Laura M. Rowland, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): This training program will facilitate my becoming an independent clinical researcher. The general goal is to focus on the neurobiology of relational learning and memory in schizophrenia. The training components for this application include: (1) developing expertise in the design, methodology, and analyses of functional magnetic resonance imaging (fMRI), (2) enhancing my skills in magnetic resonance spectroscopy, and (3) gaining an improved understanding of clinical diagnosis, symptom assessment, and treatment of schizophrenia. To achieve these goals, there will be (1) formal coursework in the physics of MR imaging, neurochemistry, cellular basis of learning, and cognitive neuroscience; (2) meetings with mentors/consultants; (4) seminars and journal clubs; (5) behavioral assessments training, and (6) concurrent research studies. The research will center on relational learning in schizophrenia. No published studies have used fMRI to characterize neural plasticity associated with learning in volunteers with schizophrenia. The research plan begins with a behavioral study to determine (1) the differences in relational learning between schizophrenics and normal volunteers, and (2) if schizophrenics can learn relations if given a training regimen. Preliminary data suggest that schizophrenics do not learn in a manner similar to normal controls, but that they can learn if given adequate training. The next step will use fMRI to investigate the neural plasticity underlying relational learning before and after training. Finally, we will extend this step to compare the neurochemistry underlying brain regions showing plasticity in schizophrenic volunteers who learn versus those who do not learn. We will use proton magnetic resonance spectroscopy (1H-MRS) for this phase of the project. Particular emphasis will be placed on hippocampal assessments. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): This training program will facilitate my becoming an independent clinical researcher. The general goal is to focus on the neurobiology of relational learning and memory in schizophrenia. The training components for this application include: (1) developing expertise in the design, methodology, and analyses of functional magnetic resonance imaging (fMRI), (2) enhancing my skills in magnetic resonance spectroscopy, and (3) gaining an improved understanding of clinical diagnosis, symptom assessment, and treatment of schizophrenia. To achieve these goals, there will be (1) formal coursework in the physics of MR imaging, neurochemistry, cellular basis of learning, and cognitive neuroscience; (2) meetings with mentors/consultants; (4) seminars and journal clubs; (5) behavioral assessments training, and (6) concurrent research studies. The research will center on relational learning in schizophrenia. No published studies have used fMRI to characterize neural plasticity associated with learning in volunteers with schizophrenia. The research plan begins with a behavioral study to determine (1) the differences in relational learning between schizophrenics and normal volunteers, and (2) if schizophrenics can learn relations if given a training regimen. Preliminary data suggest that schizophrenics do not learn in a manner similar to normal controls, but that they can learn if given adequate training. The next step will use fMRI to investigate the neural plasticity underlying relational learning before and after training. Finally, we will extend this step to compare the neurochemistry underlying brain regions showing plasticity in schizophrenic volunteers who learn versus those who do not learn. We will use proton magnetic resonance spectroscopy (1H-MRS) for this phase of the project. Particular emphasis will be placed on hippocampal assessments. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Schizophrenia is a severely debilitating psychiatric disorder that afflicts approximately 1% of the population and is a serious public health problem with no cure. Cognitive deficits are a core feature of the illness with learning and memory deficits being particularly disabling. Patients with severe learning and memory impairments have poorer psychosocial function and life quality. Unfortunately, there are no good treatments for learning and memory impairments in schizophrenia. Consequently, there is a need for a better understanding of the neurobiological mechanisms of learning and memory failure and success in schizophrenia. These mechanisms are potential targets for novel treatment development. The proposed study will use multimodal neuroimaging methods to investigate relational learning in schizophrenia. Functional magnetic resonance imaging (fMRI) will be used to investigate neural activation during relational learning in schizophrenia. Diffusion tensor imaging (DTI) and proton magnetic resonance spectroscopy (1H-MRS) will be used to help determine whether altered neural activation patterns in schizophrenia are related to compromised structural white matter connections or neurochemistry. The neurobiological mechanisms related to the heterogeneity of learning performance in schizophrenia will be characterized. The third aim is to examine if altered neurobiology associated with relational learning in schizophrenia has a genetic influence by examining first-degree relatives. This will be the first study to use three neuroimaging techniques to investigate relational learning in schizophrenia. The combination of these techniques is expected to provide a more comprehensive picture of altered neurobiological mechanisms associated with relational learning in schizophrenia than any one technique alone. PUBLIC HEALTH RELEVANCE: Schizophrenia is a severely debilitating psychiatric disorder that afflicts approximately 1% of the population and is a serious public health problem. There are no good treatments for learning and memory deficits, core features of the disorder that negatively impact quality of life. This study will use three neuroimaging techniques to investigate neural activation patterns, white matter circuitry, and neurochemistry associated with relational learning in schizophrenia. It is predicted that the integration of these measurements will serve as targets for the development of novel drug and behavioral treatment for learning and memory deficits in schizophrenia.

DESCRIPTION (provided by applicant): Schizophrenia a disabling psychiatric disorder that affects approximately 1% of the population. The cost to society resulting from this illness is high Despite extensive research, the underlying biochemical causes of schizophrenia remain elusive, with evidence to suggest that the dopaminergic, glutamatergic and GABAergic neurotransmitter systems all play a role in the development of symptoms. An improved understanding of regional neurotransmitter levels is a first step towards the design of new treatments. Over the last few years, there has been particular interest in the roles of glutamate (Glu), N-acetyl aspartyl glutamate (NAAG) and ?-aminobutyric acid (GABA) in schizophrenia. Glu and GABA the primary excitatory and inhibitory neurotransmitters in the human brain, respectively. NAAG is a precursor of Glu and also binds to receptors involved in the glutamatergic system. High field (7 Telsa) magnetic resonance spectroscopy (MRS), in conjunction with spectral editing techniques, has the potential to measure various neurotransmitters in vivo in the human brain, including Glu and GABA, with higher sensitivity and specificity than at lower field strengths. We have also recently demonstrated that it is possible to reliably determine NAAG in the brain using MRS. The aims of this proposal are therefore to (1) to establish that 7T MRS can reliably measure a 'neurotransmitter profile' of Glu, NAAG and GABA in multiple brain regions in patients with schizophrenia, (2) investigate the differences in neurotransmitter levels between healthy volunteers, early-stage, and later stage patients with schizophrenia, and to also measure the same compounds in first degree relatives of subjects with schizophrenia who demonstrate some of the same traits as patients with schizophrenia. Patients will also be thoroughly evaluated with neuropsychological testing, and neurotransmitter levels will be examined for correlations with both positive and negative symptoms of schizophrenia. An important reason for studying first degree relatives is that they will be unmedicated, allowing observation of disease related neurochemical changes free from the possible confounding effects of medication. The long term goal of this study is to firmly establish the role of Glu, NAAG and GABA (as well as other metabolites) in the pathophysiology of schizophrenia, and investigate their relationship to symptom severity. This knowledge will aid in the design of future treatment trials. We also expect that the establishment of these noninvasive biomarkers by high-field MRS will be useful in the future for evaluating disease severity, progression and treatment response in patients with schizophrenia.

? DESCRIPTION (provided by applicant): This is the second competitive renewal of a T32 training grant at the Maryland Psychiatric Research Center (MPRC), originally funded in 2003 (MH067533). The goal of the proposed program is to prepare MDs, PhDs and PharmDs interested in basic or clinical research for a career in translational research in schizophrenia related disorders. The MPRC, an Organized Research Center of the University of Maryland School of Medicine and division of the Department of Psychiatry, is a focused center for research on schizophrenia and related disorders, located on the grounds of the Spring Grove Hospital Center, a State of Maryland inpatient mental health facility located just outside Baltimore. Faculty at the MPRC have an integrated research program of clinical and neuroscience research involving neuroimaging, neurophysiology, biochemistry, rodent models, etiologic factors, symptoms, endophenotypes, neurocognition, domains of psychopathology and experimental therapeutics for specific pathologies associated with schizophrenia and related disorders. All faculty are successful with competitive research funding and the MPRC and the integrated and collaborative framework has supported NIMH P50 awards for over 25 years including a just completed CIDAR and just funded Conte centers. The MPRC is characterized by frequent interaction and collaboration among preclinical and clinical investigators. This background prepared faculty at MPRC to take an active role in supporting NIMH workshops developing behavioral constructs for the RDoC initiative. Scientific opportunities and collaborations are enriched with extensive involvement with other components of the University of Maryland School of Medicine and School of Pharmacy at the nearby University of Maryland Baltimore. Postdoctoral training offered under this T32 fellowship has a primary focus on both basic neuroscience and clinical investigations of schizophrenia and related disorders. All trainees are educated on the translational perspective of the MPRC and provided mentors and didactic training in both clinical and neuroscience. This renewal for a competitive five- year renewal application proposes to continue funding 5 positions a year with each a fellowship lasting for 2-3 years. This T32 program is successful in terms of recruiting and training post-doctoral fellows for a scientific career including clinician scientists. Graduates of the program lead productive, successful research-intensive careers. Details on graduates and the present fellows are provided in the progress report.

Project Summary Schizophrenia is a severely debilitating psychiatric disorder that afflicts approximately 1% of the general population and is a serious public health problem with no cure. The major excitatory and inhibitory neurotransmitter systems, glutamate and GABA, are involved in the pathophysiology of schizophrenia. A better understanding of these systems could aid in the development of novel interventions for the treatment of schizophrenia and related disorders. The only noninvasive method that provides in vivo measurement of these chemicals is proton magnetic resonance spectroscopy (MRS), but accurate measurement at short echo times is problematic due to contaminating brain macromolecule signals. Although macromolecules are regarded as a nuisance signal in MRS research, they actually may be physiological meaningful. Brain macromolecules are higher in multiple sclerosis, stroke, brain tumors, and brain macromolecules increase in rodent models of brain inflammation. This R21 project addresses a major problem faced by MRS studies of schizophrenia, whether macromolecules are different in patients with schizophrenia. There are no investigations of brain macromolecules in schizophrenia. This project will investigate macromolecule differences in brain regions known to be involved in the pathophysiology of schizophrenia and that have shown MRS differences. The relationship between brain macromolecules and clinical and cognitive symptoms will also be investigated. The results of this project will generate a better understanding of the role of brain macromolecules in schizophrenia. If macromolecules are different between patients and controls, these measures may serve as biomarkers of the illness. This will provide impetus for a more definitive R01 study. If macromolecules are not different between patients and controls, this information is still very important and will provide the research community with confidence that MRS metabolite differences are not due to differences in macromolecule levels among groups. This project will also provide brain macromolecule spectra from multiple brain regions, all acquired from adults with schizophrenia to the research community to aid in spectral analysis.