Lara C. Foland-Ross

Amygdala astrocyte reduction in subjects with major depressive disorder but not bipolar disorder

OBJECTIVESnSeveral magnetic resonance imaging studies have found changes in amygdala volumes in adults with mood disorders. The cellular basis for these changes has not been explored in detail. Specifically, it is not known whether differences in the density and/or volume of neurons or glial cells contribute to tissue volume changes seen on magnetic resonance images.nnnMETHODSnPostmortem amygdala samples were obtained from the Stanley Foundation Neuropathology Consortium from subjects diagnosed with bipolar disorder (n = 10), major depressive disorder (n = 11), and schizophrenia (n = 9), and from normal controls (n = 14). Samples were first stained with glial fibrillary acidic protein (GFAP) and counter-stained with hematoxylin to ascertain neuron and glia (astrocyte) densities.nnnRESULTSnNo significant differences in neuronal densities were found between groups. However, a reduction in the density of GFAP immunoreactive astrocytes was observed in the amygdala of subjects with major depressive disorder compared to the bipolar disorder, schizophrenia, and normal control postmortem samples.nnnCONCLUSIONSnA decrease in density of GFAP immunoreactive astrocytes in the amygdala of depressed subjects is consistent with prior histologic reports and might contribute to amygdala volume reductions reported in several in vivo neuroimaging studies.

fMRI activation in the amygdala and the orbitofrontal cortex in unmedicated subjects with major depressive disorder.

Although amygdala and frontal lobe functional abnormalities have been reported in patients with mood disorders, the literature regarding major depressive disorder (MDD) is inconsistent. Likely confounds include heterogeneity of patient samples, medication status, and analytic approach. This study evaluated the amygdala and frontal lobe activation in unmedicated MDD patients. Fifteen MDD patients and 15 matched healthy controls were scanned using fMRI during the performance of an emotional face task known to robustly activate the amygdala and prefrontal cortex (PFC). Whole-brain and region of interest analyses were performed, and correlations between clinical features and activation were examined. Significant amygdala and lateral PFC activation were seen within patient and control groups. In a between-group comparison, patients showed significantly reduced activation in the insula, temporal and occipital cortices. In MDD, the presence of anxiety symptoms was associated with decreased orbitofrontal activation. We found robust activation in both the MDD and control groups in fronto-limbic regions with no significant between-group differences using either analytic approach. The current study replicates previous research on unmedicated subjects showing no significant differences in amygdala function in depressed vs. control subjects with respect to simple tasks involving emotion observation.

Normal amygdala activation but deficient ventrolateral prefrontal activation in adults with bipolar disorder during euthymia

Functional neuroimaging studies have implicated the involvement of the amygdala and ventrolateral prefrontal cortex (vlPFC) in the pathophysiology of bipolar disorder. Hyperactivity in the amygdala and hypoactivity in the vlPFC have been reported in manic bipolar patients scanned during the performance of an affective faces task. Whether this pattern of dysfunction persists during euthymia is unclear. Using functional magnetic resonance imaging (fMRI), 24 euthymic bipolar and 26 demographically matched healthy control subjects were scanned while performing an affective task paradigm involving the matching and labeling of emotional facial expressions. Neuroimaging results showed that, while amygdala activation did not differ significantly between groups, euthymic patients showed a significant decrease in activation of the right vlPFC (BA47) compared to healthy controls during emotion labeling. Additionally, significant decreases in activation of the right insula, putamen, thalamus and lingual gyrus were observed in euthymic bipolar relative to healthy control subjects during the emotion labeling condition. These data, taken in context with prior studies of bipolar mania using the same emotion recognition task, could suggest that amygdala dysfunction may be a state-related abnormality in bipolar disorder, whereas vlPFC dysfunction may represent a trait-related abnormality of the illness. Characterizing these patterns of activation is likely to help in understanding the neural changes related to the different mood states in bipolar disorder, as well as changes that represent more sustained abnormalities. Future studies that assess mood-state related changes in brain activation in longitudinal bipolar samples would be of interest.

White matter microstructural abnormalities in bipolar disorder: A whole brain diffusion tensor imaging study

Background Bipolar disorder (BD) is a chronic mental illness characterized by severe disruptions in mood and cognition. Diffusion tensor imaging (DTI) studies suggest that white matter (WM) tract abnormalities may contribute to the clinical hallmarks of the disorder. Using DTI and whole brain voxel-based analysis, we mapped the profile of WM anomalies in BD. All patients in our sample were euthymic and lithium free when scanned. Methods Diffusion-weighted and T1-weighted structural brain images were acquired from 23 lithium-free euthymic subjects with bipolar I disorder and 19 age- and sex-matched healthy control subjects on a 1.5 T MRI scanner. Scans were processed to provide measures of fractional anisotropy (FA) and mean and radial diffusivity (MD and RD) at each WM voxel, and processed scans were nonlinearly aligned to a customized brain imaging template for statistical group comparisons. Results Relative to controls, the bipolar group showed widespread regions of lower FA, including the corpus callosum, cortical and thalamic association fibers. MD and RD were abnormally elevated in patients in many of these same regions. Conclusions Our findings agree with prior reports of WM abnormalities in the corpus callosum and further link a bipolar diagnosis with structural abnormalities of the tapetum, fornix and stria terminalis. Future studies assessing the diagnostic specificity and prognostic implications of these abnormalities would be of interest.

Amygdala reactivity in healthy adults is correlated with prefrontal cortical thickness

Recent evidence suggests that putting feelings into words activates the prefrontal cortex (PFC) and suppresses the response of the amygdala, potentially helping to alleviate emotional distress. To further elucidate the relationship between brain structure and function in these regions, structural and functional magnetic resonance imaging (MRI) data were collected from a sample of 20 healthy human subjects. Structural MRI data were processed using cortical pattern-matching algorithms to produce spatially normalized maps of cortical thickness. During functional scanning, subjects cognitively assessed an emotional target face by choosing one of two linguistic labels (label emotion condition) or matched geometric forms (control condition). Manually prescribed regions of interest for the left amygdala were used to extract percentage signal change in this region occurring during the contrast of label emotion versus match forms. A correlation analysis between left amygdala activation and cortical thickness was then performed along each point of the cortical surface, resulting in a color-coded r value at each cortical point. Correlation analyses revealed that gray matter thickness in left ventromedial PFC was inversely correlated with task-related activation in the amygdala. These data add support to a general role of the ventromedial PFC in regulating activity of the amygdala.

Mood-state effects on amygdala volume in bipolar disorder

BACKGROUNDnPrior structural neuroimaging studies of the amygdala in patients with bipolar disorder have reported higher or lower volumes, or no difference relative to healthy controls. These inconsistent findings may have resulted from combining subjects in different mood states. The prefrontal cortex has recently been reported to have a lower volume in depressed versus euthymic bipolar patients. Here we examined whether similar mood state-dependent volumetric differences are detectable in the amygdala.nnnMETHODSnForty subjects, including 28 with bipolar disorder type I (12 depressed and 16 euthymic), and 12 healthy comparison subjects were scanned on a 3T magnetic resonance image (MRI) scanner. Amygdala volumes were manually traced and compared across subject groups, adjusting for sex and total brain volume.nnnRESULTSnStatistical analyses found a significant effect of mood state and hemisphere on amygdala volume. Subsequent comparisons revealed that amygdala volumes were significantly lower in the depressed bipolar group compared to both the euthymic bipolar (p=0.005) and healthy control (p=0.043) groups.nnnLIMITATIONSnOur study was cross-sectional and some patients were medicated.nnnCONCLUSIONSnOur results suggest that mood state influences amygdala volume in subjects with bipolar disorder. Future studies that replicate these findings in unmedicated patient samples scanned longitudinally are needed.

Three-dimensional mapping of hippocampal and amygdalar structure in euthymic adults with bipolar disorder not treated with lithium.

Structural neuroimaging studies of the amygdala and hippocampus in bipolar disorder have been largely inconsistent. This may be due in part to differences in the proportion of subjects taking lithium or experiencing an acute mood state, as both factors have recently been shown to influence gray matter structure. To avoid these problems, we evaluated euthymic subjects not currently taking lithium. Thirty-two subjects with bipolar type I disorder and 32 healthy subjects were scanned using magnetic resonance imaging. Subcortical regions were manually traced, and converted to three-dimensional meshes to evaluate the main effect of bipolar illness on radial distance. Statistical analyses found no evidence for a main effect of bipolar illness in either region, although exploratory analyses found a significant age by diagnosis interaction in the right amygdala, as well as positive associations between radial distance of the left amygdala and both prior hospitalizations for mania and current medication status. These findings suggest that, when not treated with lithium or in an acute mood state, patients with bipolar disorder exhibit no structural abnormalities of the amygdala or hippocampus. Future studies, nevertheless, that further elucidate the impact of age, course of illness, and medication on amygdala structure in bipolar disorder are warranted.

Frontostriatal neuroimaging findings differ in patients with bipolar disorder who have or do not have ADHD comorbidity

BACKGROUNDnThe inferior frontal cortical (IFC)-striatal network plays an integral role in response inhibition and is compromised in patients with Bipolar Disorder (BP) or Attention-Deficit/Hyperactivity Disorder (ADHD). Prior BP functional neuroimaging studies have not accounted for ADHD comorbidity despite its high prevalence.nnnMETHODSnThe authors conducted an fMRI study using a response inhibition task (Go-NoGo) in 32 euthymic adults with BP, half with comorbid ADHD (BP/ADHD); 16 adults with ADHD alone; and 30 healthy controls. Within- and between-group whole-brain analyses were performed to assess for significant neural function differences.nnnRESULTSnAll groups activated frontal and striatal regions involved in response inhibition. ANOVA results demonstrated significant interaction effects of BP and ADHD in the anterior and posterior cingulate, left superior and middle frontal gyri and left inferior parietal lobule. Follow-up comparisons showed significant differences between BP subjects with and without ADHD. Other regions demonstrated main effects of BP (left inferior frontal gyrus, left middle frontal gyrus, right superior frontal gyrus and left insula) and ADHD (left inferior frontal gyrus, left precentral gyrus and right anterior cingulate).nnnLIMITATIONSnThis study, as the first of its kind, requires replication using large sample sizes and controlling for potential effects of medication.nnnCONCLUSIONSnEuthymic bipolar adults with comorbid ADHD have significantly different neural activation patterns from BP patients without this comorbidity. If understanding of the neurobiology of bipolar disorder is to be achieved, it is critical to control for this potential confound, something not done by most prior fMRI studies of adults with BP.

A DTI Study of Monozygotic Twins Discordant for Obsessive-Compulsive Symptoms

Introduction: Obsessive-compulsive disorder (OCD) affects approximately 2-3% of the population and is characterized by recurrent, persistent, and intrusive anxiety-provoking thoughts or images (obsessions) and subsequent repetitive behaviors (compulsions). A clinical diagnosis of OCD requires impairment, but OC symptoms (OCS) are highly prevalent in the general population (70-80%). Structural magnetic resonance imaging studies indicated several gray matter abnormalities in OCD patients compared to unaffected controls that overall point to a deficit in cortico-striatal-thalamocortical circuits. Recent diffusion tensor imaging (DTI) studies also find white matter abnormalities generally overlapping with the reported gray matter findings. However, there are still inconsistencies regarding the brain structures involved and the direction of anatomical changes. A reason for this could be the differential impact of genetic and environmental risk factors for OCD that do not necessarily lead to identical underlying neurobiological changes. Heritability for OCS ranges from 2747% in adults and 45-65% in children. If genetic factors explain 27-65% of the variability in OCS, as much as 35-73% should be accounted for by environmental stressors. The discordant monozygotic (MZ) twin design can reveal brain differences specifically due to influences of environmental risk factors. MZ twins are genetically identical; therefore differences in behavior must reflect exposure to individual-specific environment. Here we used DTI to scan twin pairs discordant for OCS to highlight white matter brain regions linked to OCS that are particularly susceptible to environmental factors.

Preliminary evidence of within-subject changes in gray matter density associated with remission of bipolar depression

A preliminary within-subjects MRI study of seven patients with a diagnosis of bipolar I disorder revealed that, compared to remission, depression was associated with gray matter density increases in subgenual prefrontal cortex, parahippocampal gyrus, and inferior temporal gyri. Decreases were observed in superior and inferior frontal gyri and anterior cingulate.