The brain in chronic CRPS pain: abnormal gray-white matter interactions in emotional and autonomic regions

Abstract

Chronic complex regional pain syndrome (CRPS) is a debilitating pain condition accompanied by autonomic abnormalities. We investigated gray matter morphometry and white matter anisotropy in CRPS patients and matched controls. Patients exhibited a disrupted relationship between white matter anisotropy and whole-brain gray matter volume; gray matter atrophy in a single cluster encompassing right insula, right ventromedial prefrontal cortex (VMPFC), and right nucleus accumbens; and a decrease in fractional anisotropy in the left cingulum-callosal bundle. Reorganization of white matter connectivity in these regions was characterized by branching pattern alterations, as well as increased (VMPFC to insula) and decreased (VMPFC to basal ganglion) connectivity. While regional atrophy differentially related to pain intensity and duration, the strength of connectivity between specific atrophied regions related to anxiety. These abnormalities encompass emotional, autonomic, and pain perception regions, implying that they likely play a critical role in the global clinical picture of CRPS.

Figure 1. Whole-brain cortical gray volume and white matter anisotropy show distinct properties in CRPS as compared to matched healthy controls

(A) Skull normalized, neocortical gray matter volume in healthy (left) and CRPS patients (right) shown as a function of age. (B) Whole-brain fractional anisotropy (mean FA calculated over individual subjects' white matter skeleton), a global measure of water diffusion over white matter tracks, in relation to whole-brain neocortical gray matter volume. The significant correlation between the two measures in healthy subjects is absent in CRPS. * p < 0.05; ** p < 0.01.

Figure 2. Brain regional gray matter density is decreased in CRPS, most prominently in the younger patients, and related to pain characteristics

(A) Voxel-based morphometry (VBM) comparison between CRPS and matched healthy control subjects indicates decreased density within a single cluster in the right hemisphere (red), spanning the ventromedial prefrontal cortex (VMPFC), anterior insula (AI), and nucleus accumbens (arrows) (n = 22 per group; p < 0.05 corrected). The scatter plot shows that this decreased gray matter density is negatively correlated to the number of years the patients have been living with CRPS. Individual control healthy subjects are shown at pain duration = 0. The histogram depicts mean (± SEMs) gray matter density within the cluster in both groups. (B, C) Subdividing the cluster to its anatomic components, right VMPFC and right AI, shows that each region differentially related to CRPS pain characteristics: right VMPFC gray matter density negatively correlated to the interaction between pain intensity and pain duration (b); while right AI gray matter density only correlated to pain duration (c). (D) Subdividing the groups into young and old, and performing VBM contrast between CRPS and healthy controls for each sub-grouping shows that decreased gray matter density in young CRPS patients was localized to the same cluster as in the whole population. In the young subjects (n = 11 per group), a statistically significant decrease in gray matter density was observed (cluster p-value = 0.012; cluster size = 4.5 cm³) with peak atrophy at right AI [coordinates, 28, 18, -12; t-value = 5.18, p = 0.02]. Gray matter density extracted from this cluster was significantly different between the groups (p < 10^-5), and showed a negative correlation with pain intensity scores (visual analog scale, 0-10). Whole-brain VBM contrast in the older sub-grouping was not significant. However, gray matter density extracted from the cluster derived from the young was significantly decreased (p<0.02) but not correlated to pain intensity in the older CRPS group. Individual control healthy subjects are shown at pain intensity = 0, and their mean gray matter density is indicated by a dashed lines. * p < 0.05; *** p < 10 ^-5. R = right.

Figure 3. Decreased regional anisotropy and connectivity in CRPS as compared to matched healthy controls

(A) Contrasting FA (tested over the entire white matter skeleton, green) between CRPS and matched controls (n = 21 per group) indicates decreased FA in CRPS, localized to a portion of the left callosal fibers (purple, shown in different orientations and magnifications; p < 0.05 corrected). The histogram depicts mean FA (± SEMs) for the two groups, for the white matter region showing decreased FA. (B) Population maps of results of probabilistic tractography when the white matter region showing decreased FA was used as the seed. Each color scale represents the population probability of a voxel belonging to the pathway tracked from the seed; voxels present in 33% (7/21, an arbitrary threshold used only for visualizing connectivity differences) of the population are shown. The tract traversing posteriorly in the healthy subjects belongs to the cingulum bundle and seems diminished in the CRPS patients. (C) Quantitative differences in probabilistic connections and branching pattern for the pathway tracked from the seed (purple in a) are shown separately for left and right hemispheres. Group averaged number of connections (± SEMs) as a function of Euclidean distance shows that long distance connections in CRPS are only less in the hemisphere ipsilateral to the seed (left). First histogram shows total number of connections from the seed, and second histogram (thinner bars) the fractal dimension D_f of branching of connections (mean ± SEMs). Both measures were significantly decreased in CRPS, again only in the hemisphere ipsilateral to the seed. *p < 0.05 ** p < 0.01. R = right; L = left.

Figure 4. Gray matter decreased density in the right VMPFC is associated with reorganization of white matter connections in CRPS

Probabilistic maps of white matter tracts (A), connections as a function of distance, total connections and fractal dimension (histograms are mean ± SEMs) (B), and individual target connectivity (C) are depicted, when the portion of right VMPFC exhibiting decreased gray matter density is used as the seed. (A & B) Ipsilateral connectivity is reduced mainly at long distances, while some regional connectivity and fractal dimension are increased contralaterally. (C) In CRPS, target connectivity (examined only ipsilateral to the seed) is significantly higher to the insula (Ins) and lower to the basal ganglion (BG), but unchanged to the thalamus (Thal), primary somatosensory cortex (SI) and visual cortex (Vis) (medians and quartiles are shown). The colored brain masks illustrate the seed and targets used in connectivity calculations. * p < 0.05; *** p < 10 ^-5.

Figure 5. Decreased gray matter density in the right anterior insula is associated with reorganization of white matter connections in CRPS

Probabilistic maps of white matter tracts (A), connections as a function of distance, total connections, and fractal dimension (histograms are mean ± SEMs) (B), and individual target connectivity (C) are depicted, when the portion of right insula exhibiting decreased gray matter density is used as a seed. (A & B) Total ipsilateral connectivity and fractal dimension are reduced in CRPS, although there are also increased connections at specific distances. Contralateral connectivity is minimal from this seed. (C) In CRPS, target connectivity is only reduced to the basal ganglia (medians and quartiles are shown). * p < 0.05; ** p < 10 ^-3.