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بخشی از مقاله انگلیسی:
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.
Introduction
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;
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.
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 NaV1.7 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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