Spinal cord-midbrain functional connectivity is related to perceived pain intensity: a combined spino-cortical FMRI study

Abstract

The dynamic interaction between ascending spinocortical nociceptive signaling and the descending control of the dorsal horn (DH) by brain regions such as the periaqueductal gray matter (PAG) plays a critical role in acute and chronic pain. To noninvasively investigate the processing of nociceptive stimuli in humans, previous fMRI studies either focused exclusively on the brain or, more recently, on the spinal cord. However, to relate neuronal responses in the brain to responses in the spinal cord and to assess the functional interplay between both sites in normal and aberrant conditions, fMRI of both regions within one experiment is necessary. Employing a new MRI acquisition protocol with two separate slice stacks, individually adapted resolutions and parameter settings that are dynamically updated to the optimized settings for the respective region we assessed neuronal activity in the spinal cord and in the brain within one measurement at 3 T. Using a parametric pain paradigm with thermal stimulation to the left radial forearm, we observed BOLD responses in the ipsilateral DH of the spinal segment C6 and corresponding neuronal responses in typical pain-processing brain regions. Based on correlations of adjusted time series, we are able to reveal functional connectivity between the spinal C6-DH and the thalamus, primary somatosensory cortex, bilateral insula, bilateral striatum, and key structures of the descending pain-modulatory system such as the PAG, the hypothalamus, and the amygdala. Importantly, the individual strength of the spinal-PAG coupling predicted individual pain ratings highlighting the functional relevance of this system during physiological pain signaling.

Keywords: PAG; fMRI; functional connectivity; pain; spinal cord.

Figure 1.

BOLD responses to painful thermal stimulation in the brain. A, BOLD responses corresponding to the high-intensity thermal condition exhibit a typical pattern of pain-sensitive brain regions including thalamus, SI, SII, insula, ACC, striatum, and the midbrain. B, During the low thermal intensity condition a similar but much weaker pattern exists. C, The pain-specific contrast high-intensity stimulation > low-intensity stimulation reveals the same pattern of brain regions constituting the pain network in the brain. Percentage signal changes (PSCs) were extracted from peak voxels of the respective contrast. Error bars indicate SE. For a complete list of brain areas, see Table 1. No significant BOLD responses were observed for the contrast low intensity > high intensity. The color bars indicate t values, and the visualization threshold is set to p < 0.005. x, y, and z indicate MNI coordinates. A, anticipation; L, low-intensity thermal stimulation; H, high-intensity thermal stimulation; V, visual analog scale rating; Fron, middle frontal gyrus; Ins, insular cortex; Mid, midbrain.

Figure 2.

BOLD responses to painful thermal stimulation in the spinal cord. A, Brainstem and spinal portions of the average structural image, with the blue line indicating the spinal level of the transverse section in B and C, and with the red line (1 mm below) indicating the spinal level of the transverse section in D. The level corresponds to the segment C6. B, C, Pain-related BOLD responses during the high-intensity (B) and low-intensity (C) thermal stimulation thresholded at p < 0.05 and p < 0.005 uncorrected for multiple comparisons. Responses are located ipsilateral to the side of stimulation in the deeper sections of the DH of the spinal segment C6. D, BOLD responses that are significantly stronger during the high-intensity thermal stimulation compared with the low thermal intensity stimulation were observed in the superficial layers of the spinal cord ipsilateral to the side of stimulation. E, Spatial relationship between significantly activated voxels and substructures of the spinal cord. Clusters in the left part of the image are overlaid on the mean structural MEDIC image; the right part of the image shows an individual normalized MEDIC image to illustrate substructures of the spinal cord. While we observed BOLD responses to the high-intensity thermal stimulation (blue) in central portions of the spinal cord at the transition of the DH to the ventral horn, responses that are significantly stronger during high-intensity stimulation compared with low-intensity stimulation (red) were located in the outer layers of the DH close to the Lissauer tract. The visualization threshold is set to p < 0.05 corrected for multiple comparisons. For illustration purposes both clusters are projected into one section. Blue refers to the spinal level indicated by the blue line in A, and red refers to the spinal level indicated by the red line in A. F, Spinal cord anatomy: (1) central canal, (2) ventral horn, (3) dorsal horn, (4) Lissauer tract, (5) dorsal root, (6) ventral root, (7) CSF. G, H, Percentage signal changes (PSCs) were extracted from the peak voxel of the high thermal intensity stimulation contrast (G) and the high > low thermal intensity stimulation contrast (H). The color bars indicate t values. Error bars indicate SE. A, anticipation; L, low-intensity thermal stimulation; H, high-intensity thermal stimulation; V, visual analog scale rating.

Figure 3.

Functional connectivity between the spinal DH and the brain based on adjusted time series correlations. A, Based on the seed voxel in the spinal cord determined by the high-intensity > low-intensity contrast, functional coupling is observed between the C6-DH and the SI, SII, the bilateral insula, striatum, PAG/midbrain, bilateral amygdala, and hypothalamus. B, Positive correlation between the individual mean pain rating and the individual strength of functional connectivity in the PAG. The scatter plot is obtained from the peak of the overlap between the area showing a positive correlation of behavioral ratings and connectivity strength and the area showing a significant connectivity with the spinal DH as such. The visualization threshold is set to p < 0.005, uncorrected for multiple comparisons. The color bars indicate t values. Error bars indicate SE. PE, parameter estimates; Hypoth, hypothalamus; Amg, amygdala; Put, putamen; Ins, Insula.

Figure 4.

Spinal level of the main effect of pain in three independent fMRI studies that used the same site of stimulation. A, Eippert et al., 2009 (green), Sprenger et al., 2012 (red), and the current study (blue) applied painful thermal stimuli with a Peltier thermode to the left radial forearm. The y and z coordinates of the “main effect of pain” activation are shown overlaid on the single subject T1 image that was used for the normalization procedure in these studies. B, For illustration purposes the slightly different x-coordinates were projected into the median sagittal plane.