Neural correlates of Disruptive Behavior Disorder and the effects of a methylphenidate challenge

In chapter 2, we assessed the acute effects of a single methylphenidate administration on amygdala reactivity during fear learning and fear reversal learning. As hypothesized, DBD-patients in the placebo condition (DBD-PCB) showed lower amygdala reactivity during the acquisition of fear compared to healthy controls (HCs) and to DBD patients in the MPH condition (DBD-MPH). These findings suggest a normalizing effect of MPH on amygdala functioning during the acquisition of fear in DBD. Contrary our hypothesis, at the group level there was no difference in reactivity between the groups in the vmPFC during fear reversal learning. In exploratory subgroup analyses it was found that amygdala hypoactivation and the subsequent normalizing effect of MPH seemed to be driven by a subgroup of DBD-patients without comorbid ADHD. In chapter 3, we assessed whether brain activity during the extinction of previously acquired fear was associated with the persistence or desistence of DBD and psychopathic traits. As hypothesized, DBD-P and DBD-D were both associated with increased reactivity of ACC and insula during fear extinction, compared to HCs. Furthermore, impulsive-irresponsible psychopathic traits were positive associated with hyperreactivity in the amygdala, insula and ACC. Moreover, these impulsive-irresponsible traits mediated the association of neural reactivity in the ACC and persisting and desisting of DBD. The acute effect of methylphenidate administration on reward and punishment sensitivity was investigated in chapter 4. We hypothesized that - compared to HCs – DBD-patients have deviancies in both reward and punishment processing and that a single dose of methylphenidate could (temporary) normalize these deviancies. DBD-PCB showed - compared to HCs - significantly lower amygdala responsiveness during reward receipt or omission. DBD-MPH showed, compared to HCs, similar amygdala responsiveness during omission of a reward suggesting normalization of amygdala reactivity during reward omission. In contrast to our hypotheses, there was no suggested normalization of amygdala responsiveness during reward receipt. Furthermore, compared to DBD-MPH, DBD-PCB showed higher nucleus accumbens reactivity when anticipating a potential reward. In chapter 5, we assessed the effects of a single dose of methylphenidate on resting state connectivity of the nucleus accumbens (NAcc), amygdala and ventral tegmental area (VTA) with other brain areas. We hypothesized that DBD-PCB, compared to HCs, would show aberrances in resting state connectivity and a normalizing effect of methylphenidate. Compared to HCs, DBD-PCB showed higher connectivity between the NAcc seed and the occipital cortex, posterior cingulate cortex (PCC), precuneus and inferior parietal lobule (IPL). Furthermore, compared to HCs, DBD-PCB had higher connectivity of the amygdala seed with the precuneus and PCC. Compared to DBD-MPH, DBD-PCB had higher connectivity between NAcc seed and occipital cortex, IPL, and medial frontal gyrus. Both NAcc and amygdala seeds showed no connectivity differences in the DBD-MPH compared to the HCs group, suggesting that MPH normalizes the increased functional connectivity between mesolimbic seed regions and areas involved in moral decision making, visual processing and attention. In chapter 6 we assessed gray matter volume (GMV), white matter volume (WMV), and WM integrity of DBD-patients and HCs. In line with previous studies, DBD-patients had decreased GMV of the amygdala, insula, and inferior frontal cortex (IFG). While the previous literature of white matter integrity in DBD adolescents was inconsistent, with some studies reporting higher WM integrity and others reporting lower WM integrity, in this thesis we reported both higher and lower WM integrity in DBD-patients. Compared to HCs, DBD-patients had a cluster with higher WM integrity and a cluster with lower WM integrity within the uncinate fasciculus (UF), the white matter tract connecting the amygdala, insula and IFG.