Brainstem, thalamus, and cortex: FMRI evidence for midbrain reticular formation involvement in a human model of neuropathic pain

Abstract

Hyperalgesia (often associated with neuropathic pain) is the clinical manifestation of plastic changes in pain processing. It can be evident at the site of injury - primary hyperalgesia – or outside it – secondary hyperalgesia. Our aim was to investigate the neural correlates of punctate mechanical secondary hyperalgesia. We used the heat/capsaicin sensitization model (45°C thermal stimulus followed by topical application of 0.075% capsaicin) to induce secondary hyperalgesia on the anteromedial surface of the lower legs in 12 healthy volunteers. We used whole-brain, high field (3T) functional magnetic resonance imaging (fMRI) to look at the brain activation elicited by mechanical stimulation with a 26 gram von Frey filament (254.8 mNewtons, 0.546 mm diameter) in the area of secondary hyperalgesia and compared it with the response to stimulation of normal, untreated skin, in the same subjects in a different session. Following heat/capsaicin treatment, all subjects developed an area of secondary hyperalgesia. The paired test between the brain activation maps in response to punctate stimulation of the secondary hyperalgesia area and the respective activation maps to control site stimulation showed activation in the cerebellum, the midbrain periaqueductal gray (PAG) and nucleus cuneiformis (NCF), the thalamus bilaterally, the left secondary somatosensory cortex (SII) and the left primary somatosensory cortex (SI), the anterior and posterior cingulate cortices, the right middle frontal gyrus, the right inferior parietal and right precuneus. Animal studies have established role for the rostral ventromedial medulla (RVM) in the development and maintenance of central sensitization and secondary hyperalgesia. The PAG and the NCF are the major source of input to the RVM and therefore in a position to modulate its output. We believe this is the first evidence in humans for a role of the NCF and PAG in secondary hyperalgesia.