André Mouraux

From the neuromatrix to the pain matrix (and back)

Pain is a conscious experience, crucial for survival. To investigate the neural basis of pain perception in humans, a large number of investigators apply noxious stimuli to the body of volunteers while sampling brain activity using different functional neuroimaging techniques. These responses have been shown to originate from an extensive network of brain regions, which has been christened the Pain Matrix and is often considered to represent a unique cerebral signature for pain perception. As a consequence, the Pain Matrix is often used to understand the neural mechanisms of pain in health and disease. Because the interpretation of a great number of experimental studies relies on the assumption that the brain responses elicited by nociceptive stimuli reflect the activity of a cortical network that is at least partially specific for pain, it appears crucial to ascertain whether this notion is supported by unequivocal experimental evidence. Here, we will review the original concept of the “Neuromatrix” as it was initially proposed by Melzack and its subsequent transformation into a pain-specific matrix. Through a critical discussion of the evidence in favor and against this concept of pain specificity, we show that the fraction of the neuronal activity measured using currently available macroscopic functional neuroimaging techniques (e.g., EEG, MEG, fMRI, PET) in response to transient nociceptive stimulation is likely to be largely unspecific for nociception.

Across-trial averaging of event-related EEG responses and beyond

Internally and externally triggered sensory, motor and cognitive events elicit a number of transient changes in the ongoing electroencephalogram (EEG): event-related brain potentials (ERPs), event-related synchronization and desynchronization (ERS/ERD), and event-related phase resetting (ERPR). To increase the signal-to-noise ratio of event-related brain responses, most studies rely on across-trial averaging in the time domain, a procedure that is, however, blind to a significant fraction of the elicited cortical activity. Here, we outline the key concepts underlying the limitations of time-domain averaging and consider three alternative methodological approaches that have received increasing interest: time-frequency decomposition of the EEG (using the continuous wavelet transform), blind source separation of the EEG (using Independent Component Analysis) and the analysis of event-related brain responses at the level of single trials. In addition, we provide practical guidelines on the implementation of these methods and on the interpretation of the results they produce.

Nociceptive laser-evoked brain potentials do not reflect nociceptive-specific neural activity.

Brief radiant laser pulses can be used to activate cutaneous Adelta and C nociceptors selectively and elicit a number of transient brain responses [laser-evoked potentials (LEPs)] in the ongoing EEG. LEPs have been used extensively in the past 30 years to gain knowledge about the cortical mechanisms underlying nociception and pain in humans, by assuming that they reflect at least neural activities uniquely or preferentially involved in processing nociceptive input. Here, by applying a novel blind source separation algorithm (probabilistic independent component analysis) to 124-channel event-related potentials elicited by a random sequence of nociceptive and non-nociceptive somatosensory, auditory, and visual stimuli, we provide compelling evidence that this assumption is incorrect: LEPs do not reflect nociceptive-specific neural activity. Indeed, our results indicate that LEPs can be entirely explained by a combination of multimodal neural activities (i.e., activities also elicited by stimuli of other sensory modalities) and somatosensory-specific, but not nociceptive-specific, neural activities (i.e., activities elicited by both nociceptive and non-nociceptive somatosensory stimuli). Regardless of the sensory modality of the eliciting stimulus, the magnitude of multimodal activities correlated with the subjective rating of saliency, suggesting that these multimodal activities are involved in stimulus-triggered mechanisms of arousal or attentional reorientation.

Tagging the Neuronal Entrainment to Beat and Meter

Feeling the beat and meter is fundamental to the experience of music. However, how these periodicities are represented in the brain remains largely unknown. Here, we test whether this function emerges from the entrainment of neurons resonating to the beat and meter. We recorded the electroencephalogram while participants listened to a musical beat and imagined a binary or a ternary meter on this beat (i.e., a march or a waltz). We found that the beat elicits a sustained periodic EEG response tuned to the beat frequency. Most importantly, we found that meter imagery elicits an additional frequency tuned to the corresponding metric interpretation of this beat. These results provide compelling evidence that neural entrainment to beat and meter can be captured directly in the electroencephalogram. More generally, our results suggest that music constitutes a unique context to explore entrainment phenomena in dynamic cognitive processing at the level of neural networks.

Gamma-Band Oscillations in the Primary Somatosensory Cortex—A Direct and Obligatory Correlate of Subjective Pain Intensity

Electroencephalographic gamma band oscillations (GBOs) induced over the human primary somatosensory cortex (SI) by nociceptive stimuli have been hypothesized to reflect cortical processing involved directly in pain perception, because their magnitude correlates with pain intensity. However, as stimuli perceived as more painful are also more salient, an alternative interpretation of this correlation is that GBOs reflect unspecific stimulus-triggered attentional processing. In fact, this is suggested by recent observations that other features of the electroencephalographic (EEG) response correlate with pain perception when stimuli are presented in isolation, but not when their saliency is reduced by repetition. Here, by delivering trains of three nociceptive stimuli at a constant 1 s interval, and using different energies to elicit graded pain intensities, we demonstrate that GBOs recorded over SI always predict the subjective pain intensity, even when saliency is reduced by repetition. These results provide evidence for a close relationship between GBOs and the cortical activity subserving pain perception.

Non-phase locked electroencephalogram (EEG) responses to CO2 laser skin stimulations may reflect central interactions between A∂- and C-fibre afferent volleys

OBJECTIVE: By co-activating A partial partial differential- and C-fibre nociceptors, intense CO2 laser heat stimuli produce a dual sensation, composed of first and second pain, but induce only a single A partial partial differential-fibre related late laser evoked potential (LEP). However, when avoiding concomitant activation of A partial partial differential-fibres, C-fibre related ultra-late LEPs are recorded. This poorly understood phenomenon was re-investigated using a method which, unlike time-domain averaging, reveals electroencephalogram (EEG) changes whether or not phase-locked to stimulus onset. METHODS: CO2 laser stimuli were applied to the dorsum of the hand. Reaction-time was used to discriminate between A partial partial differential- and C-fibre mediated detections. Analyses were performed using a method based on the time-frequency wavelet transform of EEG epochs. RESULTS: This study revealed: (1) a novel non-phase-locked component related to the activation of A partial partial differential-fibres occurring at similar latencies as the late LEP; and (2) a widespread post-stimulus event-related desynchronization (ERD) induced by both A partial partial differential- and C-fibres.CONCLUSIONS: A partial partial differential- and C-fibre related LEPs could be electrophysiological correlates of similar brain processes, which, when already engaged by A partial partial differential-fibres, cannot or do not need to be reactivated by the later arriving C-fibre afferent volley. A partial partial differential-fibre related ERD could reflect a transient change of state of brain structures generating these responses.

Selective Neuronal Entrainment to the Beat and Meter Embedded in a Musical Rhythm

Fundamental to the experience of music, beat and meter perception refers to the perception of periodicities while listening to music occurring within the frequency range of musical tempo. Here, we explored the spontaneous building of beat and meter hypothesized to emerge from the selective entrainment of neuronal populations at beat and meter frequencies. The electroencephalogram (EEG) was recorded while human participants listened to rhythms consisting of short sounds alternating with silences to induce a spontaneous perception of beat and meter. We found that the rhythmic stimuli elicited multiple steady state-evoked potentials (SS-EPs) observed in the EEG spectrum at frequencies corresponding to the rhythmic pattern envelope. Most importantly, the amplitude of the SS-EPs obtained at beat and meter frequencies were selectively enhanced even though the acoustic energy was not necessarily predominant at these frequencies. Furthermore, accelerating the tempo of the rhythmic stimuli so as to move away from the range of frequencies at which beats are usually perceived impaired the selective enhancement of SS-EPs at these frequencies. The observation that beat- and meter-related SS-EPs are selectively enhanced at frequencies compatible with beat and meter perception indicates that these responses do not merely reflect the physical structure of the sound envelope but, instead, reflect the spontaneous emergence of an internal representation of beat, possibly through a mechanism of selective neuronal entrainment within a resonance frequency range. Taken together, these results suggest that musical rhythms constitute a unique context to gain insight on general mechanisms of entrainment, from the neuronal level to individual level.

Low intensity intra-epidermal electrical stimulation can activate Aδ-nociceptors selectively.

&NA; In the past 30 years, the study of nociception has relied mostly on thermal stimulation to activate nociceptors selectively. However, thermal stimulation suffers from some important limitations. For this reason, investigators have proposed intra‐epidermal electrical stimulation (IES) as an alternative method to activate nociceptors selectively. This method relies on the fact that nociceptors are located mainly in the epidermis, while non‐nociceptive fibres terminate more deeply in the dermis. Therefore, provided that the difference in receptor depth is sufficient, electric currents spatially restricted to the epidermal layers might activate nociceptors selectively. Here, we examined whether or not IES provides a fully selective nociceptive input. In a first experiment, we used capsaicin to induce a selective denervation of capsaicin‐sensitive nociceptors, and thereby test whether the responses to IES are mediated by this population of afferent fibres. We found that capsaicin abolishes both the behavioural and the electrophysiological responses to IES applied at twice the perceptual threshold. In a second experiment, we applied a nerve pressure block to the superficial radial nerve to induce a temporally dissociated impairment of A&bgr;‐, A&dgr;‐ and C‐fibre afferents, and thereby determine the fibre populations contributing to the responses elicited by IES. We found that the time course of the blockade of the responses to IES follows closely the time course of the blockade of A&dgr;‐fibres, but not of A&bgr;‐fibres. Taken together, our results provide converging evidence that A&dgr;‐nociceptors can be activated selectively using IES, provided that low intensities of stimulation are used.

Characterizing the Cortical Activity through Which Pain Emerges from Nociception

Nociception begins when Aδ- and C-nociceptors are activated. However, the processing of nociceptive input by the cortex is required before pain can be consciously experienced from nociception. To characterize the cortical activity related to the emergence of this experience, we recorded, in humans, laser-evoked potentials elicited by physically identical nociceptive stimuli that were either perceived or unperceived. Infrared laser pulses, which selectively activate skin nociceptors, were delivered to the hand dorsum either as a pair of rapidly succeeding and spatially displaced stimuli (two-thirds of trials) or as a single stimulus (one-third of trials). After each trial, subjects reported whether one or two distinct painful pinprick sensations, associated with Aδ-nociceptor activation, had been perceived. The psychophysical feedback after each pair of stimuli was used to adjust the interstimulus interval (ISI) of the subsequent pair: when a single percept was reported, ISI was increased by 40 ms; when two distinct percepts were reported, ISI was decreased by 40 ms. This adaptive algorithm ensured that the probability of perceiving the second stimulus of the pair tended toward 0.5. We found that the magnitude of the early-latency N1 wave was similar between perceived and unperceived stimuli, whereas the magnitudes of the later N2 and P2 waves were reduced when stimuli were unperceived. These findings suggest that the N1 wave represents an early stage of sensory processing related to the ascending nociceptive input, whereas the N2 and P2 waves represent a later stage of processing related, directly or indirectly, to the perceptual outcome of this nociceptive input.

A novel approach for enhancing the signal-to-noise ratio and detecting automatically event-related potentials (ERPs) in single trials

Brief radiant laser pulses can be used to activate cutaneous Adelta and C nociceptors selectively and elicit a number of transient brain responses in the ongoing EEG (N1, N2 and P2 waves of laser-evoked brain potentials, LEPs). Despite its physiological and clinical relevance, the early-latency N1 wave of LEPs is often difficult to measure reliably, because of its small signal-to-noise ratio (SNR), thus producing unavoidable biases in the interpretation of the results. Here, we aimed to develop a method to enhance the SNR of the N1 wave and measure its peak latency and amplitude in both average and single-trial waveforms. We obtained four main findings. First, we suggest that the N1 wave can be better detected using a central-frontal montage (Cc-Fz), as compared to the recommended temporal-frontal montage (Tc-Fz). Second, we show that the N1 wave is optimally detected when the neural activities underlying the N2 wave, which interfere with the scalp expression of the N1 wave, are preliminary isolated and removed using independent component analysis (ICA). Third, we show that after these N2-related activities are removed, the SNR of the N1 wave can be further enhanced using a novel approach based on wavelet filtering. Fourth, we provide quantitative evidence that a multiple linear regression approach can be applied to these filtered waveforms to obtain an automatic, reliable and unbiased estimate of the peak latency and amplitude of the N1 wave, both in average and single-trial waveforms.