Unit on Neuroscience and Novel Therapeutics

National Institute Of Mental Health

Investigators

Linked publications, trials & patents

Abstract

First, in 2022, our program completed a multiple baseline novel frustration-exposure intervention for youth with severe irritability based on extinction principles. The results of the study have been submitted for publication; N=41 youth were randomized; preliminary analyses demonstrated that irritability scores decreased significantly from the start of therapy to end of therapy. NNT acquires pre-treatment behavioral and task-based fMRI data to test the hypothesis that pre-treatment behavioral deficits in inhibition predict poorer treatment response. Second, in 2022, we submitted a paper for publication examining the brain changes associated with cognitive behavioral therapy in youth with anxiety. Across two randomized controlled trials, unmedicated children with an anxiety disorder diagnosis completed task-based functional magnetic resonance imaging pre- and post-treatment. For benchmarking purposes, age-matched healthy comparison youth completed two scans over the same time span. Pretreatment, patients with an anxiety disorder exhibited altered activation in fronto-parietal attention networks and limbic regions relative to healthy control children. Hyperactivation in fronto-parietal networks normalized over treatment, whereas limbic response remained elevated post-treatment. Findings inform future treatment studies and suggest the potential value of adjunct treatments that more directly target limbic change to enhance CBT efficacy. Third, we leverage technology to assess symptoms by utilizing digitally based event sampling (ecological momentary assessment). Last year we validated our metric. This year, we revised and resubmitted a second manuscript demonstrating differences in fluctuations in positive and negative affect in youth with different psychiatric disorders. In addition, we developed a cognitive inhibition mobile application to probe children's inhibitory control. Over 150 youth have completed the task remotely. Preliminary data demonstrate the validity, and reliability of the mobile app relative to in clinic standardized behavioral tasks. These assessments provide the foundation for scalable, target-based interventions which are more easily disseminated, facilitating public health impact. Fourth, we published a paper demonstrating abnormal amygdala-prefrontal connectivity during a threat orienting task in 351 youth with varying degrees of irritability and anxiety. Fifth, as threats engage evolutionarily conserved processes, our translational perspective has been supported by two Bench-to-Bedside Awards. Specifically, we reverse translated the Human Intruder Paradigm, (Kalin & Shelton 1989) into two clinical paradigms. Our fMRI (N=90) and eye-tracking (N=60) tasks parallel work in non-human primates. Ultimately, these mechanistic studies will allow for more targeted interventions for pathological irritability. Finally, the acute onset of the COVID-19 pandemic provided a rare opportunity to utilize existing pre-stress clinical and neural data to predict stress-related increases in psychopathology and associated neural dysfunction. We published a study demonstrating increased anxiety and depression in youth during the early waves of the COVID-19 pandemic. Leveraging existing fMRI data, we found increased prefrontal activity was associated with more anxiety during the pandemic.