Gian Domenico Iannetti

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.

A role for the brainstem in central sensitisation in humans. Evidence from functional magnetic resonance imaging

&NA; Animal studies have established a role for the brainstem reticular formation, in particular the rostral ventromedial medulla (RVM), in the development and maintenance of central sensitisation and its clinical manifestation, secondary hyperalgesia. Similar evidence in humans is lacking, as neuroimaging studies have mainly focused on cortical changes. To fully characterise the supraspinal contributions to central sensitisation in humans, we used whole‐brain functional magnetic resonance imaging at 3 T, to record brain responses to punctate mechanical stimulation in an area of secondary hyperalgesia. We used the heat/capsaicin sensitisation model to induce secondary hyperalgesia on the right lower leg in 12 healthy volunteers. A paired t‐test was used to compare activation maps obtained during punctate stimulation of the secondary hyperalgesia area and those recorded during control punctate stimulation (same body site, untreated skin, separate session). The following areas showed significantly increased activation (Z>2.3, corrected P<0.01) during hyperalgesia: contralateral brainstem, cerebellum, bilateral thalamus, contralateral primary and secondary somatosensory cortices, bilateral posterior insula, anterior and posterior cingulate cortices, right middle frontal gyrus and right parietal association cortex. Brainstem activation was localised to two distinct areas of the midbrain reticular formation, in regions consistent with the location of nucleus cuneiformis (NCF) and rostral superior colliculi/periaqueductal gray (SC/PAG). The PAG and the NCF are the major sources of input to the RVM, and therefore in an ideal position to modulate its output. These results suggest that structures in the mesencephalic reticular formation, possibly the NCF and PAG, are involved in central sensitisation in humans.

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.

Determinants of Laser-Evoked EEG Responses: Pain Perception or Stimulus Saliency?

Although laser-evoked electroencephalographic (EEG) responses are increasingly used to investigate nociceptive pathways, their functional significance remains unclear. The reproducible observation of a robust correlation between the intensity of pain perception and the magnitude of the laser-evoked N1, N2, and P2 responses has led some investigators to consider these responses a direct correlate of the neural activity responsible for pain intensity coding in the human cortex. Here, we provide compelling evidence to the contrary. By delivering trains of three identical laser pulses at four different energies, we explored the modulation exerted by the temporal expectancy of the stimulus on the relationship between intensity of pain perception and magnitude of the following laser-evoked brain responses: the phase-locked N1, N2, and P2 waves, and the non-phase-locked laser-induced synchronization (ERS) and desynchronization (ERD). We showed that increasing the temporal expectancy of the stimulus through stimulus repetition at a constant interstimulus interval 1) significantly reduces the magnitudes of the laser-evoked N1, N2, P2, and ERS; and 2) disrupts the relationship between the intensity of pain perception and the magnitude of these responses. Taken together, our results indicate that laser-evoked EEG responses are not determined by the perception of pain per se, but are mainly determined by the saliency of the eliciting nociceptive stimulus (i.e., its ability to capture attention). Therefore laser-evoked EEG responses represent an indirect readout of the function of the nociceptive system.

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.

Operculoinsular cortex encodes pain intensity at the earliest stages of cortical processing as indicated by amplitude of laser-evoked potentials in humans

Converging evidence from different functional imaging studies indicates that the intensity of activation of different nociceptive areas (including the operculoinsular cortex, the primary somatosensory cortex, and the anterior cingulate gyrus) correlates with perceived pain intensity in the human brain. Brief radiant laser pulses excite selectively Adelta and C nociceptors in the superficial skin layers, provide a purely nociceptive input, and evoke brain potentials (laser-evoked potentials, LEPs) that are commonly used to assess nociceptive pathways in physiological and clinical studies. Adelta-related LEPs are constituted of different components. The earliest is a lateralised, small negative component (N1) which could be generated by the operculoinsular cortex. The major negative component (N2) seems to be mainly the result of activation in the bilateral operculoinsular cortices and contralateral primary somatosensory cortex, and it is followed by a positive component (P2) probably generated by the cingulate gyrus. Currently, early and late LEP components are considered to be differentially sensitive to the subjective variability of pain perception: the late N2-P2 complex strongly correlates with perceived pain, whereas the early N1 component is thought to be a pre-perceptual sensory response. To obtain physiological information on the roles of the pain-related brain areas in healthy humans, we examined the relationship between perceived pain intensity and latency and amplitude of the early (N1) and late (N2, P2) LEP components. We found that the amplitude of the N1 component correlated significantly with the subjective pain ratings, both within and between subjects. Furthermore, we showed that the N2 and P2 late LEP components are differentially sensitive to the perceived sensation, and demonstrated that the N2 component mainly explains the previously described correlation between perceived pain and the amplitude of the N2-P2 vertex complex of LEPs. Our findings confirm the notion that pain intensity processing is distributed over several brain areas, and suggest that the intensity coding of a noxious stimulus occurs already at the earliest stage of perception processing, in the operculoinsular region and, possibly, the primary somatosensory area.

Placebo conditioning and placebo analgesia modulate a common brain network during pain anticipation and perception

ABSTRACT The neural mechanisms whereby placebo conditioning leads to placebo analgesia remain unclear. In this study we aimed to identify the brain structures activated during placebo conditioning and subsequent placebo analgesia. We induced placebo analgesia by associating a sham treatment with pain reduction and used fMRI to measure brain activity associated with three stages of the placebo response: before, during and after the sham treatment, while participants anticipated and experienced brief laser pain. In the control session participants were explicitly told that the treatment was inactive. The sham treatment group reported a significant reduction in pain rating (p = 0.012). Anticipatory brain activity was modulated during placebo conditioning in a fronto‐cingulate network involving the left dorsolateral prefrontal cortex (DLPFC), medial frontal cortex and the anterior mid‐cingulate cortex (aMCC). Identical areas were modulated during anticipation in the placebo analgesia phase with the addition of the orbitofrontal cortex (OFC). However, during altered pain experience only aMCC, post‐central gyrus and posterior cingulate demonstrated altered activity. The common frontal cortical areas modulated during anticipation in both the placebo conditioning and placebo analgesia phases have previously been implicated in placebo analgesia. Our results suggest that the main effect of placebo arises from the reduction of anticipation of pain during placebo conditioning that is subsequently maintained during placebo analgesia.

Laser-evoked potentials: normative values.

OBJECTIVEnLaser-evoked potentials (LEPs) currently represent the most reliable and widely agreed method of investigating the A delta-fibre pathways. Many studies dealt with the usefulness of LEPs in peripheral and central nervous system diseases. We aimed at gaining normative values for LEP data.nnnMETHODSnUsing a CO2 laser stimulator we recorded LEPs after face, hand, and foot stimulation in 100 normal subjects. We measured the perceptive threshold, latency and amplitude of the main vertex components, and their side-to-side differences. We also studied the correlations between LEP data and age and body height, as well as gender differences.nnnRESULTSnLaser perceptive threshold increased and LEP amplitude decreased from face to foot (P<0.0001). The latency of hand and foot-LEPs correlated significantly with body height (P<0.0001). The amplitude, though not the latency, correlated with age (P<0.0001). LEP data did not significantly differ between genders (P>0.1).nnnCONCLUSIONSnThis study provides normative values for the main LEP data and their absolute and side-to-side limits, highlighting the physiological differences related to, body height, age, gender and stimulation site.nnnSIGNIFICANCEnOur data may help to improve the clinical reliability of LEPs as a diagnostic tool.

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.

Simultaneous recording of laser-evoked brain potentials and continuous, high-field functional magnetic resonance imaging in humans

Simultaneous recording of event-related electroencephalographic (EEG) and functional magnetic resonance imaging (fMRI) responses has the potential to provide information on how the human brain reacts to an external stimulus with unique spatial and temporal resolution. However, in most studies combining the two techniques, the acquisition of functional MR images has been interleaved with the recording of evoked potentials. In this study we investigated the feasibility of recording pain-related evoked potentials during continuous and simultaneous collection of blood oxygen level-dependent (BOLD) functional MR images at 3 T. Brain potentials were elicited by selective stimulation of cutaneous Adelta and C nociceptors using brief radiant laser pulses (laser-evoked potentials, LEPs). MR-induced artifacts on EEG data were removed using a novel algorithm. Latencies, amplitudes, and scalp distribution of LEPs recorded during fMRI were not significantly different from those recorded in a control session outside of the MR scanner using the same equipment and experimental design. Stability tests confirmed that MR-image quality was not impaired by the evoked potential recording, beyond signal loss related to magnetic susceptibility differences local to the electrodes. fMRI results were consistent with our previous studies of brain activity in response to nociceptive stimulation. These results demonstrate the feasibility of recording reliable pain-related LEPs and fMRI responses simultaneously. Because LEPs collected during fMRI and those collected in a control session show remarkable similarity, for many experimental designs the integration of LEP and fMRI data collected in separate, single-modality acquisitions may be appropriate. Truly simultaneous recording of LEPs and fMRI is still desirable in specific experimental conditions, such as single-trial, learning, and pharmacological studies.