as weight gain, extrapyramidal side effects, and prolactin elevation require consideration when evaluating the risk benefit ratio for individual patients. Here we review published studies of risperidone for the treatment of bipolar disorder and schizophrenia in children and adolescents to provide practitioners with an overview of published data on the efficacy and safety of risperidone in these patient populations.     

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.     

Fronto-limbic brain abnormalities in juvenile onset bipolar disorder.

BACKGROUND: Advances in brain imaging techniques and cognitive neuropsychology have brought new possibilities for the in vivo study of the pathophysiology of neuropsychiatric disorders, including bipolar disorder (BD). Recently, such studies have been extended to the pediatric age range. Here we review the neuroimaging and neuropsychological studies conducted in BD children and adolescents. METHODS: A review of the peer-reviewed published literature was conducted in Medline for the period of 1966 to April 2005. RESULTS: Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) studies suggest abnormalities in fronto-limbic structures in pediatric BD patients, similar to those found in adults. A notable exception in pediatric BD patients is smaller amygdala volumes compared to healthy controls, contrary to what has been reported in most adult studies. CONCLUSIONS: Further research evaluating children and adolescents is needed to study the normal neurodevelopmental process and to answer how and when the illness processes that result in bipolar disorder exert their effects on the developing brain.     

Structural abnormalities of ventrolateral and orbitofrontal cortex in patients with familial bipolar disorder

Objectives: Abnormalities of ventral prefrontal function have been widely reported in bipolar disorder, but reports of structural abnormalities in the same region are less consistent. We examined the presence and location of ventral prefrontal abnormalities in a large sample of individuals with bipolar disorder and their relationship to gender, psychotic symptoms, and age. Methods: Structural magnetic resonance imaging brain scans were carried out on 66 individuals with bipolar disorder, type I, and 66 controls. Voxel‐based morphometry was used to examine differences in grey and white matter density between the groups and their relationship with a lifetime occurrence of psychotic symptoms and age. Results: Reductions in grey matter density were seen in the left and right lateral orbital gyri and the right inferior frontal gyrus, while white matter density reductions were seen in the corona radiata and the left temporal stem. In contrast, hallucinations and positive symptoms were associated with grey matter reduction in the left middle temporal gyrus. Age was more strongly associated with the right inferior frontal gyrus grey matter reductions in the bipolar group than in the controls, but not with any other finding. Conclusion: Abnormalities of the ventral prefrontal cortex are likely to be involved in the aetiopathology of bipolar disorder, while hallucinations appear to be more closely associated with temporal lobe abnormality, extending earlier work in schizophrenia. Further prospective studies are required to comprehensively address the trajectory of these findings.     

MRI study of thalamus volumes in juvenile patients with bipolar disorder

In vivo imaging studies suggest functional abnormalities of the thalamus in adult patients with bipolar disorder, but the presence of anatomical abnormalities is controversial. Our objective in this study was to compare the thalamus volumes of children and adolescents with bipolar disorder versus healthy controls to determine whether any morphological abnormalities exist early in illness course. We studied 16 patients with bipolar disorder according to DSM-IV criteria (mean age+/-SD=15.5+/-3.4 years) and 21 healthy control subjects (mean age+/-SD=16.9+/-3.8 years). Blinded examiners measured thalamic gray matter volumes with a semiautomated technique. Analysis of covariance, with age, gender, and intracranial brain volume as covariates, revealed no significant differences in left and right thalamic volumes between patients with bipolar disorder and healthy controls. Our findings indicate there are no significant differences in thalamus size between children and adolescents with bipolar disorder and healthy comparison subjects, in contrast to available findings for schizophrenia and first-break psychosis. Any differences in thalamus size that may exist between patients with bipolar disorder and healthy controls must amount to small effect sizes.     

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.     

White matter abnormalities observed in bipolar disorder: a diffusion tensor imaging study

OBJECTIVES: An increased incidence in white matter abnormalities is among the most frequently reported brain change in patients with bipolar disorder. The objective of the present study was to examine white matter tract integrity, using diffusion tensor imaging (DTI), in bipolar patients and healthy comparison subjects. METHODS: Eleven DSM-IV bipolar I patients and 10 healthy age- and sex-matched controls were studied. DTI data were acquired on a 1.5 Tesla scanner. Fractional anisotropy (FA) and diffusivity (trace) were determined from axial images using region of interest (ROI) analyses. The ROIs were manually placed in the midline and forward projecting arms of the genu (anterior) and the midline of the splenium (posterior) of the corpus callosum. RESULTS: Bipolar patients had significantly higher FA in the midline of the genu compared with healthy controls. Regional white matter differences were also observed, with significantly lower FA in the genu than forward projecting regions in both groups and lower FA in the genu than the splenium in controls. CONCLUSIONS: Diffusion tensor imaging revealed significant microstructural differences in the genu, as measured by elevated FA in bipolar patients compared with healthy controls. These preliminary findings further support the hypothesis that anomalous frontal brain mechanisms may be associated with bipolar disorder.