Systematic review and co-ordinate based meta-analysis to summarize the utilization of functional brain imaging in conjunction with human models of peripheral and central sensitization.

BACKGROUND AND OBJECTIVE: Functional magnetic resonance imaging, in conjunction with models of peripheral and/or central sensitization, has been used to assess analgesic efficacy in healthy humans. This review aims to summarize the use of these techniques to characterize brain mechanisms of hyperalgesia/allodynia and to evaluate the efficacy of analgesics. DATABASES AND DATA TREATMENT: Searches were performed (PubMed-Medline, Cochrane, Web of Science and Clinicaltrials.gov) to identify and review studies. A co-ordinate based meta-analysis (CBMA) was conducted to quantify neural activity that was reported across multiple independent studies in the hyperalgesic condition compared to control, using GingerALE software. RESULTS: Of 217 publications, 30 studies met the inclusion criteria. They studied nine different models of hyperalgesia/allodynia assessed in the primary (14) or secondary hyperalgesia zone (16). Twenty-three studies focused on neural correlates of hyperalgesic conditions and showed consistent changes in the somatosensory cortex, prefrontal cortices, insular cortex, anterior cingulate cortex, thalamus and brainstem. The CBMA on 12 studies that reported activation coordinates for a contrast comparing the hyperalgesic state to control produced six activation clusters (significant at false discovery rate of 0.05) with more peaks for secondary (17.7) than primary zones (7.3). Seven studies showed modulation of brain activity by analgesics in five of the clusters but also in four additional regions. CONCLUSIONS: This meta-analysis revealed substantial but incomplete overlap between brain areas related to neural mechanisms of hyperalgesia and those reflecting the efficacy of analgesic drugs. Studies testing in the secondary zone were more sensitive to evaluate analgesic efficacy on central sensitization at brainstem or thalamocortical levels. SIGNIFICANCE: Experimental pain models that provide a surrogate for features of pathological pain conditions in healthy humans and functional imaging techniques are both highly valuable research tools. This review shows that when used together, they provide a wealth of information about brain activity during pain states and analgesia. These tools are promising candidates to help bridge the gap between animal and human studies, to improve translatability and provide opportunities for identification of new targets for back-translation to animal studies.

Intra-operative electroencephalogram frontal alpha-band spectral analysis and postoperative delirium in cardiac surgery: A prospective cohort study.

BACKGROUND: Postoperative delirium (POD) remains a frequent complication after cardiac surgery, with pre-operative cognitive status being one of the main predisposing factors. However, performing complete pre-operative neuropsychological testing is challenging. The magnitude of frontal electroencephalographic (EEG) α oscillations during general anaesthesia has been related to pre-operative cognition and could constitute a functional marker for brain vulnerability. OBJECTIVE: We hypothesised that features of intra-operative α-band activity could predict the occurrence of POD. DESIGN: Single-centre prospective observational study. SETTING: University hospital, from 15 May 2019 to 15 December 2021. PATIENTS: Adult patients undergoing elective cardiac surgery. MAIN OUTCOME MEASURES: Pre-operative cognitive status was assessed by neuropsychological tests and scored as a global z score. A 5-min EEG recording was obtained 30 min after induction of anaesthesia. Anaesthesia was maintained with sevoflurane. Power and peak frequency in the α-band were extracted from the frequency spectra. POD was assessed using the Confusion Assessment Method for Intensive Care Unit, the Confusion Assessment Method and a chart review. RESULTS: Sixty-five (29.5%) of 220 patients developed POD. Delirious patients were significantly older with median [IQR] ages of 74 [64 to 79] years vs. 67 [59 to 74] years; P  < 0.001) and had lower pre-operative cognitive z scores (-0.52 ±â€Š1.14 vs. 0.21 ±â€Š0.84; P  < 0.001). Mean α power (-14.03 ±â€Š4.61 dB vs. -11.59 ±â€Š3.37 dB; P  < 0.001) and maximum α power (-11.36 ±â€Š5.28 dB vs. -8.85 ±â€Š3.90 dB; P  < 0.001) were significantly lower in delirious patients. Intra-operative mean α power was significantly associated with the probability of developing POD (adjusted odds ratio, 0.88; 95% confidence interval (CI), 0.81 to 0.96; P  = 0.007), independently of age and only whenever cognitive status was not considered. CONCLUSION: A lower intra-operative frontal α-band power is associated with a higher incidence of POD after cardiac surgery. Intra-operative measures of α power could constitute a means of identifying patients at risk of this complication. TRIAL REGISTRATION: NCT03706989.

Poor preoperative performance at Clock Drawing Test is associated with postoperative decline in olfaction in older patients: an observational pilot study.

BACKGROUND: Decline in olfaction may occur after general anesthesia, but the exact incidence and underlying physiopathology remain scarcely investigated. Olfactory dysfunction arises with aging and is known to be linked to cognitive impairment. In this pilot study, we evaluated the incidence of immediate postoperative decline in olfaction and its association with a preoperative cognitive test, performance at Clock Drawing Test (CDT), in a group of older patients. METHODS: This pilot study is a sub-analysis of a prospective observational study. Patients ≥ 65 years old and scheduled for elective non-cardiac surgery under sevoflurane-based anesthesia were enrolled. CDT was part of the preoperative evaluation. We assessed olfaction on the day before and the day after surgery (between 16 and 26 h postoperatively) using the Sniffin' Sticks 12-item identification test, which consists of pen-like devices displaying 12 different odors. Postoperative decline in olfaction was defined as a decrease of at least 1 standard deviation in the olfactory score. RESULTS: We included a total of 93 patients, among whom 19 (20.4%) presented a postoperative decline in olfaction. The incidence of postoperative decline in olfaction was higher in the "CDT low-score" (score ≤ 5/8) group (11/34, 32.4%) than in the "CDT high-score" (score ≥ 6/8) group (8/58, 13.6%) (P = 0.030). Despite adjusting for confounding variables, CDT score remained independently associated with immediate postoperative decline in olfactory identification function (OR 0.67, 95% CI 0.48 to 0.94, P = 0.022). CONCLUSIONS: Postoperative decline in olfaction occurred in 20.4% of older patients and was associated with poor preoperative performance at CDT. TRIAL REGISTRATION: This study was retrospectively registered on https://clinicaltrials.gov/ under the NCT04700891 number (principal investigator: Victoria Van Regemorter), in December 2020.

Comparison between pupillometry and numeric pain rating scale for pain assessments in communicating adult patients in the emergency department.

OBJECTIVE: The adequate assessment of pain in the emergency department (ED) can be challenging. Two dynamic pupillary measures used in conscious subjects after a surgical procedure were previously shown to correlate to the magnitude of ongoing pain. The objective of this study was to test the ability of dynamic measures derived from pupillometry to evaluate pain intensity in conscious adult patients admitted to the ED. METHODS: This prospective, interventional, single-centre study was performed between August 2021 and January 2022 (NCT05019898). An assessment of self-reported pain intensity was performed on ED admission by the triage nurse using a numeric rating scale (NRS). This was followed by two dynamic measures derived from pupillometry that were previously correlated with pain perception: the pupillary unrest under ambient light (PUAL) and the pupillary light reflex (PLR). RESULTS: Among the 313 analysed patients, the median age was 41 years, and 52% were women. No correlation was found between self-reported pain ratings and PUAL (r = 0.007) or PLR (baseline diameter r = -0.048; decrease r = 0.024; latency r = 0.019; slope = -0.051). Similarly, the pupillometry measures could not discriminate patients with moderate to severe pain (defined as NRS ≥4). CONCLUSIONS: Pupillometry does not appear to be an effective tool to evaluate pain in the ED environment. Indeed, too many factors influencing the sympathetic system-and thus the dynamic pupillary measures-are not controllable in the ED. SIGNIFICANCE: Pupillometry does not appear to be an effective tool to evaluate pain in the ED environment. There are several possible explanations for these negative results. The factors influencing the sympathetic system-and thus the PD fluctuations-are controllable in the postoperative period but not in the ED (e.g. full bladder, hypothermia). In addition, numerous psychological phenomena can impact pupillometry measurements such as emotional reactions or cognitive tasks. These phenomena are particularly difficult to control in the ED environment.

Influence of skin type and laser wavelength on laser-evoked potentials.

BACKGROUND: Infrared laser stimulation is a valuable tool in pain research, its primary application being the recording of laser-evoked brain potentials (LEPs). Different types of laser stimulators, varying in their skin penetrance, are likely to have a large influence on the LEPs, when stimulating different skin types. The aim of this study was to investigate how LEPs depend on laser type and skin location. METHODS: Two different laser stimulators (CO2 and Nd:YAP) were used to compare LEPs in healthy subjects. Stimuli were delivered to the hand dorsum and palm to investigate the effects of skin type on the evoked responses. Stimulus-evoked brain responses were recorded using EEG and perceived intensity ratings were recorded. Computational modelling was used to investigate the observed differences. RESULTS: LEPs evoked by stimulation of the hairy skin were similar between CO2 and Nd:YAP stimulation. In contrast, LEPs elicited from the palm were markedly different and barely present for CO2 stimulation. There was a significant interaction between laser type and skin type (RM-ANOVA, p < 0.05) likely due to smaller CO2 LEPs in the palm. CO2 stimuli to the palm also elicited significantly lower perceived intensities. The computational model showed that the observed differences were explainable by the laser absorption characteristics and skin thickness affecting the temperature profile at the dermo-epidermal junction (DEJ). CONCLUSIONS: This study shows that LEP elicitation depends on the combination of laser penetrance and skin type. Low penetrance stimuli, from a CO2 laser, elicited significantly lower LEPs and perceived intensities in the palm. SIGNIFICANCE: This study showed that the elicitation of laser-evoked potentials in healthy humans greatly depends on the combination of laser stimulator type and skin type. It was shown that high penetrance laser stimuli are capable of eliciting responses in both hairy and glabrous skin, whereas low penetrance stimuli barely elicited responses from the glabrous skin. Computational modelling was used to demonstrate that the results could be fully explained by the combination of laser type and skin thickness.

Pain-free default mode network connectivity contributes to tonic experimental pain intensity beyond the role of negative mood and other pain-related factors.

BACKGROUND: Alterations in the default mode network (DMN) connectivity across pain stages suggest a possible DMN involvement in the transition to persistent pain. AIM: This study examined whether pain-free DMN connectivity at lower alpha oscillations (8-10 Hz) accounts for a unique variation in experimental peak pain intensity beyond the contribution of factors known to influence pain intensity. METHODS: Pain-free DMN connectivity was measured with electroencephalography prior to 1 h of capsaicin-evoked pain using a topical capsaicin patch on the right forearm. Pain intensity was assessed on a (0-10) numerical rating scale and the association between peak pain intensity and baseline measurements was examined using hierarchical multiple regression in 52 healthy volunteers (26 women). The baseline measurements consisted of catastrophizing (helplessness, rumination, magnification), vigilance, depression, negative and positive affect, sex, age, sleep, fatigue, thermal and mechanical pain thresholds and DMN connectivity (medial prefrontal cortex [mPFC]-posterior cingulate cortex [PCC], mPFC-right angular gyrus [rAG], mPFC-left Angular gyrus [lAG], rAG-mPFC and rAG-PCC). RESULTS: Pain-free DMN connectivity increased the explained variance in peak pain intensity beyond the contribution of other factors (ΔR2 = 0.10, p = 0.003), with the final model explaining 66% of the variation (R2 = 0.66, ANOVA: p < 0.001). In this model, negative affect (ß = 0.51, p < 0.001), helplessness (ß = 0.49, p = 0.007), pain-free mPFC-lAG connectivity (ß = 0.36, p = 0.003) and depression (ß = -0.39, p = 0.009) correlated significantly with peak pain intensity. Interestingly, negative affect and depression, albeit both being negative mood indices, showed opposing relationships with peak pain intensity. CONCLUSIONS: This work suggests that pain-free mPFC-lAG connectivity (at lower alpha) may contribute to individual variations in pain-related vulnerability. SIGNIFICANCE: These findings could potentially lead the way for investigations in which DMN connectivity is used in identifying individuals more likely to develop chronic pain.

The test-retest reliability of large and small fiber nerve excitability testing with threshold tracking.

Objective: Standard nerve excitability testing (NET) predominantly assesses Aα- and Aß-fiber function, but a method examining small afferents would be of great interest in pain studies. Here, we examined the properties of a novel perception threshold tracking (PTT) method that preferentially activates Aδ-fibers using weak currents delivered by a novel multipin electrode and compared its reliability with NET. Methods: Eighteen healthy subjects (mean age:34.06 ±â€¯2.0) were examined three times with motor and sensory NET and PTT in morning and afternoon sessions on the same day (intra-day reliability) and after a week (inter-day reliability). NET was performed on the median nerve, while PTT stimuli were delivered through a multipin electrode located on the forearm. During PTT, subjects indicated stimulus perception via a button press and the intensity of the current was automatically increased or decreased accordingly by Qtrac software. This allowed changes in the perception threshold to be tracked during strength-duration time constant (SDTC) and threshold electrotonus protocols. Results: The coefficient of variation (CoV) and interclass coefficient of variation (ICC) showed good-excellent reliability for most NET parameters. PTT showed poor reliability for both SDTC and threshold electrotonus parameters. There was a significant correlation between large (sensory NET) and small (PTT) fiber SDTC when all sessions were pooled (r = 0.29, p = 0.03). Conclusions: Threshold tracking technique can be applied directly to small fibers via a psychophysical readout, but with the current technique, the reliability is poor. Significance: Further studies are needed to examine whether Aß-fiber SDTC may be a surrogate biomarker for peripheral nociceptive signalling.

Perceptual simultaneity between nociceptive and visual stimuli depends on their spatial congruence.

To protect our body against physical threats, it is important to integrate the somatic and extra-somatic inputs generated by these stimuli. Temporal synchrony is an important parameter determining multisensory interaction, and the time taken by a given sensory input to reach the brain depends on the length and conduction velocity of the specific pathways through which it is transmitted. Nociceptive inputs are transmitted through very slow conducting unmyelinated C and thinly myelinated Aδ nociceptive fibers. It was previously shown that to perceive a visual stimulus and a thermo-nociceptive stimulus applied on the hand as coinciding in time, the nociceptive stimulus must precede the visual one by 76 ms for nociceptive inputs conveyed by Aδ fibers and 577 ms for inputs conveyed by C fibers. Since spatial proximity is also hypothesized to contribute to multisensory interaction, the present study investigated the effect of spatial congruence between visual and nociceptive stimuli. Participants judged the temporal order of visual and nociceptive stimuli, with the visual stimuli flashed either next to the stimulated hand or next to the opposite unstimulated hand, and with nociceptive stimuli evoking responses mediated by either Aδ or C fibers. The amount of time by which the nociceptive stimulus had to precede the visual stimulus for them to be perceived as appearing concomitantly was smaller when the visual stimulus occurred near the hand receiving the nociceptive stimulus as compared to when it occurred near the contralateral hand. This illustrates the challenge for the brain to process the synchrony between nociceptive and non-nociceptive stimuli to enable their efficient interaction to optimize defensive reaction against physical dangers.

Neural evidence for functional roles of tactile and visual feedback in the application of myoelectric prosthesis.

Objective. The primary purpose of this study was to investigate the electrophysiological mechanism underlying different modalities of sensory feedback and multi-sensory integration in typical prosthesis control tasks.Approach. We recruited 15 subjects and developed a closed-loop setup for three prosthesis control tasks which covered typical activities in the practical prosthesis application, i.e. prosthesis finger position control (PFPC), equivalent grasping force control (GFC) and box and block control (BABC). All the three tasks were conducted under tactile feedback (TF), visual feedback (VF) and tactile-visual feedback (TVF), respectively, with a simultaneous electroencephalography (EEG) recording to assess the electroencephalogram (EEG) response underlying different types of feedback. Behavioral and psychophysical assessments were also administered in each feedback condition.Results. EEG results showed that VF played a predominant role in GFC and BABC tasks. It was reflected by a significantly lower somatosensory alpha event-related desynchronization (ERD) in TVF than in TF and no significant difference in visual alpha ERD between TVF and VF. In PFPC task, there was no significant difference in somatosensory alpha ERD between TF and TVF, while a significantly lower visual alpha ERD was found in TVF than in VF, indicating that TF was essential in situations related to proprioceptive position perception. Tactile-visual integration was found when TF and VF were congruently implemented, showing an obvious activation over the premotor cortex in the three tasks. Behavioral and psychophysical results were consistent with EEG evaluations.Significance. Our findings could provide neural evidence for multi-sensory integration and functional roles of tactile and VF in a practical setting of prosthesis control, shedding a multi-dimensional insight into the functional mechanisms of sensory feedback.

Spatial summation of cold and warm detection: Evidence for increased precision when brisk stimuli are delivered over larger area.

Cold and warm stimuli delivered over a larger skin area tend to be more easily detected/elicit stronger sensations, a phenomenon referred to as spatial summation. The aim of the present study was to clarify how stimulation area affects thermal detection processes by evaluating whether increasing the stimulation area simply reduces the detection threshold or also reduces the uncertainty of the detection process. Psychometric functions were fitted to the detection performance of 16 healthy subjects. Stimuli (duration: 200 ms; rate of change: 300 °C/s) were delivered to the volar forearm using a Peltier-effect contact thermode and three different stimulation surfaces (23 mm2, 69 mm2, and 116 mm). Stimulation intensities were selected trial-by-trial by the psi marginal method to optimize estimation of slope and threshold parameters of the psychometric function. The raw data (100 stimulus-response pairs per subject per surface and per modality) was used to fit group-level hierarchical models of cold and warm detection, allowing to assess the effect of stimulation surface and account for inter-individual variability. Increasing stimulation area led to a compression of the psychometric function towards baseline skin temperature (reduced threshold and steeper slope), suggesting that spatial summation reflects a change in the precision of the neural representation of the stimulus which in turn influences the ability of the nervous system to distinguish true stimuli from sensory noise. Regardless of area, with the stimulation settings used in this study, cold detection appeared easier than warm detection, possibly because of structural and functional differences between cold- and warm-sensitive afferents.

Confidence of probabilistic predictions modulates the cortical response to pain.

Pain typically evolves over time, and the brain needs to learn this temporal evolution to predict how pain is likely to change in the future and orient behavior. This process is termed temporal statistical learning (TSL). Recently, it has been shown that TSL for pain sequences can be achieved using optimal Bayesian inference, which is encoded in somatosensory processing regions. Here, we investigate whether the confidence of these probabilistic predictions modulates the EEG response to noxious stimuli, using a TSL task. Confidence measures the uncertainty about the probabilistic prediction, irrespective of its actual outcome. Bayesian models dictate that the confidence about probabilistic predictions should be integrated with incoming inputs and weight learning, such that it modulates the early components of the EEG responses to noxious stimuli, and this should be captured by a negative correlation: when confidence is higher, the early neural responses are smaller as the brain relies more on expectations/predictions and less on sensory inputs (and vice versa). We show that participants were able to predict the sequence transition probabilities using Bayesian inference, with some forgetting. Then, we find that the confidence of these probabilistic predictions was negatively associated with the amplitude of the N2 and P2 components of the vertex potential: the more confident were participants about their predictions, the smaller the vertex potential. These results confirm key predictions of a Bayesian learning model and clarify the functional significance of the early EEG responses to nociceptive stimuli, as being implicated in confidence-weighted statistical learning.

Chronic temporomandibular disorders are associated with higher propensity to develop central sensitization: a case-control study.

ABSTRACT: Temporomandibular disorders (TMD) include a group of musculoskeletal disorders that may involve increased responsiveness of nociceptive neurons in the central nervous system (ie, central sensitization). To test this hypothesis further, this study examined whether, as compared with healthy subjects, patients with chronic TMD have a greater propensity to develop secondary mechanical hyperalgesia-a phenomenon that can be confidently attributed to central sensitization. In this case-control study, we assessed the area of secondary mechanical hyperalgesia induced experimentally by delivering high-frequency electrical stimulation (HFS) to the volar forearm skin in 20 participants with chronic TMD and 20 matched healthy controls. High-frequency electrical stimulation consisted in 12 trains of constant-current electrical pulses (5 mA) delivered at 42 Hz. The area of secondary mechanical hyperalgesia was evaluated 30 minutes after applying HFS. The area of secondary mechanical hyperalgesia induced by HFS was on average 76% larger in the chronic TMD group (M = 67.7 cm 2 , SD = 28.2) than in the healthy control group (M = 38.4 cm 2 , SD = 14.9; P = 0.0003). Regarding secondary outcomes, there was no group difference in the intensity of secondary mechanical hyperalgesia, but allodynia to cotton after HFS was more frequent in the chronic TMD group. To the best of our knowledge, this is the first study to show that individuals with chronic TMD have an increased propensity to develop secondary hyperalgesia in a site innervated extratrigeminally. Our results contribute to a better understanding of the pathophysiology of chronic TMD.

High-speed heating of the skin using a contact thermode elicits brain responses comparable to CO2 laser-evoked potentials.

OBJECTIVE: To compare nociceptive event-related brain potentials elicited by a high-speed contact-thermode vs an infrared CO2 laser stimulator. METHODS: Contact heat-evoked potentials (CHEPs) and CO2 laser-evoked potentials (LEPs) were recorded in healthy volunteers using a high-speed contact-thermode (>200 °C/s) and a temperature-controlled CO2 laser. In separate experiments, stimuli were matched in terms of target surface temperature (55 °C) and intensity of perception. A finite-element model of skin heat transfer was used to explain observed differences. RESULTS: For 55 °C stimuli, CHEPs were reduced in amplitude and delayed in latency as compared to LEPs. For perceptually matched stimuli (CHEPs: 62 °C; LEPs: 55 °C), amplitudes were similar, but CHEPs latencies remained delayed. These differences could be explained by skin thermal inertia producing differences in the heating profile of contact vs radiant heat at the dermo-epidermal junction. CONCLUSIONS: Provided that steep heating ramps are used, and that target temperature is matched at the dermo-epidermal junction, contact and radiant laser heat stimulation elicit responses of similar magnitude. CHEPs are delayed compared to LEPs. SIGNIFICANCE: CHEPs could be used as an alternative to LEPs for the diagnosis of neuropathic pain. Dedicated normative values must be used to account for differences in skin thermal transfer.

Characterization of vagus nerve stimulation-induced pupillary responses in epileptic patients.

BACKGROUND: Modulation of the locus coeruleus (LC)-noradrenergic system is a key mechanism of vagus nerve stimulation (VNS). Activation of the LC produces pupil dilation, and the VNS-induced change in pupil diameter was demonstrated in animals as a possible dose-dependent biomarker for treatment titration. OBJECTIVE: This study aimed to characterize VNS-induced pupillary responses in epileptic patients. METHODS: Pupil diameter was recorded in ten epileptic patients upon four stimulation conditions: three graded levels of VNS intensity and a somatosensory control stimulation (cutaneous electrical stimulation over the left clavicle). For each block, the patients rated the intensity of stimulation on a numerical scale. We extracted the latency of the peak pupil dilation and the magnitude of the early (0-2.5 s) and late components (2.5-5 s) of the pupil dilation response (PDR). RESULTS: VNS elicited a peak dilation with longer latency compared to the control condition (p = 0.043). The magnitude of the early PDR was significantly correlated with the intensity of perception (p = 0.046), whereas the late PDR was not (p = 0.19). There was a significant main effect of the VNS level of intensity on the magnitude of the late PDR (p = 0.01) but not on the early PDR (p = 0.2). The relationship between late PDR magnitude and VNS intensity was best fit by a Gaussian model (inverted-U). CONCLUSIONS: The late component of the PDR might reflect specific dose-dependent effects of VNS, as compared to control somatosensory stimulation. The inverted-U relationship of late PDR with VNS intensity might indicate the engagement of antagonist central mechanisms at high stimulation intensities.

No evidence for an effect of selective spatial attention on the development of secondary hyperalgesia: A replication study.

Central sensitization refers to the increased responsiveness of nociceptive neurons in the central nervous system after repeated or sustained peripheral nociceptor activation. It is hypothesized to play a key role in the development of chronic pain. A hallmark of central sensitization is an increased sensitivity to noxious mechanical stimuli extending beyond the injured location, known as secondary hyperalgesia. For its ability to modulate the transmission and the processing of nociceptive inputs, attention could constitute a promising target to prevent central sensitization and the development of chronic pain. It was recently shown that the experimental induction of central sensitization at both forearms of healthy volunteers using bilateral high-frequency electrocutaneous stimulation (HFS), can be modulated by encouraging participants to selectively focus their attention to one arm, to the detriment of the other arm, resulting in a greater secondary hyperalgesia on the attended arm as compared to the unattended one. Given the potential value of the question being addressed, we conducted a preregistered replication study in a well-powered independent sample to assess the robustness of the effect, i.e., the modulatory role of spatial attention on the induction of central sensitization. This hypothesis was tested using a double-blind, within-subject design. Sixty-seven healthy volunteers performed a task that required focusing attention toward one forearm to discriminate innocuous vibrotactile stimuli while HFS was applied on both forearms simultaneously. Our results showed a significant increase in mechanical sensitivity directly and 20 min after HFS. However, in contrast to the previous study, we did not find a significant difference in the development of secondary hyperalgesia between the attended vs. unattended arms. Our results question whether spatial selective attention affects the development of secondary hyperalgesia. Alternatively, the non-replication could be because the bottom-up capture of attention caused by the HFS-mediated sensation was too strong in comparison to the top-down modulation exerted by the attentional task. In other words, the task was not engaging enough and the HFS pulses, including those on the unattended arm, were too salient to allow a selective focus on one arm and modulate nociceptive processing.

Investigating the Origin of TMS-evoked Brain Potentials Using Topographic Analysis.

The combination of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) represents an increasingly popular tool to non-invasively probe cortical excitability in humans. TMS-evoked brain potentials (TEPs) are composed of successive components reflecting the propagation of activity from the site of stimulation, thereby providing information on the state of brain networks. However, TMS also generates peripherally evoked sensory activity which contributes to TEP waveforms and hinders their interpretation.In the present study, we examined whether topographic analysis of TEPs elicited by stimulation of two distinct cortical targets can disentangle confounding signals from the genuine TMS-evoked cortical response. In 20 healthy subjects, TEPs were evoked by stimulation of the left primary motor cortex (M1) and the left angular gyrus (AG). Topographic dissimilarity analysis and microstate analysis were used to identify target-specific TEP components. Furthermore, we explored the contribution of cortico-spinal activation by comparing TEPs elicited by stimulation below and above the threshold to evoke motor responses.We observed topographic dissimilarity between M1 and AG TEPs until approximately 80 ms post-stimulus and identified early TEP components that likely reflect specific TMS-evoked activity. Later components peaking at 100 and 180 ms were similar in both datasets and attributed to sensory-evoked activity. Analysis of sub- and supra-threshold M1 TEPs revealed a component at 17 ms that possibly reflects the cortico-spinal output of the stimulated area. Moreover, supra-threshold M1 activation influenced the topography of almost all later components. Together, our results demonstrate the utility of topographic analysis for the evaluation and interpretation of TMS-evoked EEG responses.

IMI2-PainCare-BioPain-RCT2 protocol: a randomized, double-blind, placebo-controlled, crossover, multicenter trial in healthy subjects to investigate the effects of lacosamide, pregabalin, and tapentadol on biomarkers of pain processing observed by non-invasive neurophysiological measurements of human spinal cord and brainstem activity.

BACKGROUND: IMI2-PainCare-BioPain-RCT2 is one of four similarly designed clinical studies aiming at profiling a set of functional biomarkers of drug effects on specific compartments of the nociceptive system that could serve to accelerate the future development of analgesics. IMI2-PainCare-BioPain-RCT2 will focus on human spinal cord and brainstem activity using biomarkers derived from non-invasive neurophysiological measurements. METHODS: This is a multisite, single-dose, double-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD) and pharmacokinetic (PK) study in healthy subjects. Neurophysiological biomarkers of spinal and brainstem activity (the RIII flexion reflex, the N13 component of somatosensory evoked potentials (SEP) and the R2 component of the blink reflex) will be recorded before and at three distinct time points after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol), and placebo, given as a single oral dose in separate study periods. Medication effects on neurophysiological measures will be assessed in a clinically relevant hyperalgesic condition (high-frequency electrical stimulation of the skin), and in a non-sensitized normal condition. Patient-reported outcome measures (pain ratings and predictive psychological traits) will also be collected; and blood samples will be taken for pharmacokinetic modelling. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split between the two primary endpoints, namely the percentage amplitude changes of the RIII area and N13 amplitude under tapentadol. Remaining treatment arm effects on RIII, N13 and R2 recovery cycle are key secondary confirmatory analyses. Complex statistical analyses and PK-PD modelling are exploratory. DISCUSSION: The RIII component of the flexion reflex is a pure nociceptive spinal reflex widely used for investigating pain processing at the spinal level. It is sensitive to different experimental pain models and to the antinociceptive activity of drugs. The N13 is mediated by large myelinated non-nociceptive fibers and reflects segmental postsynaptic response of wide dynamic range dorsal horn neurons at the level of cervical spinal cord, and it could be therefore sensitive to the action of drugs specifically targeting the dorsal horn. The R2 reflex is mediated by large myelinated non-nociceptive fibers, its circuit consists of a polysynaptic chain lying in the reticular formation of the pons and medulla. The recovery cycle of R2 is widely used for assessing brainstem excitability. For these reasons, IMI2-PainCare-BioPain-RCT2 hypothesizes that spinal and brainstem neurophysiological measures can serve as biomarkers of target engagement of analgesic drugs for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification. TRIAL REGISTRATION: This trial was registered on 02 February 2019 in EudraCT ( 2019-000755-14 ).