NOCIONS Research topics
Neural processes underlying pain perception and its modulation
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.
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.
TMS and tDCS
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.
EEG frequency tagging
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.
Laser-evoked brain potentials
In 1975, Mor and Carmon introduced infrared laser stimulators as tools to explore nociception in humans. Allowing brief, synchronous, and selective activation of cutaneous Adelta- and C-fibre nociceptors, laser heat stimulators are now used extensively to study nociception in humans.
Cool-evoked brain potentials
A few studies showed that brisk innocuous cooling of the skin can be used to elicit CEPs related to the activation of cool-sensitive Adelta fibers [34, 41]. However, the responses reported in these previous studies had a low signal-to-noise ratio (SNR), probably due to the limited cooling ramps achieved by the cooling devices, leading to poor time-locking of the activity generatedin cool-sensitive afferents. Recently, we recorded CEPs using a thermode prototype developed by Pr A. Dufour (Strasbourg University) . The device is able to generate very steep cooling ramps of up to 300°C/s. Brisk innocuous cooling of the skin using such ramps elicit CEPs with a high SNR, opening new possibilities to study cool and cold perception in humans.
Nociceptive stimuli induce changes in the magnitude of oscillatory brain activity which is not phase locked, possible related to nociception or pain. This induced activity was found as a brief increase in gamma power in the 40-100 Hz frequency range, whose magnitude appears to correlate better with subjective pain intensity than the amplitude of phase-locked evoked potentials and could thus be a more specific marker for nociception. Besides gamma band oscillations (GBOs), nociceptive stimuli also induce changes in the magnitude of oscillations in other frequency bands, such as a suppression of alpha-band (7-13 Hz) and beta-band oscillations (13-30 Hz), a respective rebound of beta-band oscillations, and an increase in power of low-frequency delta oscillations (0-5 Hz).
Pain and cognition
Pain and the peripersonal space
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.
Pain and working memory
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.
Sensitization, hyperalgesia and neuropathic pain
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.
Chronic 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.
Olfactory function and dysfunction
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 hypothesize 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 develop 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.
Active and passive dynamic touch
This project focuses 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.