Pain imaging in health and disease--how far have we come?

Abstract

Since modern brain imaging of pain began 20 years ago, networks in the brain related to pain processing and those related to different types of pain modulation, including placebo, have been identified. Functional and anatomical connectivity of these circuits has begun to be analyzed. Imaging in patients suggests that chronic pain is associated with altered function and structural abnormalities in pain modulatory circuits. Moreover, biochemical alterations associated with chronic pain are being identified that provide information on cellular correlates as well as potential mechanisms of structural changes. Data from these brain imaging studies reinforce the idea that chronic pain leads to brain changes that could have functional significance.

Figure 1. Ascending pain pathways in the human brain.

(A) Schematic representation of ascending pain pathways and brain regions involved in pain processing. (B) The color-coded regions superimposed on an anatomical MRI (coronal slice). Red, S1; orange, S2; green, ACC; light blue, insula; yellow, thalamus; purple, PFC; dark blue, primary motor cortex (M1). SMA, supplemental motor area; PCC, posterior cingulate cortex; BG, basal ganglia; HT, hypothalamus; Amyg, amygdala, PB, parabrachial nuclei. Adapted from European Journal of Pain (7).

Figure 2. Descending pain modulatory pathways that might be involved in psychological modulation of pain.

One pathway involves descending input from the ACC to the PFC and then to the PAG. Another descending pathway arrives at the PAG from the insula via the amygdala. A descending pathway from the PAG through the RVM to the dorsal horn of the spinal cord influences nociceptive afferent transmission. Adapted from Science (8) and Nature Reviews Neuroscience (42).

Figure 3. Clinical pain is shifted in the insula.

(A) Localization of rostral (green) and caudal (blue) anterior insula, as defined in ref. , in the human brain. (B) Peak activations found in imaging studies investigating acute experimental pain in healthy subjects (purple spheres) and clinical pain in patients (black spheres). Clinical pain studies investigated ongoing neuropathic pain, provoked mechanical allodynia in neuropathic pain patients, angina pectoris, cluster headache, or punctate hyperalgesia in CRPS. Clinical pain is located significantly more anterior than acute pain (Mann-Whitney-Wilcoxon test, P < 0.001). (C) The mean localization of anterior insular activation in studies investigating clinical pain (black), acute experimental pain in healthy subjects (purple), interoception (yellow), and anxiety or non-painful stimuli with highly aversive content (red). In addition, cognitive or emotional modulation of acute experimental pain in healthy subjects is depicted (blue). Clinical pain is located as anterior as aversive stimuli or interoception (Mann-Whitney-Wilcoxon tests, P = 0.9 and P = 0.4, respectively). Ellipsoids are relative in size to the standard deviation in the y direction. Coordinates are in MNI standard stereotaxic space. y refers to anterior-posterior (nose to back of the head); z refers to superior-inferior (head to feet). Reproduced with permission from NeuroImage (64). Refer to ref. for a complete list of references.

Figure 4. Localization of gray matter decreases in chronic pain conditions that have been reported for insula (A), ACC (B), and PFC (C) (for references, see text).

Each sphere represents a peak of gray matter decrease. Note that more than one peak per region was included when reported in a study. Coordinates are in MNI standard stereotaxic space. x refers to left-right (negative numbers in the left hemisphere, positive numbers in the right hemisphere). The anterior commissure corresponds to 0 mm in all three directions. In C, gray matter decreases are only depicted if they are located in the PFC, while the yellow volume encompasses all of frontal cortex, including precentral gyrus. Similarly, decreases in supplementary motor area and premotor cortex are not included. The volume for the insula (red) and frontal cortex (yellow) are based on the MNI Structural Atlas (120, 121), thresholded so that every voxel in the volume falls within the respective brain region (insula or frontal cortex) in at least 5% of individuals. The ACC volume (orange) is based on the Harvard-Oxford Cortical Structural Atlas, equally thresholded at 5%. The MNI Structural Atlas and the Harvard-Oxford Cortical Structural Atlas were used as implemented in fslview of the fsl software suite ( http://www.fmrib.ox.ac.uk/fsl). The size of the spheres representing the localization of gray matter decreases is arbitrary.