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BackgroundAnxiety, evoked by continuous inspiration of a 5 – 8% CO2 mixture, has been found to have an analgesic eLect on self-reported pain. The precise mechanism whereby this effect obtains remains unknown.MethodsThe present study tested whether temporal summation, the psychological counterpart of wind-up, is involved in hypercapnic analgesia. 21 healthy participants received painful transcutaneous electrical stimuli of varied intensity, during continuous inhalation of 7.5% CO2 mixture and medical air, presented in a single-blinded counterbalanced order. Continuous pain ratings were acquired to measure the temporal development of the pain response. Several points and events of interest that characterise the pain response profile were extracted from the continuous data.ResultsMixed-eLects modelling demonstrated a reduction of all pain measures during inspiration of the anxiogenic mixture, but not air. This was accompanied by an increase in the psychological and physiological measures of anxiety. Analyses of the characteristic measures of temporal summation suggested that the hypercapnic mixture has an analgesic property evident from the start of the pain response. The same was true for the remainder of the response, the adaptation period, where pain ratings were also inhibited. The reduced pain ratings persisted during the remainder of the response. Anxiety was found to be a mediating factor for summative pain ratings but not the temporally sensitive TS measures, suggesting an overall, cumulative effect.ConclusionsThe findings provide an explanation for the previously observed low self-reported pain during the inhalation of an anxiogenic hypercapnic mixture.

Objective The temporal stability (test–retest reliability) of temporal summation of pain (TS) and conditioned pain modulation (CPM) has yet to be established in healthy older adults. The purpose of this study was to compare the temporal stability of TS and CPM in healthy older and younger adults and to investigate factors that might influence TS and CPM stability. Methods In a test–retest study, 40 healthy older adults and 30 healthy younger adults completed two sessions of quantitative sensory testing within a two-week period that included TS of heat pain, TS of mechanical pain, and CPM with pressure pain thresholds and suprathreshold heat pain as test stimuli and a cold water immersion as a conditioning stimulus. Participants also completed self-report measures of situational catastrophizing, anxiety, clinical pain, and physical activity. Absolute and relative stability were examined for each variable. Bivariate correlations examined the associations of age, clinical, behavioral, and psychological variables with the intra-individual stability of TS and CPM. Results The results revealed moderate to excellent stability for the TS measures and poor to moderate stability for CPM. The results also revealed significant age differences for two of the TS measures and CPM, with younger adults having greater stability compared with older adults. Additionally, the magnitude and stability of psychological factors were correlated with stability of TS. Conclusions These findings suggest that TS and CPM may be more reliable in younger compared with older adults. Furthermore, psychological states may be an important factor influencing the stability of TS in healthy adults.

In this chapter the contribution offered by the study of the spinal reflexes to the understanding of migraine physiopathology is discussed: how the spinal reflexes contributed to the insight that the abnormal pain processing at the basis of migraine pain is not just confined to the cranial structures but represents a widespread phenomenon involving the control of pain of the whole body. The most extensively studied spinal reflex response in migraine is the nociceptive flexion or withdrawal reflex (NWR) of the lower limb. The NWR represents an objective direct measure of the functional activity of the nociceptive system in humans and, as it is modulated by descending cortico-subcortical pathways, also reflects the activity of the supraspinal control pain systems.

OBJECTIVES Despite its impact, individual factors associated with persistent low back pain (LBP) remain poorly understood. This study investigated static and dynamic pain sensitivity in adults with persistent LBP versus pain-free controls; and investigated associations between pain sensitivity and 3 clinical pain measures: recalled, resting, and movement-evoked pain (MEP). MATERIALS AND METHODS A lifespan sample of 60 adults with persistent LBP and 30 age-matched/sex-matched controls completed 4 laboratory sessions. Static pain sensitivity (pressure pain threshold [PPT], heat pain threshold) and dynamic pain sensitivity (heat pain aftersensations [AS], temporal summation [TS] of second heat pain) were measured. Demographic and clinical factors collected were education, global cognition, and perceived health. Resting and recalled pain were measured via questionnaire, and MEP via the Back Performance Scale. RESULTS LBP participants demonstrated lower PPT remotely (hand; F1,84=5.34, P=0.024) and locally (low back; F1,84=9.55, P=0.003) and also had higher AS (F1,84=6.01, P=0.016). Neither static nor dynamic pain sensitivity were associated with recalled pain (P>0.05). However, static pain sensitivity (local PPT) explained an additional 9% variance in resting pain, while dynamic pain sensitivity (AS, TS) explained an additional 10% to 12% variance in MEP. DISCUSSION This study characterized pain sensitivity measures among individuals with persistent LBP and suggests static pain sensitivity plays a larger role in resting pain while dynamic pain sensitivity plays a larger role in MEP. Future studies will confirm these relationships and elucidate the extent to which changes in static or dynamic pain sensitivity predict or mediate clinical pain among adults with persistent LBP.

ObjectivesThe expression of pain in males and females involves complex socio-psychological mechanisms. Males may report lower pain to a female experimenter to appear strong, whereas females may report higher pain to a male experimenter to appear weak and to seek protection. However, evidence to support these stereotypes is inconclusive. Individuals who catastrophise about pain rate higher pain than those who do not. How pain catastrophising interacts with the effect of the experimenter’s sex on pain reports is yet to be explored. Thus, the aim of this study was to determine whether pain catastrophising moderated the effect of the experimenter’s sex on pain reports in healthy males and females.MethodsParticipants (n=60, 30 males) were assigned to one of four experimental conditions: males tested by male experimenters, males tested by female experimenters, females tested by male experimenters, and females tested by female experimenters. Participants completed the Pain Catastrophising Scale, and then sensitivity to heat and to blunt (pressure-pain threshold) and sharp stimuli was assessed on both forearms, and to high frequency electrical stimulation (HFS) administered to one forearm.ResultsFemales reported lower pressure-pain thresholds than males irrespective of the experimenters’ sex. Females reported lower sharpness ratings to male than female experimenters only when the test stimuli were moderately or intensely sharp. Higher pain catastrophising scores were associated with higher sharpness ratings in females but not males. Additionally, higher pain catastrophising scores were associated with greater temporal summation of pain to HFS, and with lower pressure-pain thresholds in females who were tested by male experimenters.ConclusionsThese findings indicate that the experimenters’ sex and the participant’s pain catastrophising score influence pain reports, particularly in females. Awareness of these psychosocial factors is important in order to interpret pain responses in a meaningful way, especially when females are tested by male experimenters. A greater awareness of sex/gender role biases and their potential interaction with pain catastrophising may help researchers and clinicians to interpret pain reports in meaningful ways. In turn, this may help to improve delivery of treatments for patients with chronic pain.

To better understand the mechanisms underpinning work-related neck pain, this cross-sectional and single-blinded study compared somatosensory profiles among sonographers with varied neck disability levels. Based on K-mean cluster analysis of scores on the neck disability index (NDI), participants were classified into no (NDI ≤ 8%, n = 31, reference group), mild (NDI = 10%-20%, n = 43), or moderate/severe (NDI ≥ 22%, n = 18) disability groups. Data were collected on bodily pain distribution and severity and psychological measures including depression, anxiety, pain-catastrophizing, and fear-avoidance beliefs using validated scales. Participants attended 1 session of quantitative sensory testing performed according to a standardized protocol, including local and remote thermal and mechanical pain thresholds, temporal summation of pain (TSP), conditioned pain modulation, and an exercise-induced analgesia paradigm. Compared with participants with no and mild disability, those with moderate/severe disability showed more widespread pain, cold and mechanical hyperalgesia at a remote nonpainful site, and significantly higher TSP. Participants with mild disability demonstrated significantly higher TSP than those with no disability. These group differences were attenuated after adjusting for depression or anxiety, indicating these psychological factors may mediate the somatosensory changes associated with neck disability. Group differences were not found for conditioned pain modulation or exercise-induced analgesia. These findings suggest that heightened pain facilitation, rather than impaired pain inhibition may underpin nociplastic pain in participants with moderate/severe disability, and it may be associated with depression and anxiety. Clinicians should be aware that individuals with work-related neck pain presenting with moderate/severe disability display distinct somatosensory features and tailor management strategies accordingly.

Supplemental Digital Content is Available in the Text. Latinx-Americans showed greater temporal summation, adversity, and adversity correlates relative to non-Hispanic Whites. Discrimination and lifespan social status change inversely related to summation for Latinx-Americans., Introduction: Adverse life experiences disproportionately impact Latinx-Americans and are related to greater chronic pain rates. However, little is known about how adversities interact with central pain mechanisms for the development of later pain among Latinx-Americans. Objectives: The current study examined the relationship between adverse life experiences (eg, trauma and ethnic discrimination) and correlates (eg, social status) with mechanical temporal summation of pain (a proxy measure of central sensitization) between pain-free U.S. native Latinx (n = 65) and non-Hispanic White (NHW) (n = 51) adults. Methods: Participants completed self-report adverse life experience and correlational measures regarding childhood and adulthood and a mechanical temporal summation protocol. Results: Relative to NHWs, Latinx-Americans reported experiencing significantly greater trauma, discrimination, and lower social status during childhood and adulthood, along with greater temporal summation. Contrary to hypotheses, recent and lifetime experiences of ethnic discrimination significantly correlated with less temporal summation among Latinx-Americans. Decreases in objective and subjective social status across the lifespan (childhood to present day) correlated with greater temporal summation for Latinx-Americans. However, r-to-z transformation analyses confirmed that significant adversity and social status correlations observed among the Latinx group did not significantly differ from NHW participants. Conclusions: The present findings highlight the complex association between adverse experiences, adverse experience risk factors, and pain for Latinx-Americans. Given the disproportion of experienced pain and adversity among Latinx-Americans, the current findings suggest that a better understanding of the unique adversities for this sample may help elucidate the mechanisms underlying the relationship between adversities, adversity correlates, and pain risk for Latinx-Americans.

Cortical responses to visual stimuli exhibit complex temporal dynamics, including sub-additive temporal summation, response reduction with repeated or sustained stimuli (adaptation), and slower dynamics at low contrast. Multiple computational models have been proposed to account for these dynamics in several measurement domains, including single-cell recordings, psychophysics, and fMRI. It is challenging to compare these models because there are differences in model form, test stimuli, and instrument. Here we present a new dataset that is well-suited to compare models of neural temporal dynamics. The dataset is from electrocorticographic (ECoG) recordings of human visual cortex, which measures cortical neural population responses with high spatial and temporal precision. The stimuli were large, static contrast patterns and varied systematically in contrast, duration, and inter-stimulus interval (ISI). Time-varying broadband responses were computed using the power envelope of the band-pass filtered voltage time course (50-170 Hz) recorded from a total of 126 electrodes in ten epilepsy patients, covering earlier (V1-V4) and higher-order (LO, TO, IPS) retinotopic maps. In all visual regions, the ECoG broadband responses show several non-linear features: peak response amplitude saturates with high contrast and long stimulus durations; response latency decreases with increasing contrast; and the response to a second stimulus is suppressed for short ISIs and recovers for longer ISIs. These features were well predicted by a computational model (Zhou, Benson, Kay and Winawer, 2019) comprised of a small set of canonical neuronal operations: linear filtering, rectification, exponentiation, and a delayed divisive gain control. These results demonstrate that a simple computational model comprised of canonical neuronal computations captures a wide range of temporal and contrast-dependent neuronal dynamics at millisecond resolution. Finally, we present a software repository that implements models of temporal dynamics in a modular fashion, enabling the comparison of many models fit to the same data and analyzed with the same methods.

Background: The aim of this study was to assess clinical pain, pain sensitization and physical performances to profile patients with chronic painful knee osteoarthritis (OA) or pain after total knee arthroplasty (TKA). Examining the interactions between pain mechanisms and physical performances would enable us to investigate the underlying explanatory relationships between these parameters. Methods: In this explorative study, 70 patients with chronic painful knee OA (N = 46) or chronic pain after TKA (N = 24) were assessed for clinical pain, quantitative sensory profiling (mechanical pinprick pain sensitivity, temporal summation (TS) and conditioned pain modulation), physical performances (chair stand, walk and stair climb tests) and self-reported outcomes. Between-group comparisons were made using ANCOVA tests and associations between outcomes were analysed using multivariate linear regression models. Results: Overall, no differences between groups regarding clinical pain and quantitative sensory profiling outcomes were observed. Physical performances were lower in the TKA group compared with the OA group with moderate-to-large effect sizes, and a tendency towards better scores in self-reported outcomes for the OA group was observed with small-to-moderate effect sizes. Self-reported function seems to be associated with physical performances in the TKA group. Sensitization (TS) appears to be associated with poorer physical performances in the OA group. Conclusions: Similar profiles for pain intensity, signs of sensitization and conditioned pain modulation were observed. Patients with TKA seems to have impaired physical performances compared with the OA group, underlining the importance of targeting physical performances. Only the OA patients showed an association between sensitization (TS) and physical performance. Significance: Quantitative pain profiling assessment was used to assess pain intensities and pain mechanisms. We observed associations between physical performances and temporal summation in the OA group underlining the importance of assessing motor functions and pain mechanisms in the same trial. We observed lower levels of physical performances in the TKA group compared with the OA group, suggesting that examination and rehabilitation of physical performances is essential for TKA patients with chronic pain.

Introduction: The ascending pain pathway is responsible to transmit the intensity of the nociceptive stimulus up to the thalamus. Temporal summation of pain occurs when a series of nociceptive stimuli evoke pain on later stimuli. Multiple studies have been focused on the characteristics of pain in COPD patients in recent years. However, no previous studies have evaluated the ascending pain pathway function in COPD patients. Objective: The aim of this study was to evaluate the ascending pain pathway function in COPD patients and healthy people. Methods: An observational study was performed. Moderate to severe COPD patients and healthy participants were included. The Brief Pain Inventory assessed the intensity and interference of pain. Temporal summation was measured with a pressure algometer. A series of 15 stimuli with an interval of 3 s and 5 s were presented to the flexor digitorum muscle to each forearm. After-sensation magnitudes at 15 and 60 s were registered. The pain rating was evaluated with a scale from 0-100. Results: Fifty-four participants were included. All groups were similar in demographics and interference and intensity pain scores. The first stimulus of pressure thresholds was significantly different between groups (p Conclusion: The ascending pain pathway function in COPD patients showed statistical differences compared with healthy controls.

When nociceptive stimulation affects a larger body area, pain increases. This effect is called spatial summation of pain (SSp). The aim of this study was to describe SSp as a function of the size or distance of a stimulated area(s) and to test how this function is shaped by the intensity and SSp test paradigm. Thirty-one healthy volunteers participated in a within-subject experiment. Participants were exposed to area-based and distanced-based SSp. For area-based SSp, electrocutaneous noxious stimuli were applied by up to 5 electrodes (5 areas) forming a line-like pattern; for distance-based SSp, the same position and lengths of stimuli were used but only 2 electrodes were stimulated. Each paradigm was repeated using pain of low, moderate, and high intensity. It was found that the pattern of pain intensity followed a logarithmic (power) rather than a linear function. The dynamics of the pain increase were significantly different across pain intensities, with more summation occurring when pain was perceived as low. Results indicated that area-based SSp is more painful than distance-based SSp when low and moderate but not when high pain intensity is induced. Presented findings have important implications for all studies in which the spatial dimension of pain is measured. When the area or separation between nociceptive stimulation increases, pain does not increase linearly and the pattern of the pain increase is a result of the interaction between intensity and the number of nociceptive sites. A power function should be considered when predicting the size of a nociceptive source.

Background: Virtual reality (VR) applied to patients with neck pain is a promising intervention to produce positive effects when used alone or combined with exercise. Therefore, the objective of this manuscript is to compare the effects of VR versus exercise treatment on pain intensity, conditioned pain modulation (CPM), temporal summation (TS) and functional and somatosensory outcomes in patients with non-specific chronic neck pain (NS-CNP). Methods: A single-blinded, randomized clinical trial was carried out. A total sample of 44 patients with NS-CNP was randomized into a VR treatment group or neck exercises group. The intervention consisted of two treatment sessions per week, for four weeks and eight sessions. Four measurement moments (at baseline, immediately, 1 month, and 3 months after intervention) were considered. Pain intensity, CPM, TS, functional and somatosensory outcomes were measured. Results: Statistically significant differences were revealed for time factor (F = 16.40, p &lt, 0.01, &eta, p2 = 0.28) and group*time interaction for kinesiophobia (F = 3.89, p = 0.01, &eta, p2 = 0.08) showing post-hoc differences in favor of the VR group at 3 months (p &lt, 0.05, d = 0.65). Significant effects were shown for time factor (p &lt, 0.05) but not for the group*time interaction (p &gt, 0.05) for pain intensity, rotation range of motion (ROM), Neck Disability Index, pain catastrophizing, fear-avoidance beliefs, left side pressure pain threshold (PPT) and anxiety. Statistically significant differences were not found for time factor (p &gt, 0.05) and neither in group*time interaction (p &gt, 0.05) for CPM, TS, right side PPT, flexo-extension and lateral-flexion ROM. Conclusions: Kinesiophobia was the only outcome that showed differences between VR and exercise at 3 months. Nevertheless, pain intensity, CPM, TS, ROM, neck disability, pain catastrophizing, fear-avoidance beliefs, PPT and anxiety did not show differences between both interventions.

OBJECTIVES: Patients with low back pain (LBP) often demonstrate pain sensitization, high degree of pain catastrophizing, and psychological distress. This study investigated whether pain sensitization mechanisms, the Pain Catastrophizing Scale (PCS), and Start Back Screening Tool were associated with pain in recurrent LBP patients 12 weeks after consulting their general practitioner (GP). MATERIALS AND METHODS: In 45 LBP patients, pressure pain thresholds, temporal summation of pain (TSP), conditioned pain modulation (CPM), the Roland Morris Disability Questionnaire (RMDQ), and the PCS were assessed before consultation. Patients were classified into low to medium or high risk of poor prognosis on the basis of the Start Back Screening Tool. Worst pain within the last 24 hours was assessed on a visual analogue scale (VAS) at inclusion and 12 weeks after GP consultation. RESULTS: VAS scores were reduced after 12 weeks in the low-to-medium (N=30, P

This study demonstrates significant differences between the area of complete spatial summation (Ricco’s area, RA) in eyes with and without non-pathological, axial myopia. Contrast thresholds were measured for six stimuli (0.01–2.07 deg2) presented at 10º eccentricity in 24 myopic subjects and 20 age-similar non-myopic controls, with RA estimated using iterative two-phase regression analysis. To explore the effects of axial length-induced variations in retinal image size (RIS) on the measurement of RA, refractive error was separately corrected with (i) trial lenses at the anterior focal point (near constant inter-participant RIS in mm), and (ii) contact lenses (RIS changed with axial length). For spectacle corrected measurements, RA was significantly larger in the myopic group, with a significant positive correlation also being observed between RA and measures of co-localised peripheral ocular length. With contact lens correction, there was no significant difference in RA between the groups and no relationship with peripheral ocular length. The results suggest RA changes with axial elongation in myopia to compensate for reduced retinal ganglion cell density. Furthermore, as these changes are only observed when axial length induced variations in RIS are accounted for, they may reflect a functional adaptation of the axially-myopic visual system to an enlarged RIS.

Pain intensity is difficult to predict. Mostly, because of modulatory processes underlying its formation. For example, when nociceptive stimulation occupies a larger body area, pain increases disproportionally. This modulation is called spatial summation of pain (SSp) and is responsible for coding pain intensity. To predict pain based on spatial variables, a profound understanding of the SSp effect is crucial. The aim of this study was i) to describe the SSp effect as a function of the size (or distance) of a stimulated area(s), ii) to investigate the effect of pain intensity on SSp and iii) to evaluate the influence of the SS type on the magnitude of SSp. Thirty-one healthy participants took part in a within-subject experiment. Participants were exposed to area- and distanced based SSp. In the former, electrocutaneous noxious stimuli were applied by up to 5 electrodes (5 areas) forming a line-like pattern at the ulnar side of the hand, while in the latter the same position and lengths of stimuli were used but only two electrodes were stimulated (5 separations). Each paradigm was repeated using pain of low, moderate and high intensity in a random and counterbalanced order. Each stimulus was assessed on a 0-100 scale. It was found that the pattern of increase in pain followed a logarithmic rather than a linear function. The dynamics of the pain increase were statistically different across pain intensities, with more summation occurring, if stimuli were calibrated to eliciting “high” pain. SSp was resistant to saturation in the area-based but not in the distance- based SSp, where 0.8cm separation between two electrodes produced a similar pain intensity as 1.6cm and 2.4cm. Results indicate that area-based SSp is more painful than distance-based SSp when low and moderate but not when high pain intensity is induced. Presented findings have important implications for all studies, in which the spatial dimension of pain is measured. When the area or separation between nociceptive stimulation increases, pain does not increase linearly. Furthermore, the pattern of the pain increase depends on i) intensity and ii) the number of sites of nociception. In conclusion, a logarithmic function should be considered when predicting the size of a nociceptive source. This pattern is indicative for inhibitory processes underlying SSp.

Summary Objective To examine the relation of pain sensitization to altered motor activity in knee OA as assessed by hamstrings muscle co-contraction during maximal effort knee extension. Design Medial, lateral, and overall hamstring co-contraction was assessed in the Multicenter Osteoarthritis (MOST) Study cohort using electromyography during isokinetic knee extension at 60°/second. Mechanical temporal summation of pain (TS) was assessed at the right wrist and pressure pain thresholds (PPT) were assessed at the patellae; PPTs were categorized into sex-specific tertiles. Muscle co-contraction was categorized into age- and sex-specific tertiles. We evaluated the relation of measures of sensitization to muscle co-contraction using a generalized logistic regression model. Results 1633 participants were included: mean age and BMI was 67.3 ± 7.7 years and 30.3 ± 5.6 kg/m2, respectively; 58% were female. Presence of TS was associated with higher overall (OR 1.3, 95% confidence interval (CI) (1.0–1.8)), medial (1.4 (1.0–1.9), and lateral (1.3 (1.0, 1.9)) hamstring co-contraction. The lowest PPT tertile (greater sensitivity) was associated with higher overall (1.5 (1.0, 2.3)) and medial (1.5 (1.0, 2.3)) hamstring co-contraction compared with those in the highest PPT tertile. Conclusion Greater pain sensitization, as assessed by presence of TS at the wrist and low patellar PPT, was associated with greater overall and medial hamstring co-contraction during knee extension. This provides support to the possibility that peripheral and/or central nervous system alterations may not only affect pain sensitivity, but also motor function.

Objective The development of persistent pain following total knee arthroplasty (TKA) is common, but its underlying mechanisms are unknown. The goal of the study was to assess brain grey matter structure and its correlation with function of the nociceptive system in people with good and poor outcomes following TKA. Subjects Thirty-one people with LOW_PAIN ( Methods Grey matter in key brain areas related to nociception was analyzed using voxel-based morphometry (VBM). Nociceptive facilitatory and inhibitory processes were evaluated using quantitative sensory testing (QST). QST scores and grey matter density in prespecified brain regions were compared between the LOW_PAIN and HIGH_PAIN groups. Regression analyses were used to analyze the associations between the grey matter and QST scores. Results There were no between-group differences in QST measures. In the VBM analysis, the HIGH_PAIN group had a higher grey matter density in the right amygdala, right nucleus accumbens, and in the periaqueductal grey (PAG), but lower grey matter density in the dorsal part of the left caudate nucleus. Grey matter density in the right amygdala and PAG correlated positively with temporal summation of pain. Conclusions Persistent pain at six months after TKA is associated with a higher grey matter density in the regions involved in central sensitization and pain-related fear, which may contribute to the development of persistent pain after surgery.

Objectives The underlying mechanisms for individual differences in experimental pain are not fully understood, but genetic susceptibility is hypothesized to explain some of these differences. In the present study we focus on three genetic variants important for modulating experimental pain related to serotonin (SLC6A4 5-HTTLPR/rs25531 A>G), catecholamine (COMT rs4680 Val158Met) and opioid (OPRM1 rs1799971 A118G) signaling. We aimed to investigate associations between each of the selected genetic variants and individual differences in experimental pain. Methods In total 356 subjects (232 low back pain patients and 124 healthy volunteers) were genotyped and assessed with tests of heat pain threshold, pressure pain thresholds, heat pain tolerance, conditioned pain modulation (CPM), offset analgesia, temporal summation and secondary hyperalgesia. Low back pain patients and healthy volunteers did not differ in regards to experimental test results or allelic frequencies, and were therefore analyzed as one group. The associations were tested using analysis of variance and the Kruskal-Wallis test. Results No significant associations were observed between the genetic variants (SLC6A4 5-HTTLPR/rs25531 A>G, COMT rs4680 Val158Met and OPRM1 rs1799971 A118G) and individual differences in experimental pain (heat pain threshold, pressure pain threshold, heat pain tolerance, CPM, offset analgesia, temporal summation and secondary hyperalgesia). Conclusions The selected pain-associated genetic variants were not associated with individual differences in experimental pain. Genetic variants well known for playing central roles in pain perception failed to explain individual differences in experimental pain in 356 subjects. The finding is an important contribution to the literature, which often consists of studies with lower sample size and one or few experimental pain assessments.

Migraine headache is a pain condition characterized by severe and recurrent unilateral head pain. Among other mechanisms, central pain sensitization processes seem to be involved in the disorder. An experimental protocol based on slowly repeated evoked pain (SREP) has been shown to indicate pain sensitization in fibromyalgia patients and differentiate these patients from healthy individuals and rheumatoid arthritis patients. This study examined SREP sensitization in migraine patients and explored its potential usefulness as a central sensitization marker. The SREP protocol was administered to 40 episodic migraine (EM) patients not currently experiencing a headache and 40 healthy controls. SREP consisted of a series of 9 suprathreshold painful pressure stimuli of 5 s duration and a 30 s interstimulus interval. SREP sensitization was indexed by the increase in pain ratings across the stimuli. Pain threshold, pain tolerance and temporal summation of pain were also assessed. SREP sensitization was observed in EM, but not in healthy individuals (p

Recent studies highlight the importance of the temporal domain in visual processing. Critical Flicker Frequency (CFF), the frequency at which a flickering light is perceived as continuous, is a widely used measure for evaluating visual temporal processing. Another important issue to investigate is the cortical interactions arising between the flicker stimuli of both eyes. This paper presents a robust and reliable dichoptic tool for evaluating the CFF threshold in both eyes. This system is based on an analog output device used to independently drive two LEDs through a custom-written MATLAB code (using a laptop PC) for eliciting sinusoidal flickering stimuli and for psychophysically measuring the perceived CFF threshold. The luminance and phases of each LED are individually controlled, enabling the investigation of the effect of phase and luminance differences on binocular summation in subjects with different ocular pathologies. Experiments were designed to evaluate the CFF threshold through a psychophysical test, based on a discrimination task with a stimulus duration of 1 s, based on a temporal alternative forced-choice paradigm. The target stimulus temporal features were modulated using the staircase method. Subjects were requested to discriminate between a target stimulus (a flickering light at various frequencies) and a flickering light at a frequency of 120 Hz, which is significantly higher than the CFF in humans; therefore, it is perceived as constant. One of the main advantages of the introduced dichoptic presentation system is that it enables the visual temporal performance to be measured under both monocular and binocular conditions where phenomena such as temporal binocular summation (BS) can be evaluated. Moreover, the system offers great flexibility by introducing a stimulus phase shift, which enables studying how stimulus timing affects the temporal function at millisecond scale resolution. Our results confirm that no crosstalk exists between the eyes and that the system can reliably separate the stimuli presented to the eyes. Using this set-up, we observed the binocular summation of CFF for low target luminance levels. The CFF was significantly (p = 0.011) higher (5.2%) under binocular compared with monocular viewing conditions. More importantly, introducing an inter - ocular phase shift reduced the binocular CFF in normally sighted subjects. Finally, in amblyopic subjects the amblyopic eye showed a decrease of 3.9 Hz (15%) in CFF, compared with the fellow eye (p = 0.001). The ability to assess binocular temporal performance using a dichoptic display can shed light on visual temporal performance in general, and on binocular temporal summation processes in particular, both for subjects with normal binocular vision and for subjects with impaired binocular vision (e.g., amblyopic subjects). Furthermore, such a presentation set-up may facilitate the development of training paradigms aimed at improving binocular vision performance. In this paper we describe the system and methods in detail and provide all necessary computer code and other details that will enable an easy and quick adaptation of the method by scientists interested in studying the temporal resolution of the visual system in general, and in studying inter-ocular differences or interactions in particular.

Objective Evidence suggests altered pronociceptive and antinociceptive mechanisms in many chronic pain conditions. Knowledge about these mechanisms in nonspecific chronic neck pain (NSNP) would improve understanding of the causes and the design of more effective treatments. Pressure pain threshold (PPT) is often used to assess presence of altered nociceptive processing in NSNP; however, its usefulness to detect this is yet to be established. The purpose of this study was to determine the functional status of temporal summation of second pain (TSSP) and conditioned pain modulation (CPM) in NSNP and to characterize the association of both measures with PPT and clinical features of NSNP. Methods Thirty-two participants with NSNP (mean [SD] age = 44 [11] years; 27 female) and 32 age- and sex-matched healthy controls were recruited. TSSP was assessed using an electrical stimulus at the dorsum of the hand, and CPM was evaluated with the Cold Pressor Test. PPT was assessed bilaterally at the neck and tibialis anterior muscles. Results Participants with NSNP showed greater TSPP (mean difference = 0.23; 95% CI = 0.46–0.01; Cohen d = 0.51) and lower CPM (mean difference = 19.44; 95% CI = 10.42–28.46; Cohen d = 1.09). Pooled data from all participants showed lower PPTs at the neck than the tibialis anterior. However, PPT measures did not differ between groups at either location. PPT measures were not correlated with CPM and TSP. Conclusion NSNP is associated with enhanced pronociceptive and impaired antinociceptive mechanisms, which may explain long-lasting pain and failure of some treatments to resolve symptoms. However, due to the observational nature of this study, a clear cause-effect relationship cannot be established. Normal PPT values in the clinic should not be interpreted as absence of altered nociceptive processing. Impact This study fills in some gaps in knowledge. Changes in central nociceptive processing may explain persistent and recurrent symptoms in NSNP and failure of treatments to obtain long-lasting relief. Further research is required to ascertain if TSSP and CPM assessment in the clinic may help predict physical therapy treatment outcome. Whether symptomatic relief with physical therapy is mediated by an improvement in TSSP and CPM should also be explored. PPTs were unaltered in participants with NSNP despite evidence of impairment in the central pain modulatory systems. Normal PPTs should not be interpreted as evidence of unaltered central pain-related processing.

BACKGROUND Pain sensitization, defined as an increased responsiveness of nociceptive neurons to normal input, is detected in several musculoskeletal diseases, but there are no systematic reviews or meta-analyses about pain sensitization in shoulder pain. OBJECTIVES The aim of the study was to document pain sensitization rate and its impact in patients with shoulder pain. MATERIALS AND METHODS PubMed, Cochrane Library, and Web of Science were searched on January 8, 2020. Level I-IV studies, evaluating pain sensitization in musculoskeletal shoulder disorders through validated methods (questionnaires/algometry) were included. The primary outcome was pain sensitization rate. Secondary outcomes were the pain sensitivity level measured as pressure pain threshold, temporal summation, conditioned pain modulation, and suprathreshold heat pain response. Associated demographic and psychosocial factors were evaluated. RESULTS The rate of abnormal pressure pain threshold in patients with shoulder pain varied from 29% to 77%. Questionnaires detected pain sensitization in 11% to 24% of patients. This meta-analysis showed no difference in pressure pain threshold and central pain modulation but documented a significant difference in terms of suprathreshold heat pain response, indicating a hypersensitivity state in patients with shoulder pain versus asymptomatic controls. The only factor that was constantly found to correlate with higher sensitivity was a lower postoperative outcome. DISCUSSION Pain sensitization has a high rate among patients with musculoskeletal shoulder pain, regardless of the specific etiology, and this may lead to worse clinical outcome after treatment of the primary disease. The best way to assess pain sensitization still needs to be identified as the assessment methods results in used high variability in the documented pain sensitization rate.

BACKGROUND The fear-avoidance model (FAM) is a leading theoretical paradigm for explaining persistent pain following musculoskeletal injury. The model suggests that as injuries heal, pain-related outcomes are increasingly determined by psychological, rather than physiological factors. Increasing literature, however, suggests that neurophysiological processes related to pain sensitivity also play an important role in chronicity. To date, there has been limited research that has specifically explored the role of pain sensitivity within the FAM. This study addresses this gap by evaluating whether clinical measures of pain sensitivity help explain FAM-related outcomes, beyond model-relevant psychological predictors. METHODS The study sample consisted of 80 adults with chronic and widespread musculoskeletal pain. Participants completed a single testing session that included measures of all of the major constructs of the FAM, including pain catastrophizing, pain-related fear, activity avoidance (self-report and functional measures), pain-related disability, depression and pain severity, as well as a battery of quantitative sensory testing that included measures of pressure pain threshold and temporal summation of mechanical pain across eight body sites. RESULTS A series of hierarchical regression analyses revealed that after controlling for the psychological predictors of the FAM, indices of pain sensitivity significantly predicted 4 of the 5 FAM-related outcomes (p

BACKGROUND Investigation of movement and sensory profiles across STarT Back risk subgroups. METHODS A chronic low back pain cohort (n = 290) were classified as low, medium or high risk using the STarT Back Tool, and completed a repeated spinal bending task and quantitative sensory testing. Pain summation, time taken and the number of protective behaviours with repeated bending were measured. Sensory tests included two-point discrimination, temporal summation, pressure/thermal pain thresholds and conditioned pain modulation. Subgroups were profiled against movement and sensory variables. RESULTS The high-risk subgroup demonstrated greater pain summation following repeated forward bending (p

OBJECTIVE: To study the impact of therapeutic interventions on pain analgesia and endogenous pain modulation in knee osteoarthritis (KOA). DESIGN: Systematic review and meta-analysis. METHODS: We searched for KOA randomized clinical trials and observational studies with data on therapeutic interventions comparing pain intensity, temporal summation (TS), and conditioned pain modulation (CPM) scores relative to control. These data were pooled as Hedge’s g. To study the relationship between pain intensity and TS/CPM, we performed metaregression with 10,000 Monte-Carlo permutations. RESULTS: We reviewed 11 studies (559 participants). On studying all the interventions together, we found no significant changes in pain modulation, TS, or CPM. Our findings show that this lack of difference is likely because surgical and nonsurgical interventions resulted in contrary effects. Metaregression significantly correlated pain reduction with normalization of TS and CPM. CONCLUSIONS: We demonstrate an association between pain reduction and TS/CPM normalization. Though we cannot directly compare these interventions, the results allow us to draw hypotheses on potential practice schemas. Recovering defective endogenous pain modulation mechanisms may help establish long-term analgesia. However, to validate these paradigms as robust clinical biomarkers, further investigation into their mechanisms would be necessary. The registration number for this review is CRD42017072066.

Background: This study investigated (a) if a prolonged noxious stimulus (24-hr topical capsaicin) in healthy adults would impair central pain inhibitory and facilitatory systems measured as a reduction in conditioned pain modulation (CPM) and enhancement of temporal summation of pain (TSP) and (b) if acute pain relief or exacerbation (cooling and heating the capsaicin patch) during the prolonged noxious stimulus would affect central pain modulation. Methods: Twenty-eight participants (26.2 ± 1.0 years; 12 women) wore a transdermal 8% capsaicin patch on the forearm for 24 hr. Data were collected at baseline (Day 0), 1 hr, 3 hr, Day 1 (post-capsaicin application) and Day 3/4 (post-capsaicin removal) that included capsaicin-evoked pain intensity, heat pain thresholds (HPTs), TSP (10 painful cuff pressure stimuli on leg) and CPM (cuff pressure pain threshold on the leg prior vs. during painful cuff pressure conditioning on contralateral leg). After 3 hr, cold (12°C) and heat (42°C) stimuli were applied to the capsaicin patch to transiently increase and decrease pain intensity. Results: Participants reported moderate pain scores at 1 hr (2.5 ± 2.0), 3 hr (3.7 ± 2.4), and Day 1 (2.4 ± 1.8). CPM decreased 3-hr post-capsaicin (p =.001) compared to Day 0 and remained diminished while the capsaicin pain score was reduced (0.4 ± 0.7, p

Micropillar lasers with integrated saturable absorber (LSA) have been demonstrated to show important neuromimetic properties such as ultrafast excitable behavior, temporal summation, relative & absolute refractory periods and spike latency. In this work we study a LSA with self delayed connection which can show regenerative spiking. Such delayed self connections called as autpases are found in living nervous systems in regions essential for memory. The characteristic response of a single LSA is a 200 ps wide pulse emitted in response to an optical perturbation above the excitable threshold. In the presence of an external feedback, a single above threshold perturbation will trigger a train of pulses. Additional perturbations are capable of retiming an existing pulse train and adding or removing a pulse train, thus enabling all optical control of spikes. If the system is perturbed under correct conditions several times during the external cavity roundtrip time τ, we can create several coexisting pulse trains in the cavity which are essentially the input perturbation repeating with the time period τ. This can be seen as an optical buffer for spikes. However, in the long term these seemingly independent pulses interact and converge towards a stable solution. This final stable solution is based on the input sequence, thus this long term behavior can be seem as an associative memory. Numerical simulations of the Yamada model with delayed feedback and noise are presented and found to be in good agreement with the experimental observations. All the observed dynamics of spike interaction and convergence can be explained solely based with the internal dynamics of carriers.

On cellular or tissue level, electrophysiology studies during light stimulation with shaped light can potentially enable the design of effective stimulation strategies towards future cardiac therapies. In this work, we explore the use of optogenetics in probing the electrophysiology of a functional cardiac syncytium. A holographic technique with the use of a spatial light modulator allows beam shaping and precise spatiotemporal control of the origin of action potential in a cardiac-like cell line monolayer. Depolarization was performed by using a blue laser (488 nm) incident to a reflective ferroelectric liquid crystal on silicon spatial light modulator (FLCOS-SLM) which generates multiple foci on to cardiomyocyte-like cells (HL1 line) expressing the light-gated protein Channelrhodopsin-2 (ChR2). The calcium-sensitive fluorophore Cal-630 was used to visualize the cellular electrical activity and thus can be combined with ChR2 as an all-optical method to stimulate and visualize electrophysiology of cardiac-like cells in a non-contact manner. We generated single or multiple foci each with spot size of ~5 µm for optogenetic stimulation. The probability of triggering an action potential, which we refer to as excitation probability, is highly dependent on the laser intensity. The threshold intensity for a single beamlet, where approximately 50% of the laser pulses successfully trigger an action potential, is ~4 µW/μm² (n=5 regions, 5 cells analyzed per region, performed in triplicates) at frequency of 1 Hz and pulse duration of 10 ms. We also demonstrate spatial summation of membrane potential in HL1-ChR2. Generated multiple foci can render the excited cells as individual inputs to elicit action potential in a syncytium. We demonstrate the dependence of the excitation probability on the foci gap distance. Two foci, each with sub-threshold intensity of 2 µW/μm² were generated. At spacing of 50 µm, the median excitation probability increases compared to single spot stimulation with the same intensity.

The first signs of diabetic neuropathy typically result from small-diameter nerve fiber dysfunction. This review synthesized the evidence for small-diameter nerve fiber neuropathy measured via quantitative sensory testing (QST) in patients with diabetes with and without painful and non-painful neuropathies. Electronic databases were searched to identify studies in patients with diabetes with at least one QST measure reflecting small-diameter nerve fiber function (thermal or electrical pain detection threshold, contact heat-evoked potentials, temporal summation or conditioned pain modulation). Four groups were compared: patients with diabetes (1) without neuropathy, (2) with non-painful diabetic neuropathy, (3) with painful diabetic neuropathy and (4) healthy individuals. Recommended methods were used for article identification, selection, risk of bias assessment, data extraction and analysis. For the meta-analyses, data were pooled using random-effect models. Twenty-seven studies with 2422 participants met selection criteria; 18 studies were included in the meta-analysis. Patients with diabetes without symptoms of neuropathy already showed loss of nerve function for heat (standardized mean difference (SMD): 0.52, p

Many &beta, lactam antibiotics, including cephalosporins, may cause neurotoxic and proconvulsant effects. The main molecular mechanism of such effects is considered to be &gamma, aminobutyric acid type a (GABAa) receptor blockade, leading to the suppression of GABAergic inhibition and subsequent overexcitation. We found that cefepime (CFP), a cephalosporin, has a pronounced antiepileptic effect in the pentylenetetrazole (PTZ)-induced seizure model by decreasing the duration and severity of the seizure and animal mortality. This effect was specific to the PTZ model. In line with findings of previous studies, CFP exhibited a proconvulsant effect in other models, including the maximal electroshock model and 4-aminopyridine model of epileptiform activity, in vitro. To determine the antiepileptic mechanism of CFP in the PTZ model, we used whole-cell patch-clamp recordings. We demonstrated that CFP or PTZ decreased the amplitude of GABAa receptor-mediated postsynaptic currents. PTZ also decreased the current decay time constant and temporal summation of synaptic responses. In contrast, CFP slightly increased the decay time constant and did not affect summation. When applied together, CFP prevented alterations to the summation of responses by PTZ, strongly reducing the effects of PTZ on repetitive inhibitory synaptic transmission. The latter may explain the antiepileptic effect of CFP in the PTZ model.

Burning mouth syndrome (BMS) is classified into idiopathic orofacial pain conditions. Although central and peripheral neuropathic mechanisms are believed to be involved, the etiology remains to be fully elucidated. The present study examined temporal brain responses to an ongoing hot stimulus to investigate the pain modulating system in patients with BMS. The thermal stimulation sequence comprised baseline (32°C, 40 s) to warm (40°C, 32 s) to baseline (32°C, 40 s) to hot (49°C, 32 s), which was repeated four times using a Peltier thermode. These warm and hot stimuli were applied on the right palm and right lower lip in two separate sessions. Functional magnetic resonance imaging data were acquired by recording echo-planar images with a block design. Brain activity induced by purely hot stimulation (49°C vs. 40°C) applied to the palm was more pronounced than that induced by lip stimulation and in patients with BMS compared with controls. Comparison of brain activity between the first 16 s and second 16 s of the stimulus revealed pronounced time-dependent facilitation in patients with BMS during lip stimulation. These findings indicate that the pain modulating system in patients with BMS is dysregulated and that the brain in BMS is highly sensitized to pain information originating from the trigeminal system.

Background Central neuropathic extremity pain (CNEP) is the most frequent type of pain in multiple sclerosis (MS). The aim of the present study was to evaluate sensory and pain modulation profiles in MS patients with CNEP. Methods In a single-centre observational study, a group of 56 CNEP MS patients was compared with 63 pain-free MS patients and with a sex- and age-adjusted control group. Standardized quantitative sensory testing (QST) and dynamic QST (dQST) protocols comprising temporal summation and conditioned pain modulation tests were used to compare sensory profiles. Results Loss-type QST abnormalities in both thermal and mechanical QST modalities prevailed in both MS subgroups and correlated significantly with higher degree of disability expressed as Expanded Disability Status Scale (EDSS). Comparison of sensory phenotypes disclosed a higher frequency of the 'sensory loss' prototypic sensory phenotype in the CNEP subgroup (30%) compared with pain-free MS patients (6%; p = .003). Conclusion The role of aging process and higher lesion load in the spinothalamocortical pathway might be possible explanation for pain development in this particular 'deafferentation' subtype of central neuropathic pain in MS. We were unable to support the role of central sensitization or endogenous facilitatory and inhibitory mechanisms in the development of CNEP in MS. Significance This article presents higher prevalence of the 'sensory loss' prototypic sensory phenotype in multiple sclerosis patients with central extremity neuropathic pain compared to pain-free patients. Higher degree of disability underlines the possible role of higher lesion load in the somatosensory pathways in this particular 'deafferentation' type of central neuropathic pain.

SummaryActive haptic sensation is critical for object identification and manipulation, such as for tool use in humans, or prey capture in rodents. The neural circuit basis for recognizing objects through active touch alone is poorly understood. To address this gap, we combined optogenetics, two photon imaging, and high-speed behavioral tracking in mice solving a novel surface orientation discrimination task with their whiskers. We found that orientation discrimination required animals to summate input from multiple whiskers specifically along the whisker arc. Many animals discriminated the orientation of the stimulus per se, as their performance was invariant to the specific location of the presented stimulus. Two photon imaging showed that populations of neurons in the barrel cortex encoded each of the discriminated orientations, and this coding depended on integration over the whisker array. Finally, acute optogenetic inactivation of the barrel cortex strongly impaired surface orientation discrimination, and even cell-type specific optogenetic suppression of layer 4 excitatory neurons degraded performance, implying a role for superficial layers in this computation. These data suggest a model in which spatial summation over an active haptic array generates representations of an object’s surface orientations. These computations may facilitate the encoding of complex three-dimensional objects during active exploration.

Good vision proficiency and a complex set of eye movements are frequently coexisting. Even during fixation, our eyes keep moving in microscopic and erratic fashion, thus avoiding stationary scenes from fading perceptually by preventing retinal adaptation. We artificially replicate the functionalities of biological vision by exploiting this active strategy with an event-based camera. The resulting neuromorphic active system redistributes the low temporal frequency power of a static image into a range the sensor can detect and encode in the timing of events. A spectral analysis of its output attested both whitening and amplification effects already postulated in biology depending on whether or not the stimulus' contrast matched the 1/k falloff typical of natural images. Further evaluations revealed that the isotropic statistics of fixational eye movements is crucial for equalizing the response of the system to all possible stimulus orientations. Finally, the design of a biologically-realistic spiking neural network allowed the detection of stimulus' local orientation by anisotropic spatial summation of synchronous activity with both ON/OFF polarities., Proceedings of the 15th International Joint Conference on Computer Vision, Imaging and Computer Graphics Theory and Applications (VISIGRAPP 2020), ISBN:978-989-758-402-2

Akin to all damselflies, Calopteryx (family Calopterygidae), commonly known as jewel wings or demoiselles, possess dichoptic (separated) eyes with overlapping visual fields of view. In contrast, many dragonfly species possess holoptic (dorsally fused) eyes with limited binocular overlap. We have here compared the neuronal correlates of target tracking between damselfly and dragonfly sister lineages and linked these changes in visual overlap to pre-motor neural adaptations. Although dragonflies attack prey dorsally, we show that demoiselles attack prey frontally. We identify demoiselle target-selective descending neurons (TSDNs) with matching frontal visual receptive fields, anatomically and functionally homologous to the dorsally positioned dragonfly TSDNs. By manipulating visual input using eyepatches and prisms, we show that moving target information at the pre-motor level depends on binocular summation in demoiselles. Consequently, demoiselles encode directional information in a binocularly fused frame of reference such that information of a target moving toward the midline in the left eye is fused with information of the target moving away from the midline in the right eye. This contrasts with dragonfly TSDNs, where receptive fields possess a sharp midline boundary, confining responses to a single visual hemifield in a sagittal frame of reference (i.e., relative to the midline). Our results indicate that, although TSDNs are conserved across Odonata, their neural inputs, and thus the upstream organization of the target tracking system, differ significantly and match divergence in eye design and predatory strategies. VIDEO ABSTRACT.

We tested endogenous pain modulation mechanisms in adults with autism spectrum disorders (ASD). Nineteen ASD adults without intellectual disabilities were included, matched with 19 healthy volunteers on the basis of sex and chronological age. An experimental pain model was used to measure excitatory and inhibitory pain mechanisms in a single session. Statistical analyses indicated that endogenous pain modulation mechanisms in ASD group did not differ significantly from those of healthy adults. The pain scores were very disparate in ASD group with a greater range of extreme scores than in control group. Unlike schizophrenic patients, there was no systematic dysfunction of endogenous excitatory pain modulation mechanisms, but the high variability requires to be wise to interpret the results and formulate conclusion.

BackgroundOptogenetic experiments reveal functional roles of specific neurons. However, such inferences have been restricted by widespread adoption of a fixed set of stimulation parameters. Broader exploration of the parameter space can deepen insight into the mapping between selective neural activity and behavior. In this way, characteristics of the activated neurons, such as temporal integration, can be inferred.ObjectiveTo determine whether an equal-energy principle accounts for the interaction of pulse duration and optical power in optogenetic excitation.MethodsSix male TH::Cre rats worked for optogenetic (ChannelRhodopsin-2) stimulation of Ventral Tegmental Area dopamine neurons. We used a within-subject design to describe the trade-off between pulse duration and optical power in determining reward seeking. Parameters were customized for each subject on the basis of behavioral effectiveness.ResultsWithin a useful range of powers (~12.6-31.6 mW) the product of optical power and pulse duration required to produce a given level of reward seeking was roughly constant. Such reciprocity is consistent with Bloch’s law, which posits an equal-energy principle of temporal summation over short durations in human vision. The trade-off between pulse duration and power broke down at higher powers.ConclusionsOptical power can be substituted for pulse duration to scale the region of neuronal excitation in behavioral optogenetic experiments. Power and duration can be adjusted reciprocally for brief durations and lower powers. The findings demonstrate the utility of within-subject and trade-off designs in optogenetics and of parameter adjustment based on functional endpoints instead of physical properties of the stimulation.HighlightsWe provide behaviorally derived intensity-duration curves for ChannelRhodopsin-2.Duration trades off almost perfectly with power within useful ranges.This trade-off breaks down at high optical powers.Pulse duration and optical power scale the area of neuronal excitation equivalently.Behaviorally derived trade-offs can reveal optogenetic excitation mechanisms.

BACKGROUND Studies assessing athletes' pain sensitivity yield inconsistent data, which demonstrate either increased pain threshold and tolerance in athletes than controls or similar thresholds. This inconsistency may result from the variability in the type of sport practiced by the athletes and its effect on pain perception. For example, endurance athletes perform continuous intense exercise for prolonged durations, whereas strength athletes perform short bouts of extreme efforts. Consequently, endurance athletes may tolerate and modulate pain better than strength athletes. This hypothesis was tested by comparing pain perception of endurance athletes with that of strength athletes. METHODS Subjects were 19 endurance athletes (triathletes), 17 strength athletes (weightlifters and throwers) and 17 non-athlete controls. Quantitative measurements included heat-pain threshold, heat-pain tolerance, cold pressor pain ratings, temporal summation of pain (TSP) and conditioned pain modulation (CPM). Fear of pain and pain catastrophizing were also assessed. RESULTS The two athlete groups had lower pain ratings than non-athletes. However, strength athletes had higher heat-pain threshold than endurance athletes, whereas endurance athletes had higher heat-pain tolerance and stronger CPM than strength athletes and lower fear of pain levels. Longer training time correlated with TSP in endurance athletes but with CPM and heat-pain tolerance in strength athletes. CONCLUSIONS Although athletes in general seem less responsive to noxious stimuli than non-athletes, the type of sport differentially affects pain perception; whereas endurance-based sport is associated with improved pain inhibition, strength-based sport is associated with reduced pain sensitivity. These characteristics may be considered when sport is recommended for pain management. SIGNIFICANCE This study shows that different sport types are associated with different characteristics of pain perception and modulation, as well as of thoughts towards pain.

Temporal summation of pain (TSP) is a promising tool for measuring the pain modulation processes in healthy subjects and patients with chronic pain. We tried to find optimal stimulation parameters in order to elicit a robust reproducible TSP phenomenon. Twenty healthy volunteers (15 women and 5 men) completed four sessions/conditions of pulsating heat pain stimulation, applied to the left forearm with a frequency of 0.33–0.4 sec–1 using a contact heat-evoked potential stimulator. The stimulation temperature (step +0.5°C or +1.0°C up to the pain threshold, pain tolerance), pulse duration (500, 800, or 1000 msec), and number of stimuli (60 or 90) were varied. The participants rated the pain intensity at the first and every 10th heat pulse, using a numeric rating scale (NRS) 0–100. The TSP was calculated as the difference between the lowest rating and the rating of the last stimulus and was compared between conditions. The optimal condition (19 out of 20 participants responded with TSP) showed temperature at pain tolerance, pulse duration of 800 msec, and 90 stimuli. In addition, this condition showed weaker side effects (painful discomfort) than those with less (60) but longer (1000 msec) stimuli presented 1.0 degree above the pain threshold. The protocol with a relatively high stimulus repetition and a moderate pulse duration seems to be the optimal protocol to reproduce TSP. Heat stimulation with longer pulse durations and higher stimulation temperatures was less feasible.

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Ketamine is an N-methyl-d-aspartate receptor antagonist that reduces temporal summation of pain and modulates antinociception. Ketamine infusions can produce significant relief of neuropathic pain, but the treatment is resource intensive and can be associated with adverse effects. Thus, it is crucial to select patients who might benefit from this treatment. The authors tested the hypothesis that patients with enhanced temporal summation of pain and the capacity to modulate pain via the descending antinociceptive brain pathway are predisposed to obtain pain relief from ketamine. Methods Patients with refractory neuropathic pain (n = 30) and healthy controls underwent quantitative sensory testing and resting-state functional magnetic resonance imaging and then completed validated questionnaires. Patients then received outpatient intravenous ketamine (0.5 to 2 mg · kg−1 · h−1; mean dose 1.1 mg · kg−1 · h−1) for 6 h/day for 5 consecutive days. Pain was assessed 1 month later. Treatment response was defined as greater than or equal to 30% pain relief (i.e., reduction in pain scores). We determined the relationship between our primary outcome measure of pain relief with pretreatment temporal summation of pain and with brain imaging measures of dynamic functional connectivity between the default mode network and the descending antinociceptive brain pathway. Results Approximately 50% of patients achieved pain relief (mean ± SD; Responders, 61 ± 35%; Nonresponders, 7 ± 14%). Pretreatment temporal summation was associated with the effect of ketamine (ρ = −0.52, P = 0.003) and was significantly higher in Responders (median [25th, 75th] = 200 [100, 345]) compared with Nonresponders (44 [9, 92]; P = 0.001). Pretreatment dynamic connectivity was also associated with the clinical effect of ketamine (ρ = 0.51, P = 0.004) and was significantly higher in Responders (mean ± SD, 0.55 ± 0.05) compared with Nonresponders (0.51 ± 0.03; P = 0.006). Finally, the dynamic engagement of the descending antinociceptive system significantly mediated the relationship between pretreatment pain facilitation and pain relief (95% CI, 0.005 to 0.065). Conclusions These findings suggest that brain and behavioral measures have the potential to prognosticate and develop ketamine-based personalized pain therapy.

OBJECTIVES The aims of this study were twofold: 1) to evaluate the differences in pain sensitivity of patients with greater trochanteric pain syndrome (GTPS) and 2) to examine the association between pain expansion, pain severity, and pain-related central sensitization somatosensory variables in patients with GTPS. STUDY DESIGN A cross-sectional study. SETTING Primary health care centers. SUBJECTS The sample consisted of 49 participants with a mean age of 48.28 ± 8.13 years and included eight males (16.3%) and 41 females (83.7%). METHODS Conditioned pain modulation (CPM), pain location, temporal summation, pressure pain detection threshold (PPDT), and pain intensity were recorded. Pain severity was determined with the Graded Chronic Pain Scale (GCPS). RESULTS Several participants (34.7%) showed a negative conditioned pain modulation and a statistically significant negative moderate correlation (P

Spinal cord stimulation (SCS) is an established treatment option for patients with refractory chronic pain conditions. While effects of SCS on dorsal horn neuronal circuitries are intensively studied, current knowledge on the impact of SCS on descending pain pathways is scarce and relies on preclinical data. We aimed to address this topic and hypothesized a significant effect of SCS on descending pain modulation. In light of current efforts to determine the sensitivity of “static” versus “dynamic” somatosensory parameters to characterize pathophysiological pain conditions, all SCS patients were carefully investigated using both classes of somatosensory outcome parameters. Descending pain pathways were investigated by using a “Cold Pressor Test.” This test enables to evaluate the efficacy of conditioned pain modulation (CPM) at the individual level. CPM efficacy was assessed in eight neuropathic pain patients (age 55.5 ± 10.6) during the two conditions stimulator “ON” and “OFF.” The impact of SCS on “static” and “dynamic” somatosensory parameters was explored by using a quantitative sensory testing (QST) battery. CPM efficacy on pressure pain sensitivity was nearly absent during “OFF” (− 1.2 ± 5.6% facilitation), but increased significantly to 16.3 ± 3.4% inhibition during “ON” (p = 0.03). While most “static” nociceptive QST parameters, represented by mechanical/thermal pain thresholds, exhibited only small effects of SCS (p > 0.05), the wind-up ratio was strongly reduced to within the normal range during “ON” (p = 0.04; Cohen’s d = 1.0). Dynamic mechanical allodynia was abolished in six of seven patients. Our study provides first human evidence for an impact of SCS on descending pain pathways in the dorsolateral funiculus and emphasizes the significance of “dynamic” pain measures like “CPM”-efficacy and “temporal summation” to evaluate SCS treatment effects. Future prospective studies may use these measures of nociceptive processing to predict SCS therapy response.

Studies indicate that individuals with borderline personality disorder (BPD) often demonstrate attenuated pain perception, termed hypoalgesia. This study examines the hypothesis that body awareness moderates the association between BPD and pain perception. Participants consisted of 46 women diagnosed with BPD and 47 healthy controls. Sensory testing included the measurement of heat-pain thresholds, ratings of suprathreshold stimuli, measurement of temperature evoking moderate pain, and temporal summation of noxious mechanical stimuli. Body awareness was assessed by a self-report questionnaire. As hypothesized, among subjects with low levels of body awareness, those with BPD demonstrated hypoalgesia as manifested in their lower suprathreshold pain ratings and moderate pain evoked by higher temperature, in comparison with the controls. Among those with high levels of body awareness, BPD subjects demonstrated increased reactivity to pain as manifested in their higher pain ratings and moderate pain evoked by lower temperature, in comparison with the controls.

We sought to determine whether women with overactive bladder who required third line therapy would demonstrate greater central sensitization, indexed by temporal summation to heat pain stimuli, than those with overactive bladder.We recruited 39 women with overactive bladder from the urology clinic who were planning to undergo interventional therapy for medication refractory overactive bladder with onabotulinumtoxinA bladder injection or sacral neuromodulation. We also recruited 55 women with overactive bladder who were newly seen at our urology clinic or who responded to advertisements for study participation. Participants underwent quantitative sensory testing using a thermal temporal summation protocol. The primary study outcome was the degree of temporal summation as reflected in the magnitude of positive slope of the line fit to the series of 10 stimuli at a 49C target temperature. We compared the degree of temporal summation between the study groups using linear regression.Women in the group undergoing third line therapy showed significantly higher standardized temporal summation slopes than those in the nontreatment group (β = 1.57, 95% CI 0.18-2.96, t = 2.25, p = 0.027). On exploratory analyses a history of incontinence surgery or hysterectomy was associated with significantly greater temporal summation.In this study the degree of temporal summation was elevated in women undergoing third line overactive bladder therapy compared to women with overactive bladder who were not undergoing that therapy. These findings suggest there may be pathophysiological differences, specifically in afferent nerve function and processing, in some women with overactive bladder.

Background Previous studies have shown that women experience greater temporal summation (TS) of pain than men using a repetitive thermal stimulus. These studies, however, did not individualize the thermal stimulus to each subject’s thermal pain sensitivity. The aim of this study was to investigate sex differences in TS using an individualized protocol and potential mediators that have been shown to influence TS including physical activity and body composition. Methods Fifty young healthy men and women (21 men) participated in the study. Subjects completed TS testing on the right forearm using a repetitive thermal stimulus at a temperature that the subject reported 6/10 pain. Other testing included body composition (lunar iDXA), activity monitoring (Actigraph), and Pain Catastrophizing Scale (PCS). Results Women reported greater TS than men (p = 0.019), and TS was correlated with right arm lean mass (r = − 0.36, p = 0.01) and magnification subscale of PCS (r = − 0.32, p = 0.03). Mediation analysis showed a complete mediation for the relation between sex and TS by right arm lean mass (indirect effect = 2.33, 95% BCa CI [0.42, 4.58]) after controlling for the temperature, the magnification subscale of PCS, and the average time spent in moderate to vigorous physical activity. Conclusion The results of this study suggest that lean mass is a contributing factor to the sex differences in TS. Future studies should investigate whether interventions that increase lean mass have a positive effect on TS.

It has been proposed that manipulating proprioceptive signals of the equine distal limb as part of a rehabilitation process in cases of musculoskeletal pain or neurologic deficits can be used to correct postural control and restore normal motor programs. This trial has examined the effect of treatment with a light-weight and loose-fitting bell boot (82 g) on an imbalance of muscle gluteus superficialis function in horses as measured using acoustic myography (AMG). Eight horses were trained over a 60-minute period every 3 days for 6 weeks, a protocol based on preliminary findings. Acoustic myography measurements, recording the coordination, spatial and temporal summation of muscle contractions, were made at the start (baseline) and at the finish (week 6) after a warmup period and following a set procedure of physical activity. Walking, trotting, and cantering during a left-hand circle at the start of the trial revealed a slight but significant asymmetry between the left and right hind limb muscle, which improved successfully after 6 weeks of proprioception training. Data for the right-hand circle, which revealed no significant asymmetry, during walk, trot, and canter at the start, showed no change after 6 weeks of training at the walk and trot but developed an imbalance during cantering, the result of overcompensation. This study demonstrates that functional musculoskeletal asymmetry measured during periods of activity can not only be accurately detected using AMG but it also reveals an association between the program of proprioceptive training adopted and an improvement in muscular imbalance.

This study examined the effects of interstimulus interval (ISI) on heat-evoked temporal summation of second pain (TSSP) and tested whether greatest maintenance of TSSP would occur at longer ISIs in older adults. Several lines of evidence support that TSSP is associated with central sensitization and is centrally mediated. The participants were 198 community-dwelling adults divided into 3 age cohorts (18-39, 40-59, and 60-78 years of age). Six TSSP trials used a train of 10 contacts with a preheated probe that made repetitive contact with the volar forearm. Participants completed 2 trials at each ISI of 2.5, 3.5, and 4.5 seconds. The intraclass correlations for each pair of trials support the reliability of the current methodology. Temporal summation of second pain scores declined in a time-dependent manner across ISI. In addition, greater maintenance of TSSP at longer ISIs was observed in middle-aged and older age groups compared with the younger cohort. Significant associations were found between TSSP and measures of recent pain. Greater summation at longer ISIs in older adults would suggest slower decay of excitability in spinal neurons and infer increased risk for central sensitization with advancing age.

Migraineurs with aura (MWA) express higher interictal response to non-noxious and noxious experimental sensory stimuli compared with migraineurs without aura (MWoA), but whether these differences also prevail in response to everyday non-noxious stimuli is not yet explored. This is a cross-sectional study testing 53 female migraineurs (30 MWA; 23 MWoA) who underwent a wide battery of noxious psychophysical testing at a pain-free phase, and completed a Sensory Responsiveness Questionnaire and pain-related psychological questionnaires. The MWA group showed higher questionnaire-based sensory over-responsiveness (P = .030), higher magnitude of pain temporal summation (P = .031) as well as higher monthly attack frequency (P = .027) compared with the MWoA group. Overall, 45% of migraineurs described abnormal sensory (hyper- or hypo-) responsiveness; its incidence was higher among MWA (19 of 30, 63%) versus MWoA (6 of 23, 27%, P = .012), with an odds ratio of 3.58 for MWA. Sensory responsiveness scores were positively correlated with attack frequency (r = .361, P = .008) and temporal summation magnitude (r = .390, P = .004), both regardless of migraine type. MWA express higher everyday sensory responsiveness than MWoA, in line with higher response to experimental noxious stimuli. Abnormal scores of sensory responsiveness characterize people with sensory modulation dysfunction, suggesting possible underlying mechanisms overlap, and possibly high incidence of both clinical entities. Perspective This article presents findings distinguishing MWA, showing enhanced pain amplification, monthly attack frequency, and over-responsiveness to everyday sensations, compared with MWoA. Further, migraine is characterized by a high incidence of abnormal responsiveness to everyday sensation, specifically sensory over-responsiveness, that was also found related to pain.