Beyond the “Pain Matrix,” inter-run synchronization during mechanical nociceptive stimulation

Pain is a complex experience that is thought to emerge from the activity of multiple brain areas, some of which are inconsistently detected using traditional fMRI analysis. One hypothesis is that the traditional analysis of pain-related cerebral responses, by relying on the correlation of a predictor and the canonical hemodynamic response function (HRF)- the general linear model (GLM)- may under-detect the activity of those areas involved in stimulus processing that do not present a canonical HRF. In this study, we employed an innovative data-driven processing approach- an inter-run synchronization (IRS) analysis- that has the advantage of not establishing any pre-determined predictor definition. With this method we were able to evidence the involvement of several brain regions that are not usually found when using predictor-based analysis. These areas are synchronized during the administration of mechanical punctate stimuli and are characterized by a BOLD response different from the canonical HRF. This finding opens to new approaches in the study of pain imaging

Dishabituation of laser-evoked EEG responses: dissecting the effect of certain and uncertain changes in stimulus spatial location

The repetition of nociceptive stimuli of identical modality, intensity and location at short (1 s) and constant inter-stimulus interval (ISI) determines a strong habituation of the corresponding electroencephalographic (EEG) responses. To understand what determines this response habituation, we (1) examined the effect of introducing a selective change in the spatial location of the repeated stimulus (i.e., without altering its modality, intensity and timing), and (2) dissected the relative contribution of bottom-up, stimulus-driven spatial changes and top-down, cognitive expectations of such a change. Multichannel EEG was recorded while participants received a triplet of stimuli (S1-S2-S3) delivered to the hand dorsum at 1-s ISI. S3 was delivered either to the same hand as S1 and S2 or to the other hand, and participants were either explicitly informed or not informed of the location of S3. We found that, unlike the introduction of a change in the sensory modality of the repeated stimulus (Valentini et al. in J Cogn Neurosci 23:2822-2837, 2011), introducing a change in its spatial location did not produce a significant dishabituation of the laser-evoked N1, N2 and P2 peaks, but only a small amplitude increase following the P2 peak, maximal on the hemisphere contralateral to the stimulated hand. Furthermore, the magnitude of the elicited responses was not significantly affected by cognitive expectations. Altogether, these results indicate that bottom-up, stimulus-driven novelty resulting from a change in stimulus spatial location does not revert the habituation caused by repetition suppression, but determines a small increase of neural activity over the contralateral central-parietal cortex, likely reflecting shifts in spatial attention.status: publishe

High-frequency electrical stimulation of cutaneous nociceptors differentially affects pain perception elicited by homotopic and heterotopic electrical stimuli.

Animal studies have shown that high-frequency electrical stimulation (HFS) of peripheral C-fiber nociceptors induces both homo- and heterosynaptic long-term potentiation (LTP) within spinal nociceptive pathways. In humans, when HFS is applied onto the skin to activate nociceptors, single electrical stimuli are perceived more intense at the HFS site compared to a control site, a finding that was interpreted as a perceptual correlate of homosynaptic LTP. The present study aimed to investigate if after HFS the pain elicited by electrical stimuli delivered at the skin next to the HFS site is perceived as more intense compared to the pain at a control site (contralateral arm). To test this, HFS was applied to one of the two ventral forearms of twenty-four healthy participants. Before and after HFS, single electrical stimuli were delivered through the HFS electrode, through an identical electrode next to the HFS electrode and through an identical electrode at the contralateral arm. After HFS, the pain elicited by the single electrical stimuli was reduced at all three sites, with the largest reduction at the HFS site. Nevertheless, electrical stimuli delivered to the skin next to the HFS site were perceived as more intense than control stimuli. This result indicates that higher pain ratings to electrical stimuli after HFS at the HFS site cannot solely be interpreted as a perceptual correlate of homosynaptic changes. Furthermore, we show for the first time, in humans, that HFS can reduce pain elicited by single electrical stimuli delivered through the same electrode

Cerebellar Clustering and Functional Connectivity During Pain Processing

The cerebellum has been traditionally considered a sensory-motor structure, but more recently has been related to other cognitive and affective functions. Previous research and meta-analytic studies suggested that it could be involved in pain processing. Our aim was to distinguish the functional networks subserved by the cerebellum during pain processing. We used functional magnetic resonance imaging (fMRI) on 12 subjects undergoing mechanical pain stimulation and resting state acquisition. For the analysis of data, we used fuzzy c-mean to cluster cerebellar activity of each participant during nociception. The mean time courses of the clusters were used as regressors in a general linear model (GLM) analysis to explore brain functional connectivity (FC) of the cerebellar clusters. We compared our results with the resting state FC of the same cluster and explored with meta-analysis the behavior profile of the FC networks. We identified three significant clusters: cluster V, involving the culmen and quadrangular lobules (vermis IV-V, hemispheres IV-V-VI); cluster VI, involving the posterior quadrangular lobule and superior semilunar lobule (hemisphere VI, crus 1, crus 2), and cluster VII, involving the inferior semilunar lobule (VIIb, crus1, crus 2). Cluster V was more connected during pain with sensory-motor areas, cluster VI with cognitive areas, and cluster VII with emotional areas. Our results indicate that during the application of mechanical punctate stimuli, the cerebellum is not only involved in sensory functions but also with areas typically associated with cognitive and affective functions. Cerebellum seems to be involved in various aspects of nociception, reflecting the multidimensionality of pain perception.status: publishe

Nociceptive somatosensory ERPs (group-level average waveforms).

<p>There was no significant effect of cTBS on the magnitude of the N160 wave. In contrast, the magnitude of the N240 and P360 waves was significantly reduced following cTBS, regardless of whether the nociceptive stimuli were delivered ipsilateral vs. contralateral to the hemisphere onto which cTBS was applied.</p

Intensity of perception.

<p>Left panel. Following cTBS applied over M1 and S1, the intensity of the percept elicited by nociceptive stimuli delivered to the hand contralateral to the stimulated hemisphere was significantly reduced. Right panel. In contrast, cTBS did not modulate the percept elicited by non-nociceptive somatosensory stimuli.</p

S1 coil target location in in nine representative subjects of experiment S1.

<p>Left panel. The S1 target was identified using a custom MRI-guided neuronavigation system. The position of the coil was adjusted to target the post-central gyrus at a location mirroring the M1 hotspot relative to the central sulcus, i.e. the location expected to correspond to the representation of the hand within S1. The M1 (blue) and S1 (red) targets are shown on the cortical surface reconstructed from the individual MRI data of nine representative subjects. Right panel. Using our MRI-guided approach to target S1, we found that the actual location of the coil on the scalp surface was both more posterior and more lateral relative to the M1 coil position (x-axis: medial-lateral distance relative to the M1 coil position; y-axis: anterior–posterior distance relative to the M1 coil position).</p

Time-frequency analysis of the EEG responses to nociceptive somatosensory stimuli.

<p>The colour maps represent the group-level average EEG signal amplitude expressed as percentage of change relative to baseline (ER%). x-axis: time (s); y-axis: frequency (Hz). Three time-frequency regions of interest were defined: ROI-ERP circumscribing the phase-locked nociceptive ERP, ROI-ERS circumscribing an early, non phase-locked enhancement of signal power between 10–20 Hz and ROI-ERD circumscribing a long-lasting desynchronization of alpha-band power. Mirroring the effect of cTBS on the magnitude of the N240 and P360 waves, the magnitude of ROI-ERP and ROI-ERS was significantly reduced following cTBS, regardless of whether the nociceptive stimuli were delivered ipsilateral vs. contralateral to the stimulated hemisphere. The magnitude of ROI-ERD was unaffected by cTBS.</p