2012 — 2013 |
Brown, Gregory G [⬀] |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Mri Assessment of Hippocampal Volume and Function in a Mouse Model of Ptsd @ University of California San Diego
DESCRIPTION (provided by applicant): Despite the common and debilitating effects of post-traumatic stress disorder (PTSD), many current drug therapies for chronic PTSD leave residual symptoms. The development of improved therapeutic approaches for treating and/or preventing PTSD is likely to result from the better understanding of the neurobiology of PTSD that can be gained from animal model refinement. To create a model of PTSD pathology for treatment and mechanistic studies we propose to examine the association between two consistent biomarkers linked to PTSD symptom severity: (1) disruptions in hippocampal structure and function and (2) increases in CRF levels in cerebrospinal fluid (CSF). The project aims to determine if CRF hypersignaling is sufficient to induce hippocampal alterations and if these effects are reversible. The project uses a novel integration of ultra high- resolution, manganese-enhanced magnetic resonance imaging (MEMRI) with perfusion MRI to study hippocampal volume and blood flow in a transgenic mouse model of PTSD. The study's specific aim is to examine hippocampal volume and function before and after transient over expression of corticotropin releasing factor (CRFOE) in the forebrain. In a between group, longitudinal design, 24 transgenic mice that transiently over-express CRF when treated with doxycycline (Camk2a-rTta2 dox-on system combined with tet-o-CRF transgene) will be compared with 24 untreated mice at baseline, following one month of doxycline treatment for the experimental group and 100 days following termination of doxycycline treatment. Previous research has shown that the proposed transgenic mouse model has temporal and regional control over CRF expression via the Camk2a-rTta2 transgene technology. Mutant mice treated for 3 weeks with doxycycline chow exhibit an up to 2-3 fold increase in CRF mRNA in hippocampus and cortex, robust increases in CRF peptide in hippocampus, while cerebellum, brainstem and other non-forebrain regions remain unchanged. These mice also exhibit behavioral impairments on hippocampal-dependent memory tasks. The feasibility of the study is demonstrated by the establishment of the dual transgenic mouse model at UCSD and by the implementation at UCSD of an ultra high-resolution, MEMRI and mouse MRI perfusion protocols. The study design takes advantage of the repeatability of MRI and will involve imaging protocols that directly translate into human PTSD studies. The study is consistent with Objective 3 of the NIMH strategic plan to develop new and better interventions for people with mental illnesses. The potential impact of the study is related to the temporal control of CRF over-expression as a means to study the timing of interventions that might protect or reverse the hippocampal dysfunction observed in PTSD. This timing information should aid in the optimization of animal treatment studies and could provide information about the etiology of hippocampal dysfunction in stress disorders in general and PTSD in particular. PUBLIC HEALTH RELEVANCE: Despite the common and debilitating effects of post-traumatic stress disorder (PTSD), many current drug therapies for chronic PTSD leave residual symptoms. The proposed study aims to validate a mouse model of PTSD that uses magnetic resonance imaging to assess hippocampal tissue volume and blood flow before and following the transient release of corticotropin releasing factor, a neuropeptide involved in the regulation of the stress response. If successful, the mouse model could serve as a neurobiological platform for testing new interventions that protect against and/or treat PTSD.
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0.934 |
2014 — 2018 |
Brown, Gregory G [⬀] |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Neuroimaging (Ni) Core @ University of California, San Diego
NEUROIMAGING(Nl)CORE Given the adverse effects of HIV infection (HIV+) and methamphetamine use (METH+) oh brain structure and function, their combined effects, whether additive or synergistic, would be expected to produce a significant brain disorder. Moreover, as treatment of HIV infection has improved longevity and as the large cohort of METH users age, brain changes related to aging and to the comorbidities of aging are likely to contribute to HIV+ and METH+ related alterations in brain structure and function. In particular, age-related cerebrovascular disease might alter cerebral blood flow, potentiate white matter changes and alter gray matter volume. Aging is also likely to exacerbate changes in brain connectivity expected from white matter changes associated with HIV+ and METH+. Whether the aging contribution to changes of brain structure and function is additive or synergistic to that expected from HIV infection or METH use are unknown. This Core proposes to use translational multi-modal imaging to support investigations into the extent to which aging mediates brain changes associated with HIV infection, methamphetamine dependence and their interaction. To support these investigations the Nl Core Resource Objectives are to: (1) provide TMARC investigators with a core set of human and mouse imaging data; (2) provide specialized imaging protocols and advanced image analysis tools to support new directions in emerging imaging technologies; and (3) train investigators in imaging methods. The Nl Core Scientific Objectives are to: (1) investigate the separate and joint brain abnormalities underlying the neuropsychological and functional disabilities of patients with HIV infection and METH use and their interaction with aging; (2) use multimodal imaging methods to link white matter changes seen in METH use and HIV infection to alterations of functional connections among brain centers; (3) use magnetic resonance imaging protocols comparable to those used in human studies to link human imaging findings to imaging findings in mouse models of HIV infection and methamphetamine use.
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0.934 |
2021 |
Brown, Gregory K [⬀] |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Signature Project @ University of Pennsylvania
The Signature Project of the Penn Innovation in Suicide Prevention Implementation Research (INSPIRE) Center is a large-scale research study designed to examine the effectiveness and implementation of an evidence-based intervention to lower suicide risk in health care settings. The Project will leverage the methodological and administrative support of the INSPIRE Center with its focus on optimizing implementation of practice-based suicide prevention interventions for minority and disadvantaged populations. Individuals at high risk for suicide often present to acute care settings, such as emergency departments (EDs), and then typically are hospitalized or referred for outpatient mental health treatment. Yet, despite being at increased risk of suicidal behavior and suicide following an ED visit, many patients do not attend outpatient treatment. Brief evidenced-based interventions such as the Safety Planning Intervention and follow-up services (SPI+) are available to mitigate this risk and engage patients in outpatient treatment. However, such practices often can be challenging for busy ED clinicians to provide for suicidal patients. Our interdisciplinary team of suicide, implementation, health services, qualitative and quantitative researchers as well as diverse stakeholder groups of ED clinicians, health systems leaders, mental health clinicians, and patients will collaborate to improve the delivery of ED-based suicide prevention efforts. We propose a novel delivery model in which ED staff will connect patients at risk for suicide to mental health clinicians who are located external to the ED. These off-site licensed and credentialed clinicians will provide SPI+ via telehealth for ED patients prior to discharge and provide follow-up services after ED discharge as part of an innovative Suicide Prevention Consultation Center (SPCC). The Project has three Specific Aims. Aim 1 will use a stepped-wedge cluster-randomized design to evaluate the effectiveness of SPI+ delivered by SPCC clinicians via telehealth compared to SPI+ delivered by SPI+-trained ED clinicians on rates of suicidal behavior and engagement in care following ED discharge. Aim 2 will evaluate the implementation of SPI+ delivered by SPCC clinicians compared to SPI+ delivered by ED clinicians on key implementation outcomes including adoption, fidelity, acceptability, and feasibility and will also explore the mediation of clinician intentions, norms, and self-efficacy on the fidelity of SPI+. Aim 3 will evaluate the costs to ED and SPCC practices and examine potential cost offsets to the health system to provide evidence of SPCC scalability and sustainability. If successful and cost effective, use of a SPCC, external to EDs, could become a scalable model for providing suicide prevention evidenced-based practices to those at risk for suicide presenting for emergency care with the potential to save lives.
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0.91 |
2021 |
Brown, Gregory K [⬀] |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Administrative Core @ University of Pennsylvania
The Administrative (Admin) Core of the Penn INSPIRE Center will lead senior and emerging investigators in establishing, implementing, and evaluating a cutting-edge, interdisciplinary scientific agenda that leverages implementation science to optimize suicide prevention for underserved populations. Based at the Penn Perelman School of Medicine, INSPIRE will have interdisciplinary collaborations from the Penn Center for Clinical Epidemiology and Biostatistics, Children?s Hospital of Philadelphia, and the Penn School of Nursing. INSPIRE will integrate perspectives from psychology, implementation science, psychiatry, machine learning, health economics, and health information technology. Realizing the benefit of such a rich, interdisciplinary research endeavor requires strong and creative centralized leadership as well as efficient and effective coordination of services, logistics, and resources. Led by Center Co-Directors G. Brown and Oquendo, the Admin Core will be INSPIRE?s organizational, governance, and strategic-planning hub and will address three Aims. First, the Core will provide scientific and programmatic leadership to maximize integration, rigor, and synergy across Center components, investigators, and external affiliates. It will institute and coordinate an internal Center Steering Committee and Stakeholder Committee and an External Advisory Committee for transparency and input on governance, planning, and evaluation. Centralized administrative, fiscal, and organizational coordination of INSPIRE Cores and Research Projects will be effected by an experienced, efficient Administrative Support Team. Second, the Admin Core will ensure scientific innovation and responsiveness to evolving research, practice, and policy needs through the INSPIRE Pilot Studies Program that will support 10 pilot studies over the course of the Center. The Core also will establish the INSPIRE Suicide Prevention Scholars Program to engage and build capacity of both early-stage and established investigators who can make novel interdisciplinary contributions to the suicide prevention research evidence base. Third, the Admin Core will amplify the impact of our research and make INSPIRE resources available across scientific, practice, and policy communities through a dynamic INSPIRE website as well as other targeted mechanisms for wide, multi-sector dissemination of Center findings, research tools, and other products. Thus, through the Admin Core, INSPIRE Leadership will maximize generation of high-impact knowledge about suicide prevention strategies designed to be rapidly deployable in a wide range of settings serving the most vulnerable, and often disenfranchised, populations. The Core?s management strategy will emphasize shared leadership, investigator support and mentoring, and intensive engagement of stakeholders at every level (planning, evaluation, research, and dissemination) to maximize impact.
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0.91 |