From nociception to pain perception: imaging the spinal and supraspinal pathways

Abstract

Functional imaging techniques have allowed researchers to look within the brain, and revealed the cortical representation of pain. Initial experiments, performed in the early 1990s, revolutionized pain research, as they demonstrated that pain was not processed in a single cortical area, but in several distributed brain regions. Over the last decade, the roles of these pain centres have been investigated and a clearer picture has emerged of the medial and lateral pain system. In this brief article, we review the imaging literature to date that has allowed these advances to be made, and examine the new frontiers for pain imaging research: imaging the brainstem and other structures involved in the descending control of pain; functional and anatomical connectivity studies of pain processing brain regions; imaging models of neuropathic pain-like states; and going beyond the brain to image spinal function. The ultimate goal of such research is to take these new techniques into the clinic, to investigate and provide new remedies for chronic pain sufferers.

Figures

Fig. 1

Descartes’ view of pain, taken from his treatise De l’homme (Descartes, 1644). With great insight, he wrote: ‘If for example fire comes near the foot, minute particles of this fire, which you know move at great velocity, have the power to set in motion the spot of skin on the foot which they touch, and by this means pulling on the delicate thread which is attached to the spot of the skin, they open up at the same instant the pore against which the delicate thread ends, just as by pulling on one end of a rope one makes to strike at the same instant a bell which hangs at the end.’

Fig. 10

Diffusion tensor imaging (DTI) reveals connections between brainstem structures and prefrontal cortex, both of which are known to be involved in descending control of pain. In particular, these data show putative connections between the nucleus cuneiformis (NCF) to ventromedial (vm) and dorsomedial (dm) prefrontal cortex (PFC). Diffusion-weighted EPI images were acquired with 60 diffusion gradient directions on a 1.5-T Siemens Sonata scanner, and are the average of three acquisitions. The processed images are in standard space and were constructed by binarizing the tracts for each subject and adding them together across the group (i.e. to create a frequency map). Voxel values represent the total number of subjects for which tracts pass through that given voxel. Data were processed with FMRIB's diffusion tools (http://www.fmrib.ox.ac.uk/fsl; see also Behrens et al. 2003).

Fig. 2

Schematic representation of the three phases of pain, proposed by Cervero & Laird (1991). Phase 1: an acute phase, with equally short-lived response in the central nervous system (CNS). Phase 2: prolonged noxious stimulation leading to an inflammatory response, and continued discharge of peripheral nociceptors, which in turn lead to changes in excitability of dorsal horn neurons. Phase 3: peripheral nerve damage may lead to spontaneous discharge, which modifies the behaviour of dorsal horn neurons, and allows non-nociceptive peripheral nerves (e.g. brush-sensitive Aβ fibres) access to the ascending pain system. Reproduced with permission from Cervero & Laird (1991).

Fig. 3

Simple schematic of nociceptive pathways from the periphery to supraspinal regions. Black arrows represent transmission of pain signals supraspinally, which is integrated at several levels along the neuroaxis, and at almost every level influenced by descending fibres (grey arrows).

Fig. 4

Cortical areas that receive information from the spinothalamic tract. Main spinothalamic and thalamocortical projections were summarized and simplified from several reports on the central nociceptive pathways in the monkey (see Treede et al. 1999, for references: Vogt et al. 1979; Willis, 1985; Apkarian & Shi, 1994; Craig, 1996). Cortico-cortical connections are not shown. ACC, anterior cingulate cortex; CL, centrolateral nucleus; MDvc, ventrocaudal part of medial dorsal nucleus; Pf, parafascicular nucleus; SI, primary somatosensory cortex; SII, secondary somatosensory cortex; VMpo, posterior part of ventromedial nucleus; VPI, ventral posterior inferior nucleus; VPL, ventral posterior lateral nucleus; VPM, ventral posterior medial nucleus. (Note that the insula is now considered to lie between the lateral and medial systems, since it has both a sensory-discriminative and a cognitive-evaluative role in pain sensation). Reproduced with permission from Treede et al. (1999).

Fig. 5

The clusters of reduced [11C]diprenorphine binding in the patient group in comparison with controls are superimposed on to a magnetic resonance image arrayed in a standard stereotactic space (see Willoch et al. 2004 for reference: Talairach & Tournoux, 1988). Only differences passing the significance threshold of P < 0.006 are displayed. The distance note beneath each slice is distance in relation to the bicommissural line (AC–PC line). Left side of image is contralateral to the painful hemibody side. (Note that the main reductions in opioid receptor binding in the patient group are contralateral to the lesion, and are located in the contralateral posterior thalamus and posterior insula: x = 38, y = −16, z = 14.) Reproduced with permission from Willoch et al. (2004).

Fig. 6

The effect of stimulus lateralization and attention on statistical maps for each experimental condition. RA = attend to pain on right hand, RV = attend to visual stimulus during pain to right hand. L replaces R for experiments with pain delivered to the left hand. The distribution of activation sites is shown on coronal sections taken through the insula and Talairach y-coordinates shown below each image [activated voxels are significant at P (corrected) < 0.05]. Images are displayed using neurological convention, i.e. right is right, left is left. Attended painful stimulation activated more rostral regions of the anterior insula than distracted stimulation (see yellow circles on anterior coronal sections). Also demonstrated is the effect of stimulus laterality on activation of posterior insula cortex (foci of activity are highlighted with coloured circles: right-hand stimulation, red; left-hand stimulation, blue). Posterior insula activity switched sides when the stimulus was transferred from hand to hand and did not depend on the attentional context during stimulation. Reproduced with permission (Brooks et al. 2002).

Fig. 7

Insular cortex. (A) Group-combined activation map showing volumes selectively activated during pain (red) and anticipation of pain (yellow). (B) Individual subject's activation centres during pain (red triangles) and anticipation of pain (black circles). Centres associated with the anticipation of pain (black circles; mean Talairach coordinates x = 40 mm, y = 26 mm, z = 10 mm) were significantly more anterior than those associated with pain (red triangles; mean Talairach coordinates x = 38 mm, y = −1 mm, z = 11 mm) (P < 0.05). (C) Time course of fMRI signal intensity change over the period of the scan averaged across subjects. Epochs related to anticipation of pain are shaded in grey (mean ± SEM). (D) Time course of fMRI signal intensity change over the period of the scan averaged across subjects (mean ± SEM). Epochs of pain are shaded in grey. Reproduced with permission from Ploghaus et al. (1999).

Fig. 8

Pharmacological fMRI. In healthy subjects, the response to painful stimulation during three different infusion rates of the µ-opioid agonist remifentanil was compared with that under saline infusion. Results represent a mixed-effects group analysis (Z > 2.0, cluster corrected P < 0.05), and demonstrate broad activation across the pain matrix during saline infusion (bilateral insula, thalamus, ACC and contralateral S1). With increasing dose of remifentanil we see a progressive reduction in activity throughout the pain matrix. Images are displayed using radiological convention, i.e. left side of images is right side of brain and vice versa.

Fig. 9

Painful thermal stimulation of the C7 dermatome (hand) gives rise to activation in the ipsilateral dorsal portion of the spinal cord. Thermal stimulation was delivered using a block design (30 s off, 30 s on). Images were acquired using a single-shot fast spin-echo pulse sequence, which is shown at the top left. Physiological monitoring of electrocardiogram and respiratory motion allows retrospective correction for movement due to pulsation of CSF in the subarachnoid space (SAS) and for movement of the chest wall. Incorporating this information in the statistical model allows detection of activations unrelated to physiological noise. The statistical map (Z > 1.8, cluster corrected P < 0.05), top right, was obtained by masking the spine and SAS in the image, and has an associated time course shown below.