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Based on the bidirectional associations between chronic pain and sleep disorders, investigating circadian physiology in persons with chronic pain is needed. A potential contributor linking sleep disturbances in chronic pain conditions includes epigenetic alterations in genes regulating circadian clocks in persons with and without chronic pain. The purpose of this study is to examine DNA methylation differences of core circadian clock genes by chronic pain status. We hypothesize individuals with high impact chronic pain have significant DNA methylation differences in genes known to be important for circadian physiology compared to pain-free controls. Participants (n=106) aged 45-85 years, with varying degrees of chronic knee pain completed self-reported measures to determine pain impact (ie., graded chronic pain scale), along a blood draw for DNA extraction and epigenetic analysis (ie., MethylationEPIC arrays). R was used to perform methylation data preprocessing and quality control (minfi package) and differential methylation analyses focusing on the core circadian genes (PER1, PER2, PER3, DBP, CLOCK, CRY1, CRY2, ARNTL, NR1D1, and NR1D2). Individuals with high impact chronic pain had 15 differentially methylated probes (DMPs) at p<0.05, and 2 DMPs at p<0.01 compared to no pain controls. Specifically, individuals with high impact chronic pain had significant hypomethylation in a probe located at an exon of the PER3 gene and hypermethylation in a probe within an intron of the NKIRAS1 and NR1D2 genes. Future studies are needed to determine whether epigenetic alterations of these identified regions could serve to develop novel therapeutic targets. Funding: This work was supported by NIH/NIA Grants R01AG067757 (YCA); and R37AG033906 (RBF).

Aging is associated with poor sleep quality, and greater chronic pain prevalence with age-related changes in brain function as potential underlying mechanisms. The following cross-sectional study aimed to determine whether self-reported chronic musculoskeletal pain in community-dwelling older adults moderates the association between sleep quality and resting state functional brain connectivity (rsFC). Community-dwelling older individuals (mean age =73.29 years) part of the NEPAL study who completed the Pittsburg Sleep Quality Index (PSQI) and an rsFC scan were included (n=48) in the present investigation. To that end, we tested the effect of chronic pain-by-PSQI interaction on rsFC among atlas-based brain regions-of-interest, controlling for age and sex. A significant network connecting the bilateral putamen and left caudate with bilateral precentral gyrus, postcentral gyrus and juxtapositional lobule cortex, survived global multiple comparisons (FDR; q<0.05) and threshold-free network-based-statistics. Greater PSQI scores were significantly associated with greater dorsostriatal-sensorimotor rsFC in the no-pain group, suggesting that a state of somatomotor hyperarousal may be associated with poorer sleep quality in this group. However, in the pain group greater PSQI scores were associated with less dorsostriatal-sensorimotor rsFC, possibly due to a shift of striatal functions toward regulation sensorimotor aspects of the pain experience, and/or aberrant cortico-striatal loops in the presence of chronic pain. This preliminary investigation advances knowledge about the neurobiology underlying the associations between chronic pain and sleep in community-dwelling older adults that may contribute to the development of effectitractve therapies to decrease disability in geriatric populations. This work was supported by the National Institutes of Aging (NIAK01AG048259, R01AG059809, R01AG067757, and T32AG049673). A portion of this work was performed in the McKnight Brain Institute at the National High Magnetic Field Laboratory's Advanced Magnetic Resonance Imaging and Spectroscopy (AMRIS) Facility, which is supported by National Science Foundation Cooperative Agreement No. DMR-1644779 and DMR-1157490, and the State of Florida and the University of Florida Claude D. Pepper Older Americans Independence Center.

Chronic pain is driven by factors across the biopsychosocial spectrum. Previously, we demonstrated MRI-based brain-predicted age differences (brain-PAD: brain predicted age minus chronological age) to be significantly associated with pain severity in individuals with chronic knee pain. We also previously identified distinct, replicable, multidimensional psychological profiles significantly associated with clinical pain. The brain aging/psychological characteristics interface in persons with chronic pain promises elucidating factors contributing to their poor health outcomes, yet this relationship is poorly understood. We examined the interplay between previously identified psychological profiles in chronic knee pain participants (n=124), brain-PAD and clinical pain severity. Controlling for demographics and MRI scanner, we compared the brain-PAD among psychological profiles and over time. We also explored whether profile-related differences in pain severity were mediated by brain-PAD. Brain-PAD differed significantly between profiles (p=0.013), with Profile-2 (high coping; p=0.027) and Profile-3 (high negative/low positive emotions; p=0 .041) having higher brain-PAD than Profile-1 (low somatic reactivity). No significant change in profile-related brain-PAD differences over time was observed, but there was a significant decrease in brain-PAD (p=0.022) for Profile-4 (high optimism/high positive affect). Moreover, profile-related differences in pain severity at baseline were partly explained by brain-PAD; but brain-PAD did not significantly mediate the influence of variations in profiles on changes in pain severity over time. Our findings suggest that brain-PAD is integral to the previously observed relationship between psychological function and pain, and that psychological characteristics may dispose individuals with chronic knee pain for worse health outcomes, via neuropsychological processes. NIH/NIA Grants R01AG059809, R01AG067757 (YCA); R37AG033906 (RBF), and T32AG049673 (SMG). A portion of this work was performed in the McKnight Brain Institute at the National High Magnetic Field Laboratory's Advanced Magnetic Resonance Imaging and Spectroscopy (AMRIS) Facility, which is supported by National Science Foundation Cooperative Agreement No. DMR-1157490 and DMR-1644779 and the State of Florida.

Approximately 1.71 billion people globally live with musculoskeletal pain conditions, including low back pain, knee pain, and neck pain Cieza et al. (2020). In the US, an estimated 20.4% of U.S. adult had chronic pain and 8.0% of U.S. adults had high-impact chronic pain, with higher prevalence associated with advancing age Dahlhamer et al. (2018). On the other hand, between 50 and 70 million US adults have a sleep disorder (American Sleep Association). Although the link between sleep and pain is widely established, the neurobiological mechanisms underlying this relationship have yet to be fully elucidated, specifically within an aged population. As currently available sleep and chronic pain therapies are only partially effective, novel treatment approaches are urgently needed. Given the potential mechanistic role of γ-aminobutyric acid (GABA) in both conditions, and the availability of GABA supplements over the counter, the present proposal will determine the feasibility and acceptability of oral GABA administration in middle-to-older aged adults with chronic pain and sleep disorders as well as characterize the potential neurobiological mechanisms involved in both conditions. Results from the present investigation using a parallel, double-blinded, placebo-controlled study will provide novel preliminary information needed for future translational pain and sleep research.

Chronic pain is driven by factors across the biopsychosocial spectrum. Previously, we demonstrated MRI-based brain-predicted age differences (brain-PAD: brain predicted age minus chronological age) to be significantly associated with pain severity in individuals with chronic knee pain. We also previously identified four distinct, replicable, multidimensional psychological profiles significantly associated with clinical pain. The brain aging-psychological characteristics interface in persons with chronic pain promises elucidating factors contributing to their poor health outcomes, yet this relationship is barely understood. To examine the interplay between the psychological profiles in participants having chronic knee pain impacting function (n=164), brain-PAD and clinical pain severity. Controlling for demographics and MRI scanner, we compared the brain-PAD among psychological profiles, and over two years (n=90). We also explored whether profile-related differences in pain severity were mediated by brain-PAD. Brain-PAD differed significantly between profiles (p=0.039), Profile-3 (high negative/low positive emotions; p=0.047, Bonferroni-corrected) having ~4 years higher brain-PAD than Profile-1 (low somatic reactivity) and Profile-2 (high coping; p=0.027, uncorrected). No significant change in profile-related brain-PAD differences over time was observed; but there was a significant decrease in brain-PAD (p=0.045) for Profile-4 (high optimism/high positive affect). Moreover, profile-related differences in pain severity at baseline were partly explained by brain-PAD differences between Profile 3 and 1, or 2; but brain-PAD did not significantly mediate the influence of variations in profiles on changes in pain severity over time.

Knee pain, the most common cause of musculoskeletal pain (MSK), constitutes a severe public health burden. Its neurobiological causes, however, remain poorly understood. Among many possible causes, it has been proposed that sleep problems could lead to an increase in chronic pain symptomatology, which may be driven by central nervous system changes. In fact, we previously found that brain cortical thickness mediated the relationship between sleep qualities and pain severity in older adults with MSK. We also demonstrated a significant difference in a machine-learning-derived brain-aging biomarker between participants with low-and high-impact knee pain. Considering this, we examined whether brain aging was associated with self-reported sleep and pain measures, and whether brain aging mediated the relationship between sleep problems and knee pain. Exploratory Spearman and Pearson partial correlations, controlling for age, sex, race and study site, showed a significant association of brain aging with sleep related impairment and self-reported pain measures. Moreover, mediation analysis showed that brain aging significantly mediated the effect of sleep related impairment on clinical pain and physical symptoms. Our findings extend our prior work demonstrating advanced brain aging among individuals with chronic pain and the mediating role of brain-aging on the association between sleep and pain severity. Future longitudinal studies are needed to further understand whether the brain can be a therapeutic target to reverse the possible effect of sleep problems on chronic pain.

Knee osteoarthritis (KOA) is the most common cause of musculoskeletal pain (MSK), constituting a major public health burden. Sleep is among the multiple factors contributing to KOA-related pain, as sleep disturbance increases risk for worse pain-related outcomes in KOA. In addition, our lab found that brain cortical structure mediated the relationship between sleep qualities and pain severity in older adults with MSK. Further, using a machine-learning-based brain-aging biomarker (brain-PAD; brain-predicted age minus chronological age), we also found that individuals with high-impact KOA pain showed greater brain aging than their low-impact pain counterparts. Considering this, we examined whether brain-PAD mediated the relationship between KOA pain and sleep problems. KOA participants (mean age 57.9 years) were classified into low-impact (n=87), and high-impact (n=60) pain. Demographic, pain and sleep assessments were followed by a T1-weighted anatomical scan. Exploratory Spearman and Pearson partial correlations, controlling by age, sex and race, were used to determine associations of brain-PAD with clinical pain and sleep measures. We then tested if brain-PAD mediated the sleep-pain association using PROCESS 3.5 on SPSS 28. Brain-PAD correlated with the affective domain of the McGill Pain Questionnaire (MPQ) (r=0.215, p=0.010) and MPQ total score (r=0.181, p=0.033). Moreover, Brain-PAD significantly mediated (bootstrapped 95% CIs p<0.05) the effect of the short form PROMIS Sleep impairment total score on the MPQ affective, continuous and total score. Brain-PAD did not significantly mediate the sleep-pain effect. Our finding in this KOA sample extends our prior work demonstrating advanced brain aging among older individuals with chronic pain and more pain severity, implicating brain-PAD as a significant mediator of the sleep-KOA pain association. Future replication studies are needed, as well as studies to further understand if the brain can be a therapeutic target to reverse the possible effect of sleep problems on chronic pain. Funding from NIAR01AG067757.

Aging is associated with poor sleep quality and greater chronic pain prevalence, with age-related changes in brain function as potential underlying mechanisms. Objective. The following cross-sectional study aimed to determine whether self-reported chronic musculoskeletal pain in community-dwelling older adults moderates the association between sleep quality and resting state functional brain connectivity (rsFC). Methods. Community-dwelling older individuals (mean age = 73.29 years) part of the NEPAL study who completed the Pittsburg Sleep Quality Index (PSQI) and a rsFC scan were included (n = 48) in the present investigation. To that end, we tested the effect of chronic pain-by-PSQI interaction on rsFC among atlas-based brain regions-of-interest, controlling for age and sex. Results and Discussion. A significant network connecting the bilateral putamen and left caudate with bilateral precentral gyrus, postcentral gyrus, and juxtapositional lobule cortex, survived global multiple comparisons (FDR; q < 0.05) and threshold-free network-based-statistics. Greater PSQI scores were significantly associated with greater dorsostriatal-sensorimotor rsFC in the no-pain group, suggesting that a state of somatomotor hyperarousal may be associated with poorer sleep quality in this group. However, in the pain group, greater PSQI scores were associated with less dorsostriatal-sensorimotor rsFC, possibly due to a shift of striatal functions toward regulation sensorimotor aspects of the pain experience, and/or aberrant cortico-striatal loops in the presence of chronic pain. This preliminary investigation advances knowledge about the neurobiology underlying the associations between chronic pain and sleep in community-dwelling older adults that may contribute to the development of effective therapies to decrease disability in geriatric populations.

Introduction: Psychological factors have been associated with knee osteoarthritis pain severity and treatment outcomes, yet their combined contribution to phenotypic heterogeneity is poorly understood. In particular, empirically derived psychological profiles must be replicated before they can be targeted or considered for treatment studies. The objectives of this study were to (1) confirm previously identified psychological profiles using unsupervised clustering methods in persons with knee osteoarthritis pain, (2) determine the replicability of profiles using supervised machine learning in a different sample, and (3) examine associations with clinical pain, brain structure, and experimental pain.Methods: Participants included two cohorts of individuals with knee osteoarthritis pain recruited as part of the multisite UPLOAD1(n= 270, mean age = 56.8 ± 7.6, male = 37%) and UPLOAD2(n= 164, mean age = 57.73 ± 7.8, male = 36%) studies. Similar psychological constructs (e.g. optimism, coping, somatization, affect, depression, and anxiety), sociodemographic and clinical characteristics, and somatosensory function were assessed across samples. UPLOAD2participants also completed brain magnetic resonance imaging. Unsupervised hierarchical clustering analysis was first conducted in UPLOAD1data to derive clusters, followed by supervised linear discriminative analysis to predict group membership in UPLOAD2 data. Associations among cluster membership and clinical variables were assessed, controlling for age, sex, education, ethnicity/race, study site, and number of pain sites.Results: Four distinct profiles emerged in UPLOAD1and were replicated in UPLOAD2.Identified psychological profiles were associated with psychological variables (ps < 0.001), and clinical outcomes (ps =0.001–0.03), indicating good internal and external validation of the cluster solution. Significant associations between psychological profiles and somatosensory function and brain structure were also found.Conclusions: This study highlights the importance of considering the biopsychosocial model in knee osteoarthritis pain assessment and treatment.

We have previously reported that older adults with chronic musculoskeletal pain had significantly older-appearing brains compared to older controls in a small, mainly Non-Hispanic white sample of individuals. We employed a machine-learning derived brain aging biomarker that compares voxel-wise gray and white matter volume images to a statistical model that accurately predicts chronological age from neuroimaging data in healthy people. The present study aimed to extend our previous findings to a larger, younger, and more racially diverse sample of individuals with knee osteoarthritis (OA) pain. Participants (mean age=58 years) with severe (n=100) and mild knee pain (n=51) as well as age-matched controls (n=54) completed demographic, psychological and self-reported and experimental pain assessments along with a T1-weighted MRI scan. We estimated a brain-predicted age difference (brain-PAD) calculated as brain-predicted age minus chronological age. Analyses of covariances and correlations were used to determine associations of brain-PAD with pain and psychological variables. Age-matched controls had significantly "younger" brains for their age compared to individuals with the most severe knee pain (Bonferroni-p=0.023). Lower self-reported pain intensity and disability were significantly associated with a "younger" brain (p's<0.05). A "younger" brain was also significantly associated with lower mechanical and thermal pain sensitivity, greater endogenous pain inhibition, lower negative affect, lower in-vivo passive coping, and lower pain catastrophizing (p's<0.05). Our findings replicate and extend our previous findings in a larger diverse cohort of individuals with and without knee pain. Even in this younger sample, our findings suggest that chronic pain is associated with added "age-like" brain atrophy, and future studies are needed to determine whether a brain aging biomarker may help identify people with chronic pain who are at a greater risk of functional decline and poorer health outcomes. R01AG059809, R01AG067757.

There is evidence of sex differences in the prevalence of chronic musculoskeletal pain as well as in experimental pain sensitivity. However, the neurobiological mechanisms contributing to these sex differences are poorly understood, especially with respect to brain structure. The aim of the present study is to examine sex differences in brain structure in persons with knee osteoarthritis (KOA) pain. Participants (mean age=58 years) with KOA pain (n=146, 65% female) completed demographic, self-reported and experimental pain assessments including temporal summation and conditioned pain modulation along with a 3T high-resolution, T1-weighted anatomical scan at 2 study sites in the US. FreeSurfer software (v.7.1.0, http://surfer.nmr.mgh.harvard.edu) was used to examine sex differences in gray matter volume and cortical thickness as well as associations with experimental variables. Maps were set at a vertex-wise threshold of P<0.001, and cluster-level threshold was set at P<0.05, corrected for multiple comparisons, by using Monte Carlo Z simulation and 5000 iterations (Family-Wise-Error, FWE, correction). Controlling for important covariates, men compared to women with KOA had significantly lower cortical thickness in the left anterior insula (p=0.043, FWE corrected two-tailed). Cortical thickness in this region was significantly associated with punctate temporal summation (r=0.325, p=0.024) and endogenous pain inhibition (r=0.558, p=0.011) in men, but not in women (p's>0.05). The results suggest that brain morphological differences between females and men with KOA pain are associated with distinct pain modulatory measures in men, but not in women. Future studies are needed to characterize potential neurobiological mechanisms underlying endogenous pain modulatory capacity across the sexes to further understand the individualized pain experience. R01AG059809, R01AG067757.

The purpose of this study was to systematically examine somatosensory function by age and testing site across a variety of quantitative sensory testing (QST) modalities and determine if age differences were associated with brain gray matter volume and cortical thickness. Healthy younger (n=22; mean (SD) age = 21.31 (1.54) years) and older adults (n=62; mean (SD) age= 72.11 (6.69) years) were recruited as part of the Neuromodulatory Examination of Pain and Mobility Across the Lifespan study. Participants underwent mechanical and thermal detection as well as pain perception applied to two different anatomical sites (metatarsal and thenar). MRI data was collected on a 3-Tesla scanner with a 32-channel radiofrequency coil. A repeated measures ANOVA examined differences in QST by age and test site. Freesurfer examined associations between QST modalities and brain structure in older adults. Significant test site by age interaction effects were observed for warm detection threshold (p=0.018, partial eta2=0.10) and heat pain threshold (p=0.014, partial eta2=0.12). Main effects of age were observed for mechanical detection threshold, vibratory detection threshold, cold detection threshold, warm detection threshold, heat pain threshold, heat pain rating (p's<0.05). Significant interaction and main effects were not observed for cold pain rating or temporal summation. In the older participants, higher mechanical and cold detection thresholds as well as higher heat pain ratings were associated with volume across multiple brain regions using Threshold-free cluster enhancement approaches (TFCE). Older adults displayed alterations in innocuous and noxious somatosensory function compared to younger adults and these findings differ by the type of assessment as well as the location of assessment. Furthermore, in older adults, mechanical detection threshold, cold detection threshold, and heat pain rating were associated with specific changes in brain volume providing evidence for potential underlying mechanisms associated with changes in these modalities with aging. The NEPAL study was supported by the National Institutes of Aging (NIA K01AG048259). A portion of this work was performed in the McKnight Brain Institute at the National High Magnetic Field Laboratory's Advanced Magnetic Resonance Imaging and Spectroscopy (AMRIS) Facility, which is supported by National Science Foundation Cooperative Agreement No. DMR-1644779 and DMR-1157490, and the State of Florida and the University of Florida Claude D. Pepper Older Americans Independence Center. Abigail Wilson would like to acknowledge this work was supported in part/full by a Promotion of Doctoral Studies I Scholarship from the Foundation for Physical Therapy Research.