Tara A. Niendam - US grants

DESCRIPTION (provided by applicant): This K23 application proposes a training and mentored research plan that will provide the applicant with new skills related to cognitive neuroscience and functional neuroimaging that will support the development of an independent research career investigating the cognitive and neural mechanisms underlying clinical and functional outcome in individuals at ultra-high-risk (UHR) for psychosis. The proposed training plan incorporates rigorous training in fMRI methodology, and relevant coursework in statistical analysis, programming, and the responsible conduct of human research. The academic and professional environment at UC Davis provides rich resources for the implementation of this proposal, including consistent access to an experienced mentorship team, a distinguished research and clinical faculty, two on-site magnetic resonance imaging (MRI) scanners and support staff dedicated to research purposes. In addition to this outstanding research training environment, the applicant will have ongoing access to established clinical populations for subject recruitment, and a strong departmental commitment to the development of the applicant's research career. The proposed mentored research study seeks to elucidate cognitive markers of risk for clinical and functional deterioration in individuals at ultra-high-risk for psychosis using fMRI. This investigation will extend previous findings established in individuals with schizophrenia by exploring prefrontally-mediated cognitive control and the integrity of underlying neurobiological circuitry in UHR individuals and healthy matched controls. Cognitive control, which is subserved by a distributed network of brain regions, coordinates thoughts and actions in order to generate goal-directed behavior. Cognitive control impairments have been consistently demonstrated in individuals with schizophrenia and, more recently, linked to clinical and functional impairment. While impairments on behavioral measures of cognition have been observed in UHR populations, the neural mechanisms underlying such impairments have not been established. Further, the link between such cognitive impairments and deterioration in clinical and psychosocial domains has not been systematically explored. This investigation utilizes an event-related functional magnetic resonance imaging (fMRI) paradigm to examine the role of the dorsolateral prefrontal cortex (DLPFC), which serves as an integral part of the distributed cognitive control network, during a task requiring high levels of cognitive control. It is hypothesized that UHR individuals will demonstrate reduced cognitive control with concurrent reductions in DLPFC activation when compared to normal controls. Furthermore, it is predicted that connectivity between the DLPFC and the distributed neural network that supports cognitive control will also be reduced in the UHR group. Finally, relationships between cortical activation and measures of clinical symptomatology and psychosocial functioning will be examined in order to determine if dysfunction in the DLPFC circuit underlying cognitive control contributes to clinical and functional outcome in these at-risk individuals. In concordance with the goals of the current NIMH Strategic Plan, results of this investigation will provide novel information on the role of prefrontal connectivity during the period preceding psychosis onset, offering insight into potential neurobiological markers as well as the possible developmental trajectory of illness progression for those individuals who are at highest risk for developing psychosis. Further, this study will broaden our understanding of the impact of prefrontal functioning on clinical and psychosocial functioning for at-risk adolescents, enhancing early identification algorithms and contributing to the development of more effective early intervention efforts. PUBLIC HEALTH RELEVANCE: The identification of putative markers of risk for psychosis is an essential step toward enhancing early detection and intervention efforts. This research proposes to use an fMRI paradigm to investigate cognitive control processes in the prefrontal cortex to identify markers of risk for clinical and functional deterioration in youth at ultra-high risk for psychosis.

Project Summary A prolonged first episode of psychosis (FEP) without adequate treatment is the most consistent predictor of poor clinical and functional outcomes1, poor health outcomes2 and significant economic burden3. Team-based ?coordinated specialty care? (CSC)4 for early psychosis (EP) has established effectiveness in promoting clinical and functional recovery5 . EP treatment programs have expanded rapidly with increased funding across the US without formal coordination of training or implementation. While EP programs share many features, the lack of state and national coordination and data infrastructure limits the capacity for large-scale evaluation or accelerated dissemination of best practices6. Based on prior collaborations with 30 California (CA) EP programs and experiences using mobile health (MOBI mHealth) technology to measure individual outcomes in EP care, the UC Davis (UCD) team is uniquely poised to create EPI-CAL, a CA network that will contribute systematically collected outcomes data on over 1000 FEP clients per year, from 6 community and 6 university EP clinics, to a national EP network supported by the NIMH EPINET program. Building on our prior work evaluating CA EP programs, EPI-CAL programs will participate in a formative evaluation in Year 1 to define core EP clinical features, intervention targets, and outcomes needed to harmonize network input. A ?core battery? based on current measures collected at the sites, the PhenX toolkit7 and expanded to cover all critical domains, will be installed across the network in Year 2. Core client outcomes and metrics of data use for treatment decisions will be collected using the custom MOBI mHealth data network at the client, program, and state level to allow easy data analysis, interpretation and dissemination. Training and ongoing monitoring will be provided at all EPI-CAL sites to ensure appropriate implementation. EPI-CAL will contribute de-identified data to the national coordinating hub. Using the RE-AIM implementation science framework8,9, we will systematically evaluate the impact of MOBI on EP programs across 5 dimensions: reach, efficacy, adoption, implementation, and maintenance (see Figure 1). To demonstrate the network?s research capacity, in the R34 component of this application, we propose to develop and validate a measure of the Duration of Untreated Psychosis (DUP) that is feasible for use in community settings and psychometrically sound. Although DUP is a significant predictor of both short-term CSC treatment response5 and long-term outcomes10 for FEP, no measure currently exists that has been rigorously validated and is feasible for use by community providers7,11. We will utilize stakeholder feedback (clients, family members, academic experts and CSC staff) to develop a tool with standardized DUP definitions that includes anchored assessment of psychosis onset and start of treatment. Developing such a tool will allow standardized assessment of this critical moderator of CSC outcomes across the entire EPINET.