Neuroimaging revolutionizes therapeutic approaches to chronic pain

Abstract

An understanding of how the brain changes in chronic pain or responds to pharmacological or other therapeutic interventions has been significantly changed as a result of developments in neuroimaging of the CNS. These developments have occurred in 3 domains : (1) Anatomical Imaging which has demonstrated changes in brain volume in chronic pain; (2) Functional Imaging (fMRI) that has demonstrated an altered state in the brain in chronic pain conditions including back pain, neuropathic pain, and complex regional pain syndromes. In addition the response of the brain to drugs has provided new insights into how these may modify normal and abnormal circuits (phMRI or pharmacological MRI); (3) Chemical Imaging (Magnetic Resonance Spectroscopy or MRS) has helped our understanding of measures of chemical changes in chronic pain. Taken together these three domains have already changed the way in which we think of pain - it should now be considered an altered brain state in which there may be altered functional connections or systems and a state that has components of degenerative aspects of the CNS.

Figure 1

Summary of Changes in Neural Function following Nerve Injury. In the Normal State, such as the response to noxious heat (left panel), the pain system provides salient information on the nature of the stimulus, the context of the stimulus, and the emotional response to the stimulus. In the chronic pain state, for example after nerve injury (right panel), changes occur along the neural axis. In the peripheral nerve there may be loss of fibers (1), changes in function of neurons in the dorsal root ganglion (2), and alterations in the dorsal horn (3). In the central nervous system, there are changes in dorsal horn (non-afferent inputs) as well as changes in sensory processing (e.g., hyperalgesia (3 and 5)) and emotional processing (5). These changes also result in an alteration of descending modulatory influences (4) from a number of central nervous system structures (e.g., cingulate, frontal cortex, amygdala etc). The constellation of changes in peripheral and central nervous systems result in changes to the pain intensity during spontaneous and evoked pain, and emotional processing (e.g., altered reward or hedonic state) that may lead to changes in comorbid disease in chronic pain (e.g., depression or anxiety).

Figure 2

Examples of CNS Functional Measures. A. Schematic of cortical areas involved with pain processing. The highlighted areas summarize areas found active in previous functional imaging studies. Color-coding reflects the hypothesized role of each area in processing the different psychological dimensions of pain. Numbers in parentheses indicate the relative involvement of these areas during different temporal stages of the pain experience. Areas displayed include insula, anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), primary somatosensory cortex (SI), secondary somatosensory cortex (SII), inferior parietal lobe (Inf. Par), dorsolateral prefrontal cortex (DLPFC), pre-motor cortex (Pre-Mot), orbitofrontal cortex (OFC), medial prefrontal cortex (Med. PFC), posterior insula (P. Ins), anterior insula (A. Ins), hippocampus (Hip), entorhinal cortex (Ento). [Reprinted with permission from Casey and Tran, 2006]. For examples of brainstem involvement in pain processing, please refer to Tracey and Iannetti ([52]). B. Example of fMRI responses to painful phasic thermal stimulation to the forehead in a cohort of 12 subjects. (Moulton et al., unpublished observations).

Figure 3

Schematic Examples of CNS Structural Changes. Red circles signify decreased gray matter density relative to controls. A. Subjects with chronic back pain show decreases in gray matter density in bilateral dorsolateral prefrontal cortex (DLPFC) and right anterior thalamus (adapted from [25]). B. Patients with fibromyalgia show decreases in cingulate cortex (CC), medial prefrontal cortex (Med. PFC), parahippocampal gyrus (PHG) and insula (adapted from [27]). 3-D surface renderings were created using Freesurfer.

Figure 4

Example of chemical measures. The relative concentration of neurotransmitters, such as glutamate (Glu) and glycine (Gly), can be measured using MRS. Here, an in vivo proton MRS spectrum focused on the thalamus is displayed in a patient with chronic pain.