Brainstem pain control circuitry connectivity in chronic neuropathic pain

2018 
Preclinical investigations have suggested that altered functioning of brainstem pain modulation circuits may be crucial for the maintenance of some chronic pain conditions. Whilst some human psychophysical studies show that patients with chronic pain display altered pain modulation efficacy, it remains unknown if brainstem pain modulation circuits are altered in individuals with chronic pain. The aim of the present investigation was to determine whether, in humans, chronic pain following nerve injury is associated with altered on-going functioning of the brainstem descending modulation systems. Using resting-state functional magnetic resonance imaging (fMRI), we found that male and female patients with chronic neuropathic orofacial pain show increased functional connectivity between the rostral ventromedial medulla (RVM) and other brainstem pain modulatory regions, including the ventrolateral periaqueductal grey (vlPAG) and locus coeruleus. We also identified an increase in RVM functional connectivity with the region that receives orofacial nociceptor afferents, the spinal trigeminal nucleus. In addition, the vlPAG and locus coeruleus displayed increased functional connectivity strengths with higher brain regions including the hippocampus, nucleus accumbens and anterior cingulate cortex in individuals with chronic pain. These data reveal that chronic pain is associated with altered on-going functioning within the endogenous pain modulation network. These changes may underlie enhanced descending facilitation of processing at the primary synapse resulting in increased nociceptive transmission to higher brain centres. Further, our findings show that higher brain regions interact with the brainstem modulation system differently in chronic pain, possibly reflecting top-down engagement of the circuitry alongside altered reward processing in pain conditions. SIGNIFICANCE STATEMENT Experimental animal models and human psychophysical studies suggest that altered functioning of brainstem pain modulation systems contributes to the maintenance of chronic pain. However, the function of this circuitry has not yet been explored in humans with chronic pain. In this study, we report that individuals with orofacial neuropathic pain show altered functional connectivity between regions within the brainstem pain modulation network. We suggest that these changes reflect largely central mechanisms that feed back onto the primary nociceptive synapse and enhance the transfer of noxious information to higher brain regions, thus contributing to the constant perception of pain. Identifying the mechanisms responsible for the maintenance of neuropathic pain is imperative in order to develop more efficacious therapies.
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