Effects of Methylphenidate During Fear Learning in Antisocial Adolescents : A Randomized Controlled fMRI Trial

Abstract

OBJECTIVE: Although the neural underpinnings of antisocial behavior have been studied extensively, research on pharmacologic interventions targeting specific neural mechanisms remains sparse. Hypoactivity of the amygdala and ventromedial prefrontal cortex (vmPFC) has been reported in antisocial adolescents, which could account for deficits in fear learning (amygdala) and impairments in decision making (vmPFC), respectively. Limited clinical research suggests positive effects of methylphenidate, a dopamine agonist, on antisocial behavior in adolescents. Dopamine is a key neurotransmitter involved in amygdala and vmPFC functioning. The objective of this study was to investigate whether methylphenidate targets dysfunctions in these brain areas in adolescents with antisocial behavior. METHOD: A group of 42 clinical referred male adolescents (14-17 years old) with a disruptive behavior disorder performed a fear learning/reversal paradigm in a randomized double-blinded placebo-controlled pharmacologic functional magnetic resonance imaging study. Participants with disruptive behavior disorder were randomized to receive a single dose of methylphenidate 0.3 to 0.4 mg/kg (n = 22) or placebo (n = 20) and were compared with 21 matched healthy controls not receiving medication. RESULTS: In a region-of-interest analysis of functional magnetic resonance imaging data during fear learning, the placebo group showed hyporeactivity of the amygdala compared with healthy controls, whereas amygdala reactivity was normalized in the methylphenidate group. There were no group differences in vmPFC reactivity during fear reversal learning. Whole-brain analyses showed no group differences. CONCLUSION: These findings suggest that methylphenidate is a promising pharmacologic intervention for youth antisocial behavior that could restore amygdala functioning. CLINICAL TRIAL REGISTRATION INFORMATION: Fear Conditioning During Specific Conditions in Antisocial Adolescents: A Neuroimaging Study. http://www.trialregister.nl/trialreg/index.asp; NTR4088.