Genna Bebko

Abnormal anterior cingulate cortical activity during emotional n-back task performance distinguishes bipolar from unipolar depressed females.

BACKGROUND Depression in the context of bipolar disorder (BDd) is often misdiagnosed as unipolar disorder depression (UDd) leading to poor clinical outcomes for many bipolar sufferers. We examined neural circuitry supporting emotion regulation in females with either BDd or UDd as a first stage toward identifying biomarkers that may differentiate BDd from UDd. METHOD Fifty-seven females aged 18-45 years participated in this study: 23 with UDd, 18 with bipolar disorder type I depression (BDId) and 16 healthy females. During 3-T functional magnetic resonance imaging (fMRI), the participants performed an emotional face n-back (EFNBACK) task, that is an n-back task with high (2-back) and low (0-back) memory load conditions flanked by two positive, negative or neutral face distracters. This paradigm examines executive control with emotional distracters-emotion regulation. RESULTS High memory load with neutral face distracters elicited greater bilateral and left dorsal anterior midcingulate cortex (dAMCC) activity in UDd than in healthy and BDId females respectively, and greater bilateral putamen activity in both depressed groups versus healthy females. High memory load with happy face distracters elicited greater left putamen activity in UDd than in healthy females. Psychotropic medication was associated with greater putamen activity to these contrasts in UDd females. CONCLUSIONS During high memory load with neutral face distracters, elevated dAMCC activity in UDd suggests abnormal recruitment of attentional control circuitry to maintain task performance, whereas elevated putamen activity unrelated to psychotropic medication in BDId females may suggest an attentional bias toward ambiguous neutral face distracters. Differential patterns of functional abnormalities in neural circuitry supporting attentional control during emotion regulation, especially in the dAMCC, is a promising neuroimaging measure to distinguish UDd from BDId in females.

Look before you regulate: differential perceptual strategies underlying expressive suppression and cognitive reappraisal.

Successful emotion regulation is important for maintaining psychological well-being. Although it is known that emotion regulation strategies, such as cognitive reappraisal and expressive suppression, may have divergent consequences for emotional responses, the cognitive processes underlying these differences remain unclear. Here we used eye-tracking to investigate the role of attentional deployment in emotion regulation success. We hypothesized that differences in the deployment of attention to emotional areas of complex visual scenes may be a contributing factor to the differential effects of these two strategies on emotional experience. Eye-movements, pupil size, and self-reported negative emotional experience were measured while healthy young adult participants viewed negative IAPS images and regulated their emotional responses using either cognitive reappraisal or expressive suppression. Consistent with prior work, reappraisers reported feeling significantly less negative than suppressers when regulating emotion as compared to a baseline condition. Across both groups, participants looked away from emotional areas during emotion regulation, an effect that was more pronounced for suppressers. Critically, irrespective of emotion regulation strategy, participants who looked toward emotional areas of a complex visual scene were more likely to experience emotion regulation success. Taken together, these results demonstrate that attentional deployment varies across emotion regulation strategies and that successful emotion regulation depends on the extent to which people look toward emotional content in complex visual scenes.

Children with reading disorder show modality independent brain abnormalities during semantic tasks

Neuroimaging studies have suggested that left inferior frontal gyrus, left inferior parietal lobule and left middle temporal gyrus are critical for semantic processing in normal children. The goal of the present functional magnetic resonance imaging (fMRI) study was to determine whether these regions are systematically related to semantic processing in children (9- to 15-year-old) diagnosed with reading disorders (RD). Semantic judgments required participants to indicate whether two words were related in meaning. The strength of semantic association varied continuously from higher association pairs (e.g., king-queen) to lower association pairs (e.g. net-ship). We found that the correlation between association strength and activation was significantly weaker for RD children compared to controls in left middle temporal gyrus and left inferior parietal lobule for both the auditory and the visual modalities and in left inferior frontal gyrus for the visual modality. These results suggest that the RD children have abnormalities in semantic search/retrieval in the inferior frontal gyrus, integration of semantic information in the inferior parietal lobule and semantic lexical representations in the middle temporal gyrus. These deficits appear to be general to the semantic system and independent of modality.

Parsing Dimensional vs Diagnostic Category–Related Patterns of Reward Circuitry Function in Behaviorally and Emotionally Dysregulated Youth in the Longitudinal Assessment of Manic Symptoms Study

IMPORTANCE Pediatric disorders characterized by behavioral and emotional dysregulation pose diagnostic and treatment challenges because of high comorbidity, suggesting that they may be better conceptualized dimensionally rather than categorically. Identifying neuroimaging measures associated with behavioral and emotional dysregulation in youth may inform understanding of underlying dimensional vs disorder-specific pathophysiologic features. OBJECTIVE To identify, in a large cohort of behaviorally and emotionally dysregulated youth, neuroimaging measures that (1) are associated with behavioral and emotional dysregulation pathologic dimensions (behavioral and emotional dysregulation measured with the Parent General Behavior Inventory 10-Item Mania Scale [PGBI-10M], mania, depression, and anxiety) or (2) differentiate diagnostic categories (bipolar spectrum disorders, attention-deficit/hyperactivity disorder, anxiety, and disruptive behavior disorders). DESIGN, SETTING, AND PARTICIPANTS A multisite neuroimaging study was conducted from February 1, 2011, to April 15, 2012, at 3 academic medical centers: University Hospitals Case Medical Center, Cincinnati Childrens Hospital Medical Center, and University of Pittsburgh Medical Center. Participants included a referred sample of behaviorally and emotionally dysregulated youth from the Longitudinal Assessment of Manic Symptoms (LAMS) study (n = 85) and healthy youth (n = 20). MAIN OUTCOMES AND MEASURES Region-of-interest analyses examined relationships among prefrontal-ventral striatal reward circuitry during a reward paradigm (win, loss, and control conditions), symptom dimensions, and diagnostic categories. RESULTS Regardless of diagnosis, higher PGBI-10M scores were associated with greater left middle prefrontal cortical activity (r = 0.28) and anxiety with greater right dorsal anterior cingulate cortical (r = 0.27) activity to win. The 20 highest (t = 2.75) and 20 lowest (t = 2.42) PGBI-10M-scoring youth showed significantly greater left middle prefrontal cortical activity to win compared with 20 healthy youth. Disruptive behavior disorders were associated with lower left ventrolateral prefrontal cortex activity to win (t = 2.68) (all P < .05, corrected). CONCLUSIONS AND RELEVANCE Greater PGBI-10M-related left middle prefrontal cortical activity and anxiety-related right dorsal anterior cingulate cortical activity to win may reflect heightened reward sensitivity and greater attention to reward in behaviorally and emotionally dysregulated youth regardless of diagnosis. Reduced left ventrolateral prefrontal cortex activity to win may reflect reward insensitivity in youth with disruptive behavior disorders. Despite a distinct reward-related neurophysiologic feature in disruptive behavior disorders, findings generally support a dimensional approach to studying neural mechanisms in behaviorally and emotionally dysregulated youth.

Decreased amygdala-insula resting state connectivity in behaviorally and emotionally dysregulated youth

The Research Domain Criteria (RDoC) adopts a dimensional approach for examining pathophysiological processes underlying categorically defined psychiatric diagnoses. We used this framework to examine relationships among symptom dimensions, diagnostic categories, and resting state connectivity in behaviorally and emotionally dysregulated youth selected from the Longitudinal Assessment of Manic Symptoms study (n=42) and healthy control youth (n=18). Region of interest analyses examined relationships among resting state connectivity, symptom dimensions (behavioral and emotional dysregulation measured with the Parent General Behavior Inventory-10 Item Mania Scale [PGBI-10M]; dimensional severity measures of mania, depression, anxiety), and diagnostic categories (Bipolar Spectrum Disorders, Attention Deficit Hyperactivity Disorder, Anxiety Disorders, and Disruptive Behavior Disorders). After adjusting for demographic variables, two dimensional measures showed significant inverse relationships with resting state connectivity, regardless of diagnosis: 1) PGBI-10M with amygdala-left posterior insula/bilateral putamen; and 2) depressive symptoms with amygdala-right posterior insula connectivity. Diagnostic categories showed no significant relationships with resting state connectivity. Resting state connectivity between amygdala and posterior insula decreased with increasing severity of behavioral and emotional dysregulation and depression; this suggests an intrinsic functional uncoupling of key neural regions supporting emotion processing and regulation. These findings support the RDoC dimensional approach for characterizing pathophysiologic processes that cut across different psychiatric disorders.

Altered amygdala-prefrontal response to facial emotion in offspring of parents with bipolar disorder

This study aimed to identify neuroimaging measures associated with risk for, or protection against, bipolar disorder by comparing youth offspring of parents with bipolar disorder versus youth offspring of non-bipolar parents versus offspring of healthy parents in (i) the magnitude of activation within emotional face processing circuitry; and (ii) functional connectivity between this circuitry and frontal emotion regulation regions. The study was conducted at the University of Pittsburgh Medical Centre. Participants included 29 offspring of parents with bipolar disorder (mean age = 13.8 years; 14 females), 29 offspring of non-bipolar parents (mean age = 13.8 years; 12 females) and 23 healthy controls (mean age = 13.7 years; 11 females). Participants were scanned during implicit processing of emerging happy, sad, fearful and angry faces and shapes. The activation analyses revealed greater right amygdala activation to emotional faces versus shapes in offspring of parents with bipolar disorder and offspring of non-bipolar parents than healthy controls. Given that abnormally increased amygdala activation during emotion processing characterized offspring of both patient groups, and that abnormally increased amygdala activation has often been reported in individuals with already developed bipolar disorder and those with major depressive disorder, these neuroimaging findings may represent markers of increased risk for affective disorders in general. The analysis of psychophysiological interaction revealed that offspring of parents with bipolar disorder showed significantly more negative right amygdala-anterior cingulate cortex functional connectivity to emotional faces versus shapes, but significantly more positive right amygdala-left ventrolateral prefrontal cortex functional connectivity to happy faces (all P-values corrected for multiple tests) than offspring of non-bipolar parents and healthy controls. Taken together with findings of increased amygdala-ventrolateral prefrontal cortex functional connectivity, and decreased amygdala-anterior cingulate cortex functional connectivity previously shown in individuals with bipolar disorder, these connectivity patterns in offspring of parents with bipolar disorder may be risk markers for, rather than markers conferring protection against, bipolar disorder in youth. The patterns of activation and functional connectivity remained unchanged after removing medicated participants and those with current psychopathology from analyses. This is the first study to demonstrate that abnormal functional connectivity patterns within face emotion processing circuitry distinguish offspring of parents with bipolar disorder from those of non-bipolar parents and healthy controls.

Emotional Face Processing in Pediatric Bipolar Disorder: Evidence for Functional Impairments in the Fusiform Gyrus

OBJECTIVE Pediatric bipolar disorder involves poor social functioning, but the neural mechanisms underlying these deficits are not well understood. Previous neuroimaging studies have found deficits in emotional face processing localized to emotional brain regions. However, few studies have examined dysfunction in other regions of the face processing circuit. This study assessed hypoactivation in key face processing regions of the brain in pediatric bipolar disorder. METHOD Youth with a bipolar spectrum diagnosis (n = 20) were matched to a nonbipolar clinical group (n = 20), with similar demographics and comorbid diagnoses, and a healthy control group (n = 20). Youth participated in a functional magnetic resonance imaging (fMRI) scanning which employed a task-irrelevant emotion processing design in which processing of facial emotions was not germane to task performance. RESULTS Hypoactivation, isolated to the fusiform gyrus, was found when viewing animated, emerging facial expressions of happiness, sadness, fearfulness, and especially anger in pediatric bipolar participants relative to matched clinical and healthy control groups. CONCLUSIONS The results of the study imply that differences exist in visual regions of the brains face processing system and are not solely isolated to emotional brain regions such as the amygdala. Findings are discussed in relation to facial emotion recognition and fusiform gyrus deficits previously reported in the autism literature. Behavioral interventions targeting attention to facial stimuli might be explored as possible treatments for bipolar disorder in youth.

Glutamate and GABA contributions to medial prefrontal cortical activity to emotion: Implications for mood disorders

The dorsomedial prefrontal cortex (MdPFC) and anterior cingulate cortices (ACC) play a critical role in implicit emotion regulation; however the understanding of the specific neurotransmitters that mediate such role is lacking. In this study, we examined relationships between MdPFC concentrations of two neurotransmitters, glutamate and γ-amino butyric acid (GABA), and BOLD activity in ACC during performance of an implicit facial emotion-processing task. Twenty healthy volunteers, aged 20-35 years, were scanned while performing an implicit facial emotion-processing task, whereby presented facial expressions changed from neutral to one of the four emotions: happy, anger, fear, or sad. Glutamate concentrations were measured before and after the emotion-processing task in right MdPFC using magnetic resonance spectroscopy (MRS). GABA concentrations were measured in bilateral MdPFC after the emotion-processing task. Multiple regression models were run to determine the relative contribution of glutamate and GABA concentration, age, and gender to BOLD signal in ACC to each of the four emotions. Multiple regression analyses revealed a significant negative correlation between MdPFC GABA concentration and BOLD signal in subgenual ACC (p<0.05, corrected) to sad versus shape contrast. For the anger versus shape contrast, there was a significant negative correlation between age and BOLD signal in pregenual ACC (p<0.05, corrected) and a positive correlation between MdPFC glutamate concentration (pre-task) and BOLD signal in pregenual ACC (p<0.05, corrected). Our findings are the first to provide insight into relationships between MdPFC neurotransmitter concentrations and ACC BOLD signal, and could further understanding of molecular mechanisms underlying emotion processing in healthy and mood-disordered individuals.

Abnormal deactivation of the inferior frontal gyrus during implicit emotion processing in youth with bipolar disorder: attenuated by medication.

Previous neuroimaging studies of youth with bipolar disorder (BD) have identified abnormalities in emotion regulation circuitry. Using data from the Longitudinal Assessment of Manic Symptoms Cohort (a clinical sample recruited for behavioral and emotional dysregulation), we examined the impact of BD and medication on activation in these regions. Functional neuroimaging data were obtained from 15 youth with BD who currently were unmedicated with a mood stabilizer or antipsychotic (U-BD), 19 youth with medicated BD (M-BD), a non-bipolar clinical sample with high rates of disruptive behavioral disorders (non-BD, n = 59), and 29 healthy controls (HC) while they were shown task-irrelevant morphing emotional faces and shapes. Whole brain analysis was used to identify clusters that showed differential activation to emotion vs. shapes across group. To assess pair-wise comparisons and potential confounders, mean activation data were extracted only from clusters within regions previously implicated in emotion regulation (including amygdala and ventral prefrontal regions). A cluster in the right inferior frontal gyrus (IFG) showed group differences to emotion vs. shapes (159 voxels, corrected p < .05). Within this cluster, U-BD youth showed decreased activation relative to HC (p = .007) and non-BD (p = .004) youth. M-BD also showed decreased activation in this cluster relative to HC and non-BD youth, but these differences were attenuated. Results were specific to negative emotions, and not found with happy faces. IFG findings were not explained by other medications (e.g. stimulants) or diagnoses. Compared to both HC and a non-BD sample, U-BD is associated with abnormally decreased right IFG activation to negative emotions.

Behavioral and emotional dysregulation trajectories marked by prefrontal-amygdala function in symptomatic youth

BACKGROUND Neuroimaging measures of behavioral and emotional dysregulation can yield biomarkers denoting developmental trajectories of psychiatric pathology in youth. We aimed to identify functional abnormalities in emotion regulation (ER) neural circuitry associated with different behavioral and emotional dysregulation trajectories using latent class growth analysis (LCGA) and neuroimaging. METHOD A total of 61 youth (9-17 years) from the Longitudinal Assessment of Manic Symptoms study, and 24 healthy control youth, completed an emotional face n-back ER task during scanning. LCGA was performed on 12 biannual reports completed over 5 years of the Parent General Behavior Inventory 10-Item Mania Scale (PGBI-10M), a parental report of the childs difficulty regulating positive mood and energy. RESULTS There were two latent classes of PGBI-10M trajectories: high and decreasing (HighD; n=22) and low and decreasing (LowD; n=39) course of behavioral and emotional dysregulation over the 12 time points. Task performance was >89% in all youth, but more accurate in healthy controls and LowD versus HighD (p<0.001). During ER, LowD had greater activity than HighD and healthy controls in the dorsolateral prefrontal cortex, a key ER region, and greater functional connectivity than HighD between the amygdala and ventrolateral prefrontal cortex (ps<0.001, corrected). CONCLUSIONS Patterns of function in lateral prefrontal cortical-amygdala circuitry in youth denote the severity of the developmental trajectory of behavioral and emotional dysregulation over time, and may be biological targets to guide differential treatment and novel treatment development for different levels of behavioral and emotional dysregulation in youth.