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Research Paper

Chronic noncancer pain is not associated with accelerated brain aging as assessed by structural magnetic resonance imaging in patients treated in specialized outpatient clinics

Sörös, Petera,b,*; Bantel, Carstenb,c

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doi: 10.1097/j.pain.0000000000001756
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1. Introduction

Chronic pain is conceptualized as pain lasting beyond regular tissue healing time without the warning and protection function of physiological nociception.92 Chronic pain is a major health care problem affecting approximately 20% of the adult population14 and is associated with changes in cognitive and emotional processing,15 such as impairments of executive functions,9 difficulties with attention,68 and number processing,87,99 as well as an increased risk of depression.14

Although the neurophysiology of nociception is well known, the pathophysiology of chronic pain is far from evident. Acute nociceptive input quickly reshapes neural circuits on the level of the peripheral and central nervous system, such as the C fiber,55 the spinal dorsal horn,10 and the sensorimotor cortex.26,86

In several types of chronic pain, structural alterations of the brain have been demonstrated, starting with the observation that prefrontal and thalamic gray matter was decreased in chronic back pain patients.4 A decrease of gray matter has also been found in patients with chronic tension-type headache,80 migraine,78,95 episodic cluster headache,1 irritable bowel syndrome,27,83 osteoarthritis,44 and chronic complex regional pain syndrome.41 By contrast, other studies found increased gray matter in patients with chronic back pain (basal ganglia and thalamus),79 rheumatoid arthritis (basal ganglia),98 and chronic vulvar pain (hippocampus, parahippocampal gyrus, and basal ganglia).82

In coordinate-based quantitative meta-analyses across various types of chronic pain, several cortical and subcortical areas of decreased and increased gray matter were identified.17,84 In a smaller number of studies, changes in cerebral white matter have also been investigated.52 In patients with chronic musculoskeletal pain, lower fractional anisotropy, indicating impaired integrity of white fiber tracts, has been found in the corpus callosum and the cingulum.57

The functional significance of gray and white matter changes in patients with chronic pain is still unresolved.84 Whether these changes are cause or consequence76 of chronic pain and whether they represent predisposing factors or compensatory neuroplasticity63 is under debate. Moreover, the neuropathological substrates of these changes are not firmly established. Animal research suggests that rapid changes in synaptic spines and glia cells, as well as neuronal loss and, conversely, neurogenesis contribute to macroscopic changes in chronic pain.54

A decrease of total and regional gray matter is one of the hallmarks of brain aging, even in the absence of brain disease.35,88 Previously, 2 publications suggested that patients with chronic pain due to fibromyalgia and temporomandibular disorder experience accelerated or premature brain aging.53,67 Very recently, a study on elderly (>60 years) adults concluded that the brains of participants with chronic pain seemed older compared to participants without pain, based on an established machine learning approach.23 Here, we test the hypothesis that patients with chronic noncancer pain demonstrate accelerated brain aging, compared to healthy participants, using T1-weighted structural MR images and machine learning,18 in a sample of 119 participants aged between 30 and 68 years.

2. Methods

2.1. Participants

This study analyzes structural T1-weighted MR images obtained from 119 participants of the ChroPain187 and ChroPain2 studies. The combined sample comprises 59 participants with chronic noncancer pain and 60 participants free of chronic pain. Patients for ChroPain1 (n = 36) were recruited from the Pain Outpatient Clinic, University Clinic of Anesthesiology, Critical Care, Emergency Medicine, and Pain Management, Klinikum Oldenburg, located in Oldenburg, Germany. Additional patients were found through advertisements in the local daily newspaper. Patients for ChroPain2 (n = 23) were recruited at a specialized rheumatology practice in Oldenburg, Germany (Dr Markus Voglau,, and through the local ankylosing spondylitis support group. For every patient with chronic pain, a sex- and age-matched (±5 years) pain-free control participant was recruited. Control participants for ChroPain1 (n = 37) and ChroPain2 (n = 23) were identified with the help of the local newspaper, the University of Oldenburg's web page, flyers, and personal communication.

For the definition of chronic pain, we used a purely temporal definition, following the suggestions of the International Association for the Study of Pain Classification of Chronic Pain.93 The International Association for the Study of Pain defines chronic pain as pain that lasts or recurs for >3 months.93 Because we hypothesized that structural and functional changes of the brain will be more pronounced in patients with longer pain duration, we extended the minimum duration of pain to 12 months in our study. Inclusion criterion for the pain group was thus persistent pain on most days of a month for ≥12 months of mild to severe intensity. This was ascertained by reviewing clinical notes and through direct patient interviews.

Exclusion criteria for the chronic pain and the healthy control groups were as follows: neurological disorders (such as dementia, Parkinson disease, stroke, epilepsy, multiple sclerosis, traumatic brain injury, and migraine), psychiatric disorders (such as schizophrenia or major depression), substance abuse, impaired kidney or liver function, and cancer. Since some of the cognitive tests applied in the ChroPain studies depend on cultural background,87 only participants born and raised in Germany were included.

All participants provided written informed consent for participation in one of the studies. A compensation of 10 € per hour was provided. Both studies were approved by the Medical Research Ethics Board, University of Oldenburg, Germany (# 25/2015; 2017-059). ChroPain2 has been preregistered with the German Clinical Trials Register (; DRKS00012791).

2.2. Demographic and clinical data

In a structured interview, every participant was asked for the date of birth, sex, handedness, and highest degree of formal education. In addition, previous and present conditions that may lead to an exclusion from the study and complete medication records were inquired. Smoking and alcohol consumption were also recorded.

Chronic pain patients were asked to estimate the average pain intensity that they had perceived during the last 24 hours before the magnetic resonance imaging (MRI) examination by using the 11-point numerical rating scale, with 0 representing “no pain” and 10 “worst pain imaginable.”13 In addition, pain duration in years was noted.

2.3. Verbal intelligence

A standardized German vocabulary test (Wortschatztest, WST) was used to assess verbal intelligence.81 Participants were required to identify, in each of the 42 rows, an existing German word within 5 nonwords. The number of correct choices was transformed into IQ scores according to the test manual.81 WST results are highly correlated with level of education and general intelligence.77

2.4. Depression

The short German version (Allgemeine Depressionsskala, ADS-K)45 of the Center for Epidemiological Studies Depression Scale74 was used to quantify depressive symptoms. The scale consists of 15 items assessing depressive symptoms during the preceding week. Each item is answered on a 4-point Likert scale: “never or rarely” (<1 day), “sometimes” (1-2 days), “often” (3-4 days), and “always” (5-7 days of the week). The total score ranges from 0 to 45. A score of ≥ 18 supports the diagnosis of a clinically relevant depression.45

2.5. Magnetic resonance imaging

All MR images were acquired on a research-only Siemens MAGNETOM Prisma (Siemens, Erlangen, Germany) whole-body scanner at 3 T with a 64-channel head/neck coil. The scanner is located at the Neuroimaging Unit, School of Medicine and Health Sciences, University of Oldenburg, Germany. A 3-dimensional T1-weighted MPRAGE sequence was used.12 Imaging parameters for ChroPain1 were: TR: 2000 ms, TE: 2.4 ms, voxel dimensions: 0.7 × 0.7 mm2, slice thickness: 0.9 mm, 208 axial slices. Imaging parameters for ChroPain2 were: TR: 2000 ms, TE: 2 ms, voxel dimensions: 0.75 × 0.75 mm2, slice thickness: 0.75 mm, 320 axial slices. Both sequences used in-plane acceleration (GRAPPA) with a PAD factor of 2.59 Siemens prescan normalization filter was used in both sequences for on-line compensation of regional signal inhomogeneities.50

2.6. Brain age prediction

MR images were first converted from Siemens DICOM format to uncompressed NIfTI (.nii) format using dcm2niix ( Structural MR images were then analyzed with the software brainageR (version 1.0, 09 August 2018;,21 For additional methodological details, see the Supplementary Information in Cole et al. 2017 and 2018.20,21

brainageR uses SPM12 (University College London, London, United Kingdom; for image preprocessing. Using SPM12's Segment function,7 images were bias-field corrected and segmented into gray matter, white matter, and cerebrospinal fluid. Gray matter and white matter images were nonlinearly registered to a custom template, derived from the training data set (see below), using SPM12's DARTEL toolbox.5 Using FSL's slicesdir script (, default slices in sagittal, coronal, and axial directions were created for the segmented and normalized brain images. With these images, visual quality control was performed to ensure accurate image segmentation (Fig. 1).

Figure 1.:
Original T1-weighted MR images (A and D), preprocessed gray matter (B and E), and preprocessed white matter images (C and F) of a 30-year-old (upper row) and a 66-year-old pain-free control participant (lower row). Original images are in individual space, and preprocessed images were normalized to a brain template. Preprocessed gray and white matter images were then vectorized and concatenated for brain age prediction.

The individual segmented and normalized images were loaded into R ( and vectorized. Gray and white matter vectors were combined. Brain age was then predicted with a Gaussian processes regression75 using R's kernlab (kernel-based machine learning lab) package (version 0.9-27; and the previously learned regression model.

The brainageR model was trained on 2001 healthy individuals from several publicly available data sets. The following studies contributed more than 200 T1-weighted images each: the Information Extracted from Medical Images (IXI) database (, the International Consortium for Brain Mapping study (,66 and the Open Access Series of Imaging Studies (OASIS-1; For details about all studies used for the training data set, see Supplementary Information in Cole et al. 2017 and 2018.20,21 For further statistical analysis, brain age delta was calculated (predicted brain age minus chronological age).

2.7. Statistical analyses

To check for normality, a Shapiro–Wilk test was performed. To check for equality of variances, a Levene test was done. To compare the mean values of brain age delta in both groups, a traditional independent-samples Welch t test was performed30; statistical significance was set at P < 0.05. We also performed a subgroup analysis with patients and controls aged 60 years and older using Welch t test. In addition, a Bayesian independent-samples t test was calculated to compare the mean values of brain age delta in both groups using the default Cauchy prior centered on zero and with r = 0.707.61 To compare further characteristics of the chronic pain and the pain-free control group (Table 1), the Welch t test (for continuous data) and Pearson χ2 test (for categorical data) were performed.

Table 1:
Demographic and clinical characteristics of participants with and without chronic pain.

To study the association between chronic pain and brain age delta, controlling for the influences of chronological age and sex, multiple linear regression analysis was calculated with group (chronic pain patients vs pain-free controls), age, and sex as regressors (Table 2). To study the association between pain duration and brain age delta within the group of chronic pain patients, controlling for pain intensity, age, and sex, another multiple linear regression analysis was calculated with pain duration, pain intensity, age, and sex as regressors (Table 3). In both analyses, bootstrapped confidence intervals for the regression coefficients were calculated (10,000 replications, α = 0.05). A regression coefficient is regarded to be statistically significant if the confidence interval does not include zero.

Table 2:
Summaries of multiple linear regression analysis and relative weight analysis for chronic pain predicting brain age delta, adjusting for age and sex, in all participants (n = 119).
Table 3:
Summaries of multiple linear regression analysis and relative weight analysis for pain duration predicting brain age delta, adjusting for pain intensity, age, and sex, in patients with chronic pain (n = 59).

As regressors may be correlated, a relative weight analysis47 was performed to supplement multiple linear regression. Relative weight analysis decomposes the total variance predicted in a regression model (R2) into weights that reflect the proportional contribution of the included regressors.90 To test for statistical significance, bootstrapped confidence intervals for relative weights were calculated (10,000 replications, α = 0.05). A weight is considered to be statistically significant if this confidence interval does not contain zero.91

For statistical testing (except relative weight analysis), JASP version 0.10.2 ( was used.60 Relative weight analysis was performed using RWA-WEB (, a web-based interface for a program written in R.73

Individual brain age delta data ( and the results of statistical analysis ( have been published at the Open Science Framework.

3. Results

3.1. Demographic, clinical, and neuropsychological data

Demographic, clinical, and neuropsychological characteristics of the pain-free control group and the chronic pain group are presented in Table 1. Both groups were carefully matched for chronological age and sex. Formal education was significantly different between both groups, with chronic pain patients having lower levels of education. Moreover, verbal IQ was on average significantly lower in the pain group. Depression scores on the German version of the Center for Epidemiological Studies Depression were significantly higher in the pain group. Smoking habits were not significantly different between chronic pain patients and pain-free controls. Regular alcohol consumption (at least one alcoholic drink on most days of the week) was significantly more common in chronic pain patients (80%) than in pain-free controls (67%). All participants were Caucasians born and raised in Germany.

All patients with chronic pain were seen in a specialized pain clinic or by a specialist in rheumatology on a regular basis. In the chronic pain group, mean pain duration was 16 ± 11 years. On average, chronic pain patients reported a moderate level of pain (5 ± 2 on the numerical rating scale) during the 24 hours preceding the MRI. In the ChroPain1 study, the primary pain diagnoses were degenerative spinal disease (n = 22), degenerative joint disease (n = 5), abdominal pain (n = 2), and fibromyalgia (n = 7). In the ChroPain2 study, the primary pain diagnoses were rheumatoid arthritis (n = 11), ankylosing spondylitis (n = 9), psoriasis arthritis (n = 2), and CREST syndrome (n = 1). Patients of the ChroPain1 study, primarily recruited through a specialized pain clinic, received mainly opioid and nonopioid analgesics and antidepressants. Patients of the ChroPain2 study, suffering from rheumatic disease, took primarily disease-modifying antirheumatic drugs and biologics and, to a lesser extent, nonsteroidal anti-rheumatic drugs or steroids.

3.2. Association between chronological age and brain age

Figure 2A illustrates the relationship between the chronological age of each participant and the brain age predicted by brainageR (red: chronic pain patients, blue: pain-free controls).

Figure 2.:
(A) Relationship between chronological age and predicted brain age. Blue circles represent pain-free control participants (n = 60), and red circles represent patients with chronic pain (n = 59). (B) Brain age delta (predicted brain age minus chronological age) for pain-free controls (blue) and patients with chronic pain (red). The error bars symbolize mean ± SD.

3.3. Comparison of brain age delta between groups

Figure 2B shows the distribution of brain age delta in the pain-free control and chronic pain groups. The results of the Shapiro–Wilk test did not suggest deviation from normality in neither group (W = 0.983, P = 0.543 for the control group; W = 0.967, P = 0.104 for the chronic pain group). The Levene test suggested equality of variances (F = 2.227, P = 0.138). Group mean values of brain age delta were not significantly different (Welch independent-samples t test; t (111.1) = 0.333, P = 0.74, Cohen's d = 0.061).

A Bayesian independent-samples t test indicated moderate evidence in favor of the null hypothesis (BF01 = 4.875; Fig. 3).

Figure 3.:
(A) Bayesian independent samples t test for the effect size δ. The dashed line illustrates the prior distribution (default Cauchy prior centered on zero, r = 0.707), the solid line shows the posterior distribution. The 2 gray dots indicate the prior and posterior density at the test value. The probability wheel on top visualizes the evidence that the data provide for the null hypothesis (H0: effect sizes are equal) and the alternative hypothesis (auburn, H1: effect sizes are different). The median and the 95% central credible interval of the posterior distribution are shown in the top right corner. (B) The Bayes factor robustness plot. The plot indicates the Bayes factor BF01 (in favor of the null hypothesis) for the default prior (r = 0.707), a wide prior (r = 1), and an ultrawide prior (r = 1.414). All priors suggest moderate evidence for the null hypothesis, which is relatively stable across a wide range of prior distributions. Plots taken from JASP; the reporting of the results follows van Doorn et al.96

In a separate analysis that included only participants aged 60 years and above, mean brain age delta was −6.2 ± 7.9 years in pain-free participants (n = 16) and −8.7 ± 5.7 years in chronic pain patients (n = 14; Welch t test, P = 0.327, Cohen's d = 0.362).

3.4. Association between brain age delta and chronic pain and pain duration

A multiple linear regression was calculated for group predicting brain age delta, while adjusting for age and sex (n = 119, Table 2). In the traditional regression and in the relative weight analysis, the association between group and brain age delta was not significant.

In the group of chronic pain patients (n = 59), another multiple linear regression was calculated for pain duration predicting brain age delta, adjusting for pain intensity, age, and sex (Table 3). In the traditional regression and in the relative weight analysis, the association between pain duration and brain age delta was not significant.

4. Discussion

This study of 59 chronic noncancer pain patients and 60 healthy, age- and sex-matched controls with a mean age of 53 years provided no evidence for the hypothesis that chronic pain is associated with accelerated brain aging. In fact, a Bayesian independent-samples t test provided moderate evidence for the null hypothesis (ie, group mean values were equal).

Physiological aging is characterized by an inevitable—but also highly variable—decline in cognitive, motor, and sensory functions and also by changes of gray and white matter structure.71 In cross-sectional studies of healthy aging, voxel-based morphometry6 and surface-based morphometry25 have demonstrated a decrease of cortical gray matter density89 and thickness,34 predominantly in prefrontal and temporal areas. In addition, changes of white matter fiber tracts, as assessed by diffusion tensor imaging, have been investigated across age span. In a longitudinal study on participants aged between 50 and 90 years at baseline and with a follow-up after 2 years, a decline of white matter integrity was seen throughout the brain.8

In recent years, several approaches have been developed to determine the degree of physiological or pathological aging of individual adults by predicting individual brain age.19–21,39,56,58,97 These studies have used individual structural MR images of the brain, large MRI training data sets of healthy individuals, and machine learning methods to compare individual brains with the training data (for reviews, see Refs. 18,38). The results of these studies have been shown to be accurate and reliable.18 Accelerated brain aging has been demonstrated in patients with Alzheimer's disease,37 after traumatic brain injury,19 in HIV-positive individuals,22 and in psychiatric disease, such as schizophrenia, major depression, and borderline personality disorder.51 These methods are able to successfully predict conversion from mild cognitive impairment to Alzheimer's disease.40 Moreover, in a group of 669 elderly participants with a mean age of 73 years (the Lothian Birth Cohort 193628), increased brain age delta was associated with decreased physical fitness (weaker grip strength, poorer lung function, and slower walking speed), lower fluid intelligence, and increased mortality risk.21

Of note, brain age delta results derived by these methods are age dependent; brain age of younger participants is overestimated and brain age of older participants is underestimated.56 This inherent bias is driven by a regression toward the age mean of the training data set because the error in the regression model is not orthogonal to age.56,85 This explains why mean brain age delta was approximately −5 years in both groups of our study, where most participants were older than 40 years. Because we recruited a thoroughly age-matched control group for our chronic pain patients, this underestimation of individual brain age does not weaken our conclusion that individual brain age is similar in chronic pain patients and in pain-free controls.

Very recently, Cruz-Almeida and coworkers published a comparison of brain age delta between 33 elderly individuals with chronic pain (mean age: 70.6 ± 5.5 years) and 14 individuals without chronic pain (mean age: 71.5 ± 7.3 years). Although the mean predicted brain age was smaller than the chronological brain age in both groups (P = 0.592), participants with chronic pain had a larger brain age delta after adjustment for chronological age, sex, and exercise levels (analysis of covariance, F [1, 41] = 4.9; P = 0.033).23 There are major differences between Cruz-Almeida et al.'s study and our study. Importantly, our study is characterized by a considerably larger sample size (119 vs 47 participants), a younger age (the majority of participants are between 30 and 60 years of age), and a longer pain duration (15.9 ± 11 vs 6.3 ± 8.8 years). Comparing only participants aged 60 years or older in our sample did not result in a significant difference of brain age delta between groups and did not provide evidence for the notion that chronic pain accelerates brain aging in seniors only. Of note, Cruz-Almeida et al. investigated community dwelling individuals representative of the aging population, who were not necessarily treated for chronic pain. When comparing brain age delta between participants who received treatment for pain (including self-remedies) during the preceding 3 months and those who had no treatment, brain age delta was significantly smaller in the treatment group, ie, the brains of participants seeking treatment seemed younger.23 In Cruz-Almeida et al.'s study, brain age delta of participants without chronic pain (−4.0 ± 1.9 years) and participants with chronic pain seeking treatment (−3.9 ± 1.5 years) was very similar. These results closely resemble the findings in our study, where all patients with chronic pain received specialized care.

Our results have important implications for the pathogenesis of structural alterations of the brain and, ultimately, cognitive deficits in patients with chronic pain. Our results suggest that chronic pain does not induce widespread neural and glial degeneration, presumably the leading cause of age-related structural brain changes.69 By contrast, our results indirectly support recent alternative models of regional, network-specific structural and functional brain alterations in chronic pain.17,33 These models also suggest that the frequently observed cognitive deficits in chronic pain are the direct consequence of persistent nociceptive input, mediated by the aforementioned network-specific structural and functional changes, rather than the result of generalized accelerated aging of the brain.

Unfortunately, neuroimaging of the human brain, at least at 3 T, does not allow to identify the molecular or cellular mechanisms of chronic pain. Growing evidence predominantly from animal studies, however, suggests that inflammation of the central and peripheral nervous system contributes to the development of chronic pain and that novel anti-inflammatory therapies may improve chronic pain.16,46,100 Basic research for instance has shown that neuropathic pain is characterized by an ongoing neuroinflammation and is associated with the release of proinflammatory cytokines, such as interleukin 1β.3,29 Interestingly, healthy aging is also commonly associated with inflammation in the central nervous system.31 Several studies have reported elevated levels of inflammatory cytokines in the brains of aged rodents.43,62,101 Because aging seems to be associated with systemic augmentation of inflammation as well,36 it has been hypothesized that circulating inflammatory mediators prime microglia in the aging brain.32,65,70,72 These neuroinflammatory findings in chronic pain and in aging may suggest that both conditions share pathogenetic mechanisms on the molecular and cellular level.

Our study has important limitations. Chronic pain patients included here had heterogeneous diagnoses and were taken from 2 related, but separate studies. In particular, the effect of rheumatic diseases, generalized autoimmune disorders, on the brain is not well understood.48,98 Moreover, although we were able to match for age and sex, chronic pain patients and pain-free controls differed in terms of education, verbal IQ, depressive symptoms, and alcohol consumption. These differences reflect lower levels of education11 and higher incidence of depression14,24,94 of individuals with chronic pain observed in the general population.

Our study sample was also relatively young with a mean age of 53 years. We cannot rule out the possibility that pain-related changes of the brain mainly develop in higher age, eg, because of a decrease in brain plasticity and an impaired capacity to adapt to disease-specific structural changes. We performed a subgroup analysis with 16 pain-free participants and 14 chronic pain patients aged 60 years and older, and could not find significant differences in brain age delta. Due to the small sample sizes and the heterogeneity of both groups, this analysis has to be interpreted with caution.

Because all our patients received specialized medical care, we were unable to compare our results with chronic pain patients who do not seek treatment. In future studies, the relationship between chronic pain, brain morphology, medical treatment, and motivation for treatment should be investigated in greater detail. In addition, future studies should relate the extent of physical activity and exercise, which may relieve pain and improve pain-related functional impairments,2,42 to changes of brain morphology.

Conflict of interest statement

The authors have no conflicts of interest to declare.


A previous version of this article has been published through the biorxiv preprint server (

The authors thank Dr James Cole, King's College London, London, United Kingdom, for his help with setting up the brainageR software and interpreting the results. The authors also thank Katharina Koch and Melanie Spindler for their active support of the ChroPain1 and ChroPain2 studies, including recruitment, data acquisition, and data analysis. The authors are grateful for the help of Dr Markus Voglau and his team and of Mara Schier and the Selbsthilfegruppe Morbus Bechterew Oldenburg during recruitment for the ChroPain2 study. The authors also thank Katharina Grote and Gülsen Yanc for assisting with MRI data acquisition. The authors appreciate the very constructive comments by two anonymous reviewers and by Kathryn Beard on the manuscript. This work was supported by the Neuroimaging Unit, University of Oldenburg, funded by grants from the German Research Foundation (DFG; 3T MRI INST 184/152-1 FUGG and MEG INST 184/148-1 FUGG). The ChroPain1 study was also funded by an intramural grant from the School of Medicine and Health Sciences, University of Oldenburg, to C. Bantel (Forschungspool, 2015-1).


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    Chronic pain; Musculoskeletal disorders; Rheumatic disease; Magnetic resonance imaging; Brain structure; Gray matter; White matter; Aging

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