The pain matrix reloaded: A salience detection system for the body
Research highlights
▶ Nociceptive stimuli induce responses in an extensive cortical network including mainly primary (SI) and secondary (SII) somatosensory, insular and anterior cingulate (ACC) areas. ▶ The activity of this network, often referred to as the “pain matrix”, is thought to reflect the mechanisms by which a nociceptive input is transformed into a conscious percept of pain. ▶ Here, we proposed an alternative view of the functional significance of this network in which it reflects a system involved in detecting and orienting attention towards to the occurrence of salient sensory events. ▶ This system would integrate nociceptive stimuli in a multimodal cortical representation of the body and could be used to detect and react to potential threats.
Introduction
Nociception, which is initiated by the activation of peripheral nociceptors, may be defined as the activity in the peripheral and central nervous system elicited by mechanical, thermal or chemical stimuli having the potential to inflict tissue damage (Sherrington, 1906). However, nociception is not synonymous with pain, which is experienced as a conscious percept. Indeed, nociception can trigger brain responses without necessarily causing the feeling of pain (Baumgärtner et al., 2006, Hofbauer et al., 2004, Lee et al., 2009). On the other hand, pain can occur in the absence of nociceptive input (Nikolajsen and Jensen, 2006).
In the last decades, a very large number of studies have aimed at better understanding how the cortex processes nociceptive stimuli and how the experience of pain may emerge from this processing. In humans, most of these studies have relied on non-invasive functional neuroimaging techniques to sample, directly (e.g., electroencephalography [EEG], magnetoencephalography [MEG]) or indirectly (e.g., positron emission tomography [PET], functional magnetic resonance imaging [fMRI]) the neural activity triggered by various kinds of nociceptive stimuli. These studies have shown that nociceptive stimuli elicit responses within a very wide array of subcortical and cortical brain structures (see Apkarian et al., 2005, Bushnell and Apkarian, 2006, García-Larrea et al., 2003, Ingvar, 1999, Peyron et al., 2000, Porro, 2003, Rainville, 2002, Tracey and Mantyh, 2007, Treede et al., 1999). Because responses in some of these structures appear to be observed consistently across studies, and seem to be correlated with the perceived intensity of pain, they have been hypothesized to be preferentially involved in experiencing pain. Hence, structures such as the primary (SI) and secondary (SII) somatosensory, the cingulate and the insular cortices are often referred to as belonging to the so-called “pain matrix”, i.e., a network of cortical areas through which pain is generated from nociception (Ingvar, 1999, Peyron et al., 2000, Porro, 2003, Rainville, 2002, Tracey and Mantyh, 2007).1 To support the idea that this network is specifically involved in the perception of pain, investigators often put forward the following arguments: (i) that the perceived intensity of pain correlates strongly with the magnitude of the neural responses in the “pain matrix” (Bornhövd et al., 2002, Büchel et al., 2002, Coghill et al., 1999, Derbyshire et al., 1997, Iannetti et al., 2005, Tolle et al., 1999), and (ii) that factors modulating pain also modulate the magnitude of the neural responses in the “pain matrix” (Hofbauer et al., 2001, Rainville et al., 1997). Therefore, the activity of that network would constitute a “representation” (Treede et al., 1999) or a “signature” (Tracey and Mantyh, 2007) of pain in the brain, and, thereby, would provide a “window” to study the neural processes underlying pain function and dysfunction in humans (Apkarian et al., 2005). In other words, according to many authors, nociceptive input would generate a conscious percept of pain through the activity it elicits in the network constituting the “pain matrix”, and, hence, measuring the activity within this network would constitute a direct and objective measure of the actual experience of pain (Borsook et al., 2010).
It is actually difficult to provide a unique and consensual definition of the “pain matrix”. Some authors do not consider each area belonging to the “pain matrix” as specifically and individually involved in the perception of pain. Instead, they propose that the different areas form an ensemble of interplaying parts, and that it is the pattern of activation of this ensemble that contributes to the elaboration of the painful percept (e.g., Tracey and Mantyh, 2007). Other investigators consider the “pain matrix” as a collection of areas, each having specialized sub-functions, and, therefore, encoding a specific aspect of the pain experience (e.g., Ingvar, 1999, Porro, 2003, Rainville, 2002). Whatsoever, a great number of recent studies have relied on the notion that observing a pattern of brain activity similar to the so-called “pain matrix” can be considered as unequivocal and objective evidence that a given individual is experiencing pain, including in clinical pain states (Bushnell and Apkarian, 2006, Borsook et al., 2010, Ingvar, 1999).
Very recently, several studies have shown that this brain network cannot be reduced to a mere cortical “representation” of pain. Indeed, these studies have shown that the activity of the so-called “pain matrix” (i) can be clearly dissociated from the perception of pain intensity (Clark et al., 2008, Dillmann et al., 2000, Iannetti et al., 2008, Kulkarni et al., 2005, Lee et al., 2009, Mouraux et al., 2004, Mouraux and Plaghki, 2007, Seminowicz and Davis, 2007), (ii) is strongly influenced by factors independent of the intensity of the nociceptive stimulus (Hatem et al., 2007, Iannetti et al., 2008, Legrain et al., 2009a, Mouraux et al., 2004), and (iii) can be evoked by non-nociceptive and non-painful stimuli (Downar et al., 2000, Downar et al., 2003, Lui et al., 2008, Mouraux et al., in press, Mouraux and Iannetti, 2009, Tanaka et al., 2008). Importantly, these experimental observations do not question the involvement of the cortical activity in the emergence of pain. Rather, they question the notion that the cortical activity involved in the generation of pain is necessarily and specifically reflected in the “pain matrix”.
Here, we will review different studies that challenge the interpretation of the “pain matrix” as a specific cortical representation of pain, and propose a novel interpretation in which the activity of this cortical network would reflect a system involved in detecting, processing and reacting to the occurrence of salient sensory events regardless of the sensory channel through which these events are conveyed. Such a network could reflect some of the basic operations by which the brain detects stimuli that can represent a potential threat for the integrity of the body.
Section snippets
Relationship between magnitude of responses in the “pain matrix” and intensity of pain
The relationship between the perceived intensity of pain and the magnitude of the brain responses evoked by nociceptive stimuli has been studied extensively, mainly by comparing the magnitude of the brain responses elicited by nociceptive stimuli of graded intensity. Studies using PET (Coghill et al., 1999, Derbyshire et al., 1997, Tolle et al., 1999) and fMRI (Bornhövd et al., 2002, Büchel et al., 2002) have thereby shown that the magnitude of the hemodynamic responses in SI, SII, the insula
The effect of novelty and orienting of attention
Studies examining the effect of stimulus repetition on the magnitude of nociceptive-evoked brain responses have shown that when nociceptive stimuli are repeated at a short and regular inter-stimulus interval, they elicit brain responses of reduced magnitude as compared to the responses elicited by nociceptive stimuli that are presented for the first time (Iannetti et al., 2008). The effect of repetition on nociceptive-evoked brain responses is largely determined by the duration of the
Activation of the “pain matrix” by non-nociceptive inputs
Because brain structures such as the operculo-insular and cingulate cortices respond to novelty independently of the sensory modality carrying the novel information, the activation of these brain areas by nociceptive stimuli, as classically described in pain neuroimaging studies, could mainly reflect brain processes that are not directly related to the emergence of pain and that can be engaged by sensory inputs that do not originate from the activation of nociceptors. In support of this view,
A salience detection system
There is thus converging evidence to consider that the bulk of the brain responses to nociceptive stimuli that have been commonly identified using fMRI and EEG reflects a system involved in the extraction and the processing of particular sensory information from the sensory environment independently of sensory modality. The activity of the this network appears to be determined by parameters that are not always related directly to the intensity of the stimulus, and that could be characterized by
A salience detection system for the body
In the previous section, we have provided an alternative interpretation of the functional significance of the cortical network described in pain studies by proposing that it mainly reflects a multimodal network involved in the detection of salience. However, its contribution to the experience pain was not dismissed as salience detection would constitute a fundamental mechanism by which the brain detects events that are significant for the integrity of the body in order to prompt appropriate
Towards a neuropsychology of threat detection
Our hypothesis relative to the existence of a body-centered salience detection system is supported by several neuropsychological observations. For instance, Berthier et al. (1988) reported cases of pain asymbolia consecutive to operculo-insular lesions. Although the patients were able to recognize nociceptive stimuli as painful, the stimuli did not elicit a feeling of unpleasantness, nor did they elicit withdrawal motor reactions or emotional facial expressions. Moreover, in accordance with our
Conclusion
In summary, we propose that the activity of the cortical areas classically observed in response to nociceptive stimuli constitutes a network involved in detecting salient sensory events in order to prioritize their access to attentional and executive functions. Through biasing operations, the main function of the proposed salience detection system would be thus to facilitate the processing of behaviorally significant (e.g., potentially threatening) sensory input and to select the appropriate
Acknowledgments
Authors would like to thank Michael Andres, Julie Duqué, Samar Hatem, Gaëlle Meert (Université catholique de Louvain, Belgium), Geert Crombez, Gilles Pourtois (Ghent University, Belgium), and Alexandre Zénon (The Salk Institute for Biological Studies, California) for their insightful comments. G.D. Iannetti is University Research Fellow of The Royal Society, and acknowledges the support of BBSRC.
References (176)
- et al.
The contribution of the insula to motor aspects of speech production: a review and a hypothesis
Brain Lang.
(2004) - et al.
Human brain mechanisms of pain perception and regulation in health and disease
Eur. J. Pain
(2005) - et al.
Lasers and other thermal stimulators for activation of skin nociceptors in humans
Neurophysiol. Clin.
(2003) Circuitry and functional aspects of the insular lobe in primates including humans
Brain Res. Brain Res. Rev.
(1996)- et al.
The insula (Island of Reil) and its role in auditory processing. Literature review
Brain Res. Brain Res. Rev.
(2003) - et al.
Laser evoked responses to painful stimulation persist during sleep and predict subsequent arousals
Pain
(2008) - et al.
Variability of laser-evoked potentials: attention, arousal and lateralized differences
Electroencephalogr. Clin. Neurophsyiol.
(1993) - et al.
Habituation to painful stimulation involves the antinociceptive system
Pain
(2007) - et al.
Perception of pain in the minimally conscious state with PET activation: an observational study
Lancet Neurol.
(2008) - et al.
Conflict monitoring and anterior cingulate cortex: an update
Trends Cogn. Sci.
(2004)
Direct isolation of ultra-late (C-fiber) evoked brain potential by CO2 laser stimulation of tiny cutaneous surface areas in man
Neurosci. Lett.
Evoked cerebral potential correlates of C-fiber activity in man
Neurosci. Lett.
Cognitive and emotional influences in anterior cingulate cortex
Trends Cogn. Sci.
Dissociating nociceptive modulation by the duration of pain anticipation from unpredictability in the timing of pain
Clin. Neurophysiol.
Sensory and temporal information about impending pain: the influence of predictability on pain
Behav. Res. Ther.
Attentional disruption is enhanced by the threat of pain
Behav. Res. Ther.
When somatic information threatens, catastrophic thinking enhances attention interference
Pain
Hypervigilance to pain: an experimental and clinical analysis
Pain
Pain processing during three levels of noxious stimulation produces differential patterns of central activity
Pain
The influence of semantic priming on event-related potentials to painful laser-heat stimuli in humans
Neurosci. Lett.
Nociceptive responses of trigeminal neurons in SII-7b cortex of awake monkeys
Brain Res.
Neural correlates of the prolonged salience of painful stimulation
Neuroimage
Salience, relevance, and firing: a priority map for target selection
Trends Cogn. Sci.
The novelty P3: an event-related brain potential, ERP sign of the brain's evaluation of novelty
Neurosci. Biobehav. Rev.
Neglect-like symptoms in complex regional pain syndrome: results of a self-administered survey
J. Pain Symptom. Manag.
Somatosensory volleys and cortical evoked potentials: ‘First come, first served’?
Pain
Brain generators of laser-evoked potentials: from dipoles to functional significance
Neurophysiol. Clin.
Spatial maps for the control of movement
Curr. Opin. Neurobiol.
How response inhibition modulates nociceptive and non-nociceptive somatosensory brain-evoked potentials
Clin. Neurophysiol.
Influence of eye orientation on pain as a function of anxiety
Pain
Operculoinsular cortex encodes pain intensity at the earliest stages of cortical processing as indicated by amplitude of laser-evoked potentials in humans
Neuroscience
Electrophysiological studies on human pain perception
Clin. Neurophysiol.
Activation of a residual cortical network during painful stimulation in long-term postanoxic vegetative state: a 15O–H2O PET study
J. Neurol. Sci.
Mechanisms for allocating auditory attention: an auditory salience map
Curr. Biol.
Functional and dynamic properties of visual peripersonal space
Trends Cogn. Sci.
The whole body receptive field of dorsal horn multireceptive neurones
Brain Res. Rev.
Diffuse noxious inhibitory controls, DNIC: I. effects on dorsal horn convergent neurones in the rat
Pain
Attentional modulation of the nociceptive processing into the human brain: selective spatial attention, probability of stimulus occurrence, and target detection effects on laser evoked potentials
Pain
Nociceptive processing in the human brain of infrequent task-relevant and task-irrelevant noxious stimuli. A study with ERPs elicited by CO2 laser radiant heat stimuli
Pain
Electrophysiological correlates of attentional orientation in humans to strong intensity deviant nociceptive stimuli, inside and outside the focus of spatial attention
Neurosci. Lett.
Second pain event related potentials to argon laser stimuli: recording and quantification
J. Neurol. Neurosurg. Psychiatry
Characteristics, detection, and modulation of laser-evoked vertex potentials
Acta Anaesthesiol. Scand. Suppl.
Reference frames for representing visual and tactile locations in parietal cortex
Nat. Neurosci.
Laser-evoked potentials are graded and somatotopically organized anteroposteriorly in the operculoinsular cortex of anesthetized monkeys
J. Neurophysiol.
Human brain activation under controlled thermal stimulation and habituation to noxious heat: an fMRI study
Magn. Reson. Med.
Molecular and cellular limits to somatosensory specificity
Mol. Pain
Asymbolia for pain: a sensory-limbic disconnection syndrome
Ann. Neurol.
Painful stimuli evoke different stimulus-response functions in the amygdala, prefrontal, insula and somatosensory cortex: a single-trial fMRI study
Brain
The pain imaging revolution: advancing pain into the 21st century
Neuroscientist
Nerve fibre discharges, cerebral potentials and sensations induced by CO2 laser stimulation
Hum. Neurobiol.
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