Abnormal amygdala-prefrontal effective connectivity to happy faces differentiates bipolar from major depression

Background - Bipolar disorder is frequently misdiagnosed as major depressive disorder, delaying appropriate treatment and worsening outcome for many bipolar individuals. Emotion dysregulation is a core feature of bipolar disorder. Measures of dysfunction in neural systems supporting emotion regulation might therefore help discriminate bipolar from major depressive disorder. Methods - Thirty-one depressed individuals—15 bipolar depressed (BD) and 16 major depressed (MDD), DSM-IV diagnostic criteria, ages 18–55 years, matched for age, age of illness onset, illness duration, and depression severity—and 16 age- and gender-matched healthy control subjects performed two event-related paradigms: labeling the emotional intensity of happy and sad faces, respectively. We employed dynamic causal modeling to examine significant among-group alterations in effective connectivity (EC) between right- and left-sided neural regions supporting emotion regulation: amygdala and orbitomedial prefrontal cortex (OMPFC). Results - During classification of happy faces, we found profound and asymmetrical differences in EC between the OMPFC and amygdala. Left-sided differences involved top-down connections and discriminated between depressed and control subjects. Furthermore, greater medication load was associated with an amelioration of this abnormal top-down EC. Conversely, on the right side the abnormality was in bottom-up EC that was specific to bipolar disorder. These effects replicated when we considered only female subjects. Conclusions - Abnormal, left-sided, top-down OMPFC–amygdala and right-sided, bottom-up, amygdala–OMPFC EC during happy labeling distinguish BD and MDD, suggesting different pathophysiological mechanisms associated with the two types of depression.

Abnormal left and right amygdala-orbitofrontal cortical functional connectivity to emotional faces:state versus trait vulnerability markers of depression in bipolar disorder

Background - Amygdala-orbitofrontal cortical (OFC) functional connectivity (FC) to emotional stimuli and relationships with white matter remain little examined in bipolar disorder individuals (BD). Methods - Thirty-one BD (type I; n = 17 remitted; n = 14 depressed) and 24 age- and gender-ratio-matched healthy individuals (HC) viewed neutral, mild, and intense happy or sad emotional faces in two experiments. The FC was computed as linear and nonlinear dependence measures between amygdala and OFC time series. Effects of group, laterality, and emotion intensity upon amygdala-OFC FC and amygdala-OFC FC white matter fractional anisotropy (FA) relationships were examined. Results - The BD versus HC showed significantly greater right amygdala-OFC FC (p = .001) in the sad experiment and significantly reduced bilateral amygdala-OFC FC (p = .007) in the happy experiment. Depressed but not remitted female BD versus female HC showed significantly greater left amygdala-OFC FC (p = .001) to all faces in the sad experiment and reduced bilateral amygdala-OFC FC to intense happy faces (p = .01). There was a significant nonlinear relationship (p = .001) between left amygdala-OFC FC to sad faces and FA in HC. In BD, antidepressants were associated with significantly reduced left amygdala-OFC FC to mild sad faces (p = .001). Conclusions - In BD, abnormally elevated right amygdala-OFC FC to sad stimuli might represent a trait vulnerability for depression, whereas abnormally elevated left amygdala-OFC FC to sad stimuli and abnormally reduced amygdala-OFC FC to intense happy stimuli might represent a depression state marker. Abnormal FC measures might normalize with antidepressant medications in BD. Nonlinear amygdala-OFC FC–FA relationships in BD and HC require further study.

Elevated amygdala activity to sad facial expressions:a state marker of bipolar but not unipolar depression

Background - Difficulties in emotion processing and poor social function are common to bipolar disorder (BD) and major depressive disorder (MDD) depression, resulting in many BD depressed individuals being misdiagnosed with MDD. The amygdala is a key region implicated in processing emotionally salient stimuli, including emotional facial expressions. It is unclear, however, whether abnormal amygdala activity during positive and negative emotion processing represents a persistent marker of BD regardless of illness phase or a state marker of depression common or specific to BD and MDD depression. Methods - Sixty adults were recruited: 15 depressed with BD type 1 (BDd), 15 depressed with recurrent MDD, 15 with BD in remission (BDr), diagnosed with DSM-IV and Structured Clinical Interview for DSM-IV Research Version criteria; and 15 healthy control subjects (HC). Groups were age- and gender ratio-matched; patient groups were matched for age of illness onset and illness duration; depressed groups were matched for depression severity. The BDd were taking more psychotropic medication than other patient groups. All individuals participated in three separate 3T neuroimaging event-related experiments, where they viewed mild and intense emotional and neutral faces of fear, happiness, or sadness from a standardized series. Results - The BDd—relative to HC, BDr, and MDD—showed elevated left amygdala activity to mild and neutral facial expressions in the sad (p < .009) but not other emotion experiments that was not associated with medication. There were no other significant between-group differences in amygdala activity. Conclusions - Abnormally elevated left amygdala activity to mild sad and neutral faces might be a depression-specific marker in BD but not MDD, suggesting different pathophysiologic processes for BD versus MDD depression.

Right orbitofrontal corticolimbic and left corticocortical white matter connectivity differentiate bipolar and unipolar depression

Objectives - The absence of pathophysiologically relevant diagnostic markers of bipolar disorder (BD) leads to its frequent misdiagnosis as unipolar depression (UD). We aimed to determine whether whole brain white matter connectivity differentiated BD from UD depression. Methods - We employed a three-way analysis of covariance, covarying for age, to examine whole brain fractional anisotropy (FA), and corresponding longitudinal and radial diffusivity, in currently depressed adults: 15 with BD-type I (mean age 36.3 years, SD 12.0 years), 16 with recurrent UD (mean age 32.3 years, SD 10.0 years), and 24 healthy control adults (HC) (mean age 29.5 years, SD 9.43 years). Depressed groups did not differ in depression severity, age of illness onset, and illness duration. Results - There was a main effect of group in left superior and inferior longitudinal fasciculi (SLF and ILF) (all F = 9.8; p = .05, corrected). Whole brain post hoc analyses (all t = 4.2; p = .05, corrected) revealed decreased FA in left SLF in BD, versus UD adults in inferior temporal cortex and, versus HC, in primary sensory cortex (associated with increased radial and decreased longitudinal diffusivity, respectively); and decreased FA in left ILF in UD adults versus HC. A main effect of group in right uncinate fasciculus (in orbitofrontal cortex) just failed to meet significance in all participants but was present in women. Post hoc analyses revealed decreased right uncinate fasciculus FA in all and in women, BD versus HC. Conclusions - White matter FA in left occipitotemporal and primary sensory regions supporting visuospatial and sensory processing differentiates BD from UD depression. Abnormally reduced FA in right fronto-temporal regions supporting mood regulation, might underlie predisposition to depression in BD. These measures might help differentiate pathophysiologic processes of BD versus UD depression.

Frontopolar cortical inefficiency may underpin reward and working memory dysfunction in bipolar disorder

Objectives. Emotional dysregulation in bipolar disorder is thought to arise from dysfunction within prefrontal cortical regions involved in cognitive control coupled with increased or aberrant activation within regions engaged in emotional processing. The aim of this study was to determine the common and distinct patterns of functional brain abnormalities during reward and working memory processing in patients with bipolar disorder. Methods. Participants were 36 euthymic bipolar disorder patients and 37 healthy comparison subjects matched for age, sex and IQ. Functional magnetic resonance imaging (fMRI) was conducted during the Iowa Gambling Task (IGT) and the n-back working memory task. Results. During both tasks, patients with bipolar disorder demonstrated a pattern of inefficient engagement within the ventral frontopolar prefrontal cortex with evidence of segregation along the medial-lateral dimension for reward and working memory processing, respectively. Moreover, patients also showed greater activation in the anterior cingulate cortex during the Iowa Gambling Task and in the insula during the n-back task. Conclusions. Our data implicate ventral frontopolar dysfunction as a core abnormality underpinning bipolar disorder and confirm that overactivation in regions involved in emotional arousal is present even in tasks that do not typically engage emotional systems. © 2012 Informa Healthcare.

Assessment of social cognition in bipolar disorder

Background: Impairment in social cognition may contribute to deficits in social functioning in patients with bipolar disorder (BD). In this study, a complex social cognition task was administered during a neuroimaging session. The behavioral and neural correlates of social cogniton in patients with BD were compared to healthy comparison (HC) subjects. Methods: The task was administered to 25 HC and 25 patients with depression scores ranging from euthymic to depressed at the time of assessment. The task required participants to evaluate situations that were “enhancing” or “threatening” to self-esteem, directed at both oneself, and at other people. For instance, self-esteem enhancing scenarios involved vignettes of activities such as receiving praise during a sports game, while a threatening scenario involved, for example, receiving criticism at a party. Participants were then required to evaluate characters in the scenarios on the basis of positive (“kind”) or negative (“mean”) descriptors. Evaluations were classified from extremely negative to extremely positive. The frequencies of behavioral responses were analyzed using chi-square tests and fMRI data were analyzed using Statistical Parametric Mapping software. Results: Patients differed significantly from HCs in their evaluation of threatening scenarios, directed at both oneself and at other people (p<0.001). Patients had a lower proportion of responses in the neutral category, and more responses in the positive and negative categories, relative to HCs. Neuroimaging results reveal differential patterns of prefrontal-cortical and limbic-subcortical activation in BDs throughout the task [p<0.05 (unc.)]. Conclusions: Findings will contribute to understanding difficulty in interpersonal functioning in patients with BD.

Differential activation in temporal, cingulate and prefrontal cortices during response inhibition in bipolar disorder

Background: Increased impulsivity and aberrant response inhibition have been observed in bipolar disorder (BD). This study examined the functional abnormalities and underlying neural processes during response inhibition in BD, and its relationship to impulsivity. Methods: We assessed impulsivity using the Barratt Impulsiveness Scale (BIS) and, using functional magnetic resonance imaging (fMRI), measured neural activity in response to an Affective Go-NoGo Task, consisting of emotional facial stimuli (fear, happy, anger faces) and non-emotional control stimuli (neutral female and male faces) in euthymic BD (n=23) and healthy individuals (HI; n=25). Results: BD patients were significantly more impulsive, yet did not differ from HI on accuracy or reaction time on the emotional go/no-go task. Comparing neural patterns of activation when processing emotional Go versus emotional NoGo trials yielded increased activation in BD within temporal and cingulate cortices and within prefrontal-cortical regions in HI. Furthermore, higher BIS scores for BD were associated with slower reaction times, and indicative of compensatory cognitive strategies to counter increased impulsivity. Conclusions: These findings illustrate cognition-emotion interference in BD and the observed differences in neural activation indicate potentially altered emotion modulation. Increased activation in brain regions previously shown in emotion regulation and response inhibition tasks could represent a disease-specific marker for BD

Facial affect processing inbipolar disorder:a magnetoencephalography study

Background: Identifying biological markers to aid diagnosis of bipolar disorder (BD) is critically important. To be considered a possible biological marker, neural patterns in BD should be discriminant from those in healthy individuals (HI). We examined patterns of neuromagnetic responses revealed by magnetoencephalography (MEG) during implicit emotion-processing using emotional (happy, fearful, sad) and neutral facial expressions, in sixteen BD and sixteen age- and gender-matched healthy individuals. Methods: Neuromagnetic data were recorded using a 306-channel whole-head MEG ELEKTA Neuromag System, and preprocessed using Signal Space Separation as implemented in MaxFilter (ELEKTA). Custom Matlab programs removed EOG and ECG signals from filtered MEG data, and computed means of epoched data (0-250ms, 250-500ms, 500-750ms). A generalized linear model with three factors (individual, emotion intensity and time) compared BD and HI. A principal component analysis of normalized mean channel data in selected brain regions identified principal components that explained 95% of data variation. These components were used in a quadratic support vector machine (SVM) pattern classifier. SVM classifier performance was assessed using the leave-one-out approach. Results: BD and HI showed significantly different patterns of activation for 0-250ms within both left occipital and temporal regions, specifically for neutral facial expressions. PCA analysis revealed significant differences between BD and HI for mild fearful, happy, and sad facial expressions within 250-500ms. SVM quadratic classifier showed greatest accuracy (84%) and sensitivity (92%) for neutral faces, in left occipital regions within 500-750ms. Conclusions: MEG responses may be used in the search for disease specific neural markers.