A multisensory investigation of the functional significance of the “pain matrix”
Research highlights
► The fMRI brain responses to single nociceptive events are not specific for nociception. ► The greater part of these responses reflects multimodal neural activities. ► These activities are related to stimulus saliency, regardless of the quality of the elicited sensation. ► A small part of these responses reflects somatosensory-specific neural activity.
Introduction
A large number of neuroimaging studies have shown that when a nociceptive stimulus is applied to the skin, it elicits activity within a vast network of brain regions, often referred to as the “pain matrix”, and including the primary (S1) and secondary (S2) somatosensory cortices, the insula, and the anterior cingulate cortex (ACC) (Bushnell and Apkarian, 2005, Peyron et al., 2002, Treede et al., 1999).
It is difficult to provide a unique and consensual definition of the “pain matrix” (reviewed in Iannetti and Mouraux, 2010). The term is derived from the “neuromatrix”, which was originally proposed by Melzack in 1989. However, pain was viewed as only one of many possible perceptual outputs of this “neuromatrix”, which was thus not considered to be pain-specific (Melzack, 2005). Only in later studies the label “pain” was added to the term “neuromatrix”, leading to the current concept of a “pain matrix” (e.g., Avenanti et al., 2005, Boly et al., 2008, Borsook et al., 2010, Brooks and Tracey, 2005, Ingvar, 1999, Jones, 1998, Ploghaus et al., 1999, Talbot et al., 1991, Whyte, 2008). This relabeling introduced a fundamental deviation from the original concept, as it implied that the pattern of brain responses elicited by nociceptive stimuli reflects a pain-specific network and, hence, that functional neuroimaging could be used to “delineate the functional anatomy of different aspects of pain” (Ingvar, 1999). Some investigators have considered that it is the pattern of activation in the different structures of the “pain matrix” that constitutes, as an ensemble, the neural substrate for pain perception. In this population-coding view, the emergence of pain is not considered to result from the activation of one or more specific brain areas but to emerge “from the flow and integration of information” among these areas (Tracey, 2005). Therefore, this view differs from the original “neuromatrix” concept only in the fact that the experience of pain is considered as the only relevant output of the network. Other investigators have deviated further from the original “neuromatrix” concept, by considering the “pain matrix” as an enumeration of pain-specific brain structures. In such, the different structures constituting the “pain matrix” are considered to have “specialized subfunctions” and, thereby, to encode self-standingly different aspects of the pain experience (Ingvar, 1999). For example, sensory-discriminative aspects of pain perception are proposed to be independently and specifically represented in S1 and S2, constituting the so-called “lateral pain system” or “somatosensory node” of the “pain matrix”; while affective aspects of pain perception are proposed to be independently and specifically represented in medial brain structures such as the ACC, constituting the “medial pain system” or “affective node” (Albe-Fessard et al., 1985, Avenanti et al., 2005). A large number of recent studies have relied on this “labeled-lines” interpretation of the “pain matrix” to interpret their data (e.g., Avenanti et al., 2005, Brooks and Tracey, 2005, Derbyshire et al., 1997, Frot et al., 2008, Garcia-Larrea et al., 2002, Gracely et al., 2004, Kakigi et al., 2004, Moisset and Bouhassira, 2007, Ploner et al., 2002, Schnitzler and Ploner, 2000, Singer et al., 2004).
It has been repeatedly demonstrated that the magnitude of activity in this network correlates robustly with the intensity of perceived pain, and this has been interpreted as evidence that this network is specifically involved in “encoding” pain intensity (Baliki et al., 2009, Coghill et al., 1999, Derbyshire et al., 1997, Iannetti et al., 2005). Several studies have characterized further the functional significance of this network. Using various experimental manipulations, they have suggested that it is possible to modulate selectively the magnitude of responses in different subregions of this network, a finding interpreted as evidence that different subregions process different aspects of the pain experience (Bushnell and Apkarian, 2005, Ingvar, 1999).
However, all these observations do not justify the conclusion that this network is specifically or preferentially involved in perceiving pain (Boly et al., 2008, Brooks and Tracey, 2005, Ingvar, 1999, Jones, 1998, Melzack, 1992, Whyte, 2008). Indeed, these observations are compatible but not sufficient to justify this conclusion, and, in fact, other observations showing (i) that it is possible to disrupt the correlation between the magnitude of activity in the “pain matrix” and the magnitude of perceived pain (Iannetti et al., 2008, Treede et al., 2003) and (ii) that stimuli that are not nociceptive may elicit responses in the different subregions of the “pain matrix” (Bamiou et al., 2003, Lui et al., 2008, Menon et al., 1997, Mouraux and Iannetti, 2009) suggest the opposite: that the “pain matrix” does not reflect neural mechanisms uniquely involved in nociception.
It is interesting to note that this possibility had already been put forward by a number of early studies (e.g., Bancaud et al., 1953, Carmon et al., 1976, Stowell, 1984) but has often been dismissed by recent studies, which have considered that because the stimulus elicits a sensation of pain, it is reasonable to assume that the elicited brain responses are at least partially pain-specific (e.g., Avenanti et al., 2005, Boly et al., 2008, Borsook et al., 2010, Brooks and Tracey, 2005, Ingvar and Hsieg, 1999, Jones, 1998, Ploghaus, 1999, Stern et al., 2006, Talbot et al., 1991, Whyte, 2008, Wiech et al., 2008).
Although objecting to the use of the term “pain matrix” could appear as an academic discussion only pertaining to the realm of scientific terminology, it actually reveals a practical and urgent issue in the field of pain neuroscience. Undeniably, the brain responses triggered by nociceptive stimuli, in particular, nociceptive laser-evoked brain potentials, are extensively used in clinical practice (Cruccu et al., 2004). Recently, the fMRI responses elicited by nociceptive stimuli have even been used as medico-legal evidence (Miller, 2009), or as evidence of pain perception in minimally conscious states (Boly et al., 2008). Similarly, they have been used to draw strong conclusions about how pain is “represented” in the brain (Bushnell and Apkarian, 2005, Tracey and Mantyh, 2007, Wiech et al., 2008). For example, a number of studies have shown that the brain areas responding to painful stimuli also respond when subjects experience empathy for pain (Singer et al., 2004), and these findings have been interpreted as evidence that such experiences are generated through a mirror activation of the “pain matrix” (Ogino et al., 2007).
The aim of the present study was to functionally characterize the “pain matrix” and determine whether at least a subset of the neural activity that it refers to is unique for nociception. We addressed this question by performing two different fMRI experiments.
In a first experiment, we compared the brain responses elicited by a random sequence of intermixed nociceptive somatosensory, non-nociceptive somatosensory, auditory and visual stimuli presented in a similar attentional context and found that the brain responses triggered by nociceptive stimuli can be entirely explained by a combination of multimodal neural activities (i.e., activities elicited by all stimuli regardless of sensory modality) and somatosensory-specific but not nociceptive-specific neural activities (i.e., activities elicited by both nociceptive and non-nociceptive somatosensory stimuli). The magnitude of these multimodal brain responses was correlated with the subjective rating of stimulus saliency. To further explore the functional significance of these multimodal brain responses, and because previous studies have shown that the magnitude of the brain responses elicited by a nociceptive stimulus can be enhanced if subjects anticipate the occurrence of a possibly painful stimulus (Keltner et al., 2006, Koyama et al., 2005), we performed a second experiment in which we delivered only auditory stimuli using an oddball paradigm. We found that the spatial distribution of the responses elicited by novel and target (i.e., salient) auditory stimuli resembled closely the multimodal responses identified in the first experiment, thus indicating that these responses are elicited by salient non-nociceptive stimuli even in the absence of pain anticipation, and that their occurrence is largely determined both by the intrinsic saliency of the stimulus (bottom–up attention) and its task relevance (top–down attention). Taken together, these findings suggest that the largest part of the fMRI responses elicited by phasic nociceptive stimuli reflects non nociceptive-specific cognitive processes.
Section snippets
Participants
Fourteen healthy right-handed volunteers took part in Experiment 1 (8 males, aged 20–36 years) and Experiment 2 (14 males, aged 20–32 years), under the following inclusion criteria: no history of brain injuries, hypertension, any psychiatric or neurological disease, alcohol abuse, or drug abuse. All volunteers gave written informed consent, and all experimental procedures were approved by the local Research Ethics Committees.
Experimental design
The experiment consisted of a single fMRI acquisition, divided into four
Behavioral data
The average ratings of stimulus saliency were as follows: nociceptive somatosensory: 6.1 ± 2.2; non-nociceptive somatosensory: 5.2 ± 2.2; auditory: 5.1 ± 3.0; visual: 5.0 ± 1.7. Although the nociceptive somatosensory stimulus elicited a sensation that was qualified as clearly painful and pricking, the average ratings of saliency were not significantly different (repeated-measures ANOVA: F = 0.75; p = 0.53).
General linear model analysis
Nociceptive somatosensory, non-nociceptive somatosensory, auditory, and visual stimuli elicited
Discussion
Our study yielded four main findings. First, at least at the macroscopic level of fMRI, nociceptive and non-nociceptive somatosensory stimuli, auditory stimuli, and visual stimuli elicited extremely similar responses in the thalamus, S2, the insula, and the ACC (Fig. 2), thus indicating that a significant fraction of the neural activities determining the BOLD response within these structures are multimodal (i.e., they are elicited by all stimuli regardless of sensory modality). Second,
Conclusion
We conclude that the network of brain areas exhibiting a significant BOLD fMRI response to nociceptive stimulation, often referred to as the “pain matrix”, can also respond to any salient or behaviorally relevant stimulus, regardless of whether it is nociceptive in nature.
This conclusion has one crucial implication: the observation that a given stimulus elicits a pattern of BOLD fMRI response similar to that elicited by a nociceptive stimulus, or that a given experimental manipulation modulates
Acknowledgments
A.M. is a Marie-Curie post-doctoral Research Fellow and a “chargé de recherches” of the Belgian National Fund for Scientific Research (FNRS). A.D., M.C.L., and R.G.W. are supported by the Medical Research Council. G.D.I. is University Research Fellow of The Royal Society and acknowledges the support of the BBSRC.
References (92)
- et al.
Diencephalic mechanisms of pain sensation
Brain Res.
(1985) Circuitry and functional aspects of the insular lobe in primates including humans
Brain Res. Brain Res. Rev.
(1996)- et al.
Transcranial magnetic stimulation highlights the sensorimotor side of empathy for pain
Nat. Neurosci.
(2005) - et al.
Parsing pain perception between nociceptive representation and magnitude estimation
J. Neurophysiol.
(2009) - et al.
The insula (Island of Reil) and its role in auditory processing. Literature review
Brain Res. Brain Res. Rev.
(2003) - et al.
Encephalography; a study of the potentials evoked in man on the level with the vertex.
Rev. Neurol. (Paris)
(1953) - et al.
Behavioral manifestations induced by electric stimulation of the anterior cingulate gyrus in man
Rev. Neurol. (Paris)
(1976) - et al.
Probabilistic independent component analysis for functional magnetic resonance imaging
IEEE Trans. Med. Imaging
(2004) - et al.
Artefact detection in FMRI data using independent component analysis
Neuroimage
(2000) - et al.
Brain regions responsive to novelty in the absence of awareness
Science
(1997)
Perception of pain in the minimally conscious state with PET activation: an observational study
Lancet Neurol.
The pain imaging revolution: advancing pain into the 21st century
Neuroscientist
Conflict monitoring and anterior cingulate cortex: an update
Trends Cogn. Sci.
The hidden side of intentional action: the role of the anterior insular cortex
Brain Struct. Funct.
Two distinct regions of secondary somatosensory cortex in the rat: topographical organization and multisensory responses
J. Neurophysiol.
Nerve fibre discharges, cerebral potentials and sensations induced by CO2 laser stimulation
Hum. Neurobiol.
From nociception to pain perception: imaging the spinal and supraspinal pathways
J. Anat.
Myelinated afferent fibres responding specifically to noxious stimulation of the skin
J. Physiol.
Representation of pain in the brain
Evoked cerebral responses to noxious thermal stimuli in humans
Exp. Brain Res.
Responses to rare visual target and distractor stimuli using event-related fMRI
J. Neurophysiol.
Pain intensity processing within the human brain: a bilateral, distributed mechanism
J. Neurophysiol.
Thermosensory activation of insular cortex
Nat. Neurosci.
EFNS guidelines on neuropathic pain assessment
Eur. J. Neurol.
Topographic organization of the human primary and secondary somatosensory cortices: comparison of fMRI and MEG findings
Neuroimage
Pain processing during three levels of noxious stimulation produces differential patterns of central activity
Pain
Contributions of anterior cingulate cortex to behaviour
Brain
Somatosensory, multisensory, and task-related neurons in cortical area 7b (PF) of unanesthetized monkeys
J. Neurophysiol.
A multimodal cortical network for the detection of changes in the sensory environment
Nat. Neurosci.
A cortical network sensitive to stimulus salience in a neutral behavioral context across multiple sensory modalities
J. Neurophysiol.
A new SPM toolbox for combining probabilistic cytoarchitectonic maps and functional imaging data
Neuroimage
Salience, relevance, and firing: a priority map for target selection
Trends Cogn. Sci.
Value-dependent selection in the brain: simulation in a synthetic neural model
Neuroscience
Parallel processing of nociceptive A-delta inputs in SII and midcingulate cortex in humans
J. Neurosci.
Laser-evoked potential abnormalities in central pain patients: the influence of spontaneous and provoked pain
Brain
Pain catastrophizing and neural responses to pain among persons with fibromyalgia
Brain
From the neuromatrix to the pain matrix (and back)
Exp. Brain Res.
Operculoinsular cortex encodes pain intensity at the earliest stages of cortical processing as indicated by amplitude of laser-evoked potentials in humans
Neuroscience
Determinants of laser-evoked EEG responses: pain perception or stimulus saliency?
J. Neurophysiol.
Pain and functional imaging
Philos. Trans. R. Soc. Lond. B Biol. Sci.
The image of pain
Computational modelling of visual attention
Nat. Rev. Neurosci.
Improved optimization for the robust and accurate linear registration and motion correction of brain images
Neuroimage
The pain matrix and neuropathic pain
Brain
Human brain processing and central mechanisms of pain as observed by electro- and magneto-encephalography
J. Chin. Med. Assoc.
Mechanisms for allocating auditory attention: an auditory saliency map
Curr. Biol.
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