Yenisel Cruz-Almeida - US grants

? DESCRIPTION (provided by applicant): The primary goal of this Career Development Award (K01) is to provide the necessary training and mentoring for Dr. Cruz-Almeida to establish an independent neuroscience research program aimed at studying the neurobiological mechanisms underlying abnormal pain modulation in older adults that may account for increased clinical pain in this population. To meet these career goals the candidate has four specific training objectives in the K01: 1) Develop expertise in advanced neuroimaging techniques and analyses; 2) Increase knowledge about the neurobiology of aging; 3) Develop expertise in cognitive neuroscience; and 4) Enhance translational research skills to function as an independent investigator. These training objectives extend the candidate's previous background in the fields of neuroscience, aging, and pain psychophysics and will be achieved through guided mentorship, didactic experiences, and applied research experiences. The K01 will take place at the University of Florida (UF) College of Medicine under the direct mentorship of Dr. Roger Fillingim, with co-mentorship from Dr. Ronald Cohen, Dr. David Vaillancourt and Dr. Joseph Riley. All mentors are nationally and internationally respected experts in the fields of pain and aging (Drs. Fillingim/Riley), cognitive neuroscience and neuroimaging (Dr. Cohen) and neuroscience and neuroimaging (Dr. Vaillancourt) research. The environment is ideal for this project because the University places a strong emphasis on aging research including pain and aging studies. The necessary laboratories, equipment, and supplies needed to complete the series of studies described in this application are available to the candidate via the Institute on Aging. Recent studies show that older adults exhibit dysfunctional pain modulation characterized by increased facilitation and reduced inhibition of pain, which increases the risk for experiencing clinical pain. However, knowledge of the supraspinal mechanisms contributing to age-related dysfunctional pain modulation is lacking, specifically relating to brain structure and function. Thus, the long-term goal of the candidate's research program is to identify the neurobiological mechanisms contributing to dysfunctional pain modulation of older adults. The candidate will examine the structural (aim 1) and functional (aim 2) connectivity of cortico-striatl regions in older and younger adults and determine their associations with an individual's pain modulatory capacity (aim 3). The proposed research addresses a significant gap in the literature and is the first to evaluate the age-related changes in the neural substrates of endogenous pain modulation. The identification of key top- down modulatory brain networks will increase our understanding of age-related changes in pain processing that may ultimately lead to personalized, targeted therapies. Given the expected increase and burden of chronic pain in older adults in the coming decades, effective strategies to reduce the risk of older adults experiencing chronic pain are urgently needed. Importantly, this study will also provide the neuroimaging training and expertise to propel a promising young investigator at the intersection of pain and aging neuroscience research.

ABSTRACT Osteoarthritis (OA) represents a significant cause of disability worldwide in individuals aged 65 and older, a rapidly growing segment of our population. The knee is the most commonly affected joint with pain being the primary symptom, negatively impacting physical, cognitive, and emotional functioning. Symptomatic knee OA has been traditionally attributed to peripheral mechanisms, but measures of joint damage only modestly account for the presence or severity of OA-related pain. The neuropeptide oxytocin (OT) has been recognized as a mediator of endogenous analgesia in animal and human studies. However, little is known about the neurobiological mechanisms underlying OT's pain-relieving properties. This proposal is based on a mechanistic model of OT's analgesic effects leveraging pilot data supporting efficacy and safety of self-administered intranasal OT over 4-weeks in older individuals. Relative to placebo (P), daily administration of intranasal OT diminished self-reported pain intensity, reduced experimental pain sensitivity, and increased self-reported physical and emotional functioning. Further, participants treated with OT, compared to P, showed decreases in brain metabolite concentrations associated with inflammation. Thus, our overarching goal is to evaluate the effects of intranasal OT on pain and function in aging and to determine the extent to which central and peripheral inflammatory mechanisms contribute to these analgesic responses. We aim to 1) determine the effect of intranasal OT administration on clinical and experimental pain sensitivity in older adults with symptomatic knee OA and 2) characterize inflammatory mechanisms contributing to the inter-individual variability in analgesic responses to OT. Older adults with symptomatic knee OA will self-administer intranasal OT or P over 4 weeks using a double-blinded, parallel study design. With strong support from the University of Florida and the McKnight Brain Institute, our interdisciplinary project, using a comprehensive multi-methods approach, will be the first to determine the potential benefit of OT as a novel analgesic therapy for knee OA pain in aging. OT is currently used in obstetrics and may be an inexpensive, effective method for pain management in older adults with little potential for addiction. Embedded in a biopsychosocial framework, our proposal will help pave the way for future investigations using a mechanism-based treatment optimization strategy for individuals suffering from chronic pain.

Abstract of the proposed research that shows the relevance to AD/ADRD The susceptibility to pain depends on the balance of activity in ascending and descending pain pathways. The descending pain control system modulates pain by inhibiting or facilitating nociceptive processing. Well-established tools to study this system in humans are conditioned pain modulation (CPM) paradigms in which pain intensity ratings of test stimuli are obtained in the presence and absence of a concomitantly, remotely applied conditioning stimulus. More negative CPM responses (= reduced pain intensity ratings under concurrent stimulation) are indicative of endogenous analgesia (i.e., increased pain inhibition) and are mediated by spino-bulbo-spinal reflexes which are controlled by higher cortical brain areas. Given that the same brain regions needed for descending pain modulation are also negatively impacted in persons with Alzheimer?s Disease (AD), aberrant descending pain inhibition might contribute to altered pain processing in AD. To our knowledge no studies to date have investigated descending pain inhibition in persons with AD nor its underlying mechanisms. The proposed supplement will recruit 50 older adults diagnosed with mild AD with and without pain and undergo experimental sessions of conditioned pain modulation, a cognitive function battery and multi- modal neuroimaging consistent with the methodology used in the parent K01 award. The proposed research addresses a significant gap in the literature and would be the first to evaluate the age-related changes in the neural substrates of endogenous pain modulation in older persons with and without AD in relation to pain. The identification of key top-down modulatory brain networks impacted by pain and AD will increase our understanding of neurobiological changes in pain processing that may put individuals at risk of developing AD.

Project Summary/Abstract. Discovery and validation of strong candidate biomarkers and clinical endpoints for pain is urgently needed that can be used to facilitate the development of non-opioid pain therapeutics from discovery through Phase II clinical trials. Emerging research using a combination of biomarkers deliver individualized predictions about future brain and body health. Our own findings suggest that behavioral chronic pain characteristics are associated with multiple biological biomarkers where a greater pain burden is associated with accelerated detrimental biological processes. However, prospective research is urgently needed to determine pain?s impact on the heterogeneity of these biological processes within an individual to elucidate the underlying patterns of biological changes using a biobehavioral perspective which is needed for predicting future health and to be able to use as clinical endpoints for interventions. The proposed study will prospectively address biobehavioral factors (i.e., cognitive, psychological, social and cultural) affecting the experience and interpretation of knee pain and physical function across racial/ethnic groups over time. We will prospectively assess pain along with multiple biomarkers as predictors of cognitive, psychological and physical functional progression among middle-aged and older non- Hispanic Blacks and non-Hispanic Whites with knee pain and controls over a four-year study period. With strong support from the University of Florida, our interdisciplinary project, using a comprehensive biobehavioral multi- methods approach, we will be the first to prospectively determine the trajectory and interactions among pain, biological biomarkers and multiple domains of function within race/ethnic groups in OA pain. Findings will contribute towards increased understanding of pain and its biobehavioral basis, with the potential to reduce race/ethnic group disparities and improve pain-related health and functional outcomes.

Abstract of the proposed research that shows the relevance to AD/ADRD The susceptibility to pain depends on the balance of activity in ascending and descending pain pathways. The descending pain control system modulates pain by inhibiting or facilitating nociceptive processing. Well-established tools to study this system in humans are conditioned pain modulation (CPM) paradigms in which pain intensity ratings of test stimuli are obtained in the presence and absence of a concomitantly, remotely applied conditioning stimulus. More negative CPM responses (= reduced pain intensity ratings under concurrent stimulation) are indicative of endogenous analgesia (i.e., increased pain inhibition) and are mediated by spino-bulbo-spinal reflexes which are controlled by higher cortical brain areas. Given that the same brain regions needed for descending pain modulation are also negatively impacted in persons with Alzheimer's Disease (AD), aberrant descending pain inhibition might contribute to altered pain processing in AD. To our knowledge no studies to date have investigated descending pain inhibition in persons with AD nor its underlying mechanisms. The proposed supplement will recruit 50 older adults diagnosed with mild AD with and without pain and undergo experimental sessions of conditioned pain modulation, a cognitive function battery and multi- modal neuroimaging consistent with the methodology used in the parent R01 award and compared with individuals with knee osteoarthritis that are cognitively intact. The proposed research addresses a significant gap in the literature and would be the first to evaluate the pain-related changes in the neural substrates in older persons with and without AD in relation to pain. The identification of key top-down modulatory brain networks impacted by pain and AD will increase our understanding of neurobiological changes in pain processing that may put individuals at risk of developing AD.

ABSTRACT Osteoarthritis (OA) represents a significant cause of disability worldwide in individuals aged 65 and older, a rapidly growing segment of our population. The knee is the most commonly affected joint with pain being the primary symptom, negatively impacting physical, cognitive, and emotional functioning. Symptomatic knee OA has been traditionally attributed to peripheral mechanisms, but measures of joint damage only modestly account for the presence or severity of OA-related pain. The neuropeptide oxytocin (OT) has been recognized as a mediator of endogenous analgesia in animal and human studies. However, little is known about the neurobiological mechanisms underlying OT's pain-relieving properties. This proposal is based on a mechanistic model of OT's analgesic effects leveraging pilot data supporting efficacy and safety of self-administered intranasal OT over 4-weeks in older individuals. Relative to placebo (P), daily administration of intranasal OT diminished self-reported pain intensity, reduced experimental pain sensitivity, and increased self-reported physical and emotional functioning. Further, participants treated with OT, compared to P, showed decreases in brain metabolite concentrations associated with inflammation. Thus, our overarching goal is to evaluate the effects of intranasal OT on pain and function in aging and to determine the extent to which central and peripheral inflammatory mechanisms contribute to these analgesic responses. We aim to 1) determine the effect of intranasal OT administration on clinical and experimental pain sensitivity in older adults with symptomatic knee OA and 2) characterize inflammatory mechanisms contributing to the inter-individual variability in analgesic responses to OT. Older adults with symptomatic knee OA will self-administer intranasal OT or P over 4 weeks using a double-blinded, parallel study design. With strong support from the University of Florida and the McKnight Brain Institute, our interdisciplinary project, using a comprehensive multi-methods approach, will be the first to determine the potential benefit of OT as a novel analgesic therapy for knee OA pain in aging. OT is currently used in obstetrics and may be an inexpensive, effective method for pain management in older adults with little potential for addiction. Embedded in a biopsychosocial framework, our proposal will help pave the way for future investigations using a mechanism-based treatment optimization strategy for individuals suffering from chronic pain.

Project Summary/Abstract. Discovery and validation of strong candidate biomarkers and clinical endpoints for pain is urgently needed that can be used to facilitate the development of non-opioid pain therapeutics from discovery through Phase II clinical trials. Emerging research using a combination of biomarkers deliver individualized predictions about future brain and body health. Our own findings suggest that behavioral chronic pain characteristics are associated with multiple biological biomarkers where a greater pain burden is associated with accelerated detrimental biological processes. However, prospective research is urgently needed to determine pain?s impact on the heterogeneity of these biological processes within an individual to elucidate the underlying patterns of biological changes using a biobehavioral perspective which is needed for predicting future health and to be able to use as clinical endpoints for interventions. The proposed study will prospectively address biobehavioral factors (i.e., cognitive, psychological, social and cultural) affecting the experience and interpretation of knee pain and physical function across racial/ethnic groups over time. We will prospectively assess pain along with multiple biomarkers as predictors of cognitive, psychological and physical functional progression among middle-aged and older non- Hispanic Blacks and non-Hispanic Whites with knee pain and controls over a four-year study period. With strong support from the University of Florida, our interdisciplinary project, using a comprehensive biobehavioral multi- methods approach, we will be the first to prospectively determine the trajectory and interactions among pain, biological biomarkers and multiple domains of function within race/ethnic groups in OA pain. Findings will contribute towards increased understanding of pain and its biobehavioral basis, with the potential to reduce race/ethnic group disparities and improve pain-related health and functional outcomes.

Project Summary/Abstract. Discovery and validation of strong candidate biomarkers and clinical endpoints for pain is urgently needed that can be used to facilitate the development of non-opioid pain therapeutics from discovery through Phase II clinical trials. Emerging research using a combination of biomarkers deliver individualized predictions about future brain and body health. Our own findings suggest that behavioral chronic pain characteristics are associated with multiple biological biomarkers where a greater pain burden is associated with accelerated detrimental biological processes. However, prospective research is urgently needed to determine pain?s impact on the heterogeneity of these biological processes within an individual to elucidate the underlying patterns of biological changes using a biobehavioral perspective which is needed for predicting future health and to be able to use as clinical endpoints for interventions. The proposed study will prospectively address biobehavioral factors (i.e., cognitive, psychological, social and cultural) affecting the experience and interpretation of knee pain and physical function across racial/ethnic groups over time. We will prospectively assess pain along with multiple biomarkers as predictors of cognitive, psychological and physical functional progression among middle-aged and older non- Hispanic Blacks and non-Hispanic Whites with knee pain and controls over a four-year study period. With strong support from the University of Florida, our interdisciplinary project, using a comprehensive biobehavioral multi- methods approach, we will be the first to prospectively determine the trajectory and interactions among pain, biological biomarkers and multiple domains of function within race/ethnic groups in OA pain. Findings will contribute towards increased understanding of pain and its biobehavioral basis, with the potential to reduce race/ethnic group disparities and improve pain-related health and functional outcomes.

Project Summary/Abstract Santa Fe College (SF) and the University of Florida (UF) seek to continue the SF2UF program, a partnership designed to increase the number of underrepresented (UR) students who transfer from SF to UF, graduate with baccalaureate degrees, and continue to careers in biomedical and behavioral science-related disciplines. For the purposes of the SF2UF project, UR students are those who meet at least one of the following criteria:1) individuals from racial and ethnic groups that are underrepresented in health-related sciences (Blacks or African Americans, Hispanics or Latinos, American Indians or Alaska Natives, Native Hawaiians and other Pacific Islanders), 2) individuals with disabilities, and 3) individuals from disadvantaged backgrounds (per NIH NOT- OD-20-031). The SF2UF program design is based on three foundational principles: 1) the first two years of college are the most critical for recruitment and retention of students in the sciences; 2) early and consistent participation in high-quality mentored research increases retention and academic performance, especially among UR students; and 3) addressing mental health and wellness with students should be an essential component of a training program for UR undergraduate transfer students. The program has five measurable specific aims as performance targets: 1) increase by 25% the number of freshman students at SF enrolled in the program-associated courses who are considering a career as a research scientist, 2) recruit 29 trainees into the SF2UF program over five years, 2) achieve 100% of the trainees successfully transferring to UF or another four-year institution, 3) retain at least 90% of the trainees for the full three-year training period, 4) graduate at least 90% of the trainees with a B.S. degree within four years of joining the program, and 5) achieve at least 75% of the trainees continuing to a post-baccalaureate degree programs ? including at least 60% continuing to a Ph.D. degree program ? within two years of earning the BS degree. The SF2UF program aims to achieve these targets with novel educational programs at SF, and an integrated research mentoring and career development experience at SF and UF designed to prepare the trainees for matriculation to a competitive Ph.D. program.