Abstract
Some studies suggest that methylphenidate (MPH) might be an effective treatment for antisocial and aggressive behavior in adolescence. However, little is known about the mechanism of action of MPH in adolescents with this kind of psychopathology. MPH is a dopamine and norepinephrine reuptake inhibitor and thus it is likely to affect dopaminergic mesocorticolimbic pathways. This is the first study to investigate the effect of MPH on resting-state connectivity of three mesolimbic seed regions with the rest of the brain in clinical referred male adolescents with a disruptive behavior disorder (DBD). Thirty-six male DBD adolescents and 31 male healthy controls (HCs) were included. DBD subjects were randomly allocated to a single dose of MPH (DBD-MPH, n = 20) or placebo (DBD-PCB, n = 16). Seed-based resting-state functional connectivity of the nucleus accumbens (NAcc), amygdala, and ventral tegmental area (VTA) with the rest of the brain was compared between groups. The NAcc seed showed increased connectivity in DBD-PCB compared to HC with the occipital cortex, posterior cingulate cortex (PCC), precuneus, and inferior parietal lobule (IPL) and increased connectivity in DBD-PCB compared to DBD-MPH with occipital cortex, IPL, and medial frontal gyrus. The amygdala seed showed increased connectivity in DBD-PCB compared to HC with the precuneus and PCC. The VTA seed showed increased connectivity in the DBD-MPH compared to the DBD-PCB group with a cluster in the postcentral gyrus and a cluster in the supplementary motor cortex/superior frontal gyrus. Both NAcc and amygdala seeds showed no connectivity differences in the DBD-MPH compared to the HC group, indicating that MPH normalizes the increased functional connectivity of mesolimbic seed regions with areas involved in moral decision making, visual processing, and attention.
Highlights
Antisocial behavior in children and adolescents constitutes a huge problem for society
18 were excluded (5 healthy controls (HCs) and 13 disruptive behavior disorder (DBD)): 2 HC because they met diagnostic criteria for oppositional defiant disorder (ODD) and/or ADHD and 4 DBD because they did not meet DBD criteria on the Diagnostic Interview Schedule for Children (DISC-IV), 1 HC and 1 DBD because of an IQ < 80, and 2 HC, 5 DBD-PCB, and 3 DBDMPH subjects because of excessive head motion based on their average motion statistic [mean framewise displacement calculated according to the Jenkinson method [41]]
Post-hoc testing revealed that both DBD groups used more tobacco compared to the HC group and that the DBD-MPH group used more cannabis compared to the HC and the DBD-PCB groups
Summary
Antisocial behavior in children and adolescents constitutes a huge problem for society. A recent meta-analysis [14] of whole-brain fMRI studies has revealed that compared to healthy controls (HCs), patients with DBD show decreased activations in the anterior cingulate cortex (ACC), the medial frontal cortex (MFC), and the ventral striatum (VS), while region-of-interest analyses revealed abnormal amygdala activations [e.g., [15, 16]], i.e., brain areas that are part of the mesolimbic fronto-striatal dopamine pathway. In this pathway, the ventral tegmental area (VTA) releases dopamine and projects via the medial forebrain bundle to the nucleus accumbens (NAcc) and to other limbic structures, including the septum, hippocampus, amygdala, orbitofrontal cortex (OFC), ACC, and mPFC [17]. We hypothesized that [1] male adolescent DBD patients compared to HCs show an abnormal resting-state connectivity pattern of the subcortical NAcc, amygdala, and VTA seeds with cortical areas involved in emotion and reward processing and [2] MPH will normalize this abnormal connectivity pattern within the mesolimbic pathways in male adolescent DBD patients
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