Melissa A. Brotman

Amygdala Activation During Emotion Processing of Neutral Faces in Children With Severe Mood Dysregulation Versus ADHD or Bipolar Disorder

OBJECTIVE To understand disorder-unique and common pathophysiology, studies in multiple patient groups with overlapping symptoms are needed. Deficits in emotion processing and hyperarousal symptoms are prominent features of bipolar disorder, attention deficit hyperactivity disorder (ADHD), and severe mood dysregulation. The authors compared amygdala response during emotional and nonemotional ratings of neutral faces in youths with these disorders as well as a group of healthy comparison youths. METHOD Blood-oxygen-level-dependent (BOLD) signal in the amygdala was examined in children with bipolar disorder (N=43), ADHD (N=18), and severe mood dysregulation (N=29) and healthy comparison subjects (N=37). During functional magnetic resonance imaging (fMRI), participants attended to emotional and nonemotional aspects of neutral faces. RESULTS While rating subjective fear of neutral faces, youths with ADHD demonstrated left amygdala hyperactivity relative to the other three groups, whereas youths with severe mood dysregulation demonstrated hypoactivity. CONCLUSIONS These findings support the role of unique neural correlates in face-emotion processing among youths with bipolar disorder, ADHD, and severe mood dysregulation.

Facial Emotion Labeling Deficits in Children and Adolescents at Risk for Bipolar Disorder

OBJECTIVE Research has revealed facial emotion labeling deficits in children and adolescents with bipolar disorder. To assess whether such impairments may be an endophenotype for bipolar disorder, the authors examined facial emotion identification proficiency in children who were at risk for bipolar disorder because they had a first-degree relative with the illness. METHOD The facial expressions subtests of the Diagnostic Analysis of Nonverbal Accuracy scale were administered to 52 patients with bipolar disorder, 24 at-risk youths, and 78 control subjects, all 4-18 years of age. RESULTS Compared with the control group, both the bipolar and at-risk groups made more errors identifying facial emotions. The number of errors did not differ significantly between the bipolar and at-risk groups. CONCLUSIONS Deficits in facial emotion labeling may be a risk marker for bipolar disorder. Further study is needed to determine the neural mechanisms involved, as well as to explore other emotional processing impairments in youths at risk for bipolar disorder and to identify genetic associations.

Neural connectivity in children with bipolar disorder: impairment in the face emotion processing circuit.

BACKGROUND Pediatric bipolar disorder (BD), a highly debilitating illness, is characterized by amygdala abnormalities, i.e., volume reduction and hyperactivation during face processing. Evidence of perturbed amygdala functional connectivity with other brain regions would implicate a distributed neural circuit in the pathophysiology of BD, and would further elucidate the neural mechanisms associated with BD face emotion misinterpretation. METHODS Thirty-three BD and 24 healthy age, gender, and IQ-matched subjects completed a functional magnetic resonance imaging (fMRI) task of face emotion identification in which attention was directed to emotional (hostility, fearfulness) and nonemotional (nose width) aspects of faces. Voxel-wise analyses examined whole brain functional connectivity with the left amygdala. RESULTS Compared to healthy subjects, BD subjects had significantly reduced connectivity between the left amygdala and two regions: right posterior cingulate/precuneus and right fusiform gyrus/parahippocampal gyrus. Deficits were evident regardless of mood state and comorbid diagnoses. CONCLUSIONS BD youth exhibit deficient connectivity between the amygdala and temporal association cortical regions previously implicated in processing facial expressions and social stimuli. In conjunction with previously documented volumetric and functional perturbations in these brain regions, dysfunction in this distributed neural circuit may begin to clarify the pathophysiology of the face emotion misperceptions and social deficits seen in BD youth.

The Affective Reactivity Index: a concise irritability scale for clinical and research settings

Background Irritable mood has recently become a matter of intense scientific interest. Here, we present data from two samples, one from the United States and the other from the United Kingdom, demonstrating the clinical and research utility of the parent- and self-report forms of the Affective Reactivity Index (ARI), a concise dimensional measure of irritability. Methods The US sample (n = 218) consisted of children and adolescents recruited at the National Institute of Mental Health meeting criteria for bipolar disorder (BD, n = 39), severe mood dysregulation (SMD, n = 67), children at family risk for BD (n = 35), or were healthy volunteers (n = 77). The UK sample (n = 88) was comprised of children from a generic mental health setting and healthy volunteers from primary and secondary schools. Results Parent- and self-report scales of the ARI showed excellent internal consistencies and formed a single factor in the two samples. In the US sample, the ARI showed a gradation with irritability significantly increasing from healthy volunteers through to SMD. Irritability was significantly higher in SMD than in BD by parent-report, but this did not reach significance by self-report. In the UK sample, parent-rated irritability was differentially related to emotional problems. Conclusions Irritability can be measured using a concise instrument both in a highly specialized US, as well as a general UK child mental health setting.

Randomized double-blind placebo-controlled trial of lithium in youths with severe mood dysregulation.

OBJECTIVE The diagnosis and treatment of youth with severe nonepisodic irritability and hyperarousal, a syndrome defined as severe mood dysregulation (SMD) by Leibenluft, has been the focus of increasing concern. We conducted the first randomized double-blind, placebo-controlled trial in SMD youth, choosing lithium on the basis of its potential in treating irritability and aggression and neuro-metabolic effects. METHODS SMD youths 7-17 years were tapered off their medications. Those who continued to meet SMD criteria after a 2-week, single-blind, placebo run-in were randomized to a 6-week double-blind trial of either lithium (n = 14) or placebo (n = 11). Clinical outcome measures were: (1) Clinical Global Impressions-Improvement (CGI-I) score less than 4 at trials end and (2) the Positive and Negative Syndrome Scale (PANSS) factor 4 score. Magnetic resonance spectroscopy (MRS) outcome measures were myoinositol (mI), N-acetyl-aspartate (NAA), and combined glutamate/glutamine (GLX), all referenced to creatine (Cr). RESULTS In all, 45% (n = 20/45) of SMD youths were not randomized due to significant clinical improvement during the placebo run-in. Among randomized patients, there were no significant between-group differences in either clinical or MRS outcome measures. CONCLUSION Our study suggests that although lithium may not result in significant clinical or neurometabolic alterations in SMD youths, further SMD treatment trials are warranted given its prevalence.

Risk for Bipolar Disorder is Associated with Face-Processing Deficits across Emotions.

OBJECTIVE Youths with euthymic bipolar disorder (BD) have a deficit in face-emotion labeling that is present across multiple emotions. Recent research indicates that youths at familial risk for BD, but without a history of mood disorder, also have a deficit in face-emotion labeling, suggesting that such impairments may be an endophenotype for BD. It is unclear whether this deficit in at-risk youths is present across all emotions or if the impairment presents initially as an emotion-specific dysfunction that then generalizes to other emotions as the symptoms of BD become manifest. METHOD Thirty-seven patients with pediatric BD, 25 unaffected children with a first-degree relative with BD, and 36 typically developing youths were administered the Emotional Expression Multimorph Task, a computerized behavioral task, which presents gradations of facial emotions from 100% neutrality to 100% emotional expression (happiness, surprise, fear, sadness, anger, and disgust). RESULTS Repeated-measures analysis of covariance revealed that, compared with the control youths, the patients and the at-risk youths required significantly more intense emotional information to identify and correctly label face emotions. The patients with BD and the at-risk youths did not differ from each other. Group-by-emotion interactions were not significant, indicating that the group effects did not differ based on the facial emotion. CONCLUSIONS The youths at risk for BD demonstrate nonspecific deficits in face-emotion recognition, similar to patients with the illness. Further research is needed to determine whether such deficits meet all the criteria for an endophenotype.

The Status of Irritability in Psychiatry: A Conceptual and Quantitative Review

Objective Research and clinical interest in irritability have been on the rise in recent years. Yet several questions remain about the status of irritability in psychiatry, including whether irritability can be differentiated from other symptoms, whether it forms a distinct disorder, and whether it is a meaningful predictor of clinical outcomes. In this article, we try to answer these questions by reviewing the evidence on how reliably irritability can be measured and its validity. Method We combine a narrative and systematic review and meta-analysis of studies. For the systematic review and meta-analysis, we searched studies in PubMed and Web of Science based on preselected criteria. A total of 163 articles were reviewed, and 24 were included. Results We found that irritability forms a distinct dimension with substantial stability across time, and that it is specifically associated with depression and anxiety in longitudinal studies. Evidence from genetic studies reveals that irritability is moderately heritable, and its overlap with depression is explained mainly by genetic factors. Behavioral and neuroimaging studies show that youth with persistent irritability exhibit altered activations in the amygdala, striatum, and frontal regions compared with age-matched healthy volunteers. Most knowledge about the treatment of irritability is based on effects of treatment on related conditions or post hoc analyses of trial data. Conclusion We identify a number of research priorities including innovative experimental designs and priorities for treatment studies, and conclude with recommendations for the assessment of irritability for researchers and clinicians.

Impaired probabilistic reversal learning in youths with mood and anxiety disorders

BACKGROUND From an affective neuroscience perspective, our understanding of psychiatric illness may be advanced by neuropsychological test paradigms probing emotional processes. Reversal learning is one such process, whereby subjects must first acquire stimulus/reward and stimulus/punishment associations through trial and error and then reverse them. We sought to determine the specificity of previously demonstrated reversal learning impairments in youths with bipolar disorder (BD) by now comparing BD youths to those with severe mood dysregulation (SMD), major depressive disorder (MDD), anxiety (ANX), and healthy controls. METHOD We administered the probabilistic response reversal (PRR) task to 165 pediatric participants aged 7-17 years with BD (n=35), SMD (n=35), ANX (n=42), MDD (n=18) and normal controls (NC; n=35). Our primary analysis compared PRR performance across all five groups matched for age, sex and IQ. RESULTS Compared to typically developing controls, probabilistic reversal learning was impaired in BD youths, with a trend in those with MDD (p=0.07). CONCLUSIONS Our results suggest that reversal learning deficits are present in youths with BD and possibly those with MDD. Further work is necessary to elucidate the specificity of neural mechanisms underlying such behavioral deficits.

Attention bias to threat faces in children with bipolar disorder and comorbid lifetime anxiety disorders

BACKGROUND Although comorbid anxiety disorders are common in children with bipolar disorder (BD), it is unclear how this comorbidity impacts the pathophysiology of the illness. METHODS Pediatric BD with lifetime anxiety (BD+ANX, n = 20), BD without lifetime anxiety (BD-ANX, n = 11), and controls (n = 14) were administered the visual-probe paradigm, which assesses attention bias to threat faces. RESULTS Bipolar disorder +ANX demonstrated a stronger bias toward threat relative to BD-ANX and controls; the latter two did not differ from each other. CONCLUSIONS Bipolar disorder +ANX showed a bias toward threat while, in two previous studies, anxious children showed a bias away from threat faces. Future studies should compare the pathophysiology of BD with and without a comorbid anxiety disorder and anxiety disorders presenting alone.

Amygdala Hyperactivation During Face Emotion Processing in Unaffected Youth at Risk for Bipolar Disorder

OBJECTIVE Youth at familial risk for bipolar disorder (BD) show deficits in face emotion processing, but the neural correlates of these deficits have not been examined. This preliminary study tests the hypothesis that, relative to healthy comparison (HC) subjects, both BD subjects and youth at risk for BD (i.e., those with a first-degree BD relative) will demonstrate amygdala hyperactivation when viewing fearful and happy faces. The at-risk youth were unaffected, in that they had no history of mood disorder. METHOD Amygdala activity was examined in 101 unrelated participants, 8 to 18 years old. Age, gender, and IQ-matched groups included BD (N = 32), unaffected at-risk (N = 13), and HC (N = 56). During functional magnetic resonance imaging, participants attended to emotional and nonemotional aspects of fearful and happy faces. RESULTS While rating their fear of fearful faces, both BD and unaffected at-risk subjects exhibited amygdala hyperactivity versus HC. There were no between-group differences in amygdala activity in response to happy faces. Post-hoc comparisons revealed that, in at-risk youth, familial risk status (offspring versus sibling), presence of Axis I diagnosis (n = 1 attention-deficit/hyperactivity disorder [ADHD], n = 1 social phobia), and history of medication exposure (n = 1) did not influence imaging findings. CONCLUSIONS We found amygdala hyperactivation in both unaffected at-risk and BD youth while rating their fear of fearful faces. These pilot data suggest that both face emotion labeling deficits and amygdala hyperactivity during face processing should receive further study as potential BD endophenotypes. Longitudinal studies should test whether amygdala hyperactivity to fearful faces predicts conversion to BD in at-risk youth.