Jarred W. Younger, PhD - US grants

[unreadable] DESCRIPTION (provided by applicant): Project Summary: Chronic administration of opioid-based analgesics has been associated with the development of increased sensitivity to pain. Research in both animals and humans suggest that this opioid induced hyperalgesia is mediated via central, neuroplastic changes. Experimental designs have been limited to animal subjects because of their invasive nature, and there is a need to characterize opioid-induced hyperalgesia in humans. New techniques such as real-time functional magnetic resonance imaging (rtfMRI) allow for the experimental, non-invasive modulation of central nervous activity in human participants and therefore presents a powerful method for exploring central mechanisms of pain. We propose a comprehensive training plan and subsequent research program into the mechanisms of opioid-induced hyperalgesia, including the use of rtfMRI experimental designs. In the K99 training phase of this grant, Dr. Younger will train at the Stanford University School of Medicine, under the direction of Sean Mackey, MD, PhD, an established pain researcher, as well as a team of collaborating mentors, including Gary Glover, PhD (radiology), David Clark, MD, PhD (opioid-induced hyperalgesia) and Ravi Prasad, PhD (clinical psychology). Training will be conducted via formal coursework, hands-on lab training, mentored research, progress review by the steering committee, regular attendance of colloquia and workshops, and teaching opportunities. The subsequent ROD independent research phase involves a series of studies designed to systematically identify and test the role of central neural structures in opioid-induced hyperalgesia. Our first aim is to characterize the central neural correlates of opioid-induced hyperalgesia in humans. Second, we propose to describe the long-term neural effects of prolonged opioid exposure. Last, we will use rtfMRI to experimentally test the role of specific brain structures in the development and maintenance of opioid-induced hyperalgesia. Relevance: Chronic pain affects millions of individuals in the United States, and a large proportion of these individuals are prescribed opioid analgesics. The long-term use of opioids may increase patients' sensitivity to pain, adding to the original complaints of pain and confusing the picture of disease progression. It is important that we understand how the brain is involved in this increased pain sensitivity and what long-term impact these changes may have. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating condition characterized by profound, chronic fatigue that is not alleviated by rest, as well as pain, post-exertional malaise, and impairments in memory and concentration. ME/CFS affects over one million women in the United States, causing significant distress and loss of function in affected individuals and a significant financial burden on society Because the underlying pathophysiology of ME/CFS is not well-understood, there are no effective treatments developed specifically for the condition, and many patients are unsatisfied with existing treatment options. Previous research provides a strong case for inflammatory involvement in ME/CFS, though no immune factors have been consistently predictive of fatigue across studies. Conventional cross-sectional research approaches may not be sufficiently sensitive for identifying ME/CFS biomarkers in cases of low-level or atypical inflammation. We have observed that women with ME/CFS demonstrate considerable day-to-day variability in their fatigue severity, and this variability may reflect rapid shifts in underlying disease mechanisms. By viewing the daily fatigue variability as an important signal, and collecting blood samples daily, we have identified a small set of serum cytokines that are strongly correlated with changes in ME/CFS 1fatigue. In this proposed study, we plan to confirm our preliminary findings of immune-fatigue relationships in a larger sample. We will collect blood samples for 25 consecutive days in 70 women with ME/CFS, as well as 20 healthy controls and 20 active fatigue controls (individuals with hypothyroidism). Blood samples will be analyzed for 51 different immune factors associated with inflammation. In addition, participants will submit daily reports of fatigue severity on handheld computers. By analyzing fatigue scores and cytokine concentrations longitudinally, we can identify cytokines that track day-to-day fluctuations in fatigue severity. This approach will allow us to develop a physiological profile that distinguishes high fatigue days from low fatigue days, providing important information about ME/CFS mechanisms. In Aim 1, we will develop a physiological model that uses serum cytokine levels to accurately predict day-to-day fluctuations in fatigue severity. In Aim 2, we will define important ME/CFS subgroups based on cytokine-fatigue relationships. In Aim 3, we will develop a temporal pathway between immune factors and fatigue that identifies early drivers of fatigue. Additionally, we will develop a specimen bank of blood samples that can be made available to other interested researchers. Intensive longitudinal immune monitoring is a unique approach to understanding ME/CFS pathophysiology. Biomarkers revealed by this research will serve as tools in the development of ME/CFS diagnostic tests, and will provide excellent targets for developing improved therapies.

PROJECT SUMMARY/ABSTRACT In this R01 project, we will test a magnetic resonance spectroscopic imaging (MRSI) technique to assess several markers of neuroinflammation across the entire brain. We will use the technique to investigate the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a condition of unknown etiology that is characterized by profound fatigue not alleviated by rest. The lack of information on ME/CFS pathophysiology has posed a substantial obstacle to the development of treatments that are specific and effective for the disorder. We hypothesize that ME/CFS is the result of low-level inflammation in the brain. Chronic activation of microglia and astrocytes provokes the release of proinflammatory agents that interact with neurons to cause symptoms of fatigue, pain sensitivity, and cognitive and mood disruption. MRSI may be able to detect that neuroinflammation by showing elevated myo-inositol, choline, lactate, brain temperature, and lower N-acetylaspartate that have been associated with abnormal microglia activation. In this five-year R01 study, we will conduct three separate studies. Study #1 examines 90 women with ME/CFS and 30 age- and body mass index-matched healthy controls. Neuroinflammatory markers will be assessed on a voxel-by- voxel basis throughout the entire brain, yielding approximately 4,000 assessments in gray matter, white matter, and cerebrospinal fluid. We hypothesize that the neuroinflammatory markers will be elevated in several brain regions in the ME/CFS group. Study #2 uses a ?good-day, bad-day? longitudinal design to examine correlation between neuroinflammatory markers and symptom severity fluctuations in 20 women with ME/CFS. We hypothesize that the higher fatigue severity days will be associated with higher levels of neuroinflammatory markers. In Study #3, we will validate the MRSI scan with positron emission tomography (PET) analysis of 18F-DPA-714, a marker of activated microglia. We expect to see spatial overlap in MRSI and PET indicators of neuroinflammation. Support for these three hypotheses would show that ME/CFS is associated with brain inflammation. This test would allow for safe and inexpensive longitudinal assessment of neuroinflammation that is not possible with positron emission tomography (PET) or lumbar puncture measures of cerebrospinal fluid. Because we collect the entire available spectrum in each voxel, we will also have the first whole-brain metabolic data in ME/CFS. The MRS data can be used to quantify other markers of interest to ME/CFS researchers, such as glutamate and glutamine. We will therefore make the entire dataset available to other researchers for secondary analyses. Ultimately, we hope this non-invasive scanning technique will aid in ME/CFS diagnosis, treatment decisions, and the development of new treatments.