Final Report Summary - IDENTIFYING PAIN (Novel approaches to identify brain responses specifically related to the perception of pain in humans)
The general objective of the research project was to characterise and progress in the understanding of the cortical mechanisms underlying the perception of pain in humans. Investigating this line of research involved the development of novel research tools to activate the nociceptive system such as infrared laser stimulation and intraepidermal electrical stimulation, as well as the development of novel signal-processing methods to analyse non-invasive functional neuroimaging data such as time-frequency and blind source separation analyses of electroencephalography (EEG) signals.
Work performed and main results
The original work plan was organised in four parts. The work performed is summarised as follows:
Part 1: Development of a new approach to study the cortical processing of nociceptive input in humans based on the recording of Steady-state evoked potentials (SS-EPs)
Previous studies had shown that the repetition of a stimulus at a given frequency of stimulation induces a sustained electro-cortical response of corresponding frequency, referred to as SS-EP. Here, we characterised, for the first time, SS-EPs elicited by the rapid periodic stimulation of cutaneous nociceptors using both CO2 laser stimulation of heat-sensitive nociceptors and direct intra-epidermal electrical stimulation of nociceptive free nerve endings. Consistent nociceptive SS-EPs were recorded using a wide range of stimulation frequencies (3-43 Hz). Source analysis of the obtained responses indicated activity originating from the Anterior cingulate cortex (ACC) and / or bilateral operculo-insular cortices. This contrasted with vibrotactile SS-EPs which originated mainly from the primary somatosensory cortex (S1) contralateral to the stimulated hemibody, thus suggesting that nociceptive and non-nociceptive somatosensory SS-EPs reflect the entrainment of distinct neuronal populations. Furthermore, at stimulation frequencies >3 Hz, the responses did not habituate over time, suggesting that they reflect obligatory stages of sensory processing. Taken together, these results indicate that the recording of nociceptive SS-EPs constitutes a novel and promising mean to study the cortical processes involved in nociception and the perception of pain. The results of this work have led to the publication of two original research articles (Mouraux et al., J Neurosci 2011; Colon et al., Neuroimage 2012) as well as a review article (Colon et al., Neurophysiologie Clinique 2012).
Part 2: Characterising the early obligatory stages of cortical nociceptive processing
A number of studies had shown that the EEG or MEG response to tactile somatosensory stimulation comprises a brief burst of high-frequency oscillations (HFO; 500-700 Hz), concomitant to the earliest low-frequency evoked potential (e.g. the N20 wave to median nerve stimulation). Here, using a novel method to generate a synchronous nociceptive afferent volley (intra-epidermal electrical stimulation), we explored whether nociceptive stimuli elicit similar HFOs. No such activity could be reliably identified in the data collected in several experiments. However, analysis of the EEG responses to a large number of stimuli delivered using a short 1-s inter-stimulus interval did allow us to identify an early and obligatory nociceptive ERP, consisting in a positive wave maximal over the scalp vertex. Based on a comparison with the lateralised scalp topography of the early responses to non-nociceptive vibrotactile stimulation, we concluded that, such as nociceptive SS-EPs, this early response may reflect activity specifically involved in the processing of nociceptive input. The results of this study are currently under review in the Journal of Neurophysiology.
Part 3: Nociceptive gamma-band EEG oscillations
In collaboration with Dr G.D. Iannetti (University College London, UK) and Dr Li Hu (Southwest University, China), we developed novel techniques (i) to quantify pain-related brain responses at the level of single trials, thus allowing to study the relationships between these responses and pain perception and (ii) to characterise gamma-band EEG oscillations (GBO), thought to reflect cortical activity directly related to pain perception (Zhang et al., J Neurosci 2012). Most importantly, we showed that unlike all the other features of the EEG response to transient nociceptive stimuli, the magnitude of nociceptive GBOs predict subjective pain intensity even when the saliency of the stimulus is reduced, for example, by stimulus repetition. The results of this work have led to several publications in peer-reviewed journals (Hatem et al., Clin Neurophysiol 2012; Mouraux & Guérit, Clin Neurophysiol 2011; Zhang et al., J Neurosci 2012; Hu et al., J Neurophysiol 2012).
Part 4: Characterising the brain responses related to the activation of C-nociceptors
Here, our objective was to develop and validate a novel approach to explore the brain responses elicited by the selective activation of C-fiber nociceptors, based on a temperature-controlled CO2 laser stimulator. Using an original psychophysical paradigm relying on reaction-times to discriminate between responses related to the activation of A-delta nociceptors and responses related to the activation of C fiber nociceptors, we showed that it is possible to reliably estimate the thermal detection thresholds of these nociceptive afferents, and obtain reliable EEG responses to C-fiber stimulation in humans. The results of this work has led to several publications in peer-reviewed scientific journals (Jankovski et al., Pain 2013; Churyukanov et al., PLOS One 2012; Mouraux et al., Neurophysiologie Clinique 2012).
Building on this work, we extended the scope of the planned research as follows:
- In collaboration with Drs G.D. Iannetti and M. Liang (University College London, UK), we developed a number of novel approaches to characterise how nociceptive input flows within the different brain regions involved in pain perception (Dynamic Causal Modelling of functional magnetic resonance imaging (fMRI) data to characterise the hierarchical organisation of nociceptive and non-nociceptive somatosensory processing within primary and secondary somatosensory cortices, as well as the functional connectivity of the network of brain regions thought to be involved in the detection of salience (Liang et al., J Neurosci 2011; Liang et al., Cereb Cortex 2012). Furthermore, we pursued the work initiated during my Marie Curie IEF, aiming at better understanding the functional significance of the brain responses underlying the so-called 'pain matrix' (Torta et al., Exp Brain Res 2012; Ronga et al., J Neurophysiol 2012; Iannetti & Mouraux PNAS 2011; Valentini et al., J Cog Neurosci 2011; Iannetti & Mouraux, Exp Brain Res 2010; Legrain et al., Prog Neurobiol 2010; Wang et al., J Neurophysiol 2010).
- In collaboration with Dr. V. Legrain and Pr. G. Crombez (Ghent University, BE), we conducted a number of studies to understand better how working memory may interfere with the ability of nociception to capture cognitive resources (Legrain et al., Cortex 2012; Legrain et al., Pain 2011; Legrain et al., PLoS One 2011).
- In collaboration with Pr. P. Rombaux (University of Louvain, BE), we implemented the EEG signal-processing techniques developed within this project to reliably characterise the EEG responses to chemosensory stimulation for the diagnosis of chemosensory dysfunction and, possibly, for the early diagnosis of neurodegenerative diseases (Huart et al., PLOS One 2012; Rombaux et al., Rhinology 2012).
- In collaboration with Pr. I. Peretz (BRAMS, University of Montreal, Canada), we developed a novel approach based on the recording of SS-EPs to study multi-sensory integration and sensori-motor synchronisation in humans (Nozaradan et al., J Neurosci 2012; Nozaradan et al., Neuroimage 2012; Nozaradan et al., J Neurosci 2011).
Impact
The impact of the project can be summarised as follows:
1. The project identified a number of novel measures of the brain responses to nociceptive input in humans, leading to a better understanding of the neurophysiological mechanisms underlying pain perception.
2. The technological advancements (e.g. nociceptive SS-EPs) open new directions for pain research in humans, and could serve as the basis for novel clinical diagnostic tools.
3. The scientific knowledge can be used in future research aiming at understanding the pathophysiological mechanisms contributing to chronic pain, potentially leading to novel or more efficient treatments, for example, by identifying patients at high risk of developing chronic pain or by providing tools for the clinical assessment of novel analgesic drugs. In fact, this knowledge constitutes the core of a Collaborative Project recently submitted for the HEALTH.2013.2.2.1-5 topic (Understanding and Controlling Pain).
4. The techniques and knowledge gained through this project also contributes to other fields of neuroscience research. For example, the signal processing tools that we developed have been made available to the scientific community as an open-source Matlab toolbox, now used by several research groups within and outside the EU. See http://nocions.webnode.com for additional information.
Work performed and main results
The original work plan was organised in four parts. The work performed is summarised as follows:
Part 1: Development of a new approach to study the cortical processing of nociceptive input in humans based on the recording of Steady-state evoked potentials (SS-EPs)
Previous studies had shown that the repetition of a stimulus at a given frequency of stimulation induces a sustained electro-cortical response of corresponding frequency, referred to as SS-EP. Here, we characterised, for the first time, SS-EPs elicited by the rapid periodic stimulation of cutaneous nociceptors using both CO2 laser stimulation of heat-sensitive nociceptors and direct intra-epidermal electrical stimulation of nociceptive free nerve endings. Consistent nociceptive SS-EPs were recorded using a wide range of stimulation frequencies (3-43 Hz). Source analysis of the obtained responses indicated activity originating from the Anterior cingulate cortex (ACC) and / or bilateral operculo-insular cortices. This contrasted with vibrotactile SS-EPs which originated mainly from the primary somatosensory cortex (S1) contralateral to the stimulated hemibody, thus suggesting that nociceptive and non-nociceptive somatosensory SS-EPs reflect the entrainment of distinct neuronal populations. Furthermore, at stimulation frequencies >3 Hz, the responses did not habituate over time, suggesting that they reflect obligatory stages of sensory processing. Taken together, these results indicate that the recording of nociceptive SS-EPs constitutes a novel and promising mean to study the cortical processes involved in nociception and the perception of pain. The results of this work have led to the publication of two original research articles (Mouraux et al., J Neurosci 2011; Colon et al., Neuroimage 2012) as well as a review article (Colon et al., Neurophysiologie Clinique 2012).
Part 2: Characterising the early obligatory stages of cortical nociceptive processing
A number of studies had shown that the EEG or MEG response to tactile somatosensory stimulation comprises a brief burst of high-frequency oscillations (HFO; 500-700 Hz), concomitant to the earliest low-frequency evoked potential (e.g. the N20 wave to median nerve stimulation). Here, using a novel method to generate a synchronous nociceptive afferent volley (intra-epidermal electrical stimulation), we explored whether nociceptive stimuli elicit similar HFOs. No such activity could be reliably identified in the data collected in several experiments. However, analysis of the EEG responses to a large number of stimuli delivered using a short 1-s inter-stimulus interval did allow us to identify an early and obligatory nociceptive ERP, consisting in a positive wave maximal over the scalp vertex. Based on a comparison with the lateralised scalp topography of the early responses to non-nociceptive vibrotactile stimulation, we concluded that, such as nociceptive SS-EPs, this early response may reflect activity specifically involved in the processing of nociceptive input. The results of this study are currently under review in the Journal of Neurophysiology.
Part 3: Nociceptive gamma-band EEG oscillations
In collaboration with Dr G.D. Iannetti (University College London, UK) and Dr Li Hu (Southwest University, China), we developed novel techniques (i) to quantify pain-related brain responses at the level of single trials, thus allowing to study the relationships between these responses and pain perception and (ii) to characterise gamma-band EEG oscillations (GBO), thought to reflect cortical activity directly related to pain perception (Zhang et al., J Neurosci 2012). Most importantly, we showed that unlike all the other features of the EEG response to transient nociceptive stimuli, the magnitude of nociceptive GBOs predict subjective pain intensity even when the saliency of the stimulus is reduced, for example, by stimulus repetition. The results of this work have led to several publications in peer-reviewed journals (Hatem et al., Clin Neurophysiol 2012; Mouraux & Guérit, Clin Neurophysiol 2011; Zhang et al., J Neurosci 2012; Hu et al., J Neurophysiol 2012).
Part 4: Characterising the brain responses related to the activation of C-nociceptors
Here, our objective was to develop and validate a novel approach to explore the brain responses elicited by the selective activation of C-fiber nociceptors, based on a temperature-controlled CO2 laser stimulator. Using an original psychophysical paradigm relying on reaction-times to discriminate between responses related to the activation of A-delta nociceptors and responses related to the activation of C fiber nociceptors, we showed that it is possible to reliably estimate the thermal detection thresholds of these nociceptive afferents, and obtain reliable EEG responses to C-fiber stimulation in humans. The results of this work has led to several publications in peer-reviewed scientific journals (Jankovski et al., Pain 2013; Churyukanov et al., PLOS One 2012; Mouraux et al., Neurophysiologie Clinique 2012).
Building on this work, we extended the scope of the planned research as follows:
- In collaboration with Drs G.D. Iannetti and M. Liang (University College London, UK), we developed a number of novel approaches to characterise how nociceptive input flows within the different brain regions involved in pain perception (Dynamic Causal Modelling of functional magnetic resonance imaging (fMRI) data to characterise the hierarchical organisation of nociceptive and non-nociceptive somatosensory processing within primary and secondary somatosensory cortices, as well as the functional connectivity of the network of brain regions thought to be involved in the detection of salience (Liang et al., J Neurosci 2011; Liang et al., Cereb Cortex 2012). Furthermore, we pursued the work initiated during my Marie Curie IEF, aiming at better understanding the functional significance of the brain responses underlying the so-called 'pain matrix' (Torta et al., Exp Brain Res 2012; Ronga et al., J Neurophysiol 2012; Iannetti & Mouraux PNAS 2011; Valentini et al., J Cog Neurosci 2011; Iannetti & Mouraux, Exp Brain Res 2010; Legrain et al., Prog Neurobiol 2010; Wang et al., J Neurophysiol 2010).
- In collaboration with Dr. V. Legrain and Pr. G. Crombez (Ghent University, BE), we conducted a number of studies to understand better how working memory may interfere with the ability of nociception to capture cognitive resources (Legrain et al., Cortex 2012; Legrain et al., Pain 2011; Legrain et al., PLoS One 2011).
- In collaboration with Pr. P. Rombaux (University of Louvain, BE), we implemented the EEG signal-processing techniques developed within this project to reliably characterise the EEG responses to chemosensory stimulation for the diagnosis of chemosensory dysfunction and, possibly, for the early diagnosis of neurodegenerative diseases (Huart et al., PLOS One 2012; Rombaux et al., Rhinology 2012).
- In collaboration with Pr. I. Peretz (BRAMS, University of Montreal, Canada), we developed a novel approach based on the recording of SS-EPs to study multi-sensory integration and sensori-motor synchronisation in humans (Nozaradan et al., J Neurosci 2012; Nozaradan et al., Neuroimage 2012; Nozaradan et al., J Neurosci 2011).
Impact
The impact of the project can be summarised as follows:
1. The project identified a number of novel measures of the brain responses to nociceptive input in humans, leading to a better understanding of the neurophysiological mechanisms underlying pain perception.
2. The technological advancements (e.g. nociceptive SS-EPs) open new directions for pain research in humans, and could serve as the basis for novel clinical diagnostic tools.
3. The scientific knowledge can be used in future research aiming at understanding the pathophysiological mechanisms contributing to chronic pain, potentially leading to novel or more efficient treatments, for example, by identifying patients at high risk of developing chronic pain or by providing tools for the clinical assessment of novel analgesic drugs. In fact, this knowledge constitutes the core of a Collaborative Project recently submitted for the HEALTH.2013.2.2.1-5 topic (Understanding and Controlling Pain).
4. The techniques and knowledge gained through this project also contributes to other fields of neuroscience research. For example, the signal processing tools that we developed have been made available to the scientific community as an open-source Matlab toolbox, now used by several research groups within and outside the EU. See http://nocions.webnode.com for additional information.