Structural changes in the hippocampus and amygdala at first episode of psychosis

Hippocampus and amygdala changes have been implicated in the pathophysiology and symptomatology of both schizophrenia (SCZ) and bipolar disorder (BD). However relationships between illness course, neuropathological changes and variations in symptomatology remain unclear. This investigation examined the associations between hippocampus and amygdala volumes and symptom dimensions in schizophrenia and bipolar disorder patients after their first episode of psychosis. Symptom severity was associated with decreases in hippocampus/amygdala complex volume across groups. In keeping with previous work bilateral hippocampus and amygdala volume reductions were also identified in the SCZ patients while in BD patients only evidence of amygdala inflation reached significance. The study concludes that there appear to be important relationships between volume changes in the hippocampus and amygdala and dimensions and severity of symptomatology in psychosis. Structural alterations are apparent in both SCZ and BD after first episode of psychosis but present differently in each illness and are more severe in SCZ.     

Associations between major psychiatric disorder polygenic risk scores and blood-based markers in UK biobank

Major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD) have both shared and discrete genetic risk factors, and are associated with peripheral abnormalities. The relationships between such genetic architectures and blood-based markers are, however, unclear.We investigated relationships between polygenic risk scores (PRS) for these disorders and peripheral markers in the UK Biobank cohort. We calculated polygenic risk scores for n = 367,329 (MDD PRS), n = 366,465 (SCZ PRS), and n = 366,383 (BD PRS) UK Biobank cohort subjects. We then examined associations between disorder PRS and 58 inflammatory/immune, hematological, bone, cardiovascular, hormone, liver, renal and diabetes-associated blood markers using two generalized linear regression models: ‘minimally adjusted’ controlling for variables such as age and sex, and ‘fully adjusted’ including additional lifestyle covariates: BMI, alcohol and smoking status, and medication intake.There were 38/58 MDD PRS, 32/58 SCZ PRS, and 20/58 BD PRS-blood marker associations detected for our minimally adjusted model. Of these, 13/38 (MDD PRS), 14/32 (SCZ PRS), and 10/20 (BD PRS) associations remained significant after controlling for lifestyle factors. Many were disorder-specific, with 8/13 unique MDD PRS associations identified. Several disorder-specific associations for MDD and SCZ were immune-related, with mostly positive and negative associations identified for MDD and SCZ PRS respectively.This study suggests that MDD, SCZ and BD have both shared and distinct peripheral markers associated with disorder-specific genetic risk. The results also implicate inflammatory dysfunction in MDD and SCZ, albeit with differences in patterns between the two conditions, and enrich our understanding of potential underlying pathophysiological mechanisms in major psychiatric disorders.     

Striatal volumes in pediatric bipolar patients with and without comorbid ADHD

The most prevalent comorbid disorder in pediatric bipolar disorder (BD) is attention-deficit/hyperactivity disorder (ADHD). As caudate volume abnormalities have been demonstrated in both BD and ADHD, this study sought to determine whether these findings could be attributed to separable effects from either diagnosis. High resolution anatomical magnetic resonance (MRI) images were obtained from youth in 4 groups: BD with comorbid ADHD (n=17), BD without comorbid ADHD (n=12), youth with ADHD alone (n=11), and healthy control subjects (n=24). Caudate, putamen, and globus pallidus volumes were manually traced for each subject using BrainImageJava software by a reliable rater blinded to diagnosis. There was a significant effect of diagnosis on striatal volumes, with ADHD associated with decreased caudate and putamen volumes, and BD associated with increased caudate, putamen, and globus pallidus volumes. Thus, the presence or absence of comorbid ADHD in patients with BD was associated with distinct alterations in caudate volumes, suggesting that these groups have different, but related, mechanisms of neuropathology.     

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.     

Structural connectivity associated with familial risk for mental illness: A meta‐analysis of diffusion tensor imaging studies in relatives of patients with severe mental disorders

Schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) are heritable conditions with overlapping genetic liability. Transdiagnostic and disorder‐specific brain changes associated with familial risk for developing these disorders remain poorly understood. We carried out a meta‐analysis of diffusion tensor imaging (DTI) studies to investigate white matter microstructure abnormalities in relatives that might correspond to shared and discrete biomarkers of familial risk for psychotic or mood disorders. A systematic search of PubMed and Embase was performed to identify DTI studies in relatives of SCZ, BD, and MDD patients. Seed‐based d Mapping software was used to investigate global differences in fractional anisotropy (FA) between overall and disorder‐specific relatives and healthy controls (HC). Our search identified 25 studies that met full inclusion criteria. A total of 1,144 relatives and 1,238 HC were included in the meta‐analysis. The overall relatives exhibited decreased FA in the genu and splenium of corpus callosum (CC) compared with HC. This finding was found highly replicable in jack‐knife analysis and subgroup analyses. In disorder‐specific analysis, compared to HC, relatives of SCZ patients exhibited the same changes while those of BD showed reduced FA in the left inferior longitudinal fasciculus (ILF). The present study showed decreased FA in the genu and splenium of CC in relatives of SCZ, BD, and MDD patients, which might represent a shared familial vulnerability marker of severe mental illness. The white matter abnormalities in the left ILF might represent a specific familial risk for bipolar disorder.     

Cortical-basal ganglia imbalance in schizophrenia patients and unaffected first-degree relatives

Structural brain changes are amongst the most robust biological alterations in schizophrenia, and their investigation in unaffected relatives is important for an assessment of the contribution of genetic factors. In this cross-sectional morphometry study we investigated whether volume changes in SZ are linked with genetic vulnerability and whether these effects are separated from secondary illness effects. We compared density of grey and white matter using high-resolution 3D-anatomical MRI imaging data in 31 SZ patients, 29 first-degree relatives and 38 matched healthy controls, using Voxel-Based Morphometry (VBM) with SPM8. Volume of basal ganglia was also compared by manual segmentation. We found increased grey matter in the striatum, globus pallidus internus and thalamus and decreased grey matter in the parahippocampal and cingulate gyri both in SZ patients and relatives. Additionally, SZ patients had decreased volume of temporal, frontal and limbic grey and white matter in comparison with relatives and controls. Relatives showed intermediate values in many of these areas. Increased volume in the thalamus and parts of the basal ganglia and decreased volume of cortical areas and underlying white matter were thus associated with schizophrenia and its genetic vulnerability. These results suggest that brain morphological changes associated with SZ are in part determined by genetic risk factors and are not entirely explained by effects of medication or changes secondary to illness.     

The influence of polygenic risk for bipolar disorder on neural activation assessed using fMRI

Genome-wide association studies (GWAS) have demonstrated a significant polygenic contribution to bipolar disorder (BD) where disease risk is determined by the summation of many alleles of small individual magnitude. Modelling polygenic risk scores may be a powerful way of identifying disrupted brain regions whose genetic architecture is related to that of BD. We determined the extent to which common genetic variation underlying risk to BD affected neural activation during an executive processing/language task in individuals at familial risk of BD and healthy controls. Polygenic risk scores were calculated for each individual based on GWAS data from the Psychiatric GWAS Consortium Bipolar Disorder Working Group (PGC-BD) of over 16 000 subjects. The familial group had a significantly higher polygene score than the control group (P=0.04). There were no significant group by polygene interaction effects in terms of association with brain activation. However, we did find that an increasing polygenic risk allele load for BD was associated with increased activation in limbic regions previously implicated in BD, including the anterior cingulate cortex and amygdala, across both groups. The findings suggest that this novel polygenic approach to examine brain-imaging data may be a useful means of identifying genetically mediated traits mechanistically linked to the aetiology of BD.     

Use of magnetic resonance imaging for anatomical phenotyping of the R6/2 mouse model of Huntington's disease

Huntington's disease (HD) is a fatal, inherited neurodegenerative CAG disorder characterized by marked brain atrophy. We used magnetic resonance imaging (MRI) with manual volumetry for three dimensional (3D) morphological phenotyping of ex vivo brains of R6/2 mice, the most commonly used model of HD. High resolution 3D images were acquired for 18 week old wild-type (WT) and R6/2 mice. Although overall brain volumes were the same between genotypes, decreases in volumes were found in the cortex and striatum of R6/2 mice, with significant volume increases in the lateral ventricles and globus pallidus. There was no change in the volume of the amygdala, internal capsule or hippocampal formation. There was a significant increase in signal intensity in the globus pallidus, amygdala, cortex and striatum in R6/2 mice that may reflect neuronal atrophy. This study clearly shows the potential of MRI for morphological phenotyping of rodent models of HD and other neurological diseases. Having obtained proof-of-principle for the technique using ex vivo tissue, it is now our intention to carry out in vivo measurement of developing pathology in HD transgenic mice, and correlate this with behavioral deficits.     

Effects of childhood trauma on working memory in affective and non-affective psychotic disorders

Childhood trauma is a significant risk factor for the development of psychotic disorders, and may influence executive brain functions. We thus set out to investigate the long-term effects of childhood trauma exposure on brain function of adult chronic patients diagnosed with schizophrenia, schizoaffective disorder and (psychotic) bipolar-I disorder while performing a standard 2/0-back working memory task. Participants were 50 cases diagnosed with schizophrenia/schizoaffective disorder (SCZ), 42 cases with bipolar-I disorder (BD), and 47 healthy controls (HC). Among this sample, 56 clinical cases (SCZ?=?32; BD?=?24) and 17 HC reported significant levels of childhood trauma, while 36 clinical cases (SCZ?=?18; BD?=?18) and 30 HC did not. Effects of childhood trauma on working memory-related brain activation were examined in combined samples of clinical cases (independently of diagnosis) relative to HCs, as well as within each diagnostic category. Case–control analyses revealed increased activation of the left inferior parietal lobule as a main effect of trauma exposure. In addition, trauma exposure interacted with a diagnosis of SCZ or BD to reveal trauma-related increased activation in the cuneus in clinical cases and decreased activation in this region in controls. Disorder-specific functional alterations were also evident in the SCZ sample, but not BD. Childhood trauma exposure elicits aberrant function of parietal regions involved in working memory performance regardless of clinical status, as well as task-relevant visual regions that participates to attentional processes. Childhood trauma may therefore contribute to alterations in attention in SCZ and BD while performing an n-back working memory task.     

DNA hypomethylation of MB-COMT promoter in the DNA derived from saliva in schizophrenia and bipolar disorder

The failure in the discovery of etiology of psychiatric diseases, despite extensive genetic studies, has directed the attention of neuroscientists to the contribution of epigenetic modulations, which play important roles in fine-tuning of gene expression in response to environmental factors. Previously, we analyzed 115 human post-mortem brain samples from the frontal lobe and reported DNA hypo methylation of the membrane-bound catechol-O-methyltransferase (MB-COMT) gene promoter, associated with an increased gene expression, as a risk factor for schizophrenia (SCZ) and bipolar disorder (BD). Since most epigenetic modifications are tissue specific and the availability of brain tissue to identify epigenetic aberrations in living subjects is limited, detection of epigenetic abnormalities in other tissues that represent the brain epigenetic marks is one of the critical steps to develop diagnostic and therapeutic biomarkers for mental diseases. Here, hypothesizing that; those factors that lead to the brain MB-COMT promoter DNA hypo-methylation may also cause concurrent epigenetic aberrations in peripheral tissues, we analyzed MB-COMT promoter methylation in DNA derived from the saliva in SCZ, BD and their first-degree relatives (20 cases each) as well as 25 control subjects. Using bisulfite DNA sequencing and quantitative methylation specific PCR (qMSP), we found that similar to the brain, MB-COMT promoter was hypo-methylated (∼50%) in DNA derived from the saliva in SCZ and BD compared to the control subjects (p = 0.02 and 0.037, respectively). These studies suggest that DNA methylation analysis of MB-COMT promoter in saliva can potentially be used as an available epigenetic biomarker for disease state in SCZ and BD.     

Progressive grey matter alterations in bipolar disorder across the life span – A systematic review

Objectives

To elucidate the relationship between the course of bipolar disorder (BD) and structural brain changes across the life span, we conducted a systematic review of longitudinal imaging studies in adolescent and adult BD patients.

Methods

Eleven studies with 329 BD patients and 277 controls met our PICOS criteria (participants, intervention, comparison, outcome and study design): BD diagnosis based on DSM criteria, natural course of disease, comparison of grey matter changes in BD individuals over ≥1-year interval between scans.

Results

The selected studies yielded heterogeneous findings, partly due to varying patient characteristics, data acquisition and statistical models. Mood episodes were associated with greater grey matter loss in frontal brain regions over time. Brain volume decreased or remained stable in adolescent patients, whereas it increased in healthy adolescents. Adult BD patients showed increased cortical thinning and brain structural decline. In particular, disease onset in adolescence was associated with amygdala volume reduction, which was not reported in adult BD.

Conclusions

The evidence collected suggests that the progression of BD impairs adolescent brain development and accelerates structural brain decline across the lifespan. Age-specific changes in amygdala volume in adolescent BD suggest that reduced amygdala volume is a correlate of early onset BD. Clarifying the role of BD in brain development across the lifespan promises a deeper understanding of the progression of BD patients through different developmental episodes.     

Hippocampus, amygdala, and basal ganglia morphometrics in children after moderate-to-severe traumatic brain injury

While closed head injury frequently results in damage to the frontal and temporal lobes, damage to deep cortical structures, such as the hippocampus, amygdala, and basal ganglia, has also been reported. Five deep central structures (hippocampus, amygdala, globus pallidus, putamen, and caudate) were examined in 16 children (eight males, eight females; aged 9-16y), imaged 1 to 10 years after moderate-to-severe traumatic brain injury (TBI), and in 16 individually-matched uninjured children. Analysis revealed significant volume loss in the hippocampus, amydala, and globus pallidus of the TBI group. Investigation of relative volume loss between these structures and against five cortical areas (ventromedial frontal, superomedial frontal, lateral frontal, temporal, and parieto-occipital) revealed the hippocampus to be the most vulnerable structure following TBI (i.e. greatest relative difference between the groups). In a separate analysis excluding children with focal hippocampal abnormalities (e.g. lesions), group differences in hippocampal volume were still evident, suggesting that hippocampal damage may be diffuse rather than focal.     

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.     

Volume reduction in subcortical regions according to severity of Alzheimer’s disease

We investigated whether there exists a hierarchical vulnerability of subcortical structures with respect to the severity of Alzheimer’s disease (AD). A total of 236 subjects (179 with AD and 57 with normal cognition) underwent 1.5-T magnetic resonance (MR) imaging. The volumes of the five subcortical structures (amygdala, thalamus, putamen, globus pallidus, and caudate nucleus) and hippocampus were analyzed using a large deformation diffeomorphic metric mapping algorithm. The volume changes were evaluated according to the Clinical Dementia Rating (CDR). Correlation between the volumes of the subcortical structures and scores of the cognitive domain-specific neuropsychological tests were evaluated. Volume loss of the amygdala occurred even in the very mild stage of AD (CDR 0.5), as did volume loss in the hippocampus. Similar reductions in volume occurred in the thalamus and putamen, however during the mild (CDR 1) and moderate (CDR 2) stages of AD, respectively. The globus pallidus and caudate nucleus remained devoid of changes until the moderate stage of AD (p < 0.01). Volume loss in those subcortical structures correlated with the neuropsychological test scores (p < 0.01). Our results suggest that there is a hierarchical vulnerability in subcortical structures according to the clinical severity of AD and that subcortical volume reductions correlate with cognitive impairment.     

Association of MIF and MBL2 gene polymorphisms with attempted suicide in patients diagnosed with schizophrenia or bipolar disorder

The aim of this study to investigate the genetic polymorphisms in macrophage inhibitory factor (MIF) and mannose-binding lectin 2 (MBL2) gene in schizophrenia (SCZ) or bipolar disorder (BD) patients with attempted suicide by comparing with a non-attempted SCZ or BD patients and healthy controls. A sample of 108 patients with SCZ, 100 patients with BD and 100 healthy volunteers were included in the study. SCID-I was used to confirm the diagnosis according to DSM-IV-TR criteria. The patients were evaluated by data forms that included sociodemographic, suicidal behavior and symptom severity information. PCR-RFLP was used to determine MIF and MBL2 gene polymorphisms from DNA material. Our results demonstrated that the distributions of MBL2 genotype (AA, AB, BB), combined genotype (AA, AB/BB) and the allele frequencies (A, B) of attempted suicide patients in SCZ were significantly different from the non-attempted SCZ patients. The distributions of the MBL2 genotype of attempted suicide patients in SCZ were significantly different from the control group. The distributions of MIF genotype (GG, GC, CC), combined genotype (GG, GC/CC) and the allele frequencies (G, C) of attempted suicide patients in BD were significantly different from the non-attempted BD patients or control group. In summary MBL2 gene polymorphism may be associated with attempted suicide in SCZ and MIF gene polymorphism might be associated with attempted suicide in BD. However, further studies with other gene variants in different ethnic populations are needed to address the exact role of these polymorphisms in SCZ or BD.     

Neuroanatomical abnormalities as risk factors for bipolar disorder

OBJECTIVE: Neuroimaging studies show structural brain abnormalities in bipolar patients. Some of the abnormalities may represent biological risk factors conveying vulnerability for the disease. This paper aims to identify neuroanatomical risk factors for bipolar disorder (BD). METHODS: We reviewed magnetic resonance imaging (MRI) findings in populations in which the effects of the disease or treatment are minimal or where the chances of finding genetically coded risk factors shared within the families are increased. Such populations include unaffected relatives of bipolar patients, first-episode patients, children or adolescents with BD and patients with familial BD. RESULTS: MEDLINE search revealed 30 relevant scientific papers. Abnormalities in the volume of the striatum, left hemispheric white matter, thalamus and anterior cingulate as well as quantitative MRI signal hyperintensities were identified already in unaffected relatives of bipolar patients. Subjects in the early stages of the disease showed volume changes of the ventricles, white matter, caudate, putamen, amygdala, hippocampus and the subgenual prefrontal cortex. Reduction in the subgenual prefrontal cortex volume was replicated in three of four studies in patients with familial BD. CONCLUSIONS: Possible candidates for neuroanatomical risk factors for BD are volumetric abnormalities of the subgenual prefrontal cortex, striatum, white matter, and probably also the hippocampus and amygdala. Qualitative finding of white matter hyperintensities was already utilized as an endophenotype.     

Subcortical Gray Matter Volume Abnormalities in Healthy Bipolar Offspring: Potential Neuroanatomical Risk Marker for Bipolar Disorder?

ObjectiveA growing number of structural neuroimaging studies have shown that bipolar disorder (BD) is associated with gray matter (GM) volume abnormalities in brain regions known to support affect regulation. The goal of this study was to examine whole-brain regional GM volume in healthy bipolar offspring (HBO) relative to age-matched controls to identify possible structural abnormalities that may be associated with risk for BD.MethodParticipants were 20 youths (8-17 years old) with at least one parent diagnosed with BD, and 22 age-matched healthy individuals. All of them were free of Axis I diagnoses. High-resolution magnetic resonance imaging structural images were acquired using a 3-T Siemens scanner. Voxel-based morphometric analyses were conducted using SPM5.ResultsRelative to controls, HBO had significantly increased GM volume in left parahippocampal/hippocampal gyrus (p <.05 corrected), following whole-brain analyses. This increase was correlated with puberty but not age in HBO. Region-of-interest analyses on the amygdala and orbitomedial prefrontal cortex did not yield any significant group differences after conducting small volume correction.ConclusionsThe pattern of increased GM volume in parahippocampal/hippocampal gyrus in HBO suggests a potential marker for risk for BD. It can also be considered as a potential neuroprotective marker for the disorder because HBO were free of current psychopathology. Prospective studies examining the relationship between changes in GM volume in these regions and subsequent development of BD in HBO will allow us to elucidate further the role of this region in either conferring risk for or protecting against the development of BD.     

Genes contributing to subcortical volumes and intellectual ability implicate the thalamus

It has been shown that brain volume and general intellectual ability are to a significant extent influenced by the same genetic factors. Several cortical regions of the brain also show a genetic correlation with intellectual ability, demonstrating that intellectual functioning is probably represented in a heritable distributed network of cortical regions throughout the brain. This study is the first to investigate a genetic association between subcortical volumes and intellectual ability, taking into account the thalamus, caudate nucleus, putamen, globus pallidus, hippocampus, amygdala, and nucleus accumbens using an extended twin design. Genetic modeling was performed on a healthy adult twin sample consisting of 106 twin pairs and 30 of their siblings, IQ data was obtained from 132 subjects. Our results demonstrate that of all subcortical volumes measured, only thalamus volume is significantly correlated with intellectual functioning. Importantly, the association found between thalamus volume and intellectual ability is significantly influenced by a common genetic factor. This genetic factor is also implicated in cerebral brain volume. The thalamus, with its widespread cortical connections, may thus play a key role in human intelligence. Hum Brain Mapp 35:2632–2642, 2014. © 2013 Wiley Periodicals, Inc.     

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.     

Reduced amygdalar gray matter volume in familial pediatric bipolar disorder

OBJECTIVE: Subcortical limbic structures have been proposed to be involved in the pathophysiology of adult and pediatric bipolar disorder (BD). We sought to study morphometric characteristics of these structures in pediatric subjects with familial BD compared with healthy controls. METHOD: Twenty children and adolescents with BD I (mean age = 4.6 years, four females) and 20 healthy age, gender, and IQ-matched controls underwent high-resolution magnetic resonance imaging at 3 T. Patients were mostly euthymic and most were taking medications. Amygdala, hippocampus, thalamus, and caudate volumes were determined by manual tracings from researchers blinded to diagnosis. Analyses of covariance were performed, with total brain volume, age, and gender as covariates. RESULTS:No differences were found in the volumes of hippocampus, caudate, and thalamus between subjects with BD and controls. Subjects with BD had smaller volumes in the left and right amygdala, driven by reductions in gray matter volume. Exploratory analyses revealed that subjects with BD with past lithium or valproate exposure tended to have greater amygdalar gray matter volume than subjects with BD without such exposure. CONCLUSIONS: Children and adolescents with early-onset BD may have reduced amygdalar volumes, consistent with other studies in this population. Prolonged medication exposure to lithium or valproate may account for findings in adults with BD of increased amygdalar volume relative to controls.