ABSTRACT: Inherited erythromelalgia (IEM) is a chronic pain disorder caused by gain-of-function mutations of peripheral sodium channel Nav1.7, in which warmth triggers severe pain. Little is known about the brain representation of pain in IEM. Here we study two subjects with the IEM Nav1.7-S241T mutation using functional brain imaging (fMRI). Subjects were scanned during each of five visits. During each scan, pain was first triggered using a warming boot and subjects rated their thermal-heat pain. Next, the thermal stimulus was terminated and subjects rated stimulus-free pain. Last, subjects performed a control visual rating task. Thermal-heat induced pain mapped to the frontal gyrus, ventro-medial prefrontal cortex, superior parietal lobule, supplementary motor area, insula, primary and secondary somato-sensory motor cortices, dorsal and ventral striatum, amygdala, and hippocampus. Stimulus-free pain, by contrast, mapped mainly to the frontal cortex, including dorsal, ventral and medial prefrontal cortex, and supplementary motor area. Examination of time periods when stimulus-free pain was changing showed further activations in the valuation network including the rostral anterior cingulate cortex, striatum and amygdala, in addition to brainstem, thalamus, and insula. We conclude that, similar to other chronic pain conditions, the brain representation of stimulus-free pain during an attack in subjects with IEM engages brain areas involved in acute pain as well as valuation and learning.
