Differential fMRI Activation Patterns to Noxious Heat and Tactile Stimuli in the Primate Spinal Cord

Abstract

Mesoscale local functional organizations of the primate spinal cord are largely unknown. Using high-resolution fMRI at 9.4 T, we identified distinct interhorn and intersegment fMRI activation patterns to tactile versus nociceptive heat stimulation of digits in lightly anesthetized monkeys. Within a spinal segment, 8 Hz vibrotactile stimuli elicited predominantly fMRI activations in the middle part of ipsilateral dorsal horn (iDH), along with significantly weaker activations in ipsilateral (iVH) and contralateral (cVH) ventral horns. In contrast, nociceptive heat stimuli evoked widespread strong activations in the superficial part of iDH, as well as in iVH and contralateral dorsal (cDH) horns. As controls, only weak signal fluctuations were detected in the white matter. The iDH responded most strongly to both tactile and heat stimuli, whereas the cVH and cDH responded selectively to tactile versus nociceptive heat, respectively. Across spinal segments, iDH activations were detected in three consecutive segments in both tactile and heat conditions. Heat responses, however, were more extensive along the cord, with strong activations in iVH and cDH in two consecutive segments. Subsequent subunit B of cholera toxin tracer histology confirmed that the spinal segments showing fMRI activations indeed received afferent inputs from the stimulated digits. Comparisons of the fMRI signal time courses in early somatosensory area 3b and iDH revealed very similar hemodynamic stimulus-response functions. In summary, we identified with fMRI distinct segmental networks for the processing of tactile and nociceptive heat stimuli in the cervical spinal cord of nonhuman primates. Significance statement: This is the first fMRI demonstration of distinct intrasegmental and intersegmental nociceptive heat and touch processing circuits in the spinal cord of nonhuman primates. This study provides novel insights into the local functional organizations of the primate spinal cord for pain and touch, information that will be valuable for designing and optimizing therapeutic interventions for chronic pain management.

Keywords: MRI; hand; monkey; pain; touch.

Figure 1.

Experimental set up for fMRI of the cervical spinal cord in anesthetized monkeys at 9.4 T. A, T2-weighted middle sagittal MRI image (taken from a different imaging session with a volume coil) shows visualization of cervical spinal afferent bundles (white stripes) and the imaging field of view (white outline box) over the cervical spinal cord. D, Dorsal; V, ventral; R, rostral; C, caudal. B, Sagittal view of the spinal cord on a MTC image. Ventral roots are apparent as white bundle strips (labeled as C4–C7). Five white rectangular outlines show the placements of five axial images. C, Four coronal images taken through the dorsal (two red outlined images) and ventral (two light blue outliend images) parts of the spinal cord across both DHs and VHs. Placements of the four coronal images over the DHs and VHs are shown on the first axial image in F. GM of spinal horns appeared as two vertical higher intensity white strips on coronal images. The superintense white strips on outer layers of the spinal cord represent space filled with CSF. Cervical dorsal and ventral nerve roots (C4–C7) are visible as horizontal hyperintensity stripes residing between signal void (s) and highlighted by white arrows. D, Aligned coronal section of spinal cord tissue stained with CTB. The rectangular black line box indicates the location of CTB terminal labeling resulting from tracer injections into distal pads of digits 2 and 3. White pinholes on the opposite side represent landmarks made on the centers of C5–C7 dorsal afferents entry zones on the surface of the spinal cord. R, Right; L, left; R, rostral; C, caudal. The schematic hand insert shows the injection sites of CTB tracer on the distal finger pads of digits 2 and 3 of a right hand. E, Schematic illustration shows the spatial relationships between the dorsal nerve roots and the digit afferent terminals determined by tracer injections (for original data, see Florence et al., 1991; Qi et al., 2011). Black dots indicate the pinholes locations. F, One set of five representative anatomical axial MTC images. Unlabeled scale bars, 1 mm. R, Right; L, left; D, dorsal; V, ventral. Slices 1–5, Rostral to caudal. G, Aligned MTC anatomical (top), fMRI (middle), and the overlap (bottom) images. Red outlines in the overlap image represent the fMRI boundaries of butterfly-shaped GM and spinal cord. Blue lines indicate a corresponding alignment landmark.

Figure 2.

Representative fMRI activations to tactile and nociceptive heat stimulation of two distal finger pads in three monkeys (SM-K, SM-C, and SM-B). A, Single-run fMRI activations to tactile stimulation of two distal finger pads on right hands. B, C, Multirun average fMRI activations to tactile stimulation of two distal finger pads on right (B) and left (C) hands. D–F, Multirun average fMRI activations to 47.5°C nociceptive heat stimulation of two distal finger pads on right (D, E) and left (F) hands. Hand inserts show the locations of stimulation. All activation maps are thresholded at p < 0.05 for multirun and p < 0.01 for single run with FDR corrected; see color scale bar on image 5 for the t value range. Images 1–5, From caudal to rostral. Scale bars, 1 mm. D, Dorsal; V, ventral; L, left; R, right.

Figure 3.

Comparison of locations of fMRI responses to tactile versus nociceptive heat stimuli in the iDH. A, Cross-run (multirun) probability map of 47.5°C nociceptive heat-evoked activations in the iDH to stimulation of digits 2 and 3 on the left in one representative monkey. 4/4, Four of four runs. B, Corresponding cross-run probability map of tactile stimulation evoked activations in the same monkey. C, Overlay map of the cross-run heat and tactile activations. D, Cross-subjects (multisub) probability map of heat activations in the iDH. 5/5, Five of five subjects. E, Corresponding cross-subject probability map of tactile activations. F, Overlay map of the cross-subject heat and tactile activations. Red and green lines indicate the outlines of heat and tactile activation clusters, respectively. Yellow outlines represent the outer boundaries of the GM. Dotted white lines indicate the approximate borders of interlaminar segments within the DH. Scale bars, 1 mm.

Figure 4.

Group comparisons of fMRI response magnitudes in different parts of the spinal matter within a single spinal segment. A, C, Time courses of fMRI signal changes to unilateral tactile (A) and nociceptive heat (C) stimulation of two distal finger pads in the iDH, cDH, iVH, and cVH and one WM control region. Color lines and shadows indicate mean ± SE of the percentage fMRI signal changes. The red lines near the x-axis show the stimulation periods of 30 s for tactile and 22 s for heat, respectively. B, D, Statistical comparisons of the peak magnitudes of fMRI signal changes during tactile (B) and nociceptive heat (D) stimulation across different intraslice horn and WM regions. Each bar represents the percentage of fMRI signal changes as mean ± SE. *p < 0.05; ***p < 0.005; ****p < 0.001.

Figure 5.

Comparisons of the HRFs between the spinal DH and somatosensory area 3b (A, B) and heat and tactile (C, D) stimulation. A, B, Mean fMRI time courses (dotted color lines) and the corresponding two gamma fitting curves (solid color lines) in tactile (A) versus nociceptive heat (B) stimulation conditions. Yellow shadows indicate the durations of stimulation. C, D, Normalized and fitted fMRI time courses to tactile (blue lines) versus heat (red lines) stimulation in area 3b (C) and DH (D). Note that the durations for heat and tactile stimuli are different. Area 3b fMRI time courses reported previously (Chen et al., 2007) were used in this comparison.

Figure 6.

Spatial distributions of the magnitudes of fMRI responses to tactile versus heat stimuli in different horns and the control WM across spinal segments (image slices) along the cord. A, C, Distributions of fMRI responses magnitudes across image slices 1–5 during tactile (A) versus nociceptive heat (C) stimulation in different ROIs (four horns and one WM). B, D, Magnitudes of the fMRI responses across different ROIs (four horns and one WM) as a function of image slices 1–5 during tactile (B) versus nociceptive heat (D) stimulation. Signal magnitude is presented as mean percentage signal change + SE. *p < 0.05; **p < 0.01; ***p < 0.005; ****p < 0.001. Slices 1–5, Caudal to rostral.

Figure 7.

Schematic summary of the differential activation patterns to tactile (A) versus nociceptive heat (B) stimulation within and across spinal segments. Dark color cones indicate responses are statistically significant.