Fine-Grained Mapping of Cortical Somatotopies in Chronic Complex Regional Pain Syndrome

Abstract

It has long been thought that severe chronic pain conditions, such as complex regional pain syndrome (CRPS), are not only associated with, but even maintained by a reorganization of the somatotopic representation of the affected limb in primary somatosensory cortex (S1). This notion has driven treatments that aim to restore S1 representations in CRPS patients, such as sensory discrimination training and mirror therapy. However, this notion is based on both indirect and incomplete evidence obtained with imaging methods with low spatial resolution. Here, we used fMRI to characterize the S1 representation of the affected and unaffected hand in humans (of either sex) with unilateral CRPS. The cortical area, location, and geometry of the S1 representation of the CRPS hand were largely comparable with those of both the unaffected hand and healthy controls. We found no differential relation between affected versus unaffected hand map measures and clinical measures (pain severity, upper limb disability, disease duration). Thus, if any map reorganization occurs, it does not appear to be directly related to pain and disease severity. These findings compel us to reconsider the cortical mechanisms underlying CRPS and the rationale for interventions that aim to "restore" somatotopic representations to treat pain.SIGNIFICANCE STATEMENT This study shows that the spatial map of the fingers in somatosensory cortex is largely preserved in chronic complex regional pain syndrome (CRPS). These findings challenge the treatment rationale for restoring somatotopic representations in complex regional pain syndrome patients.

Keywords: S1; chronic pain; fMRI; plasticity; somatosensory cortex.

Copyright © 2019 Mancini, Wang et al.

Figures

Figure 1.

Preliminary results that guided the design of the finger mapping protocol. A, Comparable somatotopic representation in the contralateral S1 to unilateral and bilateral finger stimulation, at within-subject level. The map of the fingertips (d2–d5) in contralateral S1 was strikingly similar in a condition in which we stimulated the fingertips of one hand at time and in another condition whereby we stroked homologous fingertips of both hands simultaneously. B, Bootstrapping validation. We validated the results shown in A using a bootstrapping approach. Seven functional runs per condition (unilateral stimulation, bilateral stimulation) were collected in a single participant, in multiple scanning sessions. We selected, both recursively and randomly, 4 runs among the 7 collected per condition and averaged results across these 4 runs to assess intraindividual map reproducibility. The maps of the fingertips were highly reproducible in both unilateral and bilateral stimulation conditions. C, Time course of activity in the left hemisphere during unilateral fingertip stimulation. Percent modulation of BOLD response in the left S1 induced by periodic stimulation of the fingertips of the right hand and left hand. We did not observed a spatially tuned activation of the left S1 induced by left-hand stimulation.

Figure 2.

A, Phase-encoded stimulation procedure. The tip of the index finger (red, d2), middle finger (green, d3), ring finger (blue, d4), and little finger (yellow, d5) was stimulated in succession, in repeated cycles (12 cycles per run). To reduce scanning time, the homologous fingers of the right and left hands were stimulated simultaneously. B, Illustrative phase-encoded response to periodic fingertip stimulation. The figure shows the raw BOLD response in four voxels of interest (thin lines; data were motion-corrected and the linear trend removed). The locations of the voxels are marked with a star on the cortical surface of the left primary somatosensory cortex of 1 participant. Thicker lines indicate the average of the raw BOLD response across 12 cycles of stimulation. The vertical, dashed, white line is displayed to facilitate the visualization of the shift of the phase of the BOLD response across the four voxels. The F statistics of the signal at different phases are rendered on the inflated cortical surface and color-coded as in A (cluster-corrected p < 0.01). Phases corresponding to rest have been truncated.

Figure 3.

Phase maps of the hand in an illustrative control participant and 3 CRPS patients. Top, Color-coding scheme: red represents d2; green represents d3; blue represents d4; yellow represents d5. Phases corresponding to rest have been truncated. Statistical thresholding and cluster correction at p < 0.01 were applied to each individual-participant data. CS, Central sulcus. Star represents the map of the CRPS hand.

Figure 4.

Surface-based average of phase maps in controls, patients with CRPS to the right hand, and patients with CRPS to the left hand. The complex valued mapping data were averaged in a spherical surface coordinate system after morphing each subject's data into alignment with an average spherical sulcal pattern, and the F statistics were rendered back onto an average unfolded cortical surface (Freesurfer's fsaverage, inflated_average; uncorrected p < 0.05 only for illustration). Top, The color-coding scheme is as follows: red represents d2; green represents d3; blue represents d4; yellow represents d5. Phases corresponding to rest have been truncated. CS, Central sulcus; PoCS, postcentral sulcus.

Figure 5.

Area of the hand map in S1. The area of the hand map (in mm2) in the left hemisphere and right hemisphere is plotted for each group and individual participant. To facilitate comparison, data from the two CRPS groups (right hand CRPS, left hand CRPS) were pooled, after flipping the data from one group (right hand CRPS) so that the affected side is always the left hand/right hemisphere in all patients.

Figure 6.

A, B, Spatial distribution of map centroids. The location of the centroid of the hand map in each individual subject is displayed on an average spherical cortical surface. White cross represents an arbitrary reference point on the central sulcus. C, Geodesic distance (in millimeters) between each map centroid and a reference point (+) on the central sulcus. To facilitate comparison, data from the two CRPS groups (right hand CRPS, left hand CRPS) were pooled, after flipping the data from one group (right hand CRPS) so that the affected side is the left hand/right hemisphere in all patients.

Figure 7.

A, Gradients of the hand map. Gradients of a single-subject phase map are displayed as cyan arrows over a flattened (2D) cortical surface patch. The gradient points in the direction of the greatest rate of increase of the function (i.e., the direction of the phase shift in the hand map). Color-coding scheme of the hand map is as follows: red represents d2; green represents d3; blue represents d4; yellow represents d5. B, Variability of hand map gradients. The circular variance of map gradient directions is displayed for each participant and condition (side: left hemisphere, right hemisphere; group: controls, CRPS patients). Bottom, The color-coding scheme. To facilitate comparison, data from the two CRPS groups (right hand CRPS, left hand CRPS) were pooled, after flipping the data from one group (right hand CRPS) so that the affected side is the left hand/right hemisphere in all patients.