White matter involvement in chronic musculoskeletal pain

Abstract

There is emerging evidence that chronic musculoskeletal pain is associated with anatomic and functional abnormalities in gray matter. However, little research has investigated the relationship between chronic musculoskeletal pain and white matter. In this study, we used whole-brain tract-based spatial statistics and region-of-interest analyses of diffusion tensor imaging data to demonstrate that patients with chronic musculoskeletal pain exhibit several abnormal metrics of white matter integrity compared with healthy controls. Chronic musculoskeletal pain was associated with lower fractional anisotropy in the splenium of the corpus callosum and the left cingulum adjacent to the hippocampus. Patients also had higher radial diffusivity in the splenium, right anterior and posterior limbs of the internal capsule, external capsule, superior longitudinal fasciculus, and cerebral peduncle. Patterns of axial diffusivity (AD) varied: patients exhibited lower AD in the left cingulum adjacent to the hippocampus and higher AD in the anterior limbs of the internal capsule and in the right cerebral peduncle. Several correlations between diffusion metrics and clinical variables were also significant at a P < .01 level: fractional anisotropy in the left uncinate fasciculus correlated positively with total pain experience and typical levels of pain severity. AD in the left anterior limb of the internal capsule and left uncinate fasciculus was correlated with total pain experience and typical pain level. Positive correlations were also found between AD in the right uncinate and both total pain experience and pain catastrophizing. These results demonstrate that white matter abnormalities play a role in chronic musculoskeletal pain as a cause, a predisposing factor, a consequence, or a compensatory adaptation.

Perspective: Patients with chronic musculoskeletal pain exhibit altered metrics of diffusion in the brain's white matter compared with healthy volunteers, and some of these differences are directly related to symptom severity.

Keywords: Diffusion tensor imaging (DTI); chronic pain; neuroimaging; white matter.

Figure 1

Coronal (left) and axial view (right) of tract-based spatial statistical (TBSS) analysis of radial diffusivity (RD) differences between chronic musculoskeletal pain patients and healthy control participants, at the level of the thalamus. A large cluster of higher RD contained fibers of the corpus callosum, right super longitudinal fasciculus, right anterior and posterior limbs of the internal capsule, and right external capsule adjacent to the insular cortex. Clusters are significant at a level of p<0.05 after correcting for multiple comparisons using threshold-free cluster enhancement (TFCE).

Figure 2

Coronal (left) and axial view (right) of tract-based spatial statistical (TBSS) analysis of radial diffusivity (RD) differences between chronic musculoskeletal pain patients and healthy control participants, at the level of the thalamus. Cluster of higher RD contained fibers of the splenium of corpus callosum, right super longitudinal fasciculus, right cingulum bundle adjacent to the hippocampus, and right cerebral peduncle. Clusters are significant at a level of p<0.05 after correcting for multiple comparisons using threshold-free cluster enhancement (TFCE).

Figure 3

Comparison of mean FA values extracted from specific pain-related cognitive, limbic, and sensory tracts between chronic musculoskeletal pain patients and healthy volunteers. Contrasts designated with an asterisk were significant at a level of p<0.05 after correcting for both age and gender. Errors bars signify the stander errors of the means. Abbreviations: L = left, R = right, Splen = splenium of corpus callosum, AIC = anterior limb of internal capsule, CP = cerebral peduncle, Cing = cingulum bundle, Cing_Hipp = temporal lobe branch of cingulum bundle adjacent to hippocampus, EC = external capsule, PIC = posterior limb of internal capsule, SLF = superior longitudinal fasciculus, Unc = uncinate fasciculus, Whole = whole brain.

Figure 4

Comparison of mean RD values extracted from specific pain-related cognitive, limbic, and sensory tracts between chronic musculoskeletal pain patients and healthy volunteers. Contrasts designated with an asterisk were significant at a level of p<0.05 after correcting for both age and gender. Errors bars signify the stander errors of the means. Abbreviations: L = left, R = right, Splen = splenium of corpus callosum, AIC = anterior limb of internal capsule, CP = cerebral peduncle, Cing = cingulum bundle, Cing_Hipp = temporal lobe branch of cingulum bundle adjacent to hippocampus, EC = external capsule, PIC = posterior limb of internal capsule, SLF = superior longitudinal fasciculus, Unc = uncinate fasciculus, Whole = whole brain.

Figure 5

Comparison of mean AD values extracted from specific pain-related cognitive, limbic, and sensory tracts between chronic musculoskeletal pain patients and healthy volunteers. Contrasts designated with an asterisk were significant at a level of p<0.05 after correcting for both age and gender. Errors bars signify the stander errors of the means. Abbreviations: L = left, R = right, Splen = splenium of corpus callosum, AIC = anterior limb of internal capsule, CP = cerebral peduncle, Cing = cingulum bundle, Cing_Hipp = temporal lobe branch of cingulum bundle adjacent to hippocampus, EC = external capsule, PIC = posterior limb of internal capsule, SLF = superior longitudinal fasciculus, Unc = uncinate fasciculus, Whole = whole brain

Figure 6

Exploratory correlational relationships between FA and clinical measures. FA in the left uncinate fasciculus positively correlated with both (A) TOPS total pain experience and (B) MPQ typical pain rating.

Figure 7

Exploratory correlational relationships between AD and clinical measures. AD in the left uncinate anterior limb od internal capsule positively correlated with both (A) TOPS total pain experience and (B) MPQ typical pain rating, as did AD within the left uncinate fasciculus (C, D). AD within the right uncinate fasciculus also positively correlated with both (E) Pain Catastrophizing Scale score and (F) MPQ typical pain rating.