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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. |
