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The Journal of Neuroscience, November 5, 2008, 28(45):11642-11649; doi:10.1523/JNEUROSCI.2638-08.2008

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Behavioral/Systems/Cognitive
Identifying Brain Activity Specifically Related to the Maintenance and Perceptual Consequence of Central Sensitization in Humans

Michael C. Lee,^1,2 Laura Zambreanu,¹ David K. Menon,² and Irene Tracey¹

¹Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB), Department of Clinical Neurology and Nuffield Department of Anaesthetics, University of Oxford, Oxford OX3 9DU, United Kingdom, ²Department of Medicine, Division of Anaesthesia, University of Cambridge, Cambridge CB2 2QQ, United Kingdom

Correspondence should be addressed to Dr. Michael C. Lee, Centre for Functional Magnetic Resonance Imaging of the Brain, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK. Email: mlee{at}fmrib.ox.ac.uk

Central sensitization (CS) refers to an increase in the excitability of spinal dorsal horn neurons that results from, and far outlasts the initiating nociceptive input. Here, functional magnetic resonance imaging was used to examine whether supraspinal activity might contribute to the maintenance of CS in humans. A crossover parametric design was used to distinguish and control for brain activity that is related to the consequence of increased pain experienced during CS. When the intensity of pain during CS and normal states were matched, only activity within the brainstem, including the mesencephalic pontine reticular formation, and the anterior thalami remained increased during CS. Further analyses revealed that activity in the isolated brainstem area correlated positively with the force of noxious stimulation only during CS, whereas activity in the isolated thalamic area was not modulated parametrically in either CS or normal states. Additionally, the mean activity in the isolated brainstem area was increased only during CS, whereas the mean activity in the isolated thalamic area was increased in both states, albeit less so in the normal state. Together, these findings suggest a specific role of the brainstem for the maintenance of CS in humans. Regarding brain areas related to the consequence of increased pain perception during CS, we found that only cortical activity, mainly in the primary somatosensory area, was significantly correlated with intensity of pain that was attributable to both the force of noxious stimulation used and state in which noxious stimulation was applied.

Key words: central sensitization; pain; hyperalgesia; capsaicin; fMRI; brainstem

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Received June 9, 2008; revised Sept. 9, 2008; accepted Sept. 23, 2008.

Correspondence should be addressed to Dr. Michael C. Lee, Centre for Functional Magnetic Resonance Imaging of the Brain, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK. Email: mlee{at}fmrib.ox.ac.uk

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