Pain research at IONS, from bench to bedside

The last 15 years has seen important advances in understanding the cellular and molecular mechanisms of pain using animal models, as well as in understanding pain perception in humans using non-invasive techniques to sample brain activity such as electroencephalography (EEG) and functional magnetic resonance imaging (MRI). Yet, remarkably little has changed in respect to the treatment of pain, at least in terms of analgesic drugs to alleviate chronic pain. It is increasingly recognized that this failure is due to the fact that animal pain models as well as human experimental pain models do not adequately simulate multidimensional clinical pain conditions. Therefore, the need to develop translational pain research is increasingly put forward.

By integrating research conducted using pre-clinical animal models of neuropathic pain (research team of Prof. Emmanuel Hermans) with research conducted using non-invasive functional neuroimaging techniques and psychophysics to study nociception in humans (research teams of Prof. André Mouraux and Valery Legrain) and the clinical experience in pain management of researchers-clinicians of the Cliniques universitaires Saint-Luc, our aim is to develop a truly translational pain research program within the Institute of Neuroscience.

 

Research projects

Questioning the functional significance of the “pain matrix”

Investigators : André Mouraux, Giulia Liberati, Elisabeth Colon.

Neuroimaging and neurophysiological studies have shown that transient nociceptive stimuli elicit responses in an extensive cortical network including somatosensory, insular and cingulate areas, as well as frontal and parietal areas. A long-standing view in the field of pain research has been that this network, often referred to as the “pain matrix”, represents the neural activity through which pain emerges as a percept. Recently, we have performed a number of studies challenging this interpretation. First, we conducted a number of experiments showing that pain intensity can be entirely dissociated from the magnitude of the responses in the so-called “pain matrix”, and that the magnitude of the elicited brain responses are strongly influenced by the context within which the stimulus appears, in particular, stimulus novelty. Second, using EEG and fMRI, we showed that non-nociceptive stimuli as well as stimuli not perceived as painful can elicit cortical responses having a spatial distribution that is indistinguishable from that of the “pain matrix”. For these different reasons, we proposed an alternative view of the functional significance of the “pain matrix”, in which it would reflect a system involved in detecting, orientation attention towards, and reacting to the occurrence of salient and/or behaviorally-relevant sensory events. Furthermore, we postulate that 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. 

Intracerebral EEG recordings to investigate the role of the insula in nociception

Investigators : Giulia Liberati, Susana Ferrao Santos, André Mouraux.

A widely accepted notion is that one particular region of the “pain matrix”, the insula, plays a specific role in the perception of pain, and the activity recorded from this region is often considered as an objective signature of pain perception and its modulation. Taking advantage of the high spatio-temporal resolution of direct intracerebral recordings performed in patients undergoing pre-surgical evaluation of focal intractable epilepsy, we recently provided compelling evidence to the contrary. More specifically, we demonstrated that both nociceptive (laser) and non-nociceptive (vibrotactile, auditory, visual) stimuli perceived as equally intense elicit robust local field potentials (LFPs) in the anterior and posterior insula, with matching spatial distributions. These findings argue against the notion that LFPs recorded from the human insula reflect the brain activity through which pain emerges from nociception in the human brain.
Another finding that emerged from our intracerebral investigations is that nociceptive stimuli, but not tactile, auditory, and visual stimuli, elicit an early-latency burst of gamma-band oscillations (GBOs, 40-90 Hz) at several insular locations. Because perception has been proposed to emerge from temporal binding or synchronization of stimulus-evoked neural activity through GBOs, nociceptive GBOs generated in the insula could reflect cortical activity through which the perception of pain arises from nociceptive input in the human brain.  These pain-related GBOs generated in the insula could also contribute to the generation of higher-order responses aiming at preserving the individual’s integrity.
Whereas insular LFPs appear to reflect multimodal activity unspecific for pain, the selective enhancement of insular GBOs elicited by nociceptive stimuli could reflect activity related to the processing of spinothalamic input, nociception, and/or the perception of pain.

EEG frequency tagging to study the cortical activity related to sustained pain in humans

Investigators : Elisabeth Colon, André Mouraux.

Studies have shown that the periodic repetition or modulation of a stimulus can induce a sustained periodic EEG response at the frequency of stimulation and its harmonics, often referred to as steady-state evoked potential (SS-EP). Unlike event-related potentials (ERPs), which reflect phasic cortical activity triggered by a transient stimulus. SS-EPs reflect sustained cortical activity induced by the entrainment of neuronal populations responding to the stimulus. Our objective is to exploit this "EEG frequency-tagging" technique to explore the cortical activity underlying the perception of sustained pain in humans. This is achieved, for example, using a temperature-controlled CO2 laser stimulator to periodically activate heat-sensitive nociceptors of the skin. Using this technique, we showed that it is possible to isolate cortical activity specifically related to the activation of heat-sensitive C-fiber nociceptors.

Pinprick-evoked brain potentials to assess central sensitization in humans

I’m particularly interested in nociception-induced central nervous system plasticity in both acute and persistent pain conditions. In my research I focus predominantly on brain functioning as investigated by non-invasive functional neuroimaging techniques such as electroencephalography (EEG). The purpose of my research is to achieve better understanding about how the CNS changes after intense, sustained nociceptive input in normal (after acute pain) and persistent pain conditions.
 

Investigators : Emanuel van den Broeke, André Mouraux

Patients with neuropathic pain do not only show negative symptoms (i.e. a sensory deficit) related to the impairment of somatosensory pathways. Instead, they also show, paradoxical positive symptoms (ongoing pain, hyperalgesia and allodynia), indicating an increased responsiveness of nociceptive pathways. A prominent positive sign of neuropathic pain is increased sensitivity to noxious mechanical stimulation (mechanical or pinprick hyperalgesia). At present, there is no reliable and objective laboratory toolto assess these changes in the neural responsiveness to mechanonociceptive input. The mechanisms underlying these positive symptoms are different from those underlying the negative symptoms, and involve activity-dependent changes in both the peripheral and the central nervous system. Some patients can have a severe impairment without positive symptoms, while other patients can have a mild impairment but severe positive symptoms.

The mechanical hyperalgesia observed in patients with neuropathic pain is very similar to the mechanical hyperalgesia that can be induced by the sustained activation of nociceptors in healthy volunteers ("secondary hyperalgesia"). There is convincing evidence that mechanical hyperalgesia results from a facilitation of nociceptive transmission at the level of the spinal cord, i.e. central sensitization.

In an attempt to develop a biomarker for central sensitization, we recently conducted a study in which we recorded pinprick evoked brain potentials (PEPs) in the area of experimentally induced secondary mechanical hyperalgesia in healthy volunteers. We showed that when pinprick stimuli are applied in the area of secondary mechanical hyperalgesia, PEPs were significantly increased as compared to the responses elicited by stimulation of normal skin. Moreover, in a second study, we showed that this enhancement of PEPs is long lasting and follows the same time course as the mechanical hyperalgesia. These promising results suggest that the recording of PEPs could be used as a diagnostic tool to assess the positive symptoms of neuropathic pain.

Read more: http://www.nocions.org/researchers/

Capsaicin-induced neuroplasticity : mechanistic studies for understanding neuropathic pain and optimizing its treatment

Investigators : Sabien van Neerven, Ronald Deumens, Marjolein Leerink, Patrice Forget, Arnaud Steyaert, André Mouraux, Emmanuel Hermans.

The general objective of our project is to characterize the effects of topical capsaicin treatment on the changes in function and structure of nociceptive pathways associated with the development of chronic neuropathic pain and/or central sensitization. The proposed project is translational, from bench to bedside, as it will combine work performed in an animal model of neuropathic pain and work performed in patients suffering from chronic post-operative pain. Understanding how topical capsaicin may exert an effect on the central mechanisms associated with chronic pain could lead to a better understanding of these mechanisms and their actual involvement in chronic pain, thus opening new perspectives for treatment. Furthermore, it could lead to a better understanding of why some patients respond well to specific treatments such as topical capsaicin, whereas others do not. Finally, it may lead to the identification of specific patient profiles predicting response to treatment (Jensen and Finnerup 2014, Baron 2012). Such knowledge would be of high value for daily medical practice, as it would enable more individualized and effective pain treatment strategies.

TMS and tDCS combined with EEG and fMRI to characterize the organization and interdependencies between brain areas involved in nociception

Investigators : Cédric Lenoir, Maxime Algoet, Meng Liang, Diana Torta, André Mouraux.

In this project, transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) is combined with EEG and functional MRI to characterize the organization and interdependencies between different brain areas involved in processing somatosensory and nociceptive inputs and in the perception of pain in humans. Two approaches are used. In the first approach, brain responses to nociceptive stimuli are sampled using EEG and fMRI, before and after modulating the excitability of a specific brain region using repetitive TMS or tDCS. In the second approach, brain responses elicited by a single pulse of TMS applied over a given brain region are sampled using online EEG or FMRI, such as to characterize changes in functional connectivity related to central sensitization. 

Novel approaches to study the cortical representation of active touch and the perception of textures in humans

Investigators : Athanasia Moungou, David Gueorguiev, Jean-Louis Thonnard, André Mouraux.

This project is conducted within the frame of a multi-partner European project (Marie Curie Initial Training Network PROTOTOUCH), focusing on the development of (1) novel techniques to generate tactile sensations such as the perception of textures (2) novel approaches to explore the neurophysiological mechanisms underlying the sense of touch at the level of the peripheral nervous system and the central nervous system and (3) novel signal-processing methods and computational neuroscience techniques to characterize the neural encoding of the tactile input generated by finger interactions with tactile displays. It is increasingly recognized that the active perception of textures emerges from the vibrations induced by sliding the finger on the textured surface. Based on the recording of SS-EPs, we developed a new method co characterize the cortical activity related to tactile processing using a wide variety of textures, ranging from gratings to natural textures. Our experiments were conducted in passive dynamic touch, i.e. passive presentation of the stimuli by a high-precision force-feedback platform. Our results have shown that a significant part of the recorded brain responses reflect the processing of the texture-induced vibrations that are generated on our skin. Currently, our aim is to better understand the cortical differences between “active” and “passive” touch, i.e. dynamic touch with and without voluntary movement using matching stimuli, with the help of the force platform.

Temporal order judgment tasks to characterize the “neglect-like” deficits of CRPS

Investigators : Lieve Filbrich, Valery Legrain.

Adequately responding to a painful stimulus requires knowing where pain is localized on the body, but also where the cause of pain is localized in the external world. This involves for the brain to coordinate the somatotopic representation of the body and the representations of the space around the body. According to a recent theory, the spatial localization of pain depends on a cortical mapping system that integrates nociceptive (localization of the salient and threatening stimulus on the body), proprioceptive (localization of the limbs in external space) and visual information (localization of the cause/source of pain in the external world) into a multimodal and peripersonal representation of the body and the space nearby. The aim of this project is to strengthen this theory by investigating, in patients suffering from complex regional pain syndrome (CRPS), how pain in one limb affects the representation of the space surrounding the body. More specifically, using behavioral measures (temporal order judgment tasks), we characterize the “neglect-like” deficits of CRPS patients in perceiving the spatial location of visual stimuli occurring close to the body. Findings will help to understand how pain is integrated in a peripersonal representation of the body and the space nearby. They could also have an important impact on the understanding and the rehabilitation of chronic pain.

Musical rhythm and frequency-tagging to study the neural dynamics of multisensory integration and sensorimotor synchronization

Investigators : Sylvie Nozaradan, Baptiste Chemin, Isabelle Peretz, André Mouraux.

How dynamic inputs entrain brain activity to build our internal representation of the external world is one of the most challenging problems currently confronting cognitive neurosciencists. This project investigates phenomena of sensorimotor synchronization and dynamic multisensory integration by taking advantage to a specific context: musical rhythm. Entrainment to music differs from other behaviors such as speech in terms of the ubiquity of its expression across human societies, and its early development in the lifespan and in human evolution. A fundamental feature of music is rhythmic movement, which is often timed with respect to a regular pulse-like beat, reflecting the intimate coupling of auditory-motor brain processes.
To investigate the neural mechanisms underlying these phenomena, we developed an EEG approach based on the hypothesis that humans perceive the beat by synchronizing large pools of neurons at the beat frequency. This approach allows to tag and disentangle the neural activities related to auditory and sensorimotor processes, by concentrating those signal of interests on specific frequencies in the EEG spectrum. Furthermore, by directly comparing the spectrum of the rhythmic input with the EEG output, these frequency-tagging studies have shown that neural responses transform rhythmic inputs by amplifying frequencies coinciding with the perceived beat frequency. Importantly, a recent study provided key evidence regarding the functional significance of this rhythmic input-output transform by showing that the activities elicited at beat frequency are correlated with individual differences in human behavior, specifically with accuracy in tapping the beat of rhythmic patterns and with individual temporal prediction abilities. Moreover, another experiment demonstrated that this rhythmic input-output transform is shaped by body movements. Enhanced neural activities were observed when listening to a rhythm subsequently to a body movement training session as compared to a listening session before. Most importantly, this boost was selective to frequencies corresponding to the rhythm to which the participants were trained to move. Together, these results indicate a link between rhythmic input-output transforms and beat representation, making this brain transform flexible and involving connections to motor brain areas. In collaboration with Pr. L. Maillard (CHU Nancy), we have recently implemented our approach to intracranial recordings performed in epileptic patients. This allowed us to demonstrate that beat perception involves a selective neural entrainment occurring already in the primary auditory cortex, and also in the premotor cortex.

Non-invasive brain modulation using transcranial focused ultrasound (TFUS)

Investigators : Julien Lambert, Christophe Craeye, André Mouraux.

The general objective of this research project is to develop a novel non-invasive neuromodulation approach based on transcranial focused ultrasound (TFUS) and on the combination of TFUS with EEG to study the cortical processes involved in human pain perception.

Prism adaptation to alleviate pain and improve functional outcome in unilateral chronic pain

Investigators : Samar Hatem, André Mouraux, Valery Legrain.

This research project aims at (1) characterizing cognitive deficits similar to hemispatial neglect in unilateral chronic pain patients by examining the interactions between pain and visuospatial perception, (2) assessing the efficacy of prism adaptation as an original non-pharmacological approach to alleviate pain and to improve the functional outcome in unilateral chronic pain and (3) characterizing the changes in brain morphology induced by prism adaptation using high resolution MRI.

Neurophysiological mechanisms underlying neuropathic pain

Investigators : Michael Ragé, Samar Hatem, Léon Plaghki, Aleksandar Jankovski, André Mouraux.

Neuropathic pain is major healthcare problem worldwide, and pain relief often constitutes a problematic challenge to the physician. At present, laser-evoked potentials are considered to be the best available diagnostic tool to assess the function of the nociceptive system and to diagnose the neuropathic nature of pain. Currently, we are conducting a number of studies in humans aiming at better understanding the pathophysiological mechanisms leading to central and peripheral neuropathic pain. For example, the laboratory is developing new methods for the functional and structural characterization of small-fibre peripheral neuropathies (quantitative sensory testing, laser-evoked potentials, immunohistological assessment of skin biopsies), and to study the mechanisms involved in central pain related to syringomyelia.

Pain and nociception in patients with a disorder of consciousness (DOC)

Investigators : Nicolas Lejeune, Steven Laureys, André Mouraux

Management of pain in patients with a disorder of consciousness (DOC) is most probably often inadequate and raises questions about their quality of life. At present, there are no tools to assess pain perception in these patients that do not rely on residual abilities of the patient to exhibit physical signs of pain. The first goal of our project is to develop a non-invasive means to assess the ability of patients with different level of DOC to perceive pain that can be used at bedside and is independent of patient communication skills. The second goal is to examine whether, on average, the ability to process nociceptive information is more resilient to brain damage as compared to the ability to process non-nociceptive ones. The proposed approach is based on electroencephalographic (EEG) recordings of brain responses elicited by stimuli selectively activating (1) heat-sensitive nociceptor, (2) cold receptors and (3) low-threshold mechanoreceptors. Comparison of the elicited responses will allow us to evaluate the ability of the brain to process nociceptive and non-nociceptive stimuli conveyed through the lemniscal and extralemniscal pathways. Analysis of the correlation between these brain responses and stimulus-evoked behavioral and autonomic responses will allow us to identify EEG « biomarkers » for the ability to exhibit pain-related behaviors. Finally, analysis of the relationship between these brain responses and structural and resting state functional magnetic resonance imaging will allow us to examine whether the ability of the brain to respond to nociceptive or non-nociceptive somatosensory stimuli can be related to lesions of specific brain structures or ensembles of brain structures, or to differences in the state of resting state networks. Taken together, our project should provide valuable information to understand the relations between consciousness and pain perception in humans.

EEG signal processing and classification methods to characterize pain-related brain networks

Investigators : Dounia Mulders, Michel Verleysen, André Mouraux.

The general objective of this project is to develop new electrophysiological approaches and signal processing and classification methods that can be used in humans to characterize (1) the brain networks through which the experience of physiological pain emerges, (2) the individual differences in these networks that may explain individual differences in the susceptibility of patients to develop chronic pain and (3) the alterations of these networks that may be related to the development of a chronic pain state.

How visual experience influences the perception of nociceptive stimuli and pain

In this project, we investigate how visual experience influences the perception of nociceptive stimuli and pain. Specifically, we compare the cognitive abilities of people with congenital blindness and those of normal sighted people to localize nociceptive stimuli on the body space.

Neurophysiological mechanisms underlying visual-nociceptive integration in the representation of the body and the peripersonal space

This research project investigates the neurophysiological mechanisms underlying visual-nociceptive integration in the representation of the body and the peripersonal space. More specifically, the recording of steady state evoked brain potentials is used to explore how nociceptive stimulation affects the processing of external visual stimuli in order to form a meaningful multimodal representation of physical threats.

Cognitive resources required for the planning and online control of fine object manipulation

Investigators : Erwan Guillery, Jean-Louis Thonnard, André Mouraux, Valery Legrain.

In everyday life, object manipulation is among the most common tasks we perform and is usually performed concurrently to the execution of cognitive tasks. In athis project, we study the mental resources required for the planning and online control of fine upper-limb movement. Specifically, we use a novel motor-cognitive dual-task paradigm to examine the influence of a cognitive task on the different aspects of precision grip in elders and in patients presenting with a peripheral or central lesion of the nervous system.

The role of working memory in the attentional control for pain

Investigators : Valery Legrain, André Mouraux.

Disengaging attention away from a nociceptive stimulus has been shown to effectively reduce pain. However, because pain signals the occurrence of potential tissue damage, nociceptive stimuli are prompt to capture attention despite voluntary control. A recent model stresses that an effective attentional control of pain does not simply imply the disengagement of attention, but depends also on cognitive factors that guarantee that attention is maintained on the processing of pain-unrelated information without being recaptured by nociceptive stimuli. Supporting this view, experiments have shown that the ability of nociceptive stimuli to capture attention can be modulated by top-down factors. In this frame, we have explored the involvement of working memory in the control of the attentional capture by nociception. Working memory is involved in the short-term maintaining and storing of information for its immediate manipulation, and has been suggested to regulate the top-down control of attention by maintaining current processing priorities during task performance. Through a series of psychophysical experiments, we found that engaging subjects in a task involving working memory significantly reduces the distraction induced by nociceptive stimuli. Furthermore, using EEG, we found that engaging working memory reduces the magnitude of early-latency responses to the nociceptive stimulus, indicating an effect already at the earliest stages of nociceptive processing. Taken together, the present results suggest that cognitive strategies involving working memory to shield cognition from nociception could be used to alleviate pain. 

Novel approaches to assess olfactory function and dysfunction in humans

Investigators : Caroline Huart, Philippe Rombaux, André Mouraux.

Compared to other sensory modalities, the physiology and pathophysiology of olfaction remains poorly explored in humans. Yet, olfactory disorders are common in the general population, affecting up to 20% of the population. Over the recent years, the recording of ERPs triggered by the transient presentation of odorants has been receiving strong and increasing interest. The approach is not only of interest for basic researchers aiming to characterize the cortical representation of odors in humans. Indeed, it is also of great interest for clinicians currently needing objective and robust tools to diagnose disorders of olfaction. In addition, the recording of chemosensory ERPs could contribute to the early diagnosis of neurodegenerative disorders in which olfactory dysfunction is thought to constitute an early and specific sign, in particular, Alzheimer’s disease. Unfortunately, olfactory chemosensory ERPs exhibit a very low signal-to-noise ratio. Hence, although the technique is recognized as having great potential, its current usefulness remains very limited, particularly in the context of clinical diagnosis. 

In a first project, we hypothesized that the low signal-to-noise ratio of chemosensory ERPs could at least in part be due to an important amount of temporal jitter affecting the brain responses to chemosensory stimulation, itself due to the number of steps required for transduction of the chemosensory stimulus into a neural impulse. For this reason, we developed an approach to reveal olfactory EEG responses that are not strictly phase-locked to the onset of the stimulus, using a method based on the continuous wavelet transform. We found that this approach significantly enhances the signal-to-noise ratio of the elicited responses, and discloses an important fraction of the cortical activity to chemosensory stimulation that is lost by conventional time-domain averaging. By providing a more complete view of how odors are represented in the human brain, we believe that our approach could constitute the basis for a robust clinical tool to assess olfaction in humans.