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Kamelia Klejc,1 Yenisel Cruz-Almeida,2 Julia L Sheffler1 1Center for Translational Behavioral Science, Florida State University College of Medicine, Tallahassee, FL, USA; 2Center for Cognitive Aging and Memory, University of Florida, Gainesville, FL, USACorrespondence: Julia L Sheffler, Email julia.sheffler@med.fsu.eduAbstract: Chronic pain has negative physical and cognitive consequences in older adults and may lead to a poorer quality of life. Mediterranean ketogenic nutrition (MKN) is a promising nonpharmacological intervention for pain management, but long-term adherence is challenging due to the carbohydrate restrictive diet regimen. The main objective of this study was to evaluate the effects of the pilot MKN Adherence (MKNA) Program on pain in older adults with mild cognitive impairment and to assess whether improvements in self-reported pain were associated with adherence to MKN. Older adults (N = 58) aged 60– 85 with possible mild cognitive impairment were randomized to a 6-week MKNA arm or an MKN Education (MKNE) program arm. Both arms received the same nutrition education and group format; however, the MKNA arm received additional motivational interviewing and cognitive behavioral skills to enhance adherence. Changes in self-reported pain (Brief Pain Inventory, Roland Morris, Patient’s Global Impression of Change) and adherence to MKN (ketone levels, self-reported adherence) were assessed at baseline, 6-weeks, and 3-months post intervention. Both arms showed clinically significant reductions in pain. Greater adherence to MKN across the 6-week intervention was associated with higher ratings of pain-related changes on the Patient’s Global Impression of Change scale. Based on these findings, adherence to MKN may promote improvements in self-reported pain in older adults with mild cognitive impairment and findings support the need for future full-scale randomized clinical trials evaluating MKN programs on pain. Trial Registration: Clinicaltrials.gov ID: NCT04817176Keywords: ketogenic diet, ketosis, chronic pain, adherence, nutrition program

Tamara Ordonez Diaz,1,2 Roger B Fillingim,2,3 Yenisel Cruz-Almeida,2,3,&ast; Jennifer A Nichols1,2,4,&ast; 1J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA; 2Pain Research & Intervention Center of Excellence, University of Florida, Gainesville, FL, USA; 3Department of Community Dentistry and Behavioral Science, University of Florida, Gainesville, FL, USA; 4Department of Orthopaedics & Sports Medicine, University of Florida, Gainesville, FL, USA&ast;These authors contributed equally to this workCorrespondence: Jennifer A Nichols, J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, 1275 Center Drive, BMS JG-56, PO Box 116131, Gainesville, FL, 32611, USA, Tel +1(352)294-8803, Email jnichols@bme.ufl.eduPurpose: Evaluate sensory and psychological differences in individuals with thumb carpometacarpal (CMC) and/or knee osteoarthritis (OA) pain. This secondary analysis focuses on comparing the effects of OA at large and small joints in community-dwelling adults.Patients and Methods: A total of 434 individuals were recruited from communities in Gainesville, FL and Birmingham, AL. Each participant completed health and clinical history questionnaires, quantitative sensory testing, and physical functional tests. Participants were divided into four groups based on their pain (“CMC pain” (n = 33), “knee pain” (n = 71), “CMC + knee pain” (n = 81), and “pain-free” controls (n = 60)). ANCOVAs were performed to identify significant differences in experimental pain and psychological variables across groups.Results: The “CMC + knee pain” group had lower pressure pain thresholds (lateral knee site, p < 0.01) and higher temporal summation of mechanical pain (knee, p < 0.01) when compared to “CMC pain” and “pain-free” groups. The “knee pain” group had lower heat pain tolerance at the forearm site (p = 0.02) and higher mechanical pain (p < 0.01) at both tested sites in comparison to the “CMC pain” group. Lastly, the “CMC + knee pain” group had the highest self-reported pain (p < 0.01) and disability (p < 0.01) compared to all other groups.Conclusion: Results suggest knee OA compounded with CMC OA increases disease impact and decreases emotional health compared to OA at either the CMC or knee joint alone. Results also support a relationship between the number of painful joints and enhanced widespread pain sensitivity. Measuring pain at sites other than the primary OA location is important and could contribute to more holistic treatment and prevention of OA progression.Keywords: thumb, trapeziometacarpal, multi-site OA, generalized OA, quantitative sensory testing

Alisa J Johnson,1,2,&ast; Taylor Buchanan,3,&ast; Chavier Laffitte Nodarse,1,2 Pedro A Valdes Hernandez,1,2 Zhiguang Huo,4 James H Cole,5,6 Thomas W Buford,3 Roger B Fillingim,1,2,7 Yenisel Cruz-Almeida1,2,7 1Pain Research & Intervention Center of Excellence, University of Florida, Gainesville, FL, USA; 2Department of Community Dentistry & Behavioral Science, College of Dentistry, University of Florida, Gainesville, FL, USA; 3Department of Medicine, University of Alabama, Birmingham, AL, USA; 4Department of Biostatistics, College of Public Health & Health Professions College of Medicine, University of Florida, Gainesville, FL, USA; 5Centre for Medical Image Computing, Department of Computer Science, University College London, London, UK; 6Dementia Research Centre, Institute of Neurology, University College London, London, UK; 7Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA&ast;These authors contributed equally to this workCorrespondence: Yenisel Cruz-Almeida, University of Florida, PO Box 103628, 1329 SW 16th Street, Ste 5180, Gainesville, FL, 32608, USA, Tel +1 352-294-8584, Fax +1 352-273-5985, Email cryeni@ufl.eduPurpose: Knee OA-related pain varies in impact across individuals and may relate to central nervous system alterations like accelerated brain aging processes. We previously reported that older adults with chronic musculoskeletal pain had a significantly greater brain-predicted age, compared to pain-free controls, indicating an “older” appearing brain. Yet this association is not well understood. This cross-sectional study examines brain-predicted age differences associated with chronic knee osteoarthritis pain, in a larger, more demographically diverse sample with consideration for pain’s impact.Patients and Methods: Participants (mean age = 57.8 ± 8.0 years) with/without knee OA-related pain were classified according to pain’s impact on daily function (ie, impact): low-impact (n=111), and high-impact (n=60) pain, and pain-free controls (n=31). Participants completed demographic, pain, and psychosocial assessments, and T1-weighted magnetic resonance imaging. Brain-predicted age difference (brain-PAD) was compared across groups using analysis of covariance. Partial correlations examined associations of brain-PAD with pain and psychosocial variables.Results: Individuals with high-impact chronic knee pain had significantly “older” brains for their age compared to individuals with low-impact knee pain (p < 0.05). Brain-PAD was also significantly associated with clinical pain, negative affect, passive coping, and pain catastrophizing (p’s< 0.05).Conclusion: Our findings suggest that high impact chronic knee pain is associated with an older appearing brain on MRI. Future studies are needed to determine the impact of pain-related interference and pain management on somatosensory processing and brain aging biomarkers for high-risk populations and effective intervention strategies.Keywords: knee osteoarthritis, high impact chronic pain, brain aging, experimental pain, psychosocial

Yenisel Cruz-Almeida,1 Samuel J Crowley,2 Jared Tanner,2 Catherine C Price2,3 1Pain Research & Intervention Center of Excellence, University of Florida, Gainesville, FL, USA; 2Department of Clinical and Health Psychology, University of Florida, Gainesville, FL, USA; 3Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USACorrespondence: Catherine C PriceABPP/Cn Tel +1 352-273-5929Email cep23@phhp.ufl.eduIntroduction: Chronic pain is prevalent in idiopathic Parkinson’s disease (PD) with many individuals also experiencing cognitive deficits negatively impacting everyday life.Methods: In this study, we examine differences in pain severity and interference between 113 nondemented individuals with idiopathic PD who were statistically classified as having low executive function (n=24), low memory function (n=35), no cognitive deficits (n=54). The individuals with PD were also compared to matched non-PD controls (n=64).Results: PD participants with low executive function reported significantly higher pain interference (p< 0.05), despite reporting similar pain severity levels compared to other phenotypes. These differences remained statistically significant, even after accounting for important confounders such as anxiety and depression (p< 0.05).Discussion: Pain interference in those with lower executive function may represent a target for psychosocial interventions for individuals with pain and PD.Keywords: Parkinson’s disease, pain, cognitive function, profiles, phenotypes

Soamy Montesino-Goicolea,1,2 Pedro A Valdes-Hernandez,1,2 Lorraine Hoyos,3 Adam J Woods,2,4,5 Ronald Cohen,2,5 Zhiguang Huo,6 Joseph L Riley III,1,7 Eric C Porges,2,5 Roger B Fillingim,1,7 Yenisel Cruz-Almeida1,2,4,7 1Department of Community Dentistry & Behavioral Sciences, University of Florida, Gainesville, FL, USA; 2Center for Cognitive Aging and Memory, McKnight Brain Foundation, University of Florida, Gainesville, FL, USA; 3University of Central, Florida College of Medicine, Orlando, FL, USA; 4Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA; 5Department of Clinical and Health Psychology, College of Health Professions, University of Florida, Gainesville, FL, USA; 6Department of Biostatistics, College of Public Health and Health Professions College of Medicine, University of Florida, Gainesville, FL, USA; 7Institute on Aging, University of Florida, Gainesville, FL, USACorrespondence: Yenisel Cruz-AlmeidaPain Research and Intervention Center of Excellence, University of Florida, PO BOX 112610, Gainesville, FL 326010, USATel +1 352-294-5845Fax +1 352-273-5920Email cryeni@ufl.eduIntroduction: Musculoskeletal pain is prevalent in older adults representing the leading cause of disability in this population. Similarly, nearly half of older adults complain of difficulty sleeping. We aimed to explore the relationship between sleep quality with self-reported musculoskeletal pain, somatosensory and pain thresholds in community-dwelling older adults and further explore brain regions that may contribute to this association.Methods: Older adults (> 60 years old, n=69) from the NEPAL study completed demographic, pain and sleep assessments followed by a quantitative sensory testing battery. A subset (n=49) also underwent a 3T high-resolution, T1-weighted anatomical scan.Results: Poorer sleep quality using the Pittsburgh Sleep Quality Index was positively associated with self-reported pain measures (all p’s > 0.05), but not somatosensory and pain thresholds (all p’s > 0.05). Using a non-parametric threshold-free cluster enhancement (TFCE) approach, worse sleep quality was significantly associated with lower cortical thickness in the precentral, postcentral, precuneus, superior parietal, and lateral occipital regions (TFCE-FWE-corrected at p

Katie A Butera,1 Shannon R Roff,2 Thomas W Buford,3 Yenisel Cruz-Almeida4 1Department of Physical Therapy, College of Public Health and Health Professions, University of Florida, Gainesville, FL 32610, USA; 2Charles River Laboratories Inc., Frederick, MD 21701, USA; 3Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; 4Department of Aging & Geriatric Research, Institute on Aging, Pain Research & Intervention Center of Excellence, Center for Cognitive Aging & Memory, University of Florida, Gainesville, FL 32610, USA Abstract: Multisite pain, or pain that occurs simultaneously at >1 anatomical site, is more prevalent than single-site pain. While multisite pain affects over half of older adults, it remains an understudied pain entity that may have important functional implications in an aging population. Greater understanding of this complex pain entity from a biopsychosocial perspective is critical for optimizing clinical and functional outcomes in older adults with pain. Therefore, the primary purpose of this review is to summarize the relationship between multisite pain and functional outcomes in older adults to further elucidate the impact of multisite pain as a distinct entity within this population. A comprehensive literature search revealed 17 peer-reviewed articles. Multisite pain in older individuals is associated with reductions in several physical function domains: 1) lower-extremity mobility; 2) upper-extremity impairments; 3) balance and increased fall risk; and 4) general disability and poor physical function. Further, multisite pain in older individuals is associated with psychological dysfunction (eg, anxiety and depressive symptoms) and social factors (eg, income and education). Overall, this review highlights the scant literature investigating the functional implications of multisite pain in an aging population. Further, while multisite pain appears to have functional consequences, the neurobiological mechanisms contributing to this relationship are unknown. Thus, how this pain characteristic may contribute to the variability in pain-related functional outcomes among older adults is not clear. Future investigations are strongly warranted to advance the understanding of multisite pain and its broad impact on physical and psychosocial function in older adults. Keywords: multiple pain locations, multiple pain sites, social function, dysfunction, disability, physical function, social factors

Juan C Mora,1 Rene Przkora,1 Yenisel Cruz-Almeida2 1Department of Anesthesiology, Division of Pain Medicine, University of Florida, Gainesville, FL, USA; 2Department of Aging and Geriatric Research, Institute on Aging, Pain Research and Intervention Center of Excellence, University of Florida, Gainesville, FL, USA Abstract: For decades, multiple attempts to fully understand knee osteoarthritis pathophysiology and natural history have been attempted. Despite the extensive amount of research regarding this topic, there are still marked controversies. This multifactorial condition gets influenced by local, systemic, and external factors and its progression and/or response to treatments widely varies from patient to patient. Multiple therapies have been studied in the past, low impact physical activity seems to be supported by all the current medical societies while other interventions have shown conflicting findings. Newer therapies and routes of administration are under investigation and some of them have shown promising preliminary reports. This review intends to give an overview of the current knowledge of pathophysiology and non-surgical therapies available for knee osteoarthritis. Keywords: knee osteoarthritis, cartilage degeneration, non-inflammatory arthritis, intra-articular injections, corticosteroids

Yenisel Cruz-Almeida,1–3 Maria Aguirre,1,4 Heather Sorenson,4,5 Patrick Tighe,1,6 Shannon M Wallet,4,5 Joseph L Riley III1,4 1Pain Research and Intervention Center of Excellence, 2Institute on Aging, 3Department of Aging and Geriatric Research, 4Department of Community Dentistry & Behavioral Science, 5Department of Oral Biology, 6Department of Anesthesiology, University of Florida, Gainesville, FL, USA Abstract: An important consideration in mechanistic research using biomarkers should include the use of saliva as an alternative to blood. The use of saliva would allow the study of susceptible populations such as older adults where venipuncture may not be feasible. Although saliva has been most commonly used to measure cortisol and tumor necrosis factor-α (TNFα), there is limited evidence that other cytokines found in saliva significantly change in response to laboratory-induced pain. Therefore, the aim of the current preliminary study was to characterize the time course, duration and magnitude of changes of commonly measured pro- (interleukin [IL]-6, IL-8) and anti-inflammatory (IL-10, IL-4) cytokines in saliva samples and to test for age-related differences in separate experimental painful and non-painful control sessions. In addition, we also tested whether venipuncture results in significant cytokine alterations similar to a painful stimulus in a non-painful, non-venipuncture control session. All cytokines were significantly induced by the cold pressor task compared to a warm control session (p < 0.001). Specifically, healthy older adults experienced greater salivary changes in all cytokines during the cold pressor session compared to younger adults in the non-painful sessions (p < 0.001). There were no significant differences between the venipuncture and non-venipuncture sessions across all cytokines (p > 0.05). Our findings support the use of saliva as a substitute for blood in both young and older healthy individuals to measure changes after experimental pain stimulation. In addition, venipuncture alone is not sufficient to induce IL-6, IL-8, IL-10 and IL-4. Future studies in the community are urgently needed to validate and further move translational mechanistic pain research to those populations most underrepresented in clinical research. Keywords: salivary markers, experimental pain, age, venipuncture

Kelly M Naugle,1 Yenisel Cruz-Almeida,2,3 Roger B Fillingim,2,4 Roland Staud,2,5 Joseph L Riley III2,4 1Department of Kinesiology, School of Physical Education and Tourism Management, Indiana University – Purdue University Indianapolis, Indianapolis, IN, 2Pain Research and Intervention Center of Excellence, University of Florida, 3Department of Aging and Geriatric Research, College of Medicine, 4Department of Community Dentistry and Behavioral Science, 5Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA Abstract: Temporal summation (TS) of pain protocols typically involve the delivery of brief repetitive noxious stimuli held at a constant intensity and measuring the consequent increase in the perceived intensity of pain sensations. To date, no studies have examined the effect of a TS protocol on the perceived spatial dimensions of the pain experience and its interaction with age. This study used a new TS protocol that examined changes in the perceived size of the painful area in 22 younger adults and 20 older adults. Four trials of ten brief heat pulses delivered at a constant intensity were administered on the volar forearm. Interpulse intervals (IPIs) were 2.5 seconds or 3.5 seconds. Subjects rated the peak pain intensity (trials 1 and 3) or the size of the painful area (trials 2 and 4) after each pulse on a 0–100 scale. The magnitude of summation was calculated for each trial. Three seconds and 6 seconds after delivering the last heat pulse, the subjects rated the intensity or the size of any remaining pain (aftersensations). The results indicated that older adults compared to younger adults exhibited significantly greater summation of size ratings for the 2.5-second and 3.5-second IPI trials and size of pain aftersensations at 3 seconds following the 2.5-second IPI TS trial. These results suggest that aging is associated with enhanced endogenous facilitation of the perceived size of pain. The potential clinical and mechanistic implications of enhanced TS of size of pain remain unknown and warrant further investigation. Keywords: pain modulation, aging, elderly, pain facilitation, size of pain