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Brain activity associated with pain in inherited erythromelalgia: stimulus-free pain engages brain areas involved in valuation and learning

Last updated: 03-03-2020

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Brain activity associated with pain in inherited erythromelalgia: stimulus-free pain engages brain areas involved in valuation and learning

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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.

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. Functional brain imaging (fMRI) is a valuable tool for investigating brain activity associated with pain (Davis and Moayedi, 2013; Lee and Tracey, 2013 ;  Schmidt-Wilcke, 2015). 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; Lopez-Sola 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. Importantly, recent evidence suggested that some of these changes may be predictive of the risk of transition from acute to chronic pain (Baliki et al., 2012 ;  Vachon-Presseau et al., 2016). Hence, brain-imaging findings point to brain vulnerabilities to persistence of pain and to brain plasticity in response to pain (Flor et al., 1997; Karl et al., 2001; Maihofner et al., 2007 ;  Maihofner et al., 2003). Nevertheless, the pathophysiology of chronic non-cancer pain in humans remains incompletely understood. One hurdle to reaching this mechanistic understanding is the difficulty of examining how peripheral pathologies from possible tissue injuries interact with brain activity and structure to result in “chronification” of pain.

Inherited eryhthromelalgia (IEM) offers an opportunity to overcome this hurdle and shed some light on the peripheral-central interactions. IEM is a genetic model of neuropathic pain in which severe pain arises from hyperexcitability of peripheral dorsal root ganglion (DRG) neurons (Dib-Hajj et al., 2013). It is characterized by severe burning pain in the distal extremities triggered by mild warmth (Drenth and Waxman, 2007). Gain-of-function mutations in peripheral sodium channel Nav1.7 cause IEM, and thus IEM has a clear molecular basis. The majority of Nav1.7 mutations that cause IEM shift channel activation in a hyperpolarizing direction, making it easier to open the channel; when expressed within DRG neurons, these mutations produce hyper-excitability (Dib-Hajj et al., 2005 ;  Dib-Hajj et al., 2013).

Despite the fact that IEM produces pain with a clear genetic etiology and a well-established basis of peripheral hyperexcitability, little is known about the pattern of brain of activity in subjects suffering from IEM, with only one prior paper describing a single subject (Segerdahl et al., 2012). We have recently completed a fMRI study on the efficacy of the sodium channel blocking drug carbamazepine (Geha et al., 2016) in two subjects with IEM carrying the Na1.7 S241T mutation, which is known to hyperpolarize activation of Nav1.7 (Lampert et al., 2006), and produces profound hyperexcitability in DRG neurons, reducing their threshold and increasing the frequency of their firing (Yang et al., 2012). These subjects had suffered from severe pain for more than a decade due to IEM. Functional MRI data were collected as they reported their pain intensity, during a period of warming which triggered an IEM attack and after termination of the thermal stimulus, the latter allowing the measurement of brain activity associated with pain during an attack in the absence of ongoing external stimulation. Here, we present the brain representation of pain in subjects with IEM, both during exposure to warm stimuli and during the stimulus-free period of pain following cessation of the warmth challenge. We hypothesized that hyperexcitable nociceptors in IEM would activate brain areas usually seen in acute pain such as thalamus, primary sensory/motor areas, insula, and anterior cingulate cortex. In addition, we hypothesize that given the chronic nature of the condition, increased engagement of the brain limbic system would be observed while patients rate their stimulus-free IEM pain.

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