Asya Karchemskiy

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.

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.

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.

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.

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.

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.

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.

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.