Jennifer Townsend

Evidence for deficient modulation of amygdala response by prefrontal cortex in bipolar mania.

Several studies have implicated the involvement of two major components of emotion regulatory networks, the ventrolateral prefrontal cortex (VLPFC) and amygdala, in the pathophysiology of bipolar disorder. In healthy subjects, the VLPFC has been shown to negatively modulate amygdala response when subjects cognitively evaluate an emotional face by identifying and labeling the emotion it expresses. The current study used such a paradigm to assess whether the strength of this modulation was altered in bipolar subjects when manic. During functional magnetic resonance imaging (fMRI), nine manic subjects with bipolar I disorder and nine healthy subjects either named the emotion shown in a face by identifying one of two words that correctly expressed the emotion (emotion labeling task) or matched the emotion shown in a face to one of two other faces (emotion perception task). The degree to which the VLPFC regulated amygdala response during these tasks was assessed using a psychophysiological interaction (PPI) analysis. Compared with healthy subjects, manic patients had a significantly reduced VLPFC regulation of amygdala response during the emotion labeling task. These findings, taken in context with previous fMRI studies of bipolar mania, suggest that reductions in inhibitory frontal activity in these patients may lead to an increased reactivity of the amygdala.

Blunted activation in orbitofrontal cortex during mania : A functional magnetic resonance imaging study

BACKGROUND Patients with bipolar disorder have been reported to have abnormal cortical function during mania. In this study, we sought to investigate neural activity in the frontal lobe during mania, using functional magnetic resonance imaging (fMRI). Specifically, we sought to evaluate activation in the lateral orbitofrontal cortex, a brain region that is normally activated during activities that require response inhibition. METHODS Eleven manic subjects and 13 control subjects underwent fMRI while performing the Go-NoGo task, a neuropsychological paradigm known to activate the orbitofrontal cortex in normal subjects. Patterns of whole-brain activation during fMRI scanning were determined with statistical parametric mapping. Contrasts were made for each subject for the NoGo minus Go conditions. Contrasts were used in a second-level analysis with subject as a random factor. RESULTS Functional MRI data revealed robust activation of the right orbitofrontal cortex (Brodmanns area [BA] 47) in control subjects but not in manic subjects. Random-effects analyses demonstrated significantly less magnitude in signal intensity in the right lateral orbitofrontal cortex (BA 47), right hippocampus, and left cingulate (BA 24) in manic compared with control subjects. CONCLUSIONS Mania is associated with a significant attenuation of task-related activation of right lateral orbitofrontal function. This lack of activation of a brain region that is usually involved in suppression of responses might account for some of the disinhibition seen in mania. In addition, hippocampal and cingulate activation seem to be decreased. The relationship between this reduced function and the symptoms of mania remain to be further explored.

Emotion processing and regulation in bipolar disorder: a review

Townsend J, Altshuler LL. Emotion processing and regulation in bipolar disorder: a review. 
Bipolar Disord 2012: 14: 326–339.

Increased volume of the amygdala and hippocampus in bipolar patients treated with lithium

Previous structural neuroimaging studies of bipolar disorder have reported conflicting findings in limbic structures. Medication heterogeneity of patient samples may have contributed to these inconsistencies. Using structural magnetic resonance imaging we assessed whether lithium treatment was associated with differences in amygdala and hippocampal volumes in a sample of bipolar adults. A total of 49 magnetic resonance imaging scans were collected from patients who were currently treated with or without lithium. Amygdala and hippocampal volumes were analyzed using tensor-based morphometry. Statistical between-group comparisons of deformation maps showed that patients treated with lithium exhibited significantly increased volumes of the amygdala and hippocampus compared with patients who were not taking lithium. Our findings may help to explain previous inconsistencies in the bipolar literature.

Abnormalities of Visual Processing and Frontostriatal Systems in Body Dysmorphic Disorder

CONTEXT Body dysmorphic disorder (BDD) is a psychiatric disorder in which individuals are preoccupied with perceived defects in their appearance, often related to their face. Little is known about its pathophysiology, although early research provides evidence of abnormal visual processing. OBJECTIVE To determine whether patients with BDD have abnormal patterns of brain activation when visually processing their own face with high, low, or normal spatial resolution. DESIGN Case-control study. SETTING A university hospital. PARTICIPANTS Seventeen right-handed medication-free subjects with BDD and 16 matched healthy control subjects. Intervention Functional magnetic resonance imaging while viewing photographs of face stimuli. Stimuli were neutral-expression photographs of the patients own face and a familiar face (control stimuli) that were unaltered, altered to include only high spatial frequency (fine spatial resolution), or altered to include only low spatial frequency (low spatial resolution). MAIN OUTCOME MEASURE Blood oxygen level-dependent signal changes in the BDD and control groups during each stimulus type. RESULTS Subjects with BDD showed relative hyperactivity in the left orbitofrontal cortex and bilateral head of the caudate for the unaltered own-face vs familiar-face condition. They showed relative hypoactivity in the left occipital cortex for the low spatial frequency faces. Differences in activity in frontostriatal systems but not visual cortex covaried with aversiveness ratings of the faces. Severity of BDD symptoms correlated with activity in frontostriatal systems and visual cortex. CONCLUSIONS These results suggest abnormalities in visual processing and frontostriatal systems in BDD. Hypoactivation in the occipital cortex for low spatial frequency faces may indicate either primary visual system abnormalities for configural face elements or top-down modulation of visual processing. Frontostriatal hyperactivity may be associated both with aversion and with symptoms of obsessive thoughts and compulsive behaviors.

Regional brain changes in bipolar I depression: a functional magnetic resonance imaging study

OBJECTIVE To investigate neural activity in prefrontal cortex and amygdala during bipolar depression. METHODS Eleven bipolar I depressed and 17 normal subjects underwent functional magnetic resonance imaging (fMRI) while performing a task known to activate prefrontal cortex and amygdala. Whole brain activation patterns were determined using statistical parametric mapping (SPM) when subjects matched faces displaying neutral or negative affect (match condition) or matched a geometric form (control condition). Contrasts for each group for the match versus control conditions were used in a second-level random effects analysis. RESULTS Random effects between-group analysis revealed significant attenuation in right and left orbitofrontal cortex (BA47) and right dorsolateral prefrontal cortex (DLPFC) (BA9) in bipolar depressed subjects. Additionally, random effects analysis showed a significantly increased activation in left lateral orbitofrontal cortex (BA10) in the bipolar depressed versus control subjects. Within-group contrasts demonstrated significant amygdala activation in the controls and no significant amygdala activation in the bipolar depressed subjects. The amygdala between-group difference, however, was not significant. CONCLUSIONS Bipolar depression is associated with attenuated bilateral orbitofrontal (BA47) activation, attenuated right DLPFC (BA9) activation and heightened left orbitofrontal (BA10) activation. BA47 attenuation has also been reported in mania and may thus represent a trait feature of the disorder. Increased left prefrontal (BA10) activation may be a state marker to bipolar depression. Our findings suggest dissociation between mood-dependent and disease-dependent functional brain abnormalities in bipolar disorder.

Frontal-Amygdala Connectivity Alterations During Emotion Downregulation in Bipolar I Disorder

BACKGROUND The symptoms of bipolar disorder suggest dysfunction of emotion regulatory networks. In healthy control populations, downregulation of emotional responses activates the ventral lateral prefrontal cortex (vlPFC) and dampens amygdala activation. This study investigated frontal and limbic function and connectivity during emotion downregulation in euthymic subjects with bipolar I disorder (BPI) and healthy control subjects. METHODS Thirty BPI and 26 control subjects underwent functional magnetic resonance imaging scanning while performing an emotion processing task with passive viewing and emotion downregulation conditions. Contrasts were made for each group comparing the downregulation and passive viewing conditions, and these were entered into a between-group random effects analysis to assess group differences in activation. Psychophysiological interaction analyses were conducted to test for significant group differences in functional connectivity between the amygdala and inhibitory frontal regions (i.e., vlPFC). RESULTS Control subjects showed the expected robust bilateral activation of frontal and limbic regions during passive viewing and emotion downregulation tasks. Between-group analyses revealed similar activation of BPI and control subjects during passive viewing but significantly decreased activation in bilateral vlPFC, bilateral anterior and posterior cingulate, medial frontal gyrus, and bilateral dorsal lateral prefrontal cortex during emotion downregulation in subjects with BPI. Connectivity analysis demonstrated that control subjects had significantly greater negative functional connectivity between the left amygdala and bilateral vlPFC compared with subjects with BPI. CONCLUSIONS This study provides evidence that dysfunction in the neural networks responsible for emotion regulation, including the prefrontal cortex, cingulate, and subcortical structures, are present in BPI subjects, even while euthymic.

fMRI abnormalities in dorsolateral prefrontal cortex during a working memory task in manic, euthymic and depressed bipolar subjects

Neuropsychological studies of subjects with bipolar disorder suggest impairment of working memory not only in acute mood states, but also while subjects are euthymic. Using fMRI to probe working memory regions in bipolar subjects in different mood states, we sought to determine the functional neural basis for these impairments. Typical working memory areas in normal populations include dorsolateral prefrontal cortex (BA9/46) and the posterior parietal cortex (BA40). We evaluated the activation in these regions using an n-back task in 42 bipolar subjects (13 manic, 15 euthymic and 14 depressed subjects) and 14 control subjects. While both control and bipolar subjects performed similarly on the task, bipolar subjects in all three mood states showed a significant reduction in activation in right BA9/46 and right BA40. Patients with bipolar disorder exhibit significantly attenuated neural activation in working memory circuits, independent of mood state. The reduction of neural activation may suggest a trait-related deficit. Subjects with bipolar disorder activated other additional frontal and temporal regions, perhaps as a compensatory mechanism, but this remains to be further explored.

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.

Regional fMRI Hypoactivation and Altered Functional Connectivity During Emotion Processing in Nonmedicated Depressed Patients With Bipolar II Disorder

OBJECTIVE Although the amygdala and ventrolateral prefrontal cortex have been implicated in the pathophysiology of bipolar I disorder, the neural mechanisms underlying bipolar II disorder remain unknown. The authors examined neural activity in response to negative emotional faces during an emotion perception task that reliably activates emotion regulatory regions. METHOD Twenty-one nonmedicated depressed bipolar II patients and 21 healthy comparison subjects underwent functional MRI (fMRI) while performing an emotional face-matching task. Within- and between-group whole-brain fMRI activation and seed-based connectivity analyses were conducted. RESULTS In depressed bipolar II patients, random-effects between-group fMRI analyses revealed a significant reduction in activation in several regions, including the left and right ventrolateral prefrontal cortices (Brodmanns area [BA] 47) and the right amygdala, a priori regions of interest. Additionally, bipolar patients exhibited significantly reduced negative functional connectivity between the right amygdala and the right orbitofrontal cortex (BA 10) as well as the right dorsolateral prefrontal cortex (BA 46) relative to healthy comparison subjects. CONCLUSIONS These findings suggest that bipolar II depression is characterized by reduced regional orbitofrontal and limbic activation and altered connectivity in a fronto-temporal circuit implicated in working memory and emotional learning. While the amygdala hypoactivation observed in bipolar II depression is opposite to the direction seen in bipolar I mania and may therefore be state dependent, the observed orbitofrontal cortex hypoactivation is consistent with findings in bipolar I depression, mania, and euthymia, suggesting a physiologic trait marker of the disorder.