The neurobiological mechanisms of schizophrenia (SZ) remain unknown, hindering the development of effective treatments. The identification of pathogenetically-relevant disease biomarkers and their subsequent testing as measures for treatment response are critical for the field. This research proposal aims to test anatomical and functional biomarkers for declarative (i.e., relational) memory dysfunction and their associations with psychosis in patients with SZ, with an emphasis on system-level alterations within the hippocampus-neocortical (Hipp-NC) brain network. We will carry out this examination at two levels: (1) within Hipp circuitry, to test Hipp subfield contributions to relational memory (RM) dysfunction and psychosis, using high resolution functional MRI (fMRI), and (2) within the Hipp-NC network, to test system-level biomarkers, using standard resolution fMRI, and connectivity analyses (resting state fMRI, DTI). Ultimately, our goal is to define Hipp-NC-mediated systems-level 'biosignatures'for RM dysfunction and psychosis in SZ by testing inter-relations between the regional outcomes within and across Hipp circuitry and Hipp-NC networks and their association with RM behavioral and psychosis manifestation outcomes. We will conduct these experiments in 30 outpatients with SZ or schizoaffective disorder, contrasted with 30 healthy individuals. It is the testing of system-level disease biomarkers using cutting-edge high- and standard-resolution multimodal brain imaging methodology that make this proposal highly innovative. The outcomes of this research may generate novel Hipp-NC-bound biomarkers for SZ, contribute to understanding the role of Hipp-NC system in pathogenesis of cognitive dysfunction and psychosis, and aid in the future development of objective measures for treatment response in SZ and related psychotic disorders. Pursuit of the proposed studies will not only advance knowledge in this research field, but also provide a valuable framework for achieving the broader aims of the candidate's training and career development program. The candidate's immediate goal is to develop a career as an independent investigator in the field of translational neuroscience research in SZ. To achieve this goal, the candidate has organized a training program involving coursework, readings, workshops, conferences, and consultations with the mentor and the team of consultants (all actively collaborating with the mentor) who are leading experts in neuroimaging and cognitive neuroscience research in SZ, as well as system-level analytic approaches. Research and training activities will be carried out at UT Southwestern Medical Center, the Division of Translational Neuroscience Research in Schizophrenia and the Advanced Imaging Research Center that will provide an infrastructure for the candidate's proposed research and training plan. This career development Award will enable the candidate's overall goals of contributing to the understanding of neurobiology of psychosis and informing new treatment development efforts.
Schizophrenia is a severe and debilitating psychiatric disorder with unknown neurobiological mechanisms and limited treatment options. The proposed studies will examine structural and functional alterations in the brain systems underlying cognitive and psychotic symptoms in individuals with schizophrenia. The outcomes of this research have the potential to elucidate brain networks mediating memory dysfunction and psychosis, which in turn could provide clues to the pathophysiologic mechanisms of schizophrenia, aid in more reliable biologically-driven diagnosis, and inform the development of objective measures for treatment response in schizophrenia and related psychotic disorders.
|Braff, David L; Tamminga, Carol A (2017) Endophenotypes, Epigenetics, Polygenicity and More: Irv Gottesman's Dynamic Legacy. Schizophr Bull 43:10-16|
|Das, Tanusree; Ivleva, Elena I; Wagner, Anthony D et al. (2014) Loss of pattern separation performance in schizophrenia suggests dentate gyrus dysfunction. Schizophr Res 159:193-7|