Kenneth E. Towbin

Reduced Amygdala Response to Fearful Expressions in Children and Adolescents With Callous-Unemotional Traits and Disruptive Behavior Disorders

OBJECTIVE Extensive work implicates abnormal amygdala activation in emotional facial expression processing in adults with callous-unemotional traits. However, no research has examined amygdala response to emotional facial expressions in adolescents with disruptive behavior and callous-unemotional traits. Moreover, despite high comorbidity of callous-unemotional traits and attention deficit hyperactivity disorder (ADHD), no research has attempted to distinguish neural correlates of pediatric callous-unemotional traits and ADHD. METHOD Participants were 36 children and adolescents (ages 10-17 years); 12 had callous-unemotional traits and either conduct disorder or oppositional defiant disorder, 12 had ADHD, and 12 were healthy comparison subjects. Functional MRI was used to assess amygdala activation patterns during processing of fearful facial expressions. Patterns in the callous-unemotional traits group were compared with those in the ADHD and comparison groups. RESULTS In youths with callous-unemotional traits, amygdala activation was reduced relative to healthy comparison subjects and youths with ADHD while processing fearful expressions, but not neutral or angry expressions. Functional connectivity analyses demonstrated greater correlations between the amygdala and the ventromedial prefrontal cortex in comparison subjects and youths with ADHD relative to those with callous-unemotional traits. Symptom severity in the callous-unemotional traits groups was negatively correlated with connectivity between amygdala and ventromedial prefrontal cortex. CONCLUSIONS This is the first study to demonstrate reduced amygdala responsiveness in youths with callous-unemotional traits. These findings support the contention that callous and unemotional personality traits are associated with reduced amygdala response to distress-based social cues.

Choice selection and reward anticipation: An fMRI study

We examined neural activations during decision-making using fMRI paired with the wheel of fortune task, a newly developed two-choice decision-making task with probabilistic monetary gains. In particular, we assessed the impact of high-reward/risk events relative to low-reward/risk events on neural activations during choice selection and during reward anticipation. Seventeen healthy adults completed the study. We found, in line with predictions, that (i) the selection phase predominantly recruited regions involved in visuo-spatial attention (occipito-parietal pathway), conflict (anterior cingulate), manipulation of quantities (parietal cortex), and preparation for action (premotor area), whereas the anticipation phase prominently recruited regions engaged in reward processes (ventral striatum); and (ii) high-reward/risk conditions relative to low-reward/risk conditions were associated with a greater neural response in ventral striatum during selection, though not during anticipation. Following an a priori ROI analysis focused on orbitofrontal cortex, we observed orbitofrontal cortex activation (BA 11 and 47) during selection (particularly to high-risk/reward options), and to a more limited degree, during anticipation. These findings support the notion that (1) distinct, although overlapping, pathways subserve the processes of selection and anticipation in a two-choice task of probabilistic monetary reward; (2) taking a risk and awaiting the consequence of a risky decision seem to affect neural activity differently in selection and anticipation; and thus (3) common structures, including the ventral striatum, are modulated differently by risk/reward during selection and anticipation.

Obsessive compulsive disorder in children and adolescents: phenomenology and family history.

Phenomenology and family history in 21 clinically referred children and adolescents with obsessive compulsive disorder are described. Each child and family participated in a standard clinical psychiatric assessment. The most frequently reported symptoms were repeating rituals, washing, ordering and arranging, checking, and contamination concerns. Controlling behaviors involving other family members were seen in 57% of the patients. Associated psychopathology was common: 38% received an anxiety disorder diagnosis; 29% received a mood disorder diagnosis; tics were observed in 24%. Fifteen (71%) of the children had a parent with either obsessive compulsive disorder (N = 4) or obsessive-compulsive symptoms (N = 11). The clinical and research implications of these findings are discussed.

Abnormal ventromedial prefrontal cortex function in children with psychopathic traits during reversal learning.

CONTEXT Children and adults with psychopathic traits and conduct or oppositional defiant disorder demonstrate poor decision making and are impaired in reversal learning. However, the neural basis of this impairment has not previously been investigated. Furthermore, despite high comorbidity of psychopathic traits and attention-deficit/hyperactivity disorder, to our knowledge, no research has attempted to distinguish neural correlates of childhood psychopathic traits and attention-deficit/hyperactivity disorder. OBJECTIVE To determine the neural regions that underlie the reversal learning impairments in children with psychopathic traits plus conduct or oppositional defiant disorder. DESIGN Case-control study. SETTING Government clinical research institute. PARTICIPANTS Forty-two adolescents aged 10 to 17 years: 14 with psychopathic traits and oppositional defiant disorder or conduct disorder, 14 with attention-deficit/hyperactivity disorder only, and 14 healthy controls. MAIN OUTCOME MEASURE Blood oxygenation level-dependent signal as measured via functional magnetic resonance imaging during a probabilistic reversal task. RESULTS Children with psychopathic traits showed abnormal responses within the ventromedial prefrontal cortex (Brodmann area 10) during punished reversal errors compared with children with attention-deficit/hyperactivity disorder and healthy children (P < .05 corrected for multiple comparisons). CONCLUSIONS To our knowledge, this study provides the first evidence of abnormal ventromedial prefrontal cortex responsiveness in children with psychopathic traits and demonstrates this dysfunction was not attributable to comorbid attention-deficit/hyperactivity disorder. These findings suggest that reversal learning impairments in patients with developmental psychopathic traits relate to abnormal processing of reinforcement information.

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.

Neuropsychological performance in pediatric bipolar disorder

BACKGROUND Growing awareness of childhood bipolar disorder necessitates further cognitive neuroscience research to determine unique developmental differences between pediatric and adult onset bipolar disorder. We sought to examine whether neuropsychological function in children with bipolar disorder resembles that in adults with the illness and to extend our knowledge about cognitive function in pediatric bipolar disorder. METHODS We administered a computerized neuropsychological test battery known as the Cambridge Neuropsychological Test Automated Battery to a sample of 21 children and adolescents with bipolar disorder and compared them with 21 age- and gender-matched controls. RESULTS In comparison to controls, children with bipolar disorder were impaired on measures of attentional set-shifting and visuospatial memory. Post hoc analyses in pediatric bipolar disorder subjects did not show significant associations between neuropsychological performance and manic symptomatology or attention-deficit/hyperactivity disorder comorbidity. CONCLUSIONS Cambridge Neuropsychological Test Automated Battery data presented here in pediatric bipolar disorder fit well within the broader framework of known neurocognitive deficits in adult bipolar disorder. Our pediatric bipolar disorder subjects demonstrated selective deficiencies in attentional set-shifting and visuospatial memory. Our work suggests altered ventrolateral prefrontal cortex function, especially when linked to other lesion and neuroimaging studies.

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.

Clinical correlates of episodicity in juvenile mania.

OBJECTIVE Researchers debate whether the diagnostic criteria for mania should differ between children and adults. Specifically, although the Diagnostic and Statistical Manual of Mental Disorders (fourth edition; DSM-IV) requires episodic mood changes, children commonly are diagnosed as manic on the basis of chronic irritability. In this preliminary study, children carrying a diagnosis of bipolar disorder (BPD) in the community were classified as having either episodic or chronic symptoms. We hypothesized that the episodic group would be more likely to have a history of psychosis and a parental history of BPD, whereas the chronic group would be more likely to have conduct disorder. METHODS Parents of children carrying the BPD diagnosis were interviewed on the telephone to obtain psychiatric and family histories. Children were considered episodic (n = 34) if they had a history of one or more DSM-IV manic/hypomanic episodes meeting full duration criteria and chronic (n = 53) if they had no discernable episodes. RESULTS The episodic group was more likely to have had psychosis, parental history of BPD, and to have experienced each manic symptom except for irritability and psychomotor agitation. Children in the episodic group were also more likely to have had a depressive episode meeting full DSM-IV criteria and were more likely to have made a suicide attempt. Children in the chronic group were not more likely to meet criteria for conduct disorder but were more likely to exhibit violence toward others. CONCLUSIONS These preliminary data indicate that, among children being treated for BPD in the community, those with discrete episodes of mania may be more likely to have a lifetime history of psychosis and a parental history of BPD. The latter hypothesis should be tested in a sample where relatives are interviewed directly.

Practitioner Review : The assessment of bipolar disorder in children and adolescents

BACKGROUND An increasing number of youth are being diagnosed with, and treated for, bipolar disorder (BD). Controversy exists about whether youth with non-episodic irritability and symptoms of attention deficit hyperactivity disorder (ADHD) should be considered to have a developmental presentation of mania. METHOD A selective review of the literature related to this question, along with recommendations to guide clinical assessment. RESULTS Data indicate differences between youth with episodic mania and those with non-episodic irritability in longitudinal diagnostic associations, family history, and pathophysiology. In youth with episodic mania, elation and irritability are both common during manic episodes. CONCLUSIONS In diagnosing mania in youth, clinicians should focus on the presence of episodes that consist of a distinct change in mood accompanied by concurrent changes in cognition and behavior. BD should not be diagnosed in the absence of such episodes. In youth with ADHD, symptoms such as distractibility and agitation should be counted as manic symptoms only if they are markedly increased over the youths baseline symptoms at the same time that there is a distinct change in mood and the occurrence of other associated symptoms of mania. Although different techniques for diagnosing comorbid illnesses have not been compared systematically, it appears most rational to diagnose co-occurring illnesses such as ADHD only if the symptoms of the co-occurring illness are present when the youth is euthymic.

Differentiating Bipolar Disorder--Not Otherwise Specified and Severe Mood Dysregulation.

OBJECTIVE Bipolar disorder-not otherwise specified (BP-NOS) and severe mood dysregulation (SMD) are severe mood disorders that were defined to address questions about the diagnosis of bipolar disorder (BD) in youth. SMD and BP-NOS are distinct phenotypes that differ in clinical presentation and longitudinal course. The purpose of this review is to inform clinicians about the clinical features of the two phenotypes and about the research literature distinguishing them. METHOD A literature review was performed on SMD as studied in the National Institute of Mental Health Intramural Research Program and on BP-NOS in youth. For BP-NOS, the phenotype defined in the Course of Bipolar Youth study is the focus, because this has received the most study. RESULTS SMD is characterized by impairing, chronic irritability without distinct manic episodes. Most commonly, BP-NOS is characterized by manic, mixed, or hypomanic episodes that are too short to meet the DSM-IV-TR duration criterion. Research provides strong, albeit suggestive, evidence that SMD is not a form of BD; the most convincing evidence are longitudinal data indicating that youth with SMD are not at high risk to develop BD as they age. The BP-NOS phenotype appears to be on a diagnostic continuum with BD types I and II. Subjects with BP-NOS and those with BD type I have similar symptom and family history profiles, and youth with BP-NOS are at high risk to develop BD as they age. Currently, little research guides treatment for either phenotype. CONCLUSIONS Pressing research needs include identifying effective treatments for these phenotypes, ascertaining biomarkers that predict conversion from BP-NOS to BD, elucidating associations between SMD and other disorders, and defining the neural circuitry mediating each condition.