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COBRE Phase 1 Project 4: Jung //

Fronto-Subcortical Disconnection Underlying Neurocognitive Dysfunction in Schizophrenia

Principal Investigator:  Rex Jung, PhD

Mentors:  Nora Perrone-Bizzozero, PhD and Vincent Calhoun, PhD
Consultant:  Kelvin Lim, MD

We propose to use high field (3 Tesla) multimodal imaging to investigate whether general cognitive functioning in schizophrenia is related to circuit level white matter, metabolic, and volumetric changes in subcortical gray-and white-matter regions suggestive of fronto-subcortical disconnection. Simultaneous utilization of Diffusion Tensor Imaging (DTI), proton magnetic resonance spectroscopy (1H-MRS), and structural Magnetic Resonance Imaging (sMRI) will allow us to relate white matter abnormalities to both cortical and subcortical metabolic and morphological changes that, in turn, may underlie ongoing neurocognitive decline in schizophrenia.  As schizophrenia is postulated to be a disease that involves the integration of information among distributed brain circuits, we propose to use DTI, 1H-MRSI and sMRI to investigate: 1) whether fronto-subcortical network abnormalities are present in schizophrenia, 2) whether cognitive functioning in schizophrenia is related to circuit level dysfunction, and 3) whether regions beyond the identified brain circuits contribute significantly to broad cognitive functioning characteristic of schizophrenia. Diffusion Tensor Imaging, a measure of axonal/myelin integrity based on water diffusion within cellular compartments, will be measured within the superior longitudinal fasciculus, cingulum bundle, and anterior limb of the internal capsule (ALIC); N-acetylaspartate (NAA), a marker of metabolic dysfunction or neuronal loss/integrity, will be measured within the anterior cingulate gyrus, frontal white matter, ALIC, caudate nucleus, and thalamus; structural MRI, yielding a measure of cortical thickness, will be measured within the anterior cingulate gyrus and Brodmann areas 9/46 & 10. A hierarchical approach will be explored, in which cognitive functioning is predicted by cortical thinning, white matter microstructure changes, and metabolic changes within discreet fiber tracts in SP.  We will also test the hypothesis that ongoing neurocognitive impairment in schizophrenia is related to chronic disconnection of fronto-subcortical circuits, reflected in morphological contraction of discrete frontal lobe regions critical to higher cognitive functioning.  Finally, we will explore whether specific genes associated with the formation, development, and functioning of myelin are associated with circuit level dysfunction in SP. No research to date has simultaneously explored diffusivity, metabolic, and morphometric abnormalities within these critical brain circuits as they relate to neurocognitive dysfunction in schizophrenia.  We see this as a critical line of investigation that will help us understand and potentially intervene in the ongoing cognitive dysfunction that currently limits the ability of treated patients to return to more normal occupational and social functioning.

Dr. Rex Jung, PI of Project 4, began his research training at the National Institute of Aging–Gerontology Research Center, where he received a grant from the NIH–Student Summer Internship in Biomedical Research, to fund research in attention processes in the elderly.  He received his PhD in Clinical Psychology at UNM in 2001.  During his graduate work, he received several awards and scholarships, including the Gina Finzi Memorial Student Summer Fellowship from the American Lupus Foundation (1998), the UNM Benjamin Franklin Haught Revolving Scholarship in Psychology (1999), and the Mensa Research Foundation Award for Excellence in Research (2000).  His dissertation work, which produced five first-authored publications in several prestigious journals, established the relationship between broad measures of cognition and the neuronal marker N-acetylaspartate in the normal human brain (e.g., Jung et al 1999a; Jung et al 1999b).  Recently, he and colleagues reported the first study of brain morphological correlates underlying cognitive ability using Voxel Based Morphometry (Haier, Jung et al, 2004).  He is a Research Scientist at the MRN, an Assistant Research Professor within the Departments of Neurology and Psychology at UNM, and is a neuroscience consultant to Sandia National Laboratory. Dr. Jung will gain additional experience over the course of the COBRE to complement his expertise in MRS, Voxel Based Morphometry, and intellectual functioning in HNV.  Specifically, he will work closely with Dr. Lim to increase his knowledge of white matter relationships to cognitive functioning using integrated DTI and spectroscopic techniques.  He will work closely with mentor Dr. Perrone-Bizzozero to integrate genetic polymorphism information with morphometric and behavioral measures in SP.  Finally, he will work extensively with mentor Dr. Calhoun in development of methodology appropriate to fuse DTI, MRSI, sMRI, genetic, and behavioral data.

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