This phased innovation application in response to RFA-MH-16-406 seeks support for an initial (R61) 2-year phase for milestone-driven testing of a specific neural target of intervention by a novel modification of a treatment targeting organizational skills in children in 3rd to 5th grades of elementary school who have deficient organizational skills in the context of neurodevelopmental disorders. Attaining our proposed milestones would trigger support for three additional years (R33 phase) to confirm target engagement in a larger sample with random assignment to intervention vs. wait-list control conditions, to assess the relationships between target engagement and changes in functional outcomes. Organizational skills impairments contribute to school failure and to poor long-term outcomes and occur across multiple neurodevelopmental disorders. They are insufficiently addressed by medications or most existing behavioral treatments. Organizational skills training (OST) has resulted in robust, enduring improvements in a prior controlled trial. To further develop this intervention, we seek to identify the neural targets engaged by effective intervention. Our pilot data and theoretical considerations support the overarching hypothesis that intrinsic functional connectivity (iFC) between dorsal anterior cingulate cortex (dACC) and anterior ventral striatum (aVS) represents a treatable target. Accordingly, in the initial R61 phase we propose to estimate the effect size of intervention-related decreases in dACC-aVS iFC in at least 22 children with high-quality imaging and clinical data obtained both before and after modified OST (OST-m). If we meet our proposed milestones that the decrease in dACC-aVS iFC will exceed a specific effect size and account for an appreciable proportion of the variance in the improvement in organizational skills, we would proceed to the R33 phase. In the R33 phase, we would expand the study to obtain at least 86 more children randomized to the OST-m intervention or to wait-list who will provide complete high quality pre- and post-intervention/waitlist imaging and clinical data. For both phases, we will obtain state-of-the-art magnetic resonance imaging (MRI) data with a primary focus on resting-state functional MRI.
Our specific aims i n the R33 phase are to confirm target engagement in the group randomized to OST-m vs. the waitlist group; to examine the relationship between changes in the neuronal target and clinical improvements in organizational skills and academic proficiency; and to identify moderators of improvement in organizational skills by examining baseline clinical measures alone and in combination with whole-brain voxel-wise resting-state indices. Evidence supporting the validity of dACC-aVS iFC as a modifiable neural target would then support future studies to further enhance the effectiveness of cognitive/behavioral interventions in children. Importantly, even negative results will be informative regarding the OST ?dosage? required to attain substantial effects. Inconclusive results from brain imaging would still inform Bayesian priors for future studies of the neural substrates of organizational skills impairments and their amelioration.
This phased innovation application seeks support to test whether a specific neural target of intervention is affected by a modification of organizational skills training in elementary school-age children with deficient organizational skills. Positive results would support future studies to further improve their effectiveness. Even negative results would help us understand intervention dosage requirements; inconclusive brain imaging results would help us formulate better future studies to understand the brain bases of organizational skills impairments and how to best remedy them.
