Modulation of the spinal N13 SEP component by high- and low-frequency electrical stimulation. Experimental pain models matter.

OBJECTIVE: The N13 component of somatosensory evoked potential (N13 SEP) represents the segmental response of cervical dorsal horn neurons. Neurophysiological studies in healthy participants showed that capsaicin-induced central sensitization causes an increase of the N13 SEP amplitude. Consequently, in human research, this spinal component may serve as a valuable readout of central sensitization. In this study, we wanted to verify if the sensitivity of the N13 SEP for detecting central sensitization is consistent across different experimental pain models inducing central sensitization and secondary hyperalgesia, namely high and low-frequency electrical stimulation (HFS and LFS). METHODS: In 18 healthy participants, we recorded SEP after bilateral ulnar nerve stimulation before and after secondary hyperalgesia was induced through HFS and LFS applied on the ulnar nerve territory of the hand of one side. The area of secondary hyperalgesia was mapped with a calibrated 128-mN pinprick probe, and the mechanical pain sensitivity with three calibrated 16-64-256-mN pinprick probes. RESULTS: Although both HFS and LFS successfully induced secondary hyperalgesia only LFS increased the amplitude of the N13 SEP. CONCLUSIONS: These findings suggest that the sensitivity of the N13 SEP for detecting dorsal horn excitability changes may critically depend on the different experimental pain models. SIGNIFICANCE: Our results indicate that LFS and HFS could trigger central sensitization at the dorsal horn level through distinct mechanisms, however this still needs confirmation by replication studies.

Pinprick-induced gamma-band oscillations are not a useful electrophysiological marker of pinprick hypersensitivity in humans.

OBJECTIVE: This study aimed to investigate scalp gamma-band oscillations (GBOs) induced by mechanical stimuli activating skin nociceptors before and after the induction of mechanical hypersensitivity using high-frequency electrical stimulation (HFS) of the skin. METHODS: In twenty healthy volunteers, we recorded the electroencephalogram during robot-controlled mechanical pinprick stimulation (512 mN) applied at the right ventral forearm before and after HFS. RESULTS: HFS induced a significant increase in mechanical pinprick sensitivity, but this increased pinprick sensitivity was, at the group level, not accompanied by a significant increase in GBOs. Visual inspection of the individual data revealed that possible GBOs were present in eight out of twenty participants (40%) and the frequency of these GBOs varied substantially across participants. CONCLUSIONS: Based on the low number of participants showing GBOs we question the (clinical) utility of mechanically-induced GBOs as an electrophysiological marker of pinprick hypersensitivity in humans. SIGNIFICANCE: Mechanical pinprick-induced scalp GBOs are not useful for evaluating mechanical pinprick hypersensitivity in humans.

Olfactory Dysfunction Predicts Frailty and Poor Postoperative Outcome in Older Patients Scheduled for Elective Non-Cardiac Surgery.

OBJECTIVES: Frailty has been suggested to take part in the recently demonstrated link between olfactory dysfunction and overall mortality risk. Preoperative assessment of frailty is essential to detect the most vulnerable patients scheduled for surgery. The aim of this study was to evaluate whether olfactory dysfunction is a reliable predictor of preoperative frailty and postoperative outcome. DESIGN: This was a single-center prospective observational study conducted between July and October 2020 in Brussels, Belgium. SETTING AND PARTICIPANTS: 155 preoperative patients aged from 65 years old and scheduled for elective non-cardiac surgery. MEASUREMENTS: Olfactory function was examined using the Sniffin' Sticks 12-item identification test. Frailty was assessed using the Edmonton Frail Scale (EFS) and handgrip strength. The clock drawing test (CDT) from the EFS was also analyzed separately to evaluate cognitive function. Patients were followed for postoperative complications and mortality over one year. RESULTS: Olfactory dysfunction was significantly associated with the EFS score, anosmic patients having a higher median EFS score than normosmic patients (6[4-7] vs 4[2-5], p = .025). Anosmic patients had an increased odds of being frail after adjusting for possible confounding factors (OR: 6.19, 95% CI: 1.65-23.20, p = .007) and were more at risk of poor postoperative outcome (including complications and death) (OR: 4.33, 95% CI: 1.28-14.67, p = .018). CONCLUSIONS: Olfactory dysfunction is associated with preoperative frailty determined by the EFS and with poor post-surgical outcome at one-year.

Modulation of the N13 component of the somatosensory evoked potentials in an experimental model of central sensitization in humans.

The N13 component of somatosensory evoked potential (N13 SEP) represents the segmental response of dorsal horn neurons. In this neurophysiological study, we aimed to verify whether N13 SEP might reflect excitability changes of dorsal horn neurons during central sensitization. In 22 healthy participants, we investigated how central sensitization induced by application of topical capsaicin to the ulnar nerve territory of the hand dorsum modulated N13 SEP elicited by ulnar nerve stimulation. Using a double-blind placebo-controlled crossover design, we also tested whether pregabalin, an analgesic drug with proven efficacy on the dorsal horn, influenced capsaicin-induced N13 SEP modulation. Topical application of capsaicin produced an area of secondary mechanical hyperalgesia, a sign of central sensitization, and increased the N13 SEP amplitude but not the peripheral N9 nor the cortical N20-P25 amplitude. This increase in N13 SEP amplitude paralleled the mechanical hyperalgesia and persisted for 120 min. Pregabalin prevented the N13 SEP modulation associated with capsaicin-induced central sensitization, whereas capsaicin application still increased N13 SEP amplitude in the placebo treatment session. Our neurophysiological study showed that capsaicin application specifically modulates N13 SEP and that this modulation is prevented by pregabalin, thus suggesting that N13 SEP may reflect changes in dorsal horn excitability and represent a useful biomarker of central sensitization in human studies.

How different experimental models of secondary hyperalgesia change the nociceptive flexion reflex.

OBJECTIVE: In this neurophysiological study in healthy humans, we assessed how central sensitization induced by either high-frequency stimulation (HFS) or topical capsaicin application modulates features of the RIII reflex response. The ability of these stimuli to engage the endogenous pain modulatory system was also tested. METHODS: In 26 healthy participants we elicited an RIII reflex using suprathreshold stimulation of the sural nerve. Subsequently HFS or capsaicin were applied to the foot and the RIII reflex repeated after 15 minutes. Contact heating of the volar forearm served as the heterotopic test stimulus to probe activation of the endogenous pain modulatory system. RESULTS: HFS significantly reduced the pain threshold by 29% and the RIII reflex threshold by 20%. Capsaicin significantly reduced the pain threshold by 17% and the RIII reflex threshold by 18%. Both HFS and capsaicin left RIII reflex size unaffected. Numerical Rating Scale (NRS) pain scores elicited by the heterotopic noxious heat stimulus were unaffected by capsaicin and slightly increased by HFS. CONCLUSIONS: HFS and capsaicin similarly modulated the pain threshold and RIII reflex threshold, without a concomitant inhibitory effect of the endogenous pain modulatory system. SIGNIFICANCE: Our neurophysiological study supports the use of the RIII reflex in investigating central sensitization in humans.

Perceptual correlates of homosynaptic long-term potentiation in human nociceptive pathways: a replication study.

Animal studies have shown that high-frequency stimulation (HFS) of peripheral C-fibres induces long-term potentiation (LTP) within spinal nociceptive pathways. The aim of this replication study was to assess if a perceptual correlate of LTP can be observed in humans. In 20 healthy volunteers, we applied HFS to the left or right volar forearm. Before and after applying HFS, we delivered single electrical test stimuli through the HFS electrode while a second electrode at the contra-lateral arm served as a control condition. Moreover, to test the efficacy of the HFS protocol, we quantified changes in mechanical pinprick sensitivity before and after HFS of the skin surrounding both electrodes. The perceived intensity was collected for both electrical and mechanical stimuli. After HFS, the perceived pain intensity elicited by the mechanical pinprick stimuli applied on the skin surrounding the HFS-treated site was significantly higher compared to control site (heterotopic effect). Furthermore, we found a higher perceived pain intensity for single electrical stimuli delivered to the HFS-treated site compared to the control site (homotopic effect). Whether the homotopic effect reflects a perceptual correlate of homosynaptic LTP remains to be elucidated.

Central sensitization of nociceptive pathways demonstrated by robot-controlled pinprick-evoked brain potentials.

OBJECTIVE: The aim of this study was to assess the effect of central sensitization, induced by high frequency electrical stimulation of the skin (HFS), on pinprick-evoked brain potentials (PEPs) using robot-controlled mechanical pinprick stimulation and a stimulus evaluation task. METHODS: In 16 healthy volunteers HFS was applied to the right volar forearm. Robot- controlled pinprick stimuli (64 mN) were applied before and 20 minutes after HFS to the skin surrounding the area onto which HFS was applied. During pinprick stimulation, the EEG was recorded and the quality of perception and perceived intensity of the pinprick stimuli was collected. RESULTS: After HFS, the skin surrounding the site at which HFS was delivered showed increased mechanical pinprick sensitivity. Both the early-latency negative peak of PEPs and the later-latency peak were significantly increased after HFS. CONCLUSIONS: This study shows increased PEPs after HFS when they are elicited by a robot-controlled mechanical pinprick stimulator and participants are engaged in a stimulus evaluation task during pinprick stimulation. SIGNIFICANCE: This is the first study that shows a significant increase of both PEP peaks, and therefore, it provides a preferred setup for assessing the function of mechanical nociceptive pathways in the context of central sensitization.

Early gamma-oscillations as correlate of localized nociceptive processing in primary sensorimotor cortex.

Recent studies put forward the idea that stimulus-evoked gamma-band oscillations (GBOs; 30-100 Hz) play a specific role in nociception. So far, evidence for the specificity of GBOs for nociception, their possible involvement in nociceptive sensory discriminatory abilities, and knowledge regarding their cortical sources is just starting to grow. To address these questions, we used electroencephalography (EEG) to record brain activity evoked by phasic nociceptive laser stimuli and tactile stimuli applied at different intensities to the right hand and foot of 12 healthy volunteers. The EEG was analyzed in the time domain to extract phase-locked event-related brain potentials (ERPs) and in three regions of interest in the time-frequency domain (delta/theta, 40-Hz gamma, 70-Hz gamma) to extract stimulus-evoked changes in the magnitude of non-phase-locked brain oscillations. Both nociceptive and tactile stimuli, matched with respect to subjective intensity, elicited phase locked ERPs of increasing amplitude with increasing stimulus intensity. In contrast, only nociceptive stimuli elicited a significant enhancement of GBOs (65-85 Hz, 150-230 ms after stimulus onset), whose magnitude encoded stimulus intensity, whereas tactile stimuli led to a GBO decrease. Following nociceptive hand stimulation, the topographical distribution of GBOs was maximal at contralateral electrode C3, whereas maximum activity following foot stimulation was recorded at the midline electrode Cz, compatible with generation of GBOs in the representations of the hand and foot of the primary sensorimotor cortex, respectively. The differential behavior of high-frequency GBOs and low-frequency 40-Hz GBOs is indicating different functional roles and regions in sensory processing.NEW & NOTEWORTHY Gamma-band oscillations show hand-foot somatotopy compatible with generation in primary sensorimotor cortex and are present following nociceptive but not tactile stimulation of the hand and foot in humans.

Adaptation of the Sniffin' Sticks Test in South-Kivu.

AIM: The "Sniffin' Sticks" test is widely used in Europe as a standard test to assess olfaction. Several culturally-adapted versions have been developed. However, no version adapted to Sub-Saharan African populations exists. The aims of the present study were (1) to assess the applicability of the Sniffin' Sticks test in the population of South Kivu (DR Congo), and (2) to develop a culturally adapted version with normative values. MATERIALS AND METHODS: In a first study, 157 volunteers were tested with the original Sniffin' Sticks test. Based on these results, we selected odors that were poorly recognized in the identification test and replaced them by culturally adapted odors. In a second study, we assessed the modified version of the Sniffin' Sticks test in 150 volunteers and defined normative values. RESULTS: In the first study, we found that olfactory function (threshold-discrimination-identification: TDI score) significantly decreased with age and was better in females. Five odors were poorly recognized and were replaced by culturally adapted odors. In the second study, we found that this adapted version led to a higher rate of correctly identified odors. We defined normative values for the South-Kivu population (TDI score: 18-35 years: 30.4±6.0; 36-55 years: 26.2±5.3; >55 years: 25.6±5.0). CONCLUSION: This culturally adapted version of the Sniffin' Sticks test is culturally adapted to the South Kivu population. The normative values will provide the basis for clinical evaluation of pathologic subjects.

Burst-like conditioning electrical stimulation is more efficacious than continuous stimulation for inducing secondary hyperalgesia in humans.

The aim of the present study was to compare the efficacy of burst-like conditioning electrical stimulation vs. continuous stimulation of cutaneous nociceptors for inducing increased pinprick sensitivity in the surrounding unstimulated skin (a phenomenon referred to as secondary hyperalgesia). In a first experiment (n = 30), we compared the increase in mechanical pinprick sensitivity induced by 50-Hz burst-like stimulation (n = 15) vs. 5-Hz continuous stimulation (n = 15) while maintaining constant the total number of stimuli and the total duration of stimulation. We found a significantly greater increase in mechanical pinprick sensitivity in the surrounding unstimulated skin after 50-Hz burst-like stimulation compared with 5-Hz continuous stimulation (P = 0.013, Cohen's d = 0.970). Importantly, to control for the different frequency of stimulation, we compared in a second experiment (n = 40) 5-Hz continuous stimulation (n = 20) vs. 5-Hz burst-like stimulation (n = 20), this time while keeping the total number of stimuli as well as the frequency of stimulation identical. Again, we found a significantly greater increase in pinprick sensitivity after 5-Hz burst-like stimulation compared with 5-Hz continuous stimulation (P = 0.009, Cohen's d = 0.868). To conclude, our data indicate that burst-like conditioning electrical stimulation is more efficacious than continuous stimulation for inducing secondary hyperalgesia.NEW & NOTEWORTHY Burst-like electrical conditioning stimulation of cutaneous nociceptors is more efficacious than continuous stimulation for inducing heterosynaptic facilitation of mechanical nociceptive input in humans.

Development of a new psychophysical method to assess intranasal trigeminal chemosensory function.

BACKGROUND: The aim of this study was to develop a new psychophysical test to assess intranasal trigeminal chemosensory function. METHODOLOGY: The test is similar to the Sniffin’ Sticks test, but using pens impregnated with substances preferentially activating trigeminal afferents. Our test comprises detection threshold, discrimination, identification and lateralization tasks. In a first study, we evaluated healthy controls. In a second study, we evaluated the potential usefulness of this test in patients with rhinological conditions. RESULTS: Study 1: 86 controls were included. Threshold, identification and lateralization performance decreased with age. Test-retest reliability was similar to that of olfactory tests. Study 2: results of the controls group were compared to those of 59 patients (14 allergic rhinitis, 11 chronic rhinosinusitis with nasal polyps (CRSwNP), 9 without nasal polyps (CRSsNP), and 25 with an olfactory disorder (OD)). Controls had 1) lower detection thresholds compared to CRSwNP, CRSsNP and OD, 2) better discrimination and identification scores compared to OD, and 3) better lateralization scores compared to CRSwNP and CRSsNP. CONCLUSIONS: Our test allows to identify age-related changes in trigeminal chemosensory function. Trigeminal function seems to be differently affected in different pathologies. Further studies are necessary to validate our results and evaluate the impact of olfactory co-activation on the observed results.

Heterosynaptic facilitation of mechanical nociceptive input is dependent on the frequency of conditioning stimulation.

High-frequency burstlike electrical conditioning stimulation (HFS) applied to human skin induces an increase in mechanical pinprick sensitivity of the surrounding unconditioned skin (a phenomenon known as secondary hyperalgesia). The present study assessed the effect of frequency of conditioning stimulation on the development of this increased pinprick sensitivity in humans. In a first experiment, we compared the increase in pinprick sensitivity induced by HFS, using monophasic non-charge-compensated pulses and biphasic charge-compensated pulses. High-frequency stimulation, traditionally delivered with non-charge-compensated square-wave pulses, may induce a cumulative depolarization of primary afferents and/or changes in pH at the electrode-tissue interface due to the accumulation of a net residue charge after each pulse. Both could contribute to the development of the increased pinprick sensitivity in a frequency-dependent fashion. We found no significant difference in the increase in pinprick sensitivity between HFS delivered with charge-compensated and non-charge-compensated pulses, indicating that the possible contribution of charge accumulation when non-charge-compensated pulses are used is negligible. In a second experiment, we assessed the effect of different frequencies of conditioning stimulation (5, 20, 42, and 100 Hz) using charge-compensated pulses on the development of increased pinprick sensitivity. The maximal increase in pinprick sensitivity was observed at intermediate frequencies of stimulation (20 and 42 Hz). It is hypothesized that the stronger increase in pinprick sensitivity at intermediate frequencies may be related to the stronger release of substance P and/or neurokinin-1 receptor activation expressed at lamina I neurons after C-fiber stimulation.NEW & NOTEWORTHY Burstlike electrical conditioning stimulation applied to human skin induces an increase in pinprick sensitivity in the surrounding unconditioned skin (a phenomenon referred to as secondary hyperalgesia). Here we show that the development of the increase in pinprick sensitivity is dependent on the frequency of the burstlike electrical conditioning stimulation.

Spatial Patterns of Brain Activity Preferentially Reflecting Transient Pain and Stimulus Intensity.

How pain emerges in the human brain remains an unresolved question. Neuroimaging studies have suggested that several brain areas subserve pain perception because their activation correlates with perceived pain intensity. However, painful stimuli are often intense and highly salient; therefore, using both intensity- and saliency-matched control stimuli is crucial to isolate pain-selective brain responses. Here, we used these intensity/saliency-matched painful and non-painful stimuli to test whether pain-selective information can be isolated in the functional magnetic resonance imaging responses elicited by painful stimuli. Using two independent datasets, multivariate pattern analysis was able to isolate features distinguishing the responses triggered by (1) intensity/saliency-matched painful versus non-painful stimuli, and (2) high versus low-intensity/saliency stimuli regardless of whether they elicit pain. This indicates that neural activity in the so-called "pain matrix" is functionally heterogeneous, and part of it carries information related to both painfulness and intensity/saliency. The response features distinguishing these aspects are spatially distributed and cannot be ascribed to specific brain structures.

Central sensitization increases the pupil dilation elicited by mechanical pinprick stimulation.

High-frequency electrical stimulation (HFS) of skin nociceptors triggers central sensitization (CS), manifested as increased pinprick sensitivity of the skin surrounding the site of HFS. Our aim was to assess the effect of CS on pinprick-evoked pupil dilation responses (PDRs) and pinprick-evoked brain potentials (PEPs). We hypothesized that the increase in the positive wave of PEPs following HFS would result from an enhanced pinprick-evoked phasic response of the locus coeruleus-noradrenergic system (LC-NS), indicated by enhanced PDRs. In 14 healthy volunteers, 64- and 96-mN pinprick stimuli were delivered to the left and right forearms, before and 20 minutes after HFS was applied to one of the two forearms. Both PEPs and pinprick-evoked PDRs were recorded. After HFS, pinprick stimuli were perceived as more intense at the HFS-treated arm compared with baseline and control site, and this increase was similar for both stimulation intensities. Importantly, the pinprick-evoked PDR was also increased, and the increase was stronger for 64- compared with 96-mN stimulation. This is in line with our previous results showing a stronger increase of the PEP positivity at 64 vs. 96-mN stimulation and suggests that the increase in PEP positivity observed in previous studies could relate, at least in part, to enhanced LC-NS activity. However, there was no increase of the PEP positivity in the present study, indicating that enhanced LC-NS activity is not the only determinant of the HFS-induced enhancement of PEPs. Altogether, our results indicate that PDRs are more sensitive for detecting CS than PEPs. NEW & NOTEWORTHY We provide the first demonstration in humans that activity-dependent central sensitization increases pinprick-evoked autonomic arousal measured by enhanced pupil dilation response.

Brain regions preferentially responding to transient and iso-intense painful or tactile stimuli.

How pain emerges from cortical activities remains an unresolved question in pain neuroscience. A first step toward addressing this question consists in identifying brain activities that occur preferentially in response to painful stimuli in comparison to non-painful stimuli. A key confound that has affected this important comparison in many previous studies is the intensity of the stimuli generating painful and non-painful sensations. Here, we compared the brain activity during iso-intense painful and tactile sensations sampled by functional MRI in 51 healthy participants. Specifically, the perceived intensity was recorded for every stimulus and only the stimuli with rigorously matched perceived intensity were selected and compared between painful and tactile conditions. We found that all brain areas activated by painful stimuli were also activated by tactile stimuli, and vice versa. Neural responses in these areas were correlated with the perceived stimulus intensity, regardless of stimulus modality. More importantly, among these activated areas, we further identified a number of brain regions showing stronger responses to painful stimuli than to tactile stimuli when perceived intensity was carefully matched, including the bilateral opercular cortex, the left supplementary motor area and the right frontal middle and inferior areas. Among these areas, the right frontal middle area still responded more strongly to painful stimuli even when painful stimuli were perceived less intense than tactile stimuli, whereas in this condition other regions showed stronger responses to tactile stimuli. In contrast, the left postcentral gyrus, the visual cortex, the right parietal inferior gyrus, the left parietal superior gyrus and the right cerebellum had stronger responses to tactile stimuli than to painful stimuli when perceived intensity was matched. When tactile stimuli were perceived less intense than painful stimuli, the left postcentral gyrus and the right parietal inferior gyrus still responded more strongly to tactile stimuli while other regions now showed similar responses to painful and tactile stimuli. These results suggest that different brain areas may be engaged differentially when processing painful and tactile information, although their neural activities are not exclusively dedicated to encoding information of only one modality but are strongly determined by perceived stimulus intensity regardless of stimulus modality.

Temporal Profile and Limb-specificity of Phasic Pain-Evoked Changes in Motor Excitability.

A fundamental function of nociception is to trigger defensive motor responses to threatening events. Here, we explored the effects of phasic pain on the motor excitability of ipsilateral and contralateral arms. We reasoned that the occurrence of a short-lasting nociceptive stimulus should result in a specific modulation of motor excitability for muscles involved in the withdrawal of the stimulated limb. This was assessed using transcranial magnetic stimulation (TMS) of the left and right primary motor cortex to elicit motor-evoked potentials (MEPs) in three flexor and two extensor muscles of both arms. To assess the time-course of nociception-motor interactions, TMS pulses were triggered 50-2000 ms after delivering short-lasting nociceptive laser stimuli to the left or right hand. We made three main observations. First, nociceptive stimuli induced an early-latency (100 ms) enhancement of MEPs in flexor muscles of the stimulated hand. Considering its latency, this modulation is likely consequent to nociceptive-motor interactions at spinal level. This early and lateralized enhancement was followed by a later (150-400 ms) MEP reduction in extensor muscles of the stimulated hand and flexor muscles of both hands, predominant at the stimulated hand. Finally, we observed a long-lasting (600-2000 ms) MEP enhancement in muscles of the non-stimulated hand. These later effects of the nociceptive stimulus could reflect nociception-motor interactions occurring at cortical level.

EEG time-warping to study non-strictly-periodic EEG signals related to the production of rhythmic movements.

BACKGROUND: Many sensorimotor functions are intrinsically rhythmic, and are underlined by neural processes that are functionally distinct from neural responses related to the processing of transient events. EEG frequency tagging is a technique that is increasingly used in neuroscience to study these processes. It relies on the fact that perceiving and/or producing rhythms generates periodic neural activity that translates into periodic variations of the EEG signal. In the EEG spectrum, those variations appear as peaks localized at the frequency of the rhythm and its harmonics. NEW METHOD: Many natural rhythms, such as music or dance, are not strictly periodic and, instead, show fluctuations of their period over time. Here, we introduce a time-warping method to identify non-strictly-periodic EEG activities in the frequency domain. RESULTS: EEG time-warping can be used to characterize the sensorimotor activity related to the performance of self-paced rhythmic finger movements. Furthermore, the EEG time-warping method can disentangle auditory- and movement-related EEG activity produced when participants perform rhythmic movements synchronized to an acoustic rhythm. This is possible because the movement-related activity has different period fluctuations than the auditory-related activity. COMPARISON WITH EXISTING METHODS: With the classic frequency-tagging approach, rhythm fluctuations result in a spreading of the peaks to neighboring frequencies, to the point that they cannot be distinguished from background noise. CONCLUSIONS: The proposed time-warping procedure is as a simple and effective mean to study natural non-strictly-periodic rhythmic neural processes such as rhythmic movement production, acoustic rhythm perception and sensorimotor synchronization.

Attention to pain! A neurocognitive perspective on attentional modulation of pain in neuroimaging studies.

Several studies have used neuroimaging techniques to investigate brain correlates of the attentional modulation of pain. Although these studies have advanced the knowledge in the field, important confounding factors such as imprecise theoretical definitions of attention, incomplete operationalization of the construct under exam, and limitations of techniques relying on measuring regional changes in cerebral blood flow have hampered the potential relevance of the conclusions. Here, we first provide an overview of the major theories of attention and of attention in the study of pain to bridge theory and experimental results. We conclude that load and motivational/affective theories are particularly relevant to study the attentional modulation of pain and should be carefully integrated in functional neuroimaging studies. Then, we summarize previous findings and discuss the possible neural correlates of the attentional modulation of pain. We discuss whether classical functional neuroimaging techniques are suitable to measure the effect of a fluctuating process like attention, and in which circumstances functional neuroimaging can be reliably used to measure the attentional modulation of pain. Finally, we argue that the analysis of brain networks and spontaneous oscillations may be a crucial future development in the study of attentional modulation of pain, and why the interplay between attention and pain, as examined so far, may rely on neural mechanisms shared with other sensory modalities.

Peripheral vs. central determinants of vibrotactile adaptation.

Long-lasting mechanical vibrations applied to the skin induce a reversible decrease in the perception of vibration at the stimulated skin site. This phenomenon of vibrotactile adaptation has been studied extensively, yet there is still no clear consensus on the mechanisms leading to vibrotactile adaptation. In particular, the respective contributions of 1) changes affecting mechanical skin impedance, 2) peripheral processes, and 3) central processes are largely unknown. Here we used direct electrical stimulation of nerve fibers to bypass mechanical transduction processes and thereby explore the possible contribution of central vs. peripheral processes to vibrotactile adaptation. Three experiments were conducted. In the first, adaptation was induced with mechanical vibration of the fingertip (51- or 251-Hz vibration delivered for 8 min, at 40× detection threshold). In the second, we attempted to induce adaptation with transcutaneous electrical stimulation of the median nerve (51- or 251-Hz constant-current pulses delivered for 8 min, at 1.5× detection threshold). Vibrotactile detection thresholds were measured before and after adaptation. Mechanical stimulation induced a clear increase of vibrotactile detection thresholds. In contrast, thresholds were unaffected by electrical stimulation. In the third experiment, we assessed the effect of mechanical adaptation on the detection thresholds to transcutaneous electrical nerve stimuli, measured before and after adaptation. Electrical detection thresholds were unaffected by the mechanical adaptation. Taken together, our results suggest that vibrotactile adaptation is predominantly the consequence of peripheral mechanoreceptor processes and/or changes in biomechanical properties of the skin.