Elsevier

Progress in Neurobiology

Volume 93, Issue 1, January 2011, Pages 111-124
Progress in Neurobiology

The pain matrix reloaded: A salience detection system for the body

https://doi.org/10.1016/j.pneurobio.2010.10.005Get rights and content

Abstract

Neuroimaging and neurophysiological studies have shown that nociceptive stimuli elicit responses in an extensive cortical network including somatosensory, insular and cingulate areas, as well as frontal and parietal areas. This network, often referred to as the “pain matrix”, is viewed as representing the activity by which the intensity and unpleasantness of the percept elicited by a nociceptive stimulus are represented. However, recent experiments have reported (i) that pain intensity can be dissociated from the magnitude of responses in the “pain matrix”, (ii) that the responses in the “pain matrix” are strongly influenced by the context within which the nociceptive stimuli appear, and (iii) that non-nociceptive stimuli can elicit cortical responses with a spatial configuration similar to that of the “pain matrix”. For these reasons, we propose an alternative view of the functional significance of this cortical network, in which it reflects a system involved in detecting, orienting attention towards, and reacting to the occurrence of salient sensory events. This cortical network might represent a basic mechanism through which significant events for the body's integrity are detected, regardless of the sensory channel through which these events are conveyed. This function would involve the construction of a multimodal cortical representation of the body and nearby space. Under the assumption that this network acts as a defensive system signaling potentially damaging threats for the body, emphasis is no longer on the quality of the sensation elicited by noxious stimuli but on the action prompted by the occurrence of potential threats.

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.

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