Abnormal amygdala and prefrontal cortex activation to facial expressions in pediatric bipolar disorder.

OBJECTIVE: Previous functional magnetic resonance imaging (fMRI) studies in pediatric bipolar disorder (BD) have reported greater amygdala and less dorsolateral prefrontal cortex (DLPFC) activation to facial expressions compared to healthy controls. The current study investigates whether these differences are associated with the early or late phase of activation, suggesting different temporal characteristics of brain responses. METHOD: A total of 20 euthymic adolescents with familial BD (14 male) and 21 healthy control subjects (13 male) underwent fMRI scanning during presentation of happy, sad, and neutral facial expressions. Whole-brain voxelwise analyses were conducted in SPM5, using a three-way analysis of variance (ANOVA) with factors group (BD and healthy control [HC]), facial expression (happy, sad, and neutral versus scrambled), and phase (early and late, corresponding to the first and second half of each block of faces). RESULTS: There were no significant group differences in task performance, age, gender, or IQ. Significant activation from the main effect of group included greater DLPFC activation in the HC group, and greater amygdala/hippocampal activation in the BD group. The interaction of Group × Phase identified clusters in the superior temporal sulcus/insula and visual cortex, where activation increased from the early to late phase of the block for the BD but not the HC group. CONCLUSIONS: These findings are consistent with previous studies that suggest deficient prefrontal cortex regulation of heightened amygdala response to emotional stimuli in pediatric BD. Increasing activation over time in superior temporal and visual cortices suggests difficulty processing or disengaging attention from emotional faces in BD.

Brain activation to facial expressions in youth with PTSD symptoms.

OBJECTIVE: This study examined activation to facial expressions in youth with a history of interpersonal trauma and current posttraumatic stress symptoms (PTSS) compared to healthy controls (HC). DESIGN AND ANALYSIS: Twenty-three medication-naive youth with PTSS and 23 age- and gender-matched HC underwent functional magnetic resonance imaging (fMRI) while viewing fearful, angry, sad, happy, and neutral faces. Data were analyzed for group differences in location of activation, as well as timing of activation during the early versus late phase of the block. Using SPM5, significant activation (P < .05 FWE [Family-Wise Error] corrected, extent = 10 voxels) associated with the main effect of group was identified. Activation from selected clusters was extracted to SPSS software for further analysis of specific facial expressions and temporal patterns of activation. RESULTS: The PTSS group showed significantly greater activation than controls in several regions, including the amygdala/hippocampus, medial prefrontal cortex, insula, and ventrolateral prefrontal cortex, and less activation than controls in the dorsolateral prefrontal cortex (DLPFC). These group differences in activation were greatest during angry, happy, and neutral faces, and predominantly during the early phase of the block. Post hoc analyses showed significant Group × Phase interactions in the right amygdala and left hippocampus. CONCLUSIONS: Traumatic stress may impact development of brain regions important for emotion processing. Timing of activation may be altered in youth with PTSS.

Amygdalar, hippocampal, and thalamic volumes in youth at high risk for development of bipolar disorder.

Children of parents with bipolar disorder (BD), especially those with attention deficit hyperactivity disorder (ADHD) and symptoms of depression or mania, are at significantly high risk for developing BD. As we have previously shown amygdalar reductions in pediatric BD, the current study examined amygdalar volumes in offspring of parents (BD offspring) who have not yet developed a full manic episode. Youth participating in the study included 22 BD offspring and 22 healthy controls of comparable age, gender, handedness, and IQ. Subjects had no history of a manic episode, but met criteria for ADHD and moderate mood symptoms. MRI was performed on a 3T GE scanner, using a 3D volumetric spoiled gradient echo series. Amygdalae were manually traced using BrainImage Java software on positionally normalized brain stacks. Bipolar offspring had similar amygdalar volumes compared to the control group. Exploratory analyses yielded no differences in hippocampal or thalamic volumes. Bipolar offspring do not show decreased amygdalar volume, possibly because these abnormalities occur after more prolonged illness rather than as a preexisting risk factor. Longitudinal studies are needed to determine whether amygdalar volumes change during and after the development of BD.

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.

Increased subgenual cingulate cortex volume in pediatric bipolar disorder associated with mood stabilizer exposure.

OBJECTIVE: The subgenual cingulate (SGC) cortex has been implicated in the pathophysiology of mood disorders. We sought to study morphometric characteristics of the SGC in pediatric subjects with familial bipolar disorder (BD) compared with healthy controls. METHOD: Twenty children and adolescents with BD (mean age = 14.6 years, 4 females) and 20 healthy age-, gender-, and intelligence quotient-matched controls underwent high-resolution anatomical magnetic resonance imaging. Patients were primarily euthymic and most were taking medications. SGC cortex volumes were determined by manual tracings from a reliable rater, blinded to diagnosis. Analyses of covariance were performed with total cerebral gray matter and age as covariates. RESULTS: No differences were found in SGC volumes between BD subjects and healthy controls. Further analysis revealed that BD subjects with past mood stabilizer exposure had significantly increased SGC volumes compared with BD subjects without mood stabilizer exposure, and compared with controls. The increase was driven by larger bilateral posterior SGC volumes. CONCLUSIONS: Youth with familial BD do not appear to have abnormalities in SGC volume. Mood stabilizer exposure, however, may be correlated with increases in SGC volume.

Subcortical volumetric correlates of anxiety in familial pediatric bipolar disorder: a preliminary investigation.

Anxiety is a common comorbid condition in pediatric bipolar disorder (BD). However, there is little known about the effects of comorbidity on brain morphometry in this population. The aim of the present study was to examine subcortical correlates of anxiety in familial pediatric BD. The subject group comprised 120 children (mean age=12+/-3.3 years) with at least one parent diagnosed with BD. Bipolar offspring with BD were compared with bipolar offspring without BD on a measure of overall lifetime anxiety. A sub-sample of 20 bipolar offspring with BD (mean age=14.6+/-2.8 years) underwent magnetic resonance imaging (MRI) with a 3-T scanner. Correlational analyses were conducted between hippocampal and amygdalar volumes, and anxiety scores. The results showed significantly higher anxiety in bipolar offspring with BD compared to bipolar offspring without BD. There was a significant negative association between total hippocampal volume and anxiety scores. No significant association was found between total amygdalar volume and anxiety scores. Clinically, these findings suggest that anxiety comorbidity needs to be properly assessed and treated in the management of pediatric BD. This is the first study to show a negative association between hippocampal volume and anxiety in this population. The overlap between anxiety and familial pediatric BD suggests that anxiety may be one important area of future research in parsing out the heterogeneous nature and complex etiology of early-onset BD.

Limbic and corpus callosum aberrations in adolescents with bipolar disorder: a tract-based spatial statistics analysis.

BACKGROUND: Bipolar disorder (BD) is a common and debilitating condition, often beginning in adolescence. Converging evidence from genetic and neuroimaging studies indicates that white matter abnormalities may be involved in BD. In this study, we investigated white matter structure in adolescents with familial bipolar disorder using diffusion tensor imaging (DTI) and a whole brain analysis. METHODS: We analyzed DTI images using tract-based spatial statistics (TBSS), a whole-brain voxel-by-voxel analysis, to investigate white matter structure in 21 adolescents with BD, who also were offspring of at least one parent with BD, and 18 age- and IQ-matched control subjects. Fractional anisotropy (FA; a measure of diffusion anisotropy), trace values (average diffusivity), and apparent diffusion coefficient (ADC; a measure of overall diffusivity) were used as variables in this analysis. In a post hoc analysis, we correlated between FA values, behavioral measures, and medication exposure. RESULTS: Adolescents with BD had lower FA values than control subjects in the fornix, the left mid-posterior cingulate gyrus, throughout the corpus callosum, in fibers extending from the fornix to the thalamus, and in parietal and occipital corona radiata bilaterally. There were no significant between-group differences in trace or ADC values and no significant correlation between behavioral measures, medication exposure, and FA values. CONCLUSIONS: Significant white matter tract alterations in adolescents with BD were observed in regions involved in emotional, behavioral, and cognitive regulation. These results suggest that alterations in white matter are present early in the course of disease in familial BD.

Effect of divalproex on brain morphometry, chemistry, and function in youth at high-risk for bipolar disorder: a pilot study.

OBJECTIVE: Divalproex has been found efficacious in treating adolescents with and at high risk for bipolar disorder (BD), but little is known about the effects of mood stabilizers on the brain itself. We sought to examine the effects of divalproex on the structure, chemistry, and function of specific brain regions in children at high-risk for BD. METHODS: A total of 24 children with mood dysregulation but not full BD, all offspring of a parent with BD, were treated with divalproex monotherapy for 12 weeks. A subset of 11 subjects and 6 healthy controls were scanned with magnetic resonance imaging (MRI, magnetic resonance spectroscopy [MRS], and functional MRI [fMRI]) at baseline and after 12 weeks. RESULTS: There were no significant changes in amygdalar or cortical volume found over 12 weeks. Furthermore, no changes in neurometabolite ratios were found. However, we found the degree of decrease in prefrontal brain activation to correlate with degree of decrease in depressive symptom severity. CONCLUSIONS: Bipolar offspring at high risk for BD did not show gross morphometric, neurometabolite, or functional changes after 12 weeks of treatment with divalproex. Potential reasons include small sample size, short exposure to medications, or lack of significant neurobiological impact of divalproex in this particular population.

Anomalous sylvian fissure morphology in Williams syndrome.

The unusual sensitivity and attraction to auditory stimuli in people with Williams syndrome (WS) has been hypothesized to be the consequence of atypical development of brain regions surrounding the Sylvian fissure. Planum temporale surface area, which is determined in part by Sylvian fissure patterning, was examined in 42 WS and 40 control participants to determine if anomalous Sylvian fissure morphology is present in WS. WS participants had significantly reduced leftward asymmetry of the planum temporale compared to control participants, due to a significant expansion in the size of the right planum temporale. The increased right planum temporale size was largely due to WS participants (24%) who had a right hemisphere Sylvian fissure that coursed horizontally and failed to ascend into the parietal lobe. This sulcal pattern is unusual in the right hemisphere and is more commonly found in the left hemisphere of typically developing individuals. There were no control participants with this type of right hemisphere Sylvian fissure pattern. The right hemisphere Sylvian fissure sulcal patterns were also related to a measure of cortical complexity and the amount of right hemisphere occipital lobe volume, suggesting that intrinsic genetic influences leading to anomalous visual system development in WS have widespread influences on cortical morphology that are similar in manner to extrinsic embryonic visual system lesions.

Regional differences of the prefrontal cortex in pediatric PTSD: an MRI study.

Previous studies have revealed altered structural development of the frontal lobes and prefrontal cortex (PFC) in children with symptoms of posttraumatic stress disorder (PTSD). This study is the first to provide a detailed structural analysis of the PFC in children with and without PTSD symptoms. We compared gray and white matter volume in four subregions of the PFC between said groups, then explored whether volume was associated with PTSD symptom severity and functional impairment. PFC measurements were extracted from magnetic resonance imaging (MRI) data from a sample of 23 children (ages 7-14) with a history of trauma and symptoms of PTSD, who had undergone assessment for PTSD symptoms and functional impairment using the Child and Adolescent version of the Clinician-Administered PTSD Scale (CAPS-CA). These measurements were compared to data from an age-equivalent control group of 24 healthy children. Children with PTSD symptoms showed a significantly larger volume of gray matter in the delineated middle-inferior and ventral regions of the PFC than did control children. Decreased volume of gray matter in the dorsal PFC correlated with increased functional impairment scores. Results indicate that increased volume of the middle-inferior and ventral PFC may be associated with trauma and PTSD symptoms in children. Furthermore, the neuroanatomy of the dorsal PFC may influence the degree of functional impairment experienced by children with PTSD symptoms.

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.

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 = 14.6 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.

White matter development during childhood and adolescence: a cross-sectional diffusion tensor imaging study.

Maturation of brain white matter pathways is an important factor in cognitive, behavioral, emotional and motor development during childhood and adolescence. In this study, we investigate white matter maturation as reflected by changes in anisotropy and white matter density with age. Thirty-four children and adolescents aged 6-19 years received diffusion-weighted magnetic resonance imaging scans. Among these, 30 children and adolescents also received high-resolution T1-weighed anatomical scans. A linear regression model was used to correlate fractional anisotropy (FA) values with age on a voxel-by-voxel basis. Within the regions that showed significant FA changes with age, a post hoc analysis was performed to investigate white matter density changes. With increasing age, FA values increased in prefrontal regions, in the internal capsule as well as in basal ganglia and thalamic pathways, the ventral visual pathways, and the corpus callosum. The posterior limb of the internal capsule, intrathalamic connections, and the corpus callosum showed the most significant overlaps between white matter density and FA changes with age. This study demonstrates that during childhood and adolescence, white matter anisotropy changes in brain regions that are important for attention, motor skills, cognitive ability, and memory. This typical developmental trajectory may be altered in individuals with disorders of development, cognition and behavior.

N-acetylaspartate levels in bipolar offspring with and at high-risk for bipolar disorder.

OBJECTIVES: Studies have reported decreased N-acetylaspartate (NAA) in dorsolateral prefrontal cortex (DLPFC) of adults and children with bipolar disorder (BD), suggesting decreased neuronal density in this area. However, it is unclear if this finding represents neurodegeneration after or a trait marker present before BD onset. To address this question, we used proton magnetic resonance spectroscopy ((1)H-MRS) to compare DLPFC levels of NAA among bipolar offspring with early-onset BD, bipolar offspring with subsyndromal symptoms of BD and healthy children. METHODS: Participants were 9-18 years old, and included 60 offspring of parents with bipolar I or II disorder (32 with BD and 28 with subsyndromal symptoms of BD), and 26 healthy controls. (1)H-MRS at 3 T was used to study 8-cm(3) voxels placed in left and right DLPFC. RESULTS: There were no significant group differences in mean right or left DLPFC NAA/Cr ratios. Exploratory analyses of additional metabolites (myoinositol, choline) also yielded no significant group differences. NAA/Cr ratios were not correlated with age, duration of illness, or exposure to lithium or valproate. CONCLUSIONS: Our findings suggest that DLPFC NAA/Cr ratios cannot be used as a trait marker for BD. Although we did not find decreased DLPFC NAA/Cr ratios in children and adolescents with BD, it is still possible that such levels begin to decrease after longer durations of illness into adulthood. Longitudinal neuroimaging studies of patients with BD accounting for developmental and treatment factors are needed to further clarify the neurodegenerative aspects of BD.

An experiment of nature: brain anatomy parallels cognition and behavior in Williams syndrome.

Williams syndrome (WS) is a neurogenetic-neurodevelopmental disorder characterized by a highly variable and enigmatic profile of cognitive and behavioral features. Relative to overall intellect, affected individuals demonstrate disproportionately severe visual-spatial deficits and enhanced emotionality and face processing. In this study, high-resolution magnetic resonance imaging data were collected from 43 individuals with WS and 40 age- and gender-matched healthy controls. Given the distinct cognitive-behavioral dissociations associated with this disorder, we hypothesized that neuroanatomical integrity in WS would be diminished most in regions comprising the visual-spatial system and most "preserved" or even augmented in regions involved in emotion and face processing. Both volumetric analysis and voxel-based morphometry were used to provide convergent approaches for detecting the hypothesized WS neuroanatomical profile. After adjusting for overall brain volume, participants with WS showed reduced thalamic and occipital lobe gray matter volumes and reduced gray matter density in subcortical and cortical regions comprising the human visual-spatial system compared with controls. The WS group also showed disproportionate increases in volume and gray matter density in several areas known to participate in emotion and face processing, including the amygdala, orbital and medial prefrontal cortices, anterior cingulate, insular cortex, and superior temporal gyrus. These findings point to specific neuroanatomical correlates for the unique topography of cognitive and behavioral features associated with this disorder.