Environmental and sociocultural factors are associated with pain-related brain structure among diverse individuals with chronic musculoskeletal pain: intersectional considerations

Chronic musculoskeletal pain including knee osteoarthritis (OA) is a leading cause of disability worldwide. Previous research indicates ethnic-race groups differ in the pain and functional limitations experienced with knee OA. However, when socioenvironmental factors are included in analyses, group differences in pain and function wane. Pain-related brain structures are another area where ethnic-race group differences have been observed. Environmental and sociocultural factors e.g., income, education, experiences of discrimination, and social support influence brain structures. We investigate if environmental and sociocultural factors reduce previously observed ethnic-race group differences in pain-related brain structures. Data were analyzed from 147 self-identified non-Hispanic black (NHB) and non-Hispanic white (NHW), middle and older aged adults with knee pain in the past month. Information collected included health and pain history, environmental and sociocultural resources, and brain imaging. The NHB adults were younger and reported lower income and education compared to their NHW peers. In hierarchical multiple regression models, sociocultural and environmental factors explained 6–37% of the variance in pain-related brain regions. Self-identified ethnicity-race provided an additional 4–13% of explanatory value in the amygdala, hippocampus, insula, bilateral primary somatosensory cortex, and thalamus. In the rostral/caudal anterior cingulate and dorsolateral prefrontal cortex, self-identified ethnicity-race was not a predictor after accounting for environmental, sociocultural, and demographic factors. Findings help to disentangle and identify some of the factors contributing to ethnic-race group disparities in pain-related brain structures. Numerous arrays of environmental and sociocultural factors remain to be investigated. Further, the differing sociodemographic representation of our NHB and NHW participants highlights the role for intersectional considerations in future research.


Measures
Clinical pain and disability Total Pain Sites (n = 147).Participants were asked if they had pain on more days than not over the past 3 months at bilateral sites across the body (0-28 sites).Pain sites served as a covariate for global pain severity in the model since the other pain measures were limited to the knee 45 .Increasing number of pain sites has been linked to worse health outcomes and three or more pain sites are considered widespread pain 46,47 .
Brain imaging MRI acquisition.Individuals who completed a brain MRI were included in this cross-sectional analysis.Both sites (UAB and UF) acquired MRI data using a 3 Tesla Philips Achieva scanner (32-channel head coil at UF and an 8-channel head coil at UAB).T1-weighted three-dimensional magnetization-prepared rapid acquisition gradient-echo (MP-RAGE) images were acquired and used for analyses (TR: 7.0 ms, TE: 3.2 ms, flip angle: 8°, 1 mm iso voxels, FOV: 240 × 240 × 176, sagittal acquisition).MRI processing.MP-RAGE files were processed using FreeSurfer 6.0 48 .FreeSurfer is a set of software tools for the study of cortical and subcortical anatomy [49][50][51] .Segmentation of subcortical and related structures (including hippocampus, amygdala, and thalamus) was performed.The cerebral cortex was parcellated into units with respect to gyral and sulcal structure [52][53][54] .Procedures for the measurement of cortical thickness have been validated against histological analysis 55 and manual measurements 54,56 .FreeSurfer morphometric procedures have been demonstrated to show good test-retest reliability across scanner manufacturers and across field strengths 57,58 .MRI data were assessed for quality and participants were excluded for missing or insufficient quality data.
Brain structure.Participants reported knee pain consistent with or at risk for knee osteoarthritis, and also reported pain in other body sites (Mean = 6, Range 0-28 additional sites).As such, analyses were guided based on previously identified brain areas in a systematic review for musculoskeletal pain 28 and other musculoskeletal and chronic pain research 27,29,31 .The final areas were selected a priori by a team consensus and align with our other work 30 .Mean thickness values for each cortical region (Desikan-Killiany-Tourville parcellation) and subcortical volumes were exported for statistical analyses.Metrics were the bilateral mean thickness for the rostral and caudal anterior cingulate cortices (ACC), insula, medial prefrontal cortex (MPFC), primary somatosensory cortex (S1), dorsolateral prefrontal cortex (DLPFC), and thalamus, amygdala and hippocampus volumes adjusted for total intracranial volume.

Environmental and sociocultural measures
The environmental and sociocultural measures used were selected based on identification in the NIA and NIMHD Frameworks under the environmental and sociocultural level of analysis/domains of influence and available in the UPLOAD2 study.Environmental and sociocultural measures included self-reported educational level, current income, number of people living in the household, employment status, current insurance status, perceived social support and experiences of interpersonal discrimination.
Insurance Status (n = 147)-Participants were asked "Are you covered by health insurance or some other kind of health care plan?" as either 1 = yes or 0 = no.Participants who reported "unsure" were counted as missing.
The Multidimensional Scale of Perceived Social Support (MSPSS) 59 (n = 136)-The MSPSS measures the perceived social support from family, friends and significant other using a 7-point Likert scale (1 = "very strongly disagree" to 7 = "very strongly agree").Total scores are calculated as a summation of all questions with higher scores indicating greater perceived social support.
Experiences of Discrimination (EOD) questionnaire 60,61 (n = 145)-The EOD measures incidences of selfreported experiences of interpersonal discrimination over an individual's lifetime, as well as the frequency of each event, worry for each event, the reason certain events occurred, and response to certain situations on a 0 = "never", 1 = "once, 2.5 = "2 to 3 times", and 5 = "4 or more times" scale.These values are summed with higher scores signifying greater experiences of interpersonal discrimination over an individual's lifetime. www.nature.com/scientificreports/

Statistical analysis
All data were analyzed using SAS v.9.4 (Cary, NC) and SPSS 26.0 (IBM, Chicago, IL), and checked for normality, outliers, and missing values.Differences between participant characteristics by sociodemographic groups (self-reported as NHB or NHW) were analyzed using T-Test for continuous variables and Chi-Squared or Fisher Test where appropriate for categorical variables.A total of 147 participants completed brain imaging.Income (n = 3) and household number (n = 3) were imputed from data at a second time point.Individuals missing two or fewer questions on the perceived social support had their scores imputed by using the within average of individual questions (n = 8).For individuals with three questions or more missing, perceived social support (n = 2) and discrimination (n = 1) was imputed from data at a second time point.Two participants were missing data for perceived social support or discrimination and were excluded from analysis for a final sample size of 145.A sensitivity test repeating all analyses was completed excluding individuals with imputed data to confirm findings (n = 129).Consistent with findings from our previous studies, primary explanatory variables in the model included: age, self-identified sex (1 = male, 2 = female), study site (1 = UF or 2 = UAB to account for possible scanner differences), waist circumference and total pain sites.Outcome measures for the brain ROIs: ACC, insula, MPFC, S1, DLPFC thickness, and thalamus, amygdala, and hippocampus volume.Nested linear regression modeling was completed as follows: model 1) the primary explanatory variables, including age, sex, study site, waist circumference and total pain sites; model 2) primary explanatory variables from model 1 plus environmental and sociocultural variables including education, income, household number, employment, insurance status, social support and discrimination; model 3) all variables from model 2 plus ethnic-race groups who significantly differed on additional sociodemographic factors thus identified as sociodemographic groups, NHB adults (younger with lower levels of income and education) = 1 compared to and NHW adults (older with higher income/education) = 2.

Ethical approval
This study was conducted in accordance with the Declaration of Helsinki.The UPLOAD-2 study was approved by the University of Florida Institution Review Board (IRB approval number 201400209) on June 6, 2014, and the University of Alabama at Birmingham Institution Review Board (IRB approval number 40915002) on November 11, 2014.All participants provided verbal and written informed consent prior to any study procedures being conducted.

Participant characteristics
Participant characteristics are displayed in Table 1.NHB adults were significantly younger with lower education and income compared to the NHW adults.As each ethnic-race group was limited in representation, the groups differed from each other on relevant sociodemographic variables, and statistical test are not able to correct group imbalances, ethnic-race group interpretations require caution and will be framed from an intersectional perspective 62,63 .Additionally, in line with an intersectional approach, the term 'sociodemographic groups' is used to classify the NHB and NHW groups because they differ on multiple sociodemographic factors.

Associations between environmental and sociocultural factors and pain-related brain regions
Nested linear regression models for ROIs are displayed in Table 2.

Medial prefrontal cortex (MPFC) thickness
The overall models were not statistically significant (p = 0.1304, p = 0.3431, p = 0.2858).In a sensitivity analysis excluding those with imputed variables, models were not significant (p = 0.233, p = 0.454, p = 0.368).In a sensitivity analysis excluding those with imputed variables, findings were similar, however, income was no longer significant.

Discussion
Guided by the NIA and NIMHD Health Disparities Research Frameworks 2,38,39 , the current study aimed to identify the contributions of environmental and sociocultural factors on pain-related brain structures in a sociodemographically diverse group of adults reporting knee pain 41 .As hypothesized, environmental and sociocultural factors were associated with pain-related brain structures.Ethnicity-race remained a small but significant predictor across several models.It is important to note that our study included only a few of the extensive array of environmental and sociocultural factors contributing to health disparities warranting investigation 2 .Findings are presented in alignment with the National Institutes of Health reporting requirements for ethnicity and race, which can provide consistent terminology for comparisons across studies 2,64 .Despite these efforts, significant heterogeneity remains within self-identified ethnicity and race categories.We also incorporate an intersectional approach by providing more specific sociodemographic information for each group which promotes more accurate interpretations and will better inform efforts to improve health for all 63 .

Environmental and sociocultural contributions to structural differences in brain regions associated with pain processing
Associations between experiences of chronic pain and alterations in brain morphology are well-established 28,65,66 .
Our previous publications in the same study sample indicated greater gray matter across cortical and subcortical areas of the brain in the early stages of chronic MSK pain and lesser gray matter with persisting, high stage chronic pain 40,41 .Self-identified ethnicity-race was also identified as a significant predictor.Our previous research in the temporal lobe regions of the brain show socioenvironmental factors explained the sociodemographic group differences observed 36,40 .Our current findings in recognized pain-related regions of the brain are similar.Inclusion of available factors from the NIA and NIMHD Frameworks specific to the environmental and sociocultural levels of analysis/domains of influence help explain the variance observed in pain-related brain structures.Brain function and structure are highly influenced by life experiences [32][33][34][35] .By incorporating available and recognized environmental and sociocultural variables in study models, we begin the process of systematically disentangling and identifying the factors contributing to health-related outcomes at the neurobiological level 2,67,68 .Not surprisingly, age was the strongest and most consistent predictor in all of the models.Age-related changes in pain and brain structure are well recognized 40,41 .Sex differences in brain structures are also well established 30 .Less commonly considered is the cumulative impact of environmental and sociocultural experiences 36 .Our findings show that considering demographic factors (age, sex, ethnicity-race) alone is not sufficient in brain imaging analyses, inclusion of key socioenvironmental factors is also necessary.Further, to advance health disparities research and improve health for all, the heterogeneous classification of ethnicity and race requires additional "intersectional detail" regarding specific sociodemographic descriptions of the self-identified ethnicity-race groups represented.

Strengths, limitations, and future directions
The study benefitted from a large and ethnically diverse sample with data collected from two study sites (Gainesville, Florida and Birmingham, Alabama).Validated instruments and standardized procedures were used where applicable.With brain imaging data on 147 individuals, the sample size extends beyond typical pain and imaging analyses.Additionally, the sociodemographic diversity within our self-reported ethnic-race groups highlights the importance of reporting within group differences to contribute to a more informative "intersectional" understanding of the study samples represented 63 .
There are limitations to acknowledge, as the study is cross-sectional, longitudinal data will improve understanding of the relationships between environmental and sociocultural factors, pain, and pain-related brain structures.Further, participants in the study had knee pain with or at risk for knee OA with many reporting chronic www.nature.com/scientificreports/pain at other body sites.They do not represent individuals with more severe knee OA nor those with primary chronic musculoskeletal pain at other body sites.Additionally, a few of the measures capturing environmental and sociocultural variables were categorical in nature and may not optimally capture the constructs of interest.Additionally, further investigations are needed on the extensive array of factors across different levels of analysis associated with health disparities.Despite limitations in study design and measures, findings provide an important foundation for improving the understanding of the combined influence of environmental, sociocultural, demographic, and pain-related factors on pain-related brain structures.

Conclusions
Disparities in pain-related experiences are well-established.A growing body of evidence indicates the role of environmental and sociocultural factors in contributing to these observed differences.The contributions of environmental and sociocultural factors on pain-related brain structures have been minimally investigated.Our findings show that with inclusion of environmental and sociocultural factors, e.g., education, income, household number, employment, insurance status, social support, and discrimination; a significant proportion of variance within pain-related brain structures is explained.Further investigations of the vast array of additional environmental and sociocultural variables are needed to continue the processes of disentangling and identifying the factors contributing to disparities in health outcomes.Additionally, our study included a balanced representation of NHB and NHW adults.Despite this strength, significant heterogeneity remains even with a combined classification of ethnicity and race 63 .Consistent with an intersectionality theoretical framework, we provide additional sociodemographic descriptions of the self-identified ethnic-race groups represented in our study to improve interpretations and inform research efforts moving forward. https://doi.org/10.1038/s41598-024-58120-9

Table 1 .
Sample characteristics.Between group differences were established using independent samples T-Test (two-tailed), Chi-Sq or Fisher's Exact Test where appropriate.

Table 2 .
Nested linear regression analyses examining environmental and sociocultural factors in relation to ACC thickness