The Motivational Determinants of Human Action, Their Neural Bases and Functional Impact in Adolescents With Obsessive-Compulsive Disorder.

Background: Establishing the motivational influences on human action is essential for understanding choice and decision making in health and disease. Here we used tests of value-based decision making, manipulating both predicted and experienced reward values to assess the motivational control of goal-directed action in healthy adolescents and those with obsessive-compulsive disorder (OCD). Methods: After instrumental training on a two action-two outcome probabilistic task, adolescents (n = 21) underwent Pavlovian conditioning using distinct stimuli predicting either the instrumental outcomes, a third outcome, or nothing. We then assessed functional magnetic resonance imaging during choice tests in which we varied the predicted value, using specific and general Pavlovian-instrumental transfer, and the experienced value, using outcome devaluation. To establish functional significance, we tested a matched cohort of adolescents with OCD (n = 20). Results: In healthy adolescents, both predicted and experienced values influenced the performance of goal-directed actions, mediated by distinct orbitofrontal-striatal circuits involving the lateral orbitofrontal cortex (OFC) and medial OFC, respectively. However, in adolescents with OCD, choice was insensitive to changes in either predicted or experienced values. These impairments were related to hypoactivity in the lateral OFC and hyperactivity in the medial OFC during specific Pavlovian-instrumental transfer and hypoactivity in the anterior prefrontal cortex, caudate nucleus, and their connectivity in the devaluation test. Conclusions: We found that predicted and experienced values exerted a potent influence on the performance of goal-directed actions in adolescents via distinct orbitofrontal- and prefrontal-striatal circuits. Furthermore, the influence of these motivational processes was severely blunted in OCD, as was the functional segregation of circuits involving medial and lateral OFC, producing dysregulated action control.

Change Patterns During Family-Based Treatment for Pediatric Obsessive Compulsive Disorder.

Cognitive behavior therapy (CBT) for young people with obsessive compulsive disorder (OCD) has recently been enhanced to target family environment factors. However, the process of change for OCD symptoms and family factors during treatment is not well understood. Uniquely, we explored patterns of change for OCD symptoms and a range of family variables throughout Baseline, Early, Mid, and Late treatment phases of family-based CBT (FCBT) for 15 young people with OCD using multiple informants. We predicted a linear reduction in OCD symptom severity and family accommodation (FA) across treatment phases, however the investigation into other family factor change patterns was exploratory. OCD symptom severity, FA, parental distress tolerance (DT), and conflict all showed significant linear change patterns across treatment phases according to multiple informants. In addition, the largest proportion of change for these variables typically occurred during the first third of treatment, highlighting the importance of identifying participants with and without early gains in future research. Blame also showed a significant linear change pattern, although with small reductions between treatment phases. Preliminary bivariate analyses sought to better understand whether family factor change predicted subsequent OCD severity change or vice versa. Similar patterns emerged across informants, including identification of OCD severity as a significant predictor of change for Blame at subsequent treatment phases. Analyses also showed bi-directional effects for DT and OCD symptoms across informants, where DT predicted OCD severity at subsequent treatment phases and vice versa. These outcomes support further research aimed at understanding the role of family factors in pediatric OCD symptom change.

Use of pifithrin to inhibit p53-mediated signalling of TNF in dystrophic muscles of mdx mice.

Tumour Necrosis Factor (TNF) plays a major role in exacerbating necrosis of dystrophic muscle; however, the precise molecular mechanism underlying this effect of TNF is unknown. This study investigates the role that p53 plays in TNF-mediated necrosis of dystrophic myofibres by inhibiting p53 using pifithrin-alpha and three pifithrin-beta analogues. Tissue culture studies using C2C12 myoblasts established that pifithrin-alpha was toxic to differentiating myoblasts at concentrations greater than 10 muM. While non-toxic concentrations of pifithrin-alpha did not prevent the TNF-mediated inhibition of myoblast differentiation, Western blots indicated that nuclear levels of p53 were higher in TNF-treated myoblasts indicating that TNF does elevate p53. In contrast, in vivo studies in adult mdx mice showed that pifithrin-alpha significantly reduced myofibre necrosis that resulted from voluntary wheel running over 48 h. These results support the hypothesis that p53 plays some role in TNF-mediated necrosis of dystrophic muscle and present a potential new target for therapeutic interventions.