Elucidating the Neurocircuitry of Irritability with Ultra-High-Field Neuroimaging to Identify Novel Therapeutic Targets

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PROJECT SUMMARY/ABSTRACT With this Mentored Patient-Oriented Research Career Development Award, the candidate – a psychiatrist with strong background in clinical research – aspires to achieve the long-term goal of becoming an independent, federally funded investigator who (i) uses a neuroscience-informed experimental medicine approach to identify neurocircuit mechanisms and (ii) conducts clinical trials to develop the next generation of circuit-specific antide- pressant treatments in order to ameliorate the public health burden of irritability, an important yet understud- ied feature of depression that is associated with poorer quality of life and elevated levels of suicidal ideation. Candidate proposes structured research experience and formal training in (1) ultra-high-field [7 Testa (7T)] func- tional magnetic resonance imaging (fMRI), (2) the affective neuroscience of irritability [including the use of task- based fMRI to model frustrative nonreward (FNR), an evolutionarily conserved response to omission of an ex- pected reward], and (3) experimental therapeutics approach to conduct clinical trials with changes in neurocircuit function as the outcome measure of interest, that will be supervised by a team of prominent experts in neuroim- aging, psychiatric neuroscience and experimental therapeutics. To fill the knowledge gaps regarding the neu- rocircuit mechanisms of irritability, candidate’s proposed research strategy aims to identify dysfunctions in neu- rocircuitry that engender irritability (Aim 1) and determine how changes in neurocircuit function relate to changes in irritability (Aim 2). The proposed study will enroll male and female adults aged 18-55 years [n=30 healthy controls (HC) and n=60 adults with major depressive disorder (MDD)]. All subjects will undergo resting-state and task-based 7T fMRI to characterize the (i) patterns of functional connectivity (Aim 1.1) and (ii) neural responses to a behavioral task of FNR (Aim 1.2) that are associated with irritability (quantified with the 5-item irritability domain of Concise Associated Symptom Tracking scale). The MDD cohort (n=60) will then be randomized to 2 weeks of twice-weekly intravenous infusions of either ketamine (0.5 mg/kg) or midazolam (0.02 mg/kg) in a double-blind parallel-arm fashion. Clinical assessments and MRI scans will be repeated after the last infusion to evaluate pre-to-post treatment changes in neurocircuit function using resting-state (Aim 2.1) and FNR (Aim 2.2) task-based fMRI with ketamine versus midazolam and to explore the association between changes in neurocir- cuit function and irritability. Candidate’s didactic and mentored training in 7T fMRI, affective neuroscience, and experimental therapeutic approach will enable successful execution of the research strategy. Research activities, such as collecting, storing, analyzing, and interpreting data from MRI scans and from clinical assessments, will provide valuable hands-on training. Successful completion of the proposed study will allow candidate to (1) ac- quire expertise in the conduct of neuroscience-informed studies that use experimental therapeutics approach and (2) generate pilot data in order to pursue NIH funding and build this highly innovative program of research.