**4. Functional magnetic resonance imaging (fMRI) and chronic pain**

Functional magnetic resonance imaging (fMRI) was first used in the area of pain in order to demonstrate the brain areas responsible for pain perception and part of the pain "neuromatrix" [28]. Subsequently, differences in the structure and function of pain patients compared with healthy controls have been observed through fMRI of experimental pain in both groups [29]. Chronic pain patients show similar activation but with a decrease in thalamic and ACC activation. Activity in the prefrontal cortex (PFC) typically shows an increase in clinical pain conditions. This preferential activation of PFC in chronic pain conditions advocates that chronic pain states have stronger cognitive-evaluative aspect of pain [16].

As well as functional changes, structural changes have been observed through MRI in patients experiencing long-term pain. Chronic pain patients are found to show neuronal loss in significant pain pathways including the thalamus and the lateral prefrontal cortex [30]. Fibromyalgia, a patient group with a particularly complex range of sensorimotor symptoms, shows gray matter loss in the DLPFC [31], and this is believed to be consistent across different chronic pain patient groups. For instance, patients with chronic lower back pain also show reductions in gray matter in distributed regions of the pain "neuromatrix," including DLPFC. This decrease in gray matter also occurs in prolonged pain states in the general population as well as clinical groups [32], and on resolution of persistent pain, for instance when a patient with knee osteoarthritis (OA) undergoes knee arthroplasty, gray matter levels increase in parallel.

fMRI has also been used to demonstrate the effectiveness of neuromodulatory interventions, as well as the scope of the effect of stimulation. For instance, functional connectivity changes were observed in a group of neuropathic pain patients who had undergone SCS. After implantation, decreased connectivity was found between somatosensory and limbic areas of the brain, showing how central changes can be mediated by SCS [28]. Studies using combined NIBS/fMRI may provide interesting insights on the effect of neuromodulation protocols on changes in functional connectivity of the pain neuromatrix as has been done in other treatment interventions [33].
