Satoshi Minoshima, MD PhD - US grants

Patients with spinal cord or brachial plexus injury often develop chronic pain which is generally persistent and resistant to conventional pain treatments. Experimental and clinical observations suggest that abnormal central nociceptive systems contribute to such sustained neuropathic pain in chronic pain patients. We hypothesize that functional reorganization, or plasticity, of the central nociceptive system may play an important role in mechanisms of chronic pain in patients with spinal cord or brachial plexus injury. Such changes may result in altered pharmacologic responses to conventional analgesics and other pain treatments. Three experiments using positron emission tomography (PET) and neuronal activation techniques are proposed to investigate functional reorganization of the central nociceptive system and its responses to pharmacologic interventions. The PET activation method gives us opportunities to examine dynamically-modulated central nociceptive system in living humans under physiological conditions. The method can determine three-dimensional distributions of the central nociceptive activity in non-invasive and repetitive manners. To test the integrity of the central nociceptive system, quantitatively controlled laser stimuli will be used. The laser stimulation enables us to correlate between PET, psychophysical, and neurophysiological measures. By using these techniques, we will examine, first, normal patterns of the central nociceptive activity and effects of antidepressants on these systems. Second, using a longitudinal experimental design, we will determine the occurrence of cerebral functional reorganization in patients who have developed chronic pain. Third, using a cross-sectional experimental design, we will investigate patterns of cerebral functional reorganization in patients with different degrees of chronic pain and effectiveness of antidepressants. The proposed research will reveal neurophysiological insights into chronic pain and the effects of pharmacologic interventions at the cerebral level, which may help in the development of new strategies to manage and treat chronic pain patients with spinal cord or brachial plexus injury. Understanding functional reorganization in the central nociceptive system may enable preventive interventions for chronic pain. The PET method established in this research will be applicable for examining other forms of therapeutic interventions in future chronic pain research.

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is known to affect particular molecules, cells, and brain regions, often referred to as 'selective vulnerability'. Previous investigations of regional vulnerability have found classical pathologic changes (such as neurofibrillary tangles) as well as gray matter loss measured by MR imaging primarily in the medial temporal lobe in early AD. In contrast, many functional brain imaging studies of early AD have demonstrated severe metabolic reduction in the posterior cingulate and association cortices before the onset of dementia. These independent observations raise an interesting question regarding regional vulnerability of the brain in very early AD. This discordance may be attributed in part to differences in the nature AND limitations of investigational methods. For example, precise quantitative assessment of mild neurodegeneration in a large area of cortices is difficult by conventional structural imaging and histopathologic examinations. In addition, previous structural studies have focused on a limited number of a priori selected regions, such as medial temporal lobe structures, for the analysis. We investigated regional gray matter loss in the entire brain using MR imaging combined with a novel gray matter density mapping technique and found significant and region-specific gray matter loss not only in the medial temporal lobe, but also in the posterior cingulate and lateral association cortices in mild AD. In this proposal, we would like to extend our investigations to preclinical stage of AD and examine if neurodegeneration in the posterior cingulate and association cortices that are tightly interconnected with each other and directly to the entorhinal cortex is a very early and consistent pathologic process that has been overlooked. One important emphasis in our proposal is to examine vulnerability of interconnected cerebral regions, instead of a single discrete focus, to better understand regional vulnerability of very early AD. Precise delineation of regional selective vulnerability in very early disease is not only critical for better understanding of the macroscopic disease process, but also provides a basis for further regional histopathologic and molecular investigations. If very early involvement of the posterior cingulate and association cortices are found consistently, these findings will provide better markers for early detection of the disease and monitoring of disease progression.

DESCRIPTION (provided by applicant): The number of NIH-funded research projects using imaging technology has been steadily increasing at the University of Washington (UW). In addition to the wide-array of imaging resources available in the medical centers, the Department of Radiology has installed multiple dedicated research scanners (e.g., 3T MRI, PET- CT, microPET, etc) during the last 3 years to support original and collaborative research in the UW imaging sciences communities. One challenge for investigators who use imaging technology is to manage a large amount of imaging data and related analysis results. Currently, there is no centralized mechanism to store imaging data for subsequent data analysis and research use or to store "raw" acquisition data for reprocessing. Each imaging site has been operating an independent small data server system to manage data specific to its projects. This creates inefficiency in multi-modal imaging data access, difficulty in data and resource and management, and eventually cost to the funding agencies. A non-uniform data archival structure also impedes collaboration and opportunities for exploratory data analyses. To improve the overall handling of imaging data for imaging sciences conducted at the University of Washington and to help scientists and engineers focus on research investigations, we propose to purchase and install a centralized Network Attached Storage (NAS) system and to integrate the system with our existing technology and expertise. This not only will help currently funded research projects, but also will accelerate and facilitate future imaging research projects conducted under NIH auspices. PUBLIC HEALTH RELEVANCE: Research that involves imaging technology is growing rapidly. The management of a relatively large volume of imaging data, however, creates challenges for many investigators and institutions, particularly for secure archival storage with rapid access to imaging data. This shared resource "Imaging Sciences Network Attached Storage (NAS)" will help NIH-funded scientists and engineers at the University of Washington better focus on research investigations by providing an essential infrastructure of data storage. This will permit more effective access to imaging data for scientific investigations, better resource management, and cost effectiveness in ongoing operations and future grant funding.