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The hippocampus (HPC) and the lateral prefrontal cortex (LPFC) are two cortical areas of the primate brain deemed essential to cognition. Here we hypothesize that the codes mediating neuronal communication in HPC and LPFC microcircuits have distinctively evolved to serve plasticity and memory function at different spatiotemporal scales. We used a virtual reality task in which animals navigated through a maze using a joystick and selected one of two targets in the arms of the maze according to a learned context-color rule. We found that neurons and neuronal populations in both regions encode similar information about the task. Moreover, we demonstrate that many HPC neurons concentrate spikes into bursts, whereas most layer II/III LPFC neurons sparsely distribute spikes over time. As the animals learned the task HPC neurons, but not LPFC neurons, increased their burst rate as a function of performance. When integrating spike rates over short intervals, HPC neuronal ensembles reached maximum decoded information with fewer neurons than LPFC ensembles. Our results show that during associative learning HPC principal cells concentrate spikes in bursts enabling temporal summation and fast synaptic plasticity in small populations of neurons and ultimately facilitating rapid encoding of associative memories. On the other hand, layers II/III LPFC pyramidal cells fire spikes more sparsely distributed in time and over a larger number of neurons. The latter would facilitate broadcasting of signals loaded in short term memory across neuronal populations without necessarily triggering fast synaptic plasticity.

The cause for the increased sensitivity of fibromyalgia (FM) patients to painful stimuli is unclear but sensitization of dorsal horn spinal cord neurons has been suggested. There, critical changes of sensory information occur which depend on the plasticity of second-order neurons and descending pain modulation, including facilitation and inhibition. This study used repetitive stimuli that produce temporal-summation-of-second-pain (TSSP) and central sensitization, relevant mechanisms for patients with chronic pain. We examined spinal cord neural activation during TSSP in FM patients and healthy controls (HC) and used its functional connectivity with several brainstem nuclei to model the observed blood-oxygen-level-dependent (BOLD) time-course with pain ratings. Methods: 16 HC and 14 FM participants received repetitive heat stimuli to the hand at .4 Hz to achieve TSSP during functional imaging with a 3T-Philips Achieva MRI scanner. Stimuli were adjusted to each individual's pain sensitivity to achieve maximal pain ratings of 50 ± 10 on a numerical pain scale (0-100). Using a 16-channel neuro-vascular coil multiple image series were obtained from the cervical spinal cord to the brainstem using single-shot turbo-spin echo sequences. Results: During repetitive, sensitivity-adjusted heat stimuli, pain ratings of all subjects increased as predicted, consistent with TSSP. HC and FM participants had similar temporal patterns of spinal activation: initial BOLD increase followed by de-activation. Structural equation modeling showed that the observed spinal activity during TSSP was associated with more BOLD activity across/within the brainstem in FM subjects than HC, suggesting differences in pain modulation.

Spatial information of nociceptive stimuli applied in the skin of healthy humans is integrated in the spinal cord to determine the appropriate withdrawal reflex response. Double-simultaneous stimulus applied in different skin sites are integrated, eliciting a larger reflex response. The temporal characteristics of the stimuli also modulate the reflex, e.g., by temporal summation. The primary aim of this study was to investigate how the combined tempo-spatial aspects of two stimuli are integrated in the nociceptive system. This was investigated by delivering single- and double-simultaneous stimulation and sequential stimulation with different interstimulus intervals (ISIs ranging 30–500 ms) to the sole of the foot of 15 healthy subjects. The primary outcome measure was the size of the nociceptive withdrawal reflex (NWR) recorded from the tibialis anterior (TA) and biceps femoris (BF) muscles. Pain intensity was measured using a numerical rating scale (NRS) scale. Results showed spatial summation in both TA and BF when delivering simultaneous stimulation. Simultaneous stimulation provoked larger reflexes than sequential stimulation in TA, but not in BF. Larger ISIs elicited significantly larger reflexes in TA, whereas the opposite pattern occurred in BF. This differential modulation between proximal and distal muscles suggests the presence of spinal circuits eliciting a functional reflex response based on the specific tempo-spatial characteristics of a noxious stimulus. No modulation was observed in pain intensity ratings across ISIs. Absence of modulation in the pain intensity ratings argues for an integrative mechanism located within the spinal cord governed by a need for efficient withdrawal from a potentially harmful stimulus. NEW & NOTEWORTHY Tempo-spatial integration of electrical noxious stimuli was studied using the nociceptive withdrawal reflex and a perceived intensity. Tibialis anterior and biceps femoris muscles were differentially modulated by the temporal characteristics of the stimuli and stimulated sites. These findings suggest that spinal neurons are playing an important role in the tempo-spatial integration of nociceptive information, leading to a reflex response that is distributed across multiple spinal cord segments and governed by an efficient defensive withdrawal strategy.

Objectives The literature on conditioned pain modulation (CPM) is inconclusive in relation to low-back pain and it is unclear how CPM affects temporal summation as a proxy of central pain integration. The aim of this study was to examine whether the CPM effect would be different on pain induced by temporal summation than single stimuli in a group of low back pain patients. Methods A total of 149 low-back pain patients were included. CPM was examined using single, repeated and temporal summation (repeated-single difference) of mechanical pressure pain as test stimuli at an individualized, fixed supra-pain-threshold force, before and after 2 min of cold pressor test (0–2 degrees Celsius). Participants were categorized as CPM responders or non-responders according to three different criteria: simple (any pain inhibition), strict (pain inhibition of more than 10VAS) and reversed (pain inhibition or facilitation of less than 10VAS). Clinical data on back pain was collected for correlation and descriptive purposes. Results Significant modulation was observed for all three test stimuli. Effects sizes were comparable in relative terms, but repeated pressure pain modulation was greater in absolute terms. No correlations to clinical data were observed, for any measure. Conclusions The current data suggests that repeated pressure pain may be better suited as the CPM test stimuli, than single pressure pain and temporal summation of pressure pain, as the CPM effect in absolute terms was greater. Employing temporal summation as the test stimulus in a CPM paradigm may be more sensitive than a single test stimulus.

Flat morphology is a general method for obtaining increasing operators on grey-level or multivalued images from increasing operators on binary images (or sets). It relies on threshold stacking and superposition; equivalently, Boolean max and min operations are replaced by lattice-theoretical sup and inf operations. In this paper we consider the construction a flat operator on grey-level or colour images from an operator on binary images that is not increasing. Here grey-level and colour images are functions from a space to an interval in ℝ m or ℤ m (m ≥ 1). Two approaches are proposed. First, we can replace threshold superposition by threshold summation. Next, we can decompose the non-increasing operator on binary images into a linear combination of increasing operators, then apply this linear combination to their flat extensions. Both methods require the operator to have bounded variation, and then both give the same result, which conforms to intuition. Our approach is very general, it can be applied to linear combinations of flat operators, or to linear convolution filters. Our work is based on a mathematical theory of summation of real-valued functions of one variable ranging in a poset. In a second paper, we will study some particular properties of non-increasing flat operators.

Green stimuli are more difficult to detect than red stimuli in the retinal periphery, as reported previously. We examined the spatial characteristics of chromatic mechanisms using stimuli, modulated from an achromatic background to each pole of the “red–green” cardinal axis in DKL space at 20 deg eccentricity. The “blue–yellow” cardinal axis was also studied for comparison. By measuring both grating discrimination at the resolution limit (resolution acuity) and spatial summation, assessed by the Michaelis–Menten function, we demonstrated a marked “red–green” asymmetry. The resolution acuity was worse and spatial summation more extended for “green” compared to “red” stimuli, while showing significant individual variations. Ricco’s area was also measured, but not determined for “green” spots because of the poor small stimuli detection. These results cannot be explained by differences in L- and M-cone numerosity and/or spatial arrangement, but rather have postreceptoral origin, probably at the cortical level.

Background and Aims: Spinal manipulation (SM) is currently recommended for the management of back pain. Experimental studies indicate that the hypoalgesic mechanisms of SM may rely on inhibition of segmental processes related to temporal summation of pain and, possibly, on central sensitization, although this remains unclear. The aim of this study was to determine whether experimental back pain, secondary hyperalgesia, and pain-related brain activity induced by capsaicin are decreased by segmental SM.Methods: Seventy-three healthy volunteers were randomly allocated to one of four experimental groups: SM at T5 vertebral level (segmental), SM at T9 vertebral level (heterosegmental), placebo intervention at T5 vertebral level, or no intervention. Topical capsaicin was applied to the area of T5 vertebra for 40 min. After 20 min, the interventions were administered. Pressure pain thresholds (PPTs) were assessed outside the area of capsaicin application at 0 and 40 min to examine secondary hyperalgesia. Capsaicin pain intensity and unpleasantness were reported every 4 min. Frontal high-gamma oscillations were also measured with electroencephalography.Results: Pain ratings and brain activity were not significantly different between groups over time (p > 0.5). However, PPTs were significantly decreased in the placebo and control groups (p < 0.01), indicative of secondary hyperalgesia, while no hyperalgesia was observed for groups receiving SM (p = 1.0). This effect was independent of expectations and greater than placebo for segmental (p < 0.01) but not heterosegmental SM (p = 1.0).Conclusions: These results indicate that segmental SM can prevent secondary hyperalgesia, independently of expectations. This has implications for the management of back pain, particularly when central sensitization is involved.

Capacity for modulation of incoming nociceptive signals is a determinant of our tendency to attend to pain., Introduction: Evidence suggests that attention to pain is a product of both incoming sensory signals and cognitive evaluation of a stimulus. Intrinsic attention to pain (IAP) is a measure that captures an individual's natural tendency to attend to a painful stimulus and may be important in understanding why pain disrupts cognitive functioning in some individuals more than others. Objective: In this study, we explored the extent to which IAP was associated with the modulation of incoming sensory signals characteristic of a pronociceptive phenotype: temporal summation (TS) and conditioned pain modulation (CPM). Method: 44 healthy participants (23 female; Mage=23.57, S.D.=5.50) were assessed on IAP, TS and CPM. Results: We found that IAP was positively correlated with TS and CPM. A regression model showed that TS and CPM explained 39% of the variance in IAP scores. Both mechanisms seem to contribute independently to the propensity to attend to pain. Conclusion: These findings highlight that modulatory mechanisms at the spinal/supraspinal level exert a strong influence on an individual's ability to disengage from pain.

Background: Diabetic neuropathy is characterized by the paradoxical co-existence of hypo- and hyperalgesia to sensory stimuli. The literature shows consistently sensory differences between healthy and participants with diabetes. We hypothesized that due to differences in pathophysiology, advanced quantitative sensory testing (QST) might reveal sensory discrepancies between type 1 (T1D) and type 2 diabetes (T2D). Furthermore, we investigated whether vibration detection thresholds (VDT) were associated with sensory response.Method: Fifty-six adults with T1D [43 years (28–58)], 99 adults with T2D [65 years (57–71)], and 122 healthy individuals [51 years (34–64)] were included. VDT, pressure pain detection thresholds (pPDT) and tolerance (pPTT), tonic cold pain (hand-immersion in iced water), and central pain mechanisms (temporal summation and conditioned pain modulation) were tested and compared between T1D and T2D. VDT was categorized into normal (< 18 V), intermediary (18–25 V), or high (> 25 V).Results: In comparison to healthy, analysis adjusted for age, BMI, and gender revealed hypoalgesia to tibial (pPDT): p = 0.01, hyperalgesia to tonic cold pain: p < 0.01, and diminished temporal summation (arm: p < 0.01; abdomen: p < 0.01). In comparison to participants with T2D, participants with T1D were hypoalgesic to tibial pPDT: p < 0.01 and pPTT: p < 0.01, and lower VDT: p = 0.02. VDT was not associated with QST responses.Conclusion: Participants with T1D were more hypoalgesic to bone pPDT and pPTT independent of lower VDT, indicating neuronal health toward normalization. Improved understanding of differentiated sensory profiles in T1D and T2D may identify improved clinical endpoints in future trials.

Background/Introduction Most patients with atrial fibrillation (AF) report symptoms, while around one-third are asymptomatic. We hypothesized that sensory processing, in particular pain, differs in patients with symptomatic and asymptomatic AF. Purpose To assess differences in pain sensitisation in patients with symptomatic and asymptomatic AF. Methods Thirty individuals with permanent AF (15 symptomatic, 15 asymptomatic) completed the AF6 and SF-36 questionnaires and underwent quantitative pain sensitisation testing using pressure algometry at the sternum (referred pain area) and the tibialis anterior muscle (generalized pain area). The primary objective was to assess differences in pressure pain thresholds (PPT), temporal summation of pain (TSP), and conditioned pain modulation (CPM) in the two groups. The secondary objective was to determine association of demographic and clinical parameters to quantitative measures of pain sensitisation. Results The symptomatic group had lower PPTs at both tibialis (p=0.004) and sternum (p=0.01), as well as impaired CPM (p=0.025) and facilitated TSP (p=0.008) at the tibialis but not sternum, compared to the asymptomatic group. The AF6 sum score was negatively correlated to PPT on both tibialis (r=−0.50, p=0.005) and sternum (r=−0.42, p=0.02) and positively correlated to TSP of both tibialis (r=0.57, p=0.001) and sternum (r=0.45, p=0.01), but not to CPM. The physical component summary score was positively correlated to the PPT on both tibialis (r=0.52, p=0.003) and sternum (r=0.40, p=0.03) and negatively to TSP on the tibialis (r=−0.53, p=0.003) but not sternum. Conclusions Patients with symptomatic AF exhibit lower pain tolerance than patients with asymptomatic AF, as well as impaired pain inhibitory control and facilitated summation of pain, indicating that pain sensitisation may be of importance in symptomatic AF. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Department of Cardiology, Örebro University, Sweden PPTs tibialis anterior musclePPTs sternum

Individuals who engage in nonsuicidal self-injury (NSSI) have demonstrated higher pain thresholds and tolerance compared with individuals without NSSI. The objective of the study was to assess which aspects of the pain regulatory system that account for this augmented pain perception. In a cross-sectional design, 81 women, aged 18-35 (mean [SD] age, 23.4 [3.9]), were included (41 with NSSI and 40 healthy controls). A quantitative sensory testing protocol, including heat pain thresholds, heat pain tolerance, pressure pain thresholds, conditioned pain modulation (assessing central down-regulation of pain), and temporal summation (assessing facilitation of pain signals) was used. Thermal pain stimuli were assessed during fMRI scanning and NSSI behaviors and clinical symptoms were self-assessed. NSSI participants demonstrated higher pain thresholds during heat and pressure pain compared to controls. During conditioned pain modulation, NSSI participants showed a more effective central down-regulation of pain for NSSI participants. Temporal summation did not differ between the groups. There were no correlations between pain outcomes and NSSI behaviors or clinical characteristics. The fMRI analyses revealed increased activity in the primary and secondary somatosensory cortex in NSSI participants, compared to healthy controls, which are brain regions implicated in sensory aspects of pain processing. The findings suggest segregated inhibitory mechanisms for pain and emotion in NSSI, as pain insensitivity was linked to enhanced inhibitory control of pain in spite of significant impairments in emotion regulation. This may represent an endophenotype associated with a greater risk for developing self-injurious behavior.

Data Availability Statement The ASIC presented in this study is available through SCIENTIFICA INTERNATIONAL, S.L.U. Check the website: https://www.scientifica.es/, accessed on 1 January 2021., The 8-channel Multiple Use Silicon Photo-multiplier (SiPM) Integrated Circuit (MUSIC) Application specific integrated circuit (ASIC) for SiPM anode readout has been designed for applications where large photo-detection areas are required. MUSIC offers three main features: (1) Sum of the eight input channels using a differential output driver, (2) eight individual single ended (SE) analog outputs, and (3) eight individual SE binary outputs using a time over threshold technique. Each functionality, summation and individual readout includes a selectable dual-gain configuration. Moreover, the signal sum implements a dual-gain output providing a 15-bit dynamic range. The circuit contains a tunable pole zero cancellation of the SiPM recovery time constant to deal with most of the available SiPM devices in the market. Experimental tests show how MUSIC can linearly sum signals from different SiPMs and distinguish even a few photons. Additionally, it provides a single photon output pulse width at half maximum (FWHM) between 5–10 ns for the analog output and a single-photon time resolution (SPTR) around 118 ps sigma using a Hamamatsu SiPM S13360-3075CS for the binary output. Lastly, the summation mode has a power consumption of ≈200 mW, whereas the individual readout consumes ≈30 mW/ch., Marc Ribó acknowledges support by the Spanish Ministerio de Ciencia, Innovación y Universidades (MICINN), grant FPA2017-82729-C6-2-R (AEI/FEDER, UE) and grant PID2019-104114RB-C33/AEI/10.13039/501100011033. We also acknowledge financial support from the State Agency for Research of the Spanish Ministry of Science and Innovation through the “Unit of Excellence María de Maeztu 2020-2023” award to the Institute of Cosmos Sciences (CEX2019-000918-M).

Steven M Falowski, Alexander Benison Neurosurgical Associates of Lancaster, Lancaster, PA, USACorrespondence: Steven M FalowskiDirector Functional Neurosurgery, Neurosurgical Associates of Lancaster, 160 N Pointe Blvd Suite 200, Lancaster, PA, 17601 Tel +44-358-0800Email sfalowski@gmail.comBackground: Intraoperative neuromonitoring (IONM) for spinal cord stimulation (SCS) uses electromyography (EMG) responses to determine myotomal coverage as a marker for dermatomal coverage.Objective: These responses can be utilized to evaluate the effects of stimulation platforms on the nervous system.Methods: Eight patients were tested at inter-burst frequencies of 10 Hz, 20 Hz, 30 Hz, and 40 Hz using DeRidder Burst stimulation to determine the amplitude of onset of post-synaptic signal generation. Three patients had additional data recording amplitude of onset of tonic stimulation prior to and post DeRidder Burst stimulation at each inter-burst frequency. This represented post-synaptic excitability.Results: In all patients, the DeRidder Burst waveform generated EMG responses under all inter-burst frequencies including temporal summation, deeper fiber recruitment, and compounded action potentials. There was a non-significant decrease of 7.6– 7.8% in amplitudes to generate response under 40 Hz, compared to the other frequencies. However, there was a 73.1% reduction in energy requirements at 10 Hz. The enhanced post-synaptic excitability effect was demonstrated at all frequencies.Conclusion: DeRidder Burst has similar effects of temporal summation, deeper fiber recruitment, and compounded action potentials under IONM at 40 Hz, 30 Hz, 20 Hz, and 10 Hz. In addition, the hyperexcitability phenomenon was also observed regardless of the frequency. This demonstrates that postsynaptic responses captured via IONM may be a sensitive biomarker to SCS mechanism of action. In addition, lower inter-burst frequencies may have a similar clinical effect on pain relief thus reducing power consumption even further than current dosing paradigms.Keywords: electromyogram, EMG, SCS, somatosensory evoked potentials, spinal cord stimulation, SSEPS, Burst, DeRidder Burst

Objective Endogenous pain modulation can be quantified through the use of various paradigms. Commonly used paradigms include conditioned pain modulation (CPM), offset analgesia (OA), spatial summation of pain (SSP), and temporal summation of pain (TSP), which reflect spatial and temporal aspects of pro- and antinociceptive processing. Although these paradigms are regularly used and are of high clinical relevance, the underlying physiological mechanisms are not fully understood. Design The aim of this study is therefore to assess the association between these paradigms by using comparable protocols and methodological approaches. Setting University campus. Subjects Healthy and pain-free volunteers (n = 48) underwent psychophysical assessment of CPM, OA, SSP, and TSP (random order) at the same body area (volar nondominant forearm) with individualized noxious stimuli. Methods CPM included heat stimuli before, during, and after a noxious cold-water bath, whereas for OA, three heat stimuli were applied: baseline trial, offset trial, and constant trial. For the SSP paradigm, two differently sized heat stimulation areas were evaluated, whereas for TSP, the first and last stimulus of 10 consecutive short heat stimuli were assessed. A computerized visual analog scale was used to continuously evaluate pain intensity. The magnitudes of all associations between all paradigm pairs were analyzed with Spearman’s correlation, and individual influencing factors were assessed with a multivariate linear regression model. Results Weak to moderate correlations among all four paradigms were found (P > 0.05), and no distinct influencing factors were identified. Conclusions A limited association between pain modulation paradigms suggests that CPM, OA, SSP, and TSP assess distinct aspects of endogenous analgesia with different underlying physiological mechanisms.

Introduction: Quantitative sensory testing is frequently used in research to assess endogenous pain modulation mechanisms, such as Temporal Summation (TS) and Conditioned Pain Modulation (CPM), reflecting excitatory and inhibitory mechanisms, respectively. Numerous studies found that a dysregulation of these mechanisms is associated with chronic pain conditions. In turn, such a patient's “profile” (increased TS and/or weakened CPM) could be used to recommend different pharmacological treatments. However, the procedure to evaluate these mechanisms is time-consuming and requires expensive equipment that is not available in the clinical setting. In this study, we aim to identify psychological, physiological and socio-demographic markers that could serve as proxies to allow healthcare professionals to identify these pain phenotypes in clinic, and consequently optimize pharmacological treatments.Method: We aim to recruit a healthy participant cohort (n = 360) and a chronic pain patient cohort (n = 108). Independent variables will include psychological questionnaires, pain measurements, physiological measures and sociodemographic characteristics. Dependent variables will include TS and CPM, which will be measured using quantitative sensory testing in a single session. We will evaluate one prediction model and two validation models (for healthy and chronic pain participants) using multiple regression analysis between TS/CPM and our independent variables. The significance thresholds will be set at p = 0.05, respectively.Perspectives: This study will allow us to develop a predictive model to compute the pain modulation profile of individual patients based on their biopsychosocial characteristics. The development of the predictive model is the first step toward the overarching goal of providing clinicians with a set of quick and cheap tests, easily applicable in clinical practice to orient pharmacological treatments.

Center-surround antagonism, as a ubiquitous feature in visual processing, usually leads to inferior perception for a large stimulus compared to a small one. For example, it is more difficult to judge the motion direction of a large high-contrast pattern than that of a small one. However, this spatial suppression in the motion dimension was only reported for luminance motion, and was not found for chromatic motion. Given that center-surround suppression only occurs for strong visual inputs, we hypothesized that previous failure in finding spatial suppression of chromatic motion might be due to weak chromatic motion being induced with stimuli of limited parameters. In this study, we used phase-shift discrimination and motion-direction discrimination tasks to measure motion spatial suppression induced by stimuli of two spatial frequencies (0.5 and 2 cpd) and two contrasts (low and high). We found that spatial suppression of the chromatic motion was stably observed for stimuli of high spatial frequency (2 cpd) and high contrast and spatial summation occurred for stimuli of low spatial frequency (0.5 cpd). Intriguingly, there was no correlations between the motion spatial suppressions of luminance motion and chromatic motion, implying that the two types of spatial suppression are not originated from the same neural processing. Our findings indicate that spatial suppression also exists for chromatic motion, and the mechanisms underlying the spatial suppression of chromatic motion is different from that of luminance motion.

BackgroundEnhanced temporal summation (TS), measured through self-reported pain ratings, has been interpreted as indicative of central sensitisation in fibromyalgia. Greater TS in patients, however, has not been universally observed. It is also unclear whether increased pain report maintains beyond the TS period.MethodsIn this study, we measured TS through continuously reported pain ratings. Fibromyalgia-diagnosed patients (n = 17) and matched pain-free controls (n = 13) rated painful transcutaneous electrical stimulation of various intensity levels in 18 one-minute-long blocks. Pain was rated on a 101-point visual analogue scale. The resulting continuous response was divided into TS (< 15s) and adaptation (15 – 60s) periods. Average pain values were extracted for each period alongside the timing of key events such as maximal pain ratings. The difference in temporal summation and adaptation measures between fibromyalgia and control participants was analysed using mixed-effects modelling.ResultsThe average pain ratings for TS and adaptation periods were not significantly associated with fibromyalgia diagnosis but were with stimulation intensity. The same was true for the magnitude of the maximal rating during TS and the slope leading to that peak rating. The presence of fibromyalgia, however, did predict the time of the maximal TS rating, as well as the value and the time of the maximal adaptation rating.ConclusionsOur study did not find homogeneously increased TS pain ratings. Instead, by utilising continuous pain data we demonstrate for the first time that the time of TS peak rating, as well as the magnitude and time of adaptation peak rating are linked to fibromyalgia diagnosis.

Background: manual therapy (MT) has been shown to have positive effects in patients with osteoarthritis (OA)-related pain, and its use in clinical settings is recommended. However, the mechanisms of action for how these positive effects occur are not yet well understood. The aim of the present study was to investigate the influence of MT treatment on facilitatory nociception and endogenous pain modulation in patients with knee OA related pain. Methods: Twenty-eight patients with knee OA were included in this study. Pain intensity using the numerical pain rating scale (NPRS), temporal summation (TS), conditioned pain modulation (CPM), and local (knee) and distant (elbow) hyperalgesia through the pressure pain threshold (PPT), were assessed to evaluate the pain modulatory system. Patients underwent four sessions of MT treatments within 3 weeks and were evaluated at the baseline, after the first session and after the fourth session. Results: the MT treatment reduced knee pain after the first session (p = 0.03) and after the fourth session (p = 0.04). TS decreased significantly after the fourth session of MT (p = 0.02), while a significant increase in the CPM assessment was detected after the fourth session (p = 0.05). No significant changes in the PPT over the knee and elbow were found in the follow-ups. Conclusions: The results from our study suggest that MT might be an effective and safe method for improving pain and for decreasing temporal summation. European University of Madrid, Villaviciosa de Odón, Madrid 2.838 Q2 JCR 2021 0.507 Q2 SJR 2021 No data IDR 2021 UEM

PURPOSE: To examine the effect of preloading eccentric exercise on pain sensitivity in healthy volunteers. METHODS: In 20 healthy volunteers, pain-related sensations (6 items: pain, unpleasantness, fatigue, stiffness, tension, and soreness during maximum biting), and pain intensities induced by repeated electrical stimuli on the masseter and the hand palm were evaluated using a visual analog scale (VAS) of 0-100 mm. Eccentric exercise (6 min-test) or gum chewing (6 min-control) was used as preloading exercise to evaluate the effect on pain sensitivities before and after low-level clenching (15 min) performed 2 days after the preloading exercise. RESULTS: Eccentric exercise induced only low levels of pain-related sensations 2 days later. However, the time course of temporal summation induced by four repeated electrical stimuli on the masseter was influenced by the type of preloading exercise, i.e., temporal summation increased after the low-level clenching (P = 0.016) when preloading was done by the eccentric exercise, while no significant change was observed when preloading was done by the gum chewing. CONCLUSIONS: Eccentric exercise may facilitate pain sensitivity induced by subsequent low-level clenching via the central nervous system. In addition, it was demonstrated that pain sensitivity after the low-level clenching could be influenced by the type of preloading exercise. These experimental results may suggest that eccentric exercise could act as one of the triggering factors in the mechanism by which tooth clenching leads to a chronic pain condition in susceptible individuals. ispartof: ODONTOLOGY vol:109 issue:1 pages:29-40 ispartof: location:Japan status: published

Electrotactile displays provide tactile feedback using electrical currents. However, prolonged usage of them causes skin irritation and burns. This study presents a novel method to use the electrotactile display at a lower threshold by applying two subthreshold electrotactile stimuli placed nearby. This method is tested on fourteen subjects over a frequency range from 20 to 1280 Hz in the tuning curve. Two Psychophysical experiments have been conducted to measure their thresholds for individual stimuli and presented together. In the first experiment, the frequencies of both the stimuli were the same, and it showed 36% to 18% reduction in EPT of the second stimulus when the first stimulus was at 10% to 50% of its threshold. In the second experiment, Meissner and Pacinian were selectively stimulated by applying stimuli at their resonant frequencies (30 and 250 Hz, respectively), results showed slightly more reduction in the case of 250 Hz compared to 30 Hz.

Objective Pain sensitization is associated with pain severity in persons with hand OA. What contributes to pain sensitization is unclear. This study explores whether hand OA pathologies and symptom duration are related to central sensitization. Method Participants with hand OA in the Nor-Hand study underwent bilateral hand radiography and US examination. Central sensitization was assessed with pressure pain thresholds (PPT) at remote sites (wrist, trapezius and tibialis anterior muscles) and temporal summation. We examined whether hand OA pathologies, independent of each other, including structural severity (Kellgren–Lawrence sum score, presence of erosive hand OA), inflammatory severity (greyscale synovitis and power Doppler activity sum scores) and symptom duration, were related to central sensitization, adjusting for age, sex, BMI, comorbidities and OA-severity of knee/hip. Results In 291 participants (88% women, median age 61 years, interquartile range 57–66 years) Kellgren–Lawrence, greyscale synovitis and power Doppler activity sum scores were not associated with lower PPTs at remote sites. Persons with erosive hand OA had lower PPTs at the wrist (adjusted beta −0.75, 95% CI −1.32, −0.19) and tibialis anterior (adjusted beta −0.82, 95% CI −1.54, −0.09) and had greater temporal summation (adjusted beta 0.56, 95% CI 0.12, 1.01) compared with persons with non-erosive disease. No associations were found for symptom duration. Conclusions A person’s overall amount of structural or inflammatory hand OA pathologies was not associated with central sensitization. Although persons with erosive hand OA showed greater signs of central sensitization, the small differences suggest that central sensitization is mainly explained by factors other than joint pathologies.

Background Water treadmills are frequently used in the rehabilitation of dogs, for example with the purpose of re-building muscular strength after surgery. However, little is known about how different water depths and velocities affect the muscular workload during aquatic locomotion. This study used acoustic myography to assess hind limb muscle fiber activation in 25 healthy large-breed dogs walking in a water treadmill. Acoustic myography sensors were attached to the skin over the vastus lateralis of the quadriceps and the biceps femoris muscles. The dogs walked at two velocities (30 and 50 m/min) and four water depths: bottom of the pads, hock, stifle and mid-femur. Acoustic myograph signals were analyzed for changes in three muscle function parameters: efficiency/coordination (E-score) and spatial (S-score) and temporal (T-score) summation. Results Differences between E, S, and T were statistically significant compared across different speeds (30, 50) and water levels (0, 1, 2, 3) using a one-way ANOVA with multiple comparisons (Tukey; Geisser-Greenhouse correction) as well as a two-tailed one sample t-test. At 50 m/min in water at the mid-femur, the biceps femoris was less efficient (P Conclusion More muscle activation was required to walk in water at a depth at the level of the mid-femur compared to shallower water, and this exercise was more demanding for the biceps femoris, a muscle engaged in propulsion, than for vastus lateralis. These findings may help practitioners towards making more precise rehabilitation protocols.

Saccadic eye movements can drastically affect motion perception: during saccades, the stationary surround is swept rapidly across the retina and contrast sensitivity is suppressed. However, after saccades, contrast sensitivity is enhanced for color and high-spatial frequency stimuli and reflexive tracking movements known as ocular following responses (OFR) are enhanced in response to large field motion. Additionally, OFR and postsaccadic enhancement of neural activity in primate motion processing areas are well correlated. It is not yet known how this postsaccadic enhancement arises. Therefore, we tested if the enhancement can be explained by changes in the balance of centre-surround antagonism in motion processing, where spatial summation is favoured at low contrasts and surround suppression is favoured at high contrasts. We found motion perception was selectively enhanced immediately after saccades for high spatial frequency stimuli, consistent with previously reported selective postsaccadic enhancement of contrast sensitivity for flashed high spatial frequency stimuli. The observed enhancement was also associated with changes in spatial summation and suppression, as well as contrast facilitation and inhibition, suggesting that motion processing is augmented to maximise visual perception immediately after saccades. The results highlight that spatial and contrast properties of underlying neural mechanisms for motion processing can be affected by an antecedent saccade for highly detailed stimuli and are in line with studies that show behavioural and neuronal enhancement of motion processing in non-human primates.

Background: In horses, therapeutic ultrasound has been shown to be beneficial for suspensory ligament injuries, and more generally to stimulate tissue repair and reduce localized pain. However, it has yet to be examined in relation to soft tissue injuries sustained during competition or in connection with rider/saddle interactions. Aim: The aim of the present study was to examine the efficacy of topical low-frequency therapeutic ultrasound on the shoulder muscles of injured horses. Methods: Muscle mass and cellular health was assessed for M. trapezius using non-invasive multi-frequency bioimpedance, and dynamic improvements in M. trapezius and M. latissimus dorsi were examined using acoustic myography (AMG). A total of 8 injured horses (painful to palpation and atrophied) were treated using an EQ Pro Therapy unit, following a set protocol that comprised treatment every other day for 10 treatments. Pre-treatment values were then compared with post-treatment measurements (1 & 6 months later). Results: The mfBIA results for M. trapezius showed a significant improvement (P 0.05) of EQ Pro Therapy treatment for the membrane capacitance (Mc) and phase angle (PA) parameters when comparing the Pre vs Post 1 and Post 1 vs Post 2 measurements. Similar improvements were seen for the AMG measurements for M. trapezius and M. latissimus dorsi where statistically significant improvements in the muscle efficiency (E-score) and temporal summation (T-score) as well as the spatial summation (S-score) and mean of the ST-scores were noted (P 0.05 to P 0.01). Conclusion: The present findings suggest that EQ Pro Therapy treatment is efficacious in terms of equine cases involving soft tissue shoulder muscle injuries (painful to palpation and atrophied). The main improvements noted were not only increased muscle mass and cellular health but also improved force production, better coordination, and lateral balance, which persisted for at least six months after treatment.

Purpose Loss of ganglion cell inner plexiform layer (GCIPL) and visual sensitivity in the macula region are known to occur at all stages of glaucoma. While both are dependent on the underlying retinal ganglion cells (RGCs), the relationship between structure and function is modest. We hypothesize that the imprecise relationship is due to a lack of direct correspondence between in vivo measures and RGC counts, as well as the relatively large stimulus size used by standard perimetry, which exceeds spatial summation. Methods The relationship between optical coherence tomography (OCT)-derived GCIPL thickness and corresponding inner cell density from retinal flat mounts was determined for four nonhuman primates with varying stages of neuropathy. Normative data for 10-2 threshold using Goldman size I to V stimuli were established for 10 animals, 4 of which were then followed longitudinally with OCT and perimetry. The relationship between GCIPL volume, which incorporated stimulus size after removal of residual thickness, and differential light sensitivity was determined for both experimental glaucoma and healthy eyes. Results Peak inner retinal cell density was 63,052 ± 9238 cells/mm2 in the healthy eye. Cell density was related to both GCIPL thickness and eccentricity (R2 = 0.74, P < .01). For all 10-2 eccentricities, size III stimuli were greater than the critical area (P < 0.01). Based on the structural and histologic relationship, the critical area corresponds to approximately 156 RGCs. Conclusions The relationship between cell density and GCIPL thickness is dependent on retinal eccentricity. For 10-2 perimetry, perimetric loss, especially at earlier stages of neuropathy, may best be detected using size II or smaller stimuli.

This article belongs to the Special Issue Applications of Neuromodulation on Pain and Motor Learning., Percutaneous electrolysis consists of the application of a galvanic electrical current throughout an acupuncture needle. It has been previously hypothesized that needling procedures’ neurophysiological effects may be related to endogenous pain modulation (EPM). This protocol study describes the design of a double-blind (participant, assessor) randomized controlled trial with the aim to investigate whether percutaneous electrolysis is able to enhance EPM and whether the effect is different between two applications depending on the dosage of the galvanic electrical current. Seventy-two asymptomatic subjects not reporting the presence of pain symptoms the previous 6 months before the study, aged 18–40 years, are randomized into one of four groups: a control group who does not receive any intervention, a needling group who receives a needling intervention without electrical current, a low-intensity percutaneous electrolysis group (0.3 mA × 90 s), and a high-intensity percutaneous electrolysis group (three bouts of 3 mA × 3 s). Needling intervention consists of ultrasound-guided insertion of the needle on the common extensor tendon of the lateral epicondyle. The primary outcome is conditioned pain modulation (CPM), and secondary outcomes include widespread pressure pain sensitivity (pressure pain thresholds (PPT) over the lateral epicondyle, the cervical spine, and the tibialis anterior muscle) and temporal summation (TS). We expected that percutaneous electrolysis would have a greater influence on CPM than an isolated needling procedure and no intervention. In addition, we also postulated that there might be differences in outcome measures depending on the intensity of the electrical current during the percutaneous electrolysis application. This study makes a new contribution to the field of neurophysiological effects of percutaneous electrolysis and needling interventions.

Background: Conditioned pain modulation (CPM) methods are experimental procedures to assess presumed descending nociceptive modulatory pathways. Various CPM-methods are currently used, making the comparison of results difficult. The aim of this study was to compare five conditioning stimuli and to evaluate the influencing effects of personal factors on CPM-efficacy. Methods: 101 healthy pain-free adults (50 males, 51 females) participated in this cross-sectional study with repeated measures design. The CPM-method consisted of hot water immersion (46°C, HWI), cold pressor test (12°C, CPT), cold pack application, and single and double ischemic occlusion as conditioning stimuli in randomized order. Pressure pain threshold was used as test stimulus at the mm. trapezius and quadriceps for all CPM-protocols. Results: All CPM-protocols resulted in effective CPM, although cold pack application revealed smaller CPM-magnitudes compared to all other methods at both muscles, except single ischemic occlusion at the m. quadriceps. A smaller CPM-effect at the m. trapezius was shown when CPM was provoked by single ischemic occlusion compared to the CPT. Chronic stress, gender, attentional focus, age, physical activity and perceived pain are all influencing factors, in various conditioning stimuli at the mm. trapezius and quadriceps. Conclusions: CPT and HWI seem to be the most appropriate conditioned pain modulation paradigms for research settings, while single and double ischemic occlusion seem to be more useful for clinical settings. Influencing factors to be considered are gender, age, stress, physical activity, perceived pain and attentional focus to the conditioning stimulus, but depend on the test site and exerted method. Significance: Hot water immersion, cold pressor test, and single and double ischemic occlusion result in comparable CPM-effects at the mm. trapezius and quadriceps. Anti-nociceptive effects of the cold pack are mainly a result of attention towards the cold pack. Chronic stress, attentional focus towards the conditioning stimulus and perceived pain of the conditioning stimulus influenced the anti-nociceptive effects at the m. trapezius. Gender and level of physical activity influenced the anti-nociceptive effects with the other methods at the m. quadriceps.

Improving the ability to predict persistent pain after spine surgery would allow identification of patients at risk and guide treatment decisions. Quantitative sensory tests (QST) are measures of altered pain processes, but in our previous study, preoperative QST did not predict pain and disability at single time-points. Trajectory analysis accounts for time-dependent patterns. We hypothesized that QST predict trajectories of pain and disability during 1 year after low back surgery. We performed a trajectory analysis on the cohort of our previous study (n = 141). Baseline QST included electrical, pressure, heat, and cold stimulation of the low back and lower extremity, temporal summation, and conditioned pain modulation. Pain intensity and Oswestry Disability Index were measured before, and 2, 6, and 12 months after surgery. Bivariate trajectories for pain and disability were computed using group-based trajectory models. Multivariable regressions were used to identify QST as predictors of trajectory groups, with sociodemographic, psychological, and clinical characteristics as covariates. Cold pain hypersensitivity at the leg, not being married, and long pain duration independently predicted worse recovery (complete-to-incomplete, incomplete-to-no recovery). Cold pain hypersensitivity increased the odds for worse recovery by 3.8 (95% confidence intervals 1.8-8.0, P < 0.001) and 3.0 (1.3-7.0, P = 0.012) in the univariable and multivariable analyses, respectively. Trajectory analysis, but not analysis at single time-points, identified cold pain hypersensitivity as strong predictor of worse recovery, supporting altered pain processes as predisposing factor for persisting pain and disability, and a broader use of trajectory analysis. Assessment of cold pain sensitivity may be a clinically applicable, prognostic test.

The human visual system is continuously exposed to a natural environment with static and moving objects that the visual system needs to continuously integrate and process. Glass patterns (GPs) are a class of visual stimuli widely used to study how the human visual system processes and integrates form and motion signals. GPs are made of pairs of dots that elicit a strong percept of global form. A rapid succession of unique frames originates dynamic GPs. Previous psychophysical studies showed that dynamic translational GPs are easier to detect than the static version because of the spatial summation across the unique frames composing the pattern. However, it is not clear whether the same mechanism is involved in dynamic circular GPs. In the present study, we psychophysically investigated the role of the temporal and spatial summation in the perception of both translational and circular GPs. We manipulated the number of unique frames in dynamic GPs and the update rate of the frames presentation. The results suggest that spatial and temporal summation across unique frames takes place for both translational and circular GPs. Moreover, the number of unique frames and the pattern update rate equally influence the discrimination thresholds of translational and circular GPs. These results show that form and motion integration is likely to be processed similarly for translational and circular GPs.

Highlights • The combination of heat and TENS significantly improves pain pressure thresholds. • The combination of heat and TENS does not affect maximum and average pain, nor movement-evoked pain (MEP). • There is a need for standardized and sensitive assessment tools for measuring MEP., Background Low back pain is the leading cause of disability worldwide. The therapeutic management of patients with chronic LBP is challenging. Objectives The aim of this study is to evaluate the effects of heat and transcutaneous electrical nerve stimulation combined on pain relief in participants with chronic low back pain. Methods Fifty participants with chronic (≥3 months) low back pain were randomly assigned to two groups: HeatTens (n = 25) and control group (n = 25). Primary outcome was pain. Secondary outcomes were pressure pain thresholds, temporal summation, conditioned pain modulation, fear-avoidance and beliefs questionnaire, central sensitization inventory, quality of life, and medication use. The control group received no treatment and continued usual care. After four weeks of treatment, all measurements were repeated. Results Fifty individuals participated in this study. Significant higher pressure pain threshold measures after both 30 min and 4 weeks for the lower back region and the second plantar toe were found only in the experimental group. Conclusion The combination of heat and transcutaneous electrical nerve stimulation does not reduce pain scores in patients with chronic low back pain. Pressure pain threshold values significantly improved, showing beneficial effects of the experimental treatment. ClinicalTrials.gov: NCT03643731 (https://clinicaltrials.gov/ct2/show/NCT03643731).

BackgroundExercise is recommended to promote and maintain health and as treatment for more than 25 diseases and pain conditions. Exercise-induced hypoalgesia (EIH), a measure of descending pain inhibitory control, has been found to be impaired in some chronic pain conditions, but it is currently unclear if EIH is modifiable. This study investigated whether a long-term exercise intervention could modulate EIH in healthy subjects.MethodsIn 38 healthy subjects, EIH was assessed as change in pressure pain threshold (PPT) after a three-minute isometric wall squat within the first week and after approximately seven weeks of military training (MT). Further, temporal summation of pain (TSP) and Knee injury and Osteoarthritis Outcome Score (KOOS) were assessed. Physical performance capacity was assessed using the Endurance 20-m shuttle run fitness test (20MSR). Hypoalgesic (EIH > 0.0 kPa) and hyperalgesic (EIH ≤ 0.0 kPa) subgroups were defined based on baseline EIH. Change in EIH following MT was used as the primary outcome.ResultsIncreased EIH (P = 0.008), PPT (P 0.05). Subjects with a hyperalgesic EIH response at baseline (26% of the participants) presented significantly improved EIH following MT (P = 0.010). Finally, an association between 20MRS change and EIH change was found (r = 0.369, P = 0.023).ConclusionsMT increased EIH, especially in subjects who demonstrated a hyperalgesic response at baseline. Improvement in physical performance capacity was associated with an improvement in EIH, indicating that improvement in physical performance capacity may improve central pain mechanisms.

AIMS To evaluate the influence of self-reported physical activity level on painful mechanical somatosensory profile and psychosocial characteristics. METHODS A total of 90 participants, male and female, were divided into three groups based on the frequency, duration, and intensity of physical activity over the last 3 months. The classification followed a modified criterion of the short version of the International Physical Activity Questionnaire (IPAQ). Mechanical quantitative sensory tests were performed in the region of the anterior temporalis muscle and on the thenar area of the dominant hand, and psychosocial aspects were assessed using questionnaires measuring state and trait anxiety, pain catastrophizing, lifestyle, and quality of life. RESULTS There was no significant main effect of group on any of the somatosensory variables (F .416). As for psychosocial aspects, the low level of physical activity group had the lowest scores on the lifestyle questionnaire (P < .009). CONCLUSION Level of physical activity did not significantly influence mechanical somatosensory thresholds or temporal summation in the orofacial region, and worse quality of life was found in participants reporting a low level of physical activity.

Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are both complex conditions that are challenging to treat. This may be related to an incomplete understanding of their pathophysiology, itself obfuscated by their heterogeneity. The symptomatic overlap between them and their common comorbidity suggests a shared vulnerability, which might be explained by central sensitisation.19 CFS cases, 19 FM cases and 20 age and sex matched healthy controls (HC) were recruited primarily from secondary care clinics in London. Those with other pain disorders, psychiatric diagnoses and those taking centrally acting or opiate medications were excluded. Participants were asked to abstain from alcohol and over the counter analgaesia 48 h prior to assessment by static and dynamic quantitative sensory tests, including measures of temporal summation (TS) and conditioned pain modulation (CPM).CS, as defined by the presence of both enhanced TS and inefficient CPM, was present in 16 (84%) CFS cases, 18 (95%) FM cases, and none of the HC (p 0.001). Pressure pain thresholds were lower in CFS (Median222kPaIQR 146-311; p = 0.04) and FM cases (Median 189 kPa; IQR 129-272; p = 0.003) compared to HC (Median 311 kPa; IQR 245-377). FM cases differed from HC in cold-induced (FM = 22.6 °C (15.3-27.7) vs HC = 14.2 °C (9.0-20.5); p = 0.01) and heat-induced (FM = 38.0 °C (35.2-44.0) vs HC = 45.3 °C (40.1-46.8); p = 0.03) pain thresholds, where CFS cases did not.Central sensitisation may be a common endophenotype in chronic fatigue syndrome and fibromyalgia. Further research should address whether central sensitisation is a cause or effect of these disorders.

Objective Recently, there has been growing interest in the gut–brain axis because it is emerging as a player influencing the health status of the host human. It is a known fact that the gut microbiome (GM) through the gut–brain axis has been implicated in numerous diseases. We previously reported that stool condition was associated with pain perception. Stool consistency and constipation are known to be associated with GM composition. Thus, we imagine that GM composition could influence pain perception. The aim of this study was to investigate the correlations between GM composition and pain perception and psychological states in young healthy male subjects. Subjects A total of 42 healthy young male volunteers completed the present study. Methods The volunteers’ pain perceptions were assessed by pressure pain threshold, current perception threshold, temporal summation of pain, and conditioned pain modulation, and a questionnaire on psychological state was obtained. During the current perception threshold examination, we used 5, 250, and 2,000 Hz to stimulate C, Aδ, and Aβ fibers. In addition, GM composition was evaluated by using 16S rRNA analysis. Results Pressure pain threshold showed a significant and negative correlation with Bacteroidetes phylum, in contrast to a significant and positive correlation with Firmicutes phylum. Current perception threshold of Aδ and Firmicutes phylum showed a significant correlation. There was a negative correlation between anxiety state and Bifidobacterium genus. In contrast, there was no significant correlation between psychological states and pain perceptions. Conclusion The present study showed that acute pain perception was associated with GM composition in young healthy males.

To compare two pain models of myalgic TMD, delayed-onset muscle soreness (DOMS) and injections of nerve growth factor (NGF), in terms of pain-related and motor function outcomes, as well as activity-related temporal summation. Methods: Fifty age- and gender-matched healthy participants were recruited and randomized into one of three groups: to a repeated eccentric contraction task to cause DOMS (n = 20), to receive NGF injections into the masseter muscle (n = 20), or to a control group (n = 10). Mechanical sensitivity of masticatory muscles, chewing parameters, jaw function limitation, maximum bite force, and activity-related temporal summation were assessed at baseline and at days 1, 2, and 7 following the intervention. Results: Compared to baseline, both model groups showed increased mechanical sensitivity, jaw function limitation, pain on chewing, and decreased chewing efficiency, lasting longer in the NGF group than in the DOMS group (P .05). Conclusion: Both models produced similar pain- related outcomes, with the NGF model having a longer effect. Furthermore, the NGF model showed a more substantial effect on motor function, which was not seen for the DOMS model. Finally, neither of the models were able to provoke activity-related temporal summation of pain. J Oral Facial Pain Headache 2020;34:311–322. doi: 10.11607/ofph.2623

The endogenous pain system may be used as a biomarker in the pharmacological treatment of patients with CLBP, enabling an individualized, mechanism-based treatment approach., Introduction: Chronic low back pain (CLBP) is one of the most common chronic pain conditions in pain practice. Objectives: In the current study, we describe phenotypes of patients with CLBP based on the status of their endogenous pain modulatory system. Methods: Conditioned pain modulation (a measure of central pain inhibition), temporal summation (TS, a measure of pain facilitation), and offset analgesia (a measure of temporal filtering of nociception) were evaluated in 53 patients with CLBP at painful and nonpainful sites. Next, in a double-blind, randomized, placebo-controlled trial, 40 patients with defective conditioned pain modulation responses received treatment with tapentadol prolonged-release or placebo for 3 months. Results: The majority of patients (87%) demonstrated loss of central pain inhibition combined with segmentally increased TS and reduced offset analgesia at the lower back region. During treatment, tapentadol reduced pain intensity more than placebo (tapentadol −19.5 ± 2.1 mm versus placebo −7.1 ± 1.8 mm, P = 0.025). Furthermore, tapentadol significantly decreased pain facilitation by reduction of TS responses at the lower back (tapentadol −0.94 ± 1.9 versus placebo 0.01 ± 1.5, P = 0.020), which correlated with pain reduction (P < 0.001). Conclusion: Patients with CLBP demonstrated different phenotypes of endogenous pain modulation. In patients with reduced conditioned pain modulation, tapentadol produced long-term pain relief that coincided with reduction of signs of pain facilitation. These data indicate that the endogenous pain system may be used as a biomarker in the pharmacological treatment of CLBP, enabling an individualized, mechanism-based treatment approach.