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.
Highlights
Chronic pain is a burden to subjects and society
The results reported here were obtained during a double-blind cross-over study where the efficacy of carbamazepine was assessed in each of the two subjects with Inherited erythromelalgia (IEM) carrying the
Pain ratings collected during thermal heat stimulation were used in a general linear model (GLM) analysis to identify the corresponding brain activity (Fig. 1a)
Summary
Chronic pain is a burden to subjects and society. Subjects suffering from chronic pain have a poor quality of life (Currie and Wang, 2004; Knaster et al, 2012), but there is a paucity of tools to objectively assess pain experience. FMRI has been used to study multiple types of chronic pain, including chronic back pain (Baliki et al, 2006; Baliki et al, 2008b; Ceko et al, 2015; Hashmi et al, 2013; Seminowicz et al, 2011), migraine (Burstein et al, 2015; Schulte and May, 2016), neuropathic pain (Cauda et al, 2010; Cauda et al, 2009; Erpelding et al, 2014; Geha et al, 2007; Geha et al, 2008a; Khan et al, 2014; Maihofner et al, 2003; Malinen et al, 2010), knee osteoarthritis (Parks et al, 2011; Rodriguez-Raecke et al, 2009; Rodriguez-Raecke et al, 2013), fibromyalgia (Flodin et al, 2014; Kuchinad et al, 2007; Loggia et al, 2014; Loggia et al, 2013; LopezSola et al, 2016; Napadow et al, 2010; Schmidt-Wilcke et al, 2014), and chronic pelvic pain (Farmer et al, 2011) These studies have identified structural and functional alterations associated with chronic pain affecting both sensory and limbic brain systems. One hurdle to reaching this mechanistic understanding is the difficulty of examining how peripheral pathologies from possible tissue injuries
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