Representation of cold allodynia in the human brain--a functional MRI study

Cold allodynia, meaning that innocuous cold stimuli become painful, is a characteristic, but enigmatic feature of neuropathic pain. Here, we used functional magnetic resonance imaging (fMRI) and investigated brain activations underlying menthol-induced cold allodynia. 12 healthy volunteers were investigated using a block-design fMRI approach. Firstly, brain activity was measured during application of innocuous cold stimuli (at 5 degrees C above cold pain threshold) and noxious cold stimuli (at 5 degrees C below cold pain threshold) to normal skin of the forearm using a peltier- driven thermostimulator. The stimuli were adjusted to the individual cold pain threshold. Secondly, cold allodynia was induced by topical menthol and cortical activations were measured during previously innocuous cold stimulation (i.e. cold pain threshold +5 degrees C), that were then perceived as painful. On a numeric rating scale for pain (0-10) innocuous cold, cold pain and cold allodynia were rated to 0.9+/-0.3, 4.1+/-0.3 and 4.5+/-0.5, respectively. Sensory and affective components of allodynic and cold pain were equal in the McGill pain questionnaire. All tested conditions (innocuous cold, noxious cold and cold allodynia) led to significant activations of bilateral insular cortices, bilateral frontal cortices and the anterior cingulate cortex. When noxious cold and innocuous cold were compared, noxious cold contributed significantly more to activations of the posterior insula and innocuous cold contributed more to activations of ipsilateral anterior insular cortex. However, comparing cold allodynia and equally intense cold pain conditions, we found significantly increased activations in bilateral dorsolateral prefrontal cortices (DLPFC) and the brainstem (ipsilateral parabrachial nucleus) during cold allodynia. Furthermore, in contrast maps cold allodynia contributed significantly more to activations of the bilateral anterior insula, whereas the contribution to activation of the contralateral posterior insula was equal. It is concluded that cold allodynia activates a network similar to that of normal cold pain but additionally recruits bilateral DLPFC and the midbrain, suggesting that these brain areas are involved in central nociceptive sensitisation processes.