Frustrative non-reward is defined by reactions elicited in response to withdrawal or prevention of reward, most notably reactive aggression. The neural mechanisms of reactive aggression involve heightened amygdala arousal in response to frustration coupled with hypoactivity of prefrontal regions that subserve emotion regulation. This is a proposal for a randomized controlled trial of cognitive-behavioral therapy (CBT) in children with high levels of aggression aimed at explicating the brain-behavior relationship of the frustrative non-reward construct. Because CBT teaches emotion regulation skills, the first objective of the study is to examine whether positive response to CBT for aggression will be associated with decreased activity in the amygdala, the brain area associated with emotional arousal, and increased activity in the brain areas associated with cognitive control of emotion, including the dorsal anterior cingulate cortex and ventromedial prefrontal cortex. Demonstrating that a change in the key nodes of the emotion regulation circuitry is associated with a reduction of reactive aggression will provide evidence to support the validity of the frustrative non-reward construct. The second objective is to explore the moderating effects of the biomarkers of impaired socioemotional perception and reward sensitivity in aggressive children with callous-unemotional traits on response to CBT. Eighty children with high levels of aggression across multiple traditional diagnostic categories, ages 8 to 16, will be randomly assigned to receive 12 sessions of CBT or 12 sessions of Supportive Psychotherapy. Clinical outcomes will be measured by the parent-ratings of aggressive behavior collected at baseline, midpoint and endpoint evaluations and the Improvement Score of the Clinical Global Impression Scale assigned by an independent evaluator (blinded rater). Children will also perform a frustration-induction Go-NoGo task and a task of emotional face perception during fMRI scanning and EEG recording at baseline and endpoint. The frustration-induction Go-NoGo task involves viewing a stream of objects and pressing the button in response to pre-determined experimental conditions. During a portion of the task, frustration is induced by loss of points that can be exchanged for a reward. This task has been shown to engage the neural circuitry of emotion regulation in an earlier fMRI study. The main contrasts of interest for the BOLD signal will be the difference between: (1) neutral versus frustration blocks of the Go-NoGo task, (2) neutral versus emotional faces, and (3) correct versus incorrect Go trials of the Go-NoGo. The main variables of interest for the evoked-related potentials will be: (1) the N2 component to the NoGo trials, (2) P3 component to correct and Feedback-Related Negativity to the incorrect Go trials, and (3) N170 and N250 ERPs to the face perception task. Consistent with the NIMH Strategic Research Priorities, if functional neuroimaging and electrophysiological variables can identify children who respond to cognitive-behavioral therapy for aggression, this can provide a neuroscience- based classification scheme that will improve treatment outcomes for children with aggressive behavior.

Public Health Relevance

This proposal addresses the NIMH Strategic Plan by investigating neuroimaging, electrophysiological and behavioral aspects of the frustrative non-reward construct identified by the RDoC project. This is a randomized controlled trial of behavior therapy for aggression in children across multiple traditionally defined disorders aimed at developing a neuroscience-based classification scheme that will improve treatment outcomes.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZMH1-ERB-S (04))
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Garvey, Marjorie A
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Yale University
Schools of Medicine
New Haven
United States
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Tudor, Megan E; Ibrahim, Karim; Bertschinger, Emilie et al. (2016) Cognitive-Behavioral Therapy for a 9-Year-Old Girl With Disruptive Mood Dysregulation Disorder. Clin Case Stud 15:459-475
Sukhodolsky, Denis G; Smith, Stephanie D; McCauley, Spencer A et al. (2016) Behavioral Interventions for Anger, Irritability, and Aggression in Children and Adolescents. J Child Adolesc Psychopharmacol 26:58-64
Sukhodolsky, Denis G; Vander Wyk, Brent C; Eilbott, Jeffrey A et al. (2016) Neural Mechanisms of Cognitive-Behavioral Therapy for Aggression in Children and Adolescents: Design of a Randomized Controlled Trial Within the National Institute for Mental Health Research Domain Criteria Construct of Frustrative Non-Reward. J Child Adolesc Psychopharmacol 26:38-48