Individuals who suffer from long-term pain not only process pain differently, but also present with structural brain changes. Relatively recently, researchers have begun to apply diffusion-weighted imaging techniques, including DTI, to study white matter alterations in the brains of chronic pain patients. Geha and colleagues (17
) found decreased diffusion directionality (fractional anisotropy) in the cingulum of patients with complex regional pain syndrome (CRPS), which might possibly indicate decreased tract myelination or reduced parallel fiber organization. Fewer white matter connections were found to originate in the patients from this spot of altered diffusion compared with control subjects. Further, the ventral medial PFC, an area of decreased gray matter, showed an altered anatomical connectivity pattern, adding further evidence to impaired white matter connectivity in the CRPS patients of this study (17
). Some clinical significance of decreased diffusion directionality was provided by a study in fibromyalgia patients that demonstrated a relationship between decreased fractional anisotropy in the thalamocortical tract and the degree of stiffness (82
). Schmitz and colleagues assessed the concentration of white matter in migraine patients, rather than investigating diffusion properties of white matter (83
). They found that patients with a high attack frequency had decreased white matter concentration of frontal and parietal areas (83
), perhaps indicating that migraine attacks lead to white matter damage.
In contrast to the scarcity of studies investigating white matter, gray matter alterations in chronic pain patients have been frequently studied in recent years, and this literature supports the hypothesis that pain or prolonged nociceptive input leads to structural alterations. Although it might seem likely that different pain conditions are associated with unique sets of structural alterations, such comparative data are not yet available. Seemingly similar gray matter changes have been described across different chronic pain conditions, including fibromyalgia, migraine, or osteoarthritis. Consequently, we do not differentiate between etiologies in the following discussion. Regarding the direction of structural alterations, decreases in gray matter dominate the picture, although some studies have reported an increased concentration of gray matter, either exclusively (84
) or alongside gray matter decreases (85
). Decreases have mainly been described for important pain processing or modulatory regions such as the ACC, IC, thalamus, and frontal cortex (17
) as well as the (para-)hippocampus, which is thought to be particularly vulnerable to the effects of stress (82
) (Figure ). Several studies observed greater gray matter decreases with longer pain duration (17
), which might indicate that gray matter decreases are a consequence of living with pain, at least in these instances. The concept of pain or prolonged nociceptive input leading to decreased gray matter is supported by two lines of evidence. First, two longitudinal studies in patients (one study following successful hip replacement for osteoarthritis [ref. 95
], the other after spontaneous resolution of post-traumatic headache [ref. 85
]) suggest that gray matter concentrations return to baseline levels when the pain disappears. Second, a longitudinal MRI study in a rat model of neuropathic pain (spared nerve injury) demonstrated the occurrence of prefrontal gray matter alterations several months after pain induction by surgery (104
). This study provides another very interesting piece of information: the gray matter alterations in the PFC coincided with the development of anxiety-like behavior (104
), emphasizing behavioral consequences of prolonged pain states. Although the mechanisms underlying gray matter alterations in chronic pain are currently unknown, a recently conducted study suggests a possibility. DaSilva and colleagues observed that reduced thickness of sensorimotor cortex in patients with trigeminal neuralgia was co-localized with activation related to provocation of their dynamic mechanical allodynia (105
). This suggests that excessive nociceptive input might lead to gray matter reductions. This would be similar to the neurotoxicity hypothesis of depression (reviewed in ref. 106
), which postulates that an interaction between elevated levels of circulating glucocorticoids and excitatory neural activity is a major factor in long-term cerebral atrophy. However, it should be emphasized that conventional MRI cannot determine the histopathology underlying gray matter changes, including the affected cell type. Therefore, gray matter alterations demonstrated in chronic pain could be caused by changes in neuronal elements such as dendrites or synapses, glial cells, or even blood vessels or water content. To advance our understanding of the nature of gray matter alterations, future studies will have to complement anatomical MRI with other imaging techniques. One magnetic resonance–based technique that can be used to yield complementary information is proton magnetic resonance spectroscopy (1
H-MRS exploits the fact that the resonance frequency of a proton is influenced by its exact biochemical environment, meaning that the signals from individual metabolites can be differentiated. Metabolites that can be measured using this technique include the neuronal marker N-acetyl-aspartate (NAA) (107
), choline-containing compounds, which indicate membrane turnover and cellular density, and glutamate/glutamine. Studies using this technique in the context of pain are described below.
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).