CLINICAL PROBLEM: More Americans are affected by chronic pain than by heart disease, diabetes, and cancer combined. One of these pain syndromes is chronic HIV distal neuropathic pain (DNP), which has been termed an "emerging epidemic", and affects approximately 20% of all HIV patients. HIV DNP is treatment- resistant and is associated with impaired daily function, unemployment, and worse life quality. Most HIV DNP research to date has focused on the peripheral mechanisms, which has overlooked the role of brain mechanisms for HIV DNP. A better understanding of brain mechanisms for HIV DNP may be useful to identify individuals at risk for HIV DNP. Brain imaging is a tool to help understand central nervous system mechanisms and to identify candidate biomarkers, but despite its potential usefulness has never been used to investigate HIV DNP. CANDIDATE: My unique background should enable me to capitalize on the training and research proposed in this application. I obtained a Ph.D. in physics and was trained in brain neuroimaging. Afterwards I attended medical school where I developed an interest in chronic pain as well as the relationship between pain and mood disorders. Focusing on pain, I completed an anesthesia residency and a clinical fellowship in pain management, then conducted basic science functional neuroimaging pain research. As my interest in mood disorders and chronic pain deepened, I entered a clinical psychiatry residency program. In my last year of residency I focused on HIV-related pain and I have spent the past year as a part-time research fellow in NeuroAIDS investigating brain mechanisms for HIV distal neuropathic pain. TRAINING: Although I have a strong background in the basic sciences of functional neuroimaging and have completed clinical residencies, I have not been trained in the principles of clinical research nor in clinical research methods essential to my career such as methods for investigating pathophysiology of peripheral neuropathy, HIV neuromedical assessment and HIV neuropsychiatric assessment. The training proposed in this K-23 application is designed to address these shortcomings. Thereafter my long-term plans are to pursue a multi-disciplinary academic psychiatry translational research career striving to bridge basic science pain neuroimaging research with clinical pain psychiatry research. ENVIRONMENT: The University of California San Diego (UCSD) offers a unique training and research environment to investigate brain mechanisms of HIV distal neuropathic pain. This includes 1) The UCSD HIV Neurobehavioral Research Center (HNRC) facility infrastructure;2) the HNRC multidisciplinary team of neuromedical, neuropsychiatric, and neuroimaging clinical research mentors;3) The UCSD Keck Center for Functional Imaging facility;4) consultants with an outstanding track record of research in chronic pain and in neuroimaging;and 5) access to a large sample of HIV patients in San Diego at the HIV Neurobehavioral Research Program which have been previously identified to have two or more signs of neuropathy with and without HIV distal neuropathic pain. RESEARCH PLAN: The translational research objective of this application is to use multi-modal magnetic resonance (MR) neuroimaging and clinical research characterization of HIV peripheral neuropathy, in concert with standardized pain, neuropsychiatric, and neuromedical assessment, to better understand central and peripheral mechanisms of HIV DNP for 3 clinical research groups which all have 2 or more signs of peripheral neuropathy but differ in presence and duration of DNP: Group 1 - no DNP, Group 2 - DNP with pain of 1 to 3 months duration on a daily or almost daily basis (at least 5 days/week), and Group 3 - DNP with daily or almost daily pain >6 months.
Two specific aims are 1) To determine if resting state functional imaging connectivity between brain processing areas, such as the insula cortex, and resting state default mode networks will be increased for individuals with pain (Groups 2 and 3) compared to those without pain (Group 1), and 2) To determine if regional brain volumes for brain pain processing areas such as the insula will be smaller for individuals with chronic pain (Group 3) compared to those without chronic pain (Groups 1 and 2). It is hypothesized that resting state functional insula connectivity with default mode networks will be higher for those with pain (Groups 2 and 3) compared to those without pain (Group 1), and that regional insula brain volumes will be smaller in chronic pain patients (Group 3) compared to the other two groups. Over a 4-year period research participants in these groups will be recruited from individuals enrolled in clinica research studies ongoing at the UCSD HIV Neurobehavioral Research Program (HNRP). Each group will be characterized by multi-modal neuroimaging (resting state functional, gray matter structural, and white matter diffusion tensor) and clinical assessment of HIV peripheral neuropathy (skin biopsy, quantitative sensory testing, and nerve conduction testing), in concert with standardized pain, neuropsychiatric, and neuromedical assessment.

Public Health Relevance

HIV distal neuropathic pain is common and causes significant morbidity despite the current use of HIV treatments. This study investigates peripheral pain mechanisms and central brain pain mechanisms to better understand pain mechanisms for HIV distal neuropathic pain. A better understanding of peripheral and central pain mechanisms for HIV distal neuropathic pain may be useful for the development of biomarkers to identify individuals at risk for HIV distal neuropathic pain. NOTE: The critiques and criterion scores from individual reviewers are provided below in an essentially unedited form. These were prepared prior to the review meeting and may not have been updated or revised subsequent to the discussion at the meeting. Therefore, they may not fully reflect the final opinions of the individual reviewers at the close of group discussion or th final majority opinion of the group. The Resume and Summary of Discussion above summarizes the final outcome of the group discussion.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23NS079311-01A1
Application #
8541531
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Wong, May
Project Start
2013-08-01
Project End
2018-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$154,319
Indirect Cost
$11,357
Name
University of California San Diego
Department
Psychiatry
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Keltner, John R; Fennema-Notestine, Christine; Vaida, Florin et al. (2014) HIV-associated distal neuropathic pain is associated with smaller total cerebral cortical gray matter. J Neurovirol 20:209-18