Effects of Median Nerve Stimulation (Mns) Coupled With Physical Exercise on Pain Modulation: Double-blinded,randomized, Cross-over Exploratory Clinical Study

Effects of Median Nerve Stimulation (Mns) Coupled With Physical Exercise on Pain Modulation: Double-blinded,randomized, Cross-over Exploratory Clinical Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effects of Median Nerve Stimulation (Mns) Coupled With Physical Exercise on Pain Modulation: Double-blinded,randomized, Cross-over Exploratory Clinical Study Fabiana Tenório Gomes Silva, Marcel Simis, Aurore Thibaut, Felipe Fregni This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5112792/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Apr, 2026 Read the published version in Sport Sciences for Health → Version 1 posted 4 You are reading this latest preprint version Abstract Background Physical exercise (PE) and median nerve stimulation (MNS) are powerful non-pharmacological tools to control pain. However, the effects of concurrent use of these two techniques have not been explored. Therefore, combining the two treatments could increase their respective effects on pain control. We aim to test whether MNS, using a novel algorithm that varies intensity and frequency of stimulation, combined with PE modulates pain and physical activity performance. Methods Twenty-four healthy adults participated in this double-blinded, randomized, cross-over trial. Each subject underwent a control, sham and active MNS. MNS was applied for 20 minutes at rest and then for 10minutes during the warm-up period on the treadmill. Pain tests were performed at three time-points; at baseline (T0), after stimulation (T1) and after the PE (T2). In addition, during PE, the perceived exertion and pain sensation were assessed. Results We found a significant difference in the delta (T1 minus T2) between the active and the sham (p = 0.039) and between the active and the control (p = 0.041) for pressure pain threshold (PPT) on the left hand; pain thresholds being higher in the active group. Pain sensation during PE was lower for the active compared to the control group (p = 0.036). No other differences were identified. Conclusions Our findings suggest a modest effect of MNS on pain perception during PE and a supplementary effect of MNS combined with PE on PPT. Although the results are limited, this study investigates a novel approach to analyze the concurrent effect of two techniques that modulate the pain. Median Nerve Stimulation Pain Threshold Conditioned pain modulation (CPM) Physical exercise Figures Figure 1 Figure 2 Figure 3 1. Introduction Sedentary behavior is identified as the fourth risk factor for global mortality ( 1 ) and is associated with the development of diseases such as diabetes, obesity, stroke, hypertension, cancer, bone and joint disease (osteoporosis and osteoarthritis), depression, peripheral artery disease, and chronic pain, some of which are listed in the top 10 causes of death, according to the World Health Organization ( 2 – 4 ) . Physical inactivity also causes physiological changes such as the reduced activity of the endogenous pain inhibitory system ( 5 – 7 ) . Although the exact mechanism for pain relief in sedentary individuals is not yet well understood, it is proposed that there is less opioid tone in the brainstem, resulting in pain facilitation after nociceptive entry due to increases in NR1 subunit phosphorylation of the NMDA receptor and increased expression of serotonin transporter ( 8 ) which is associated with more recurrent pain complaints as well as chronic pain development ( 3 , 9 ) . Therefore, strategies that modulate the endogenous pain inhibitory system may reduce the chances of developing chronic pain diseases. Exercise is a powerful non-pharmacological tool to manage pain. Experimental pain studies in healthy and patients with various conditions have shown that physical exercise may modulate descending pain inhibition pathways modulating the pain ( 5 , 10 , 7 , 11 ) . While the underlying mechanisms of the analgesic effects of physical excise have been widely studied, they still remained to be fully uncovered. According to previous studies ( 12 – 14 ) , exercise-induced hypoalgesia (EIH) involves a complex series of phenomena and is likely caused by a combination of several factors such as activation of the endogenous opioid, cannabinoids, noradrenergics, serotoninergic and cardiovascular systems leading to activation of descending pain inhibition pathways. In relation to the activation of central inhibitory pathways, the main relay for pain modulation centrally in the rostral ventromedial medulla (RVM). There is recent evidence for the involvement of the RVM in the analgesia induced by exercise due to the increase opioid release (generated by physical exercise) leading to a reduction of phosphorylation of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor in the RVM, which would result in decreased facilitation of pain ( 8 , 12 ) . Median Nerve Stimulation (MNS), may be considered as a type of Transcutaneous electrical nerve stimulation (TENS) which has been tested to modulate pain in different conditions including healthy and patients with chronic and acute pain ( 15 , 16 ) . Although the exact mechanism of pain relief linked to the application of transcutaneous electrical stimulation is not yet fully understood, it has been postulated that it acts via the gate-control theory of pain as described by Melzack and Wall ( 17 ) which reduces the passage of the pain stimulus to the central nervous system and activates µ-opioid receptors in the spinal cord and the brainstem ( 18 ) which lead to an increase of the descending pain-inhibitory activity, thus reducing pain sensation. However, it is essential to note that the effects of peripheral electrical stimulation are likely dependent on the parameters of stimulation. Current research has tried to find the best stimulation patterns that are associated with optimal analgesic effects ( 19 , 20 ) . One interesting option is to use a variation of the parameters of stimulation, especially the intensity and frequency of stimulation. In this present study, we developed an algorithm to vary current intensities and frequencies to optimize MNS effects. We used these parameters in another study showing that this method has a significant effect on motor learning ( 21 ) . Currently, studies have shown that the combination of two modalities of treatment, which can modulate pain inhibition pathways systems lead to greater effects on pain relief than one or the other alone ( 22 , 23 ) . However, the impact of concurrent (simultaneous) methods has not been explored well. In this context, the main goal of our study is to analyze whether MNS (with parameters variation) combined with physical exercise will enhance the analgesic effect compared to physical exercise applied alone or physical exercise combining with sham MNS. Our secondary outcome is to explore the effects of MNS on time to fatigue, ratio perceiver exertion (RPE), and pain perception during physical exercise. Our hypothesis is that MNS combined with physical exercise will increase the PPT and CPM, and the MNS will reduce pain sensation during physical exercise, improving time to fatigue, increasing, thus its analgesic effect. 2. Materials and Methods 2.1 Subjects Twenty-four healthy right-hand dominant adults (12 women and 12 men; 25 mean age ±5.53 years; 68.7±16.2kg; 23.7±5 BMI) volunteered to participate in this study. All subjects completed a medical history questionnaire (PAR-Q) and the International physical activity questionnaire (IPAQ) before being enrolled in the study. Inclusion criteria were: i) able to provide informed consent to participate in the study, ii) able to perform physical activities such as treadmill, iii)18-40 years old iv) Body mass index (BMI) <27, v) to be insufficiently active (i.e., categories A or B in the International Physical Activity Questionnaire (IPAQ)). Exclusion criteria were: i) hypertension, diabetes, cardiovascular disease, ii) subjects with pacemakers, and/or implantable cardioverter-defibrillators, iii) history of asthma with active symptomatology in the past year, pulmonary disease or use of inhalers, active smoker, or history of smoking in the last 6 months, iv) physical disability, neurological and/or psychological disorder that precludes safe and adequate testing, v) conditions that may impair the ability to feel pain, vi) mental impairment with limited ability to cooperate, vii) suffering from severe depression (with a score >30 in the Beck Depression Inventory - BECK), viii) history of alcohol or drug abuse within the past 6 months as self-reported, ix) use of antiepileptic and/or hypnotic medications like carbamazepine, valproate acid, gabapentin, zolpidem, etc., x) use of medication with potential cardiovascular influence, xi) history of unexplained fainting spells as self-reported, head injury resulting in more than a momentary loss of consciousness, xii) history of neurosurgery as self-reported, epilepsy, xiv) skin lesion or open wounds around or in area of electrode application, tattoos in upper limb or along the nerve tract, xv) untreated medical conditions, such as significant anemia, important electrolyte imbalance, or hyperthyroidism and xvi) pregnancy or trying to become pregnant in the next 6 months. Subjects were informed about all procedures of the study and gave written informed consent prior to the experiment. This study was approved by the Human Ethics Committee of Psychology Institute of São Paulo University (CAAE: 54812416.7.0000.5561) conducted in accordance with the Declaration of Helsinki. 2.2. Study design This is a double-blinded, randomized, cross-over trial where subjects received control (i.e., no intervention), sham and active sensorial stimulation on different days (time of washout between the three sessions: 1 to 2 weeks). Subjects were asked to avoid strenuous physical activity and alcohol consumption 48 hours and caffeinated products and exhaustive cognitive activity 24 hours prior to each study session, as well as to maintain a good sleeping pattern and normal dietary habits during the entire duration of the protocol. The study was performed at the Institute of Physical Medicine and Rehabilitation of Hospital of Clinics of the Medical School of University of São Paulo (IMREA-HC-FM-USP). Each subject completed a total of 4 visits: visit 1: screening and baseline evaluations; visits 2 to 4: interventional visits. Each subject undertook the following procedures: a) Initial screening (exclusion and inclusion criteria) and baseline evaluation: Answer questionnaires (for medical history, depression, anxiety, and physical activity) and physical evaluation (maximal exercise test); On the same day, body weight (kg) and height (m) were measured. Body mass index was calculated as weight (kg) divided by the square of height in meters (kg/m 2 ). The subjects performed the maximal exercise test (to find the maximal speed). b) Interventional visits: The first interventional visit was made with a minimum interval of one week between one and the initial screening. Pain Pressure Thresholds (PPT), Conditioned pain modulation (CPM), and Time To Fatigue (TTF). Interventional visit - control, sham and active. The study protocol is presented in figure 1. 2.3 Procedures Anxiety assessment The anxiety status was based on the State-Trait Anxiety Inventory that is a common and important construct in the study of the human experience (24) . This is a sensitive scale for evaluation of the severity of anxiety. Depression assessment The depression was evaluated with the screening Beck Depression Inventory (BDI) score (25) . For this study, a BDI score > 30 was considered as an exclusion criterion. Physical activity level assessment The International Physical Activity Questionnaire (IPAQ) (26) was used to assess physical activity level. For this study, insufficient activity (inclusion criteria) were considered for subjects that performed less than 150 minutes of activity per week or less than five days per week. Maximal exercise test Each participant underwent an incremental exercise test to determine the maximal treadmill velocity. Firstly, there was a warm-up of five minutes walking at 4km.h -1 on a motorized treadmill (EMBRAMED ® 10200). The test consisted of an increase of 1km/h per minute until volitional exhaustion (27) . The maximal treadmill velocity was defined as the velocity achieved during the last full stage before volitional exhaustion. There was no verbal stimulation. Pressure Pain Threshold (PPT) PPT was evaluated with an algometer (Baseline ® 12-0304), with 1-cm 2 application surface and recordings displayed in kilograms of force (kgf) to establish the minimum pressure that triggered the pain at the thenar region of both hands. Recordings were taken with pressure applied at a rate of 1 kg.cm- 2 .s- 1 . PPT was performed three times for each side (right and left hand) with an interval of 10 seconds between them. The participants verbally reported the first point when pain (distinct from pressure or discomfort) occurred, then, the algometry was immediately removed, and the corresponding measurement recorded as PPT (20) . For each PPT, the pain intensity of pressure was also collected using the visual analog scale (VAS) (28) . Conditioned pain modulation (CPM) CPM was induced approximately for 1 min by having subjects immerse their right hand into a water bath maintained at 10-12˚C. After 30 seconds, the participant's pain intensity was collected using the VAS. During the following 30 seconds, the PPT procedure was repeated three times on the left hand (with an interval of 10 seconds between them). At the end of the procedure, the participant's pain intensity (VAS) of the hand into the water was asked one more time. CPM was evaluated as the mean difference in pain rating of the test stimulus applied before and during the conditioning stimulus and between the mean difference of the VAS during and in the end of CPM. We used the same protocol before in another study (29) except that we tested the left hand. Median Nerve Stimulation (MNS) Each session consisted of 20 minutes of electrical stimulation (active or sham) delivered by standard electrodes to the right wrist (median nerve) with the participant sitting on a comfortable chair. The shape of the wave was a constant rectangular wave with a random frequency range (1-4 Hz, 8-12Hz and 60-90 Hz) and intensity levels (2 to 6 mA) that changed every 2 minutes throughout of 20 minutes of stimulation. In the sham procedure, the device was turned on and only applied stimulation for the first and last 30 seconds. To control the condition, the participant stayed sited during the duration of the stimulation time (20 minutes). There was a second application of MNS, which was administered during the warm-up period on the treadmill; the duration was ten minutes prior to exercise with 70% of maximal velocity. Time To Fatigue (TTF) Each experimental visit consisted of a warm-up of ten minutes on the treadmill with the velocity of 4km/h (depending on the randomization, the MNS (sham and active condition) was applied during this warm-up time (10 minutes). After that, the velocity was changed to 70% of the maximal velocity and kept until exhaustion (without MNS). During the second part of the exercise (70% of the maximal speed), the individuals were asked (each 1 minute) about perceived exertion (Borg scale), pain sensation (VAS), and where they feel the pain (subjective question). The test was kept until the individual asked to stop. 3. Statistical analysis The normality of data variance was tested with the Shapiro-Wilk’s test, skewness, and kurtosis. In order to compare the values of PPT at rest (right and left side), PPT during CPM and pain sensation our primary outcome, we conducted a Friedman´s test to compare between the three conditions (control, sham and active rMNS) and Wilcoxon signed-rank test (two analyses (control x active and sham x active)) when the differences among the groups were found. We used the difference (i.e., delta) between post-stimulation minus post-exercise ((T1-T2) main outcome), before-stimulation minus post-stimulation ((T0-T1) exploratory analysis about MNS effects) where positive values represent hyperalgesia and negative values represent hyporalgesia. We also used a Friedman´s test to compare the values of pain sensation during total time physical exercise at different time points (i.e., 10%, 20%, 40%, 60%, 80% and 100% of total exercise time), between the three conditions (control, sham and active MNS). For posthoc analyses, we used Wilcoxon signed-rank as. We considered the p-value as < 0.05 for all the primary outcomes. We did not correct for multiple comparisons given this is an initial exploratory study (30) . 4. Results Population All volunteers had a body mass index (BMI) < 27 and were sedentary or insufficiently active, according to the IPAQ. At baseline, participants had a score of 6.95 ± 5.32 (normal) at the Beck depression inventory, a State-Trait Anxiety Inventory score of 36.45 ± 10 (state), and 37.62 ± 9.44 (trait) (scale ranges from 20 to 80). Primary Outcomes: PPT, CPM and VAS at rest We did not find a baseline difference for the PPT, VAS and CPM delta between the three conditions. We found a significant difference in PPT left between active and sham (p = 0.039) and between active and control groups (p = 0.041) when looking at the difference (i.e., delta) between PPT post-stimulation and post-exercise which show PPT increasing (meaning less pain) in the active group (See Fig. 2 ). No other comparisons reached significance level for PPT neither for CPM and VAS at rest ( See table 1) . Table I. PPT and VAS (right and left hands) and CPM T0-T1 T1-T2 T0-T1 T1-T2 PPT left PPT right Control – active rMNS Z = 0.300 ; p = 0.764 Z=-2.115 ; p = 0.041 Control – active rMNS Z=-1.358 ; p = 0.175 Z=-0.614 ; p = 0.539 Sham – active rMNS Z=-0.314 ; p = 0.753 Z=-2.115 ; p = 0.039 Sham – active rMNS Z=-1.257 ; p = 0.209 Z=-1.300 ; p = 0.194 VAS PPT left VAS PPT right Control – active rMNS Z=-0.246 ; p = 0.805 Z = 0.263 ; p = 0.793 Control – active rMNS Z=-0.157 ; p = 0.875 Z=-0.908 ; p = 0.364 Sham – active rMNS Z=-0.145 ; p = 0.885 Z = 1.011 ; p = 0.312 Sham – active rMNS Z=-0.072 ; p = 0.943 Z=-0.610 ; p = 0.542 PPT CPM left VAS CPM left Control – active rMNS Z = 0.071 ; p = 0.943 Z=-0.486 ; p = 0.627 Control – active rMNS Z = 0.880 ; p = 0.379 Z=-0.351 ; p = 0.726 Sham – active rMNS Z = 0.257 ; p = 0.797 Z=-1.115 ; p = 0.265 Sham – active rMNS Z=-0.233 ; p = 0.816 Z = 0.207 ; p = 0.836 Secondary Outcome: Pain sensation during physical exercise, Time to fatigue, perceived exertion, frequency and pain locations in lower limbs. Regarding pain sensation (VAS) during physical exercise, we found a significant difference between the active MNS and the control condition at 40% of maximal time of exercise (p = 0.036) (see Fig. 3 ) (the comparison of active vs. sham reached a trend for significance (p = 0.09) (see table 2) . The time to fatigue and perceived exertion were not significantly different between the conditions (See Table 3) . Table II. VAS and Perceived exertion during physical exercise. 10% 20% 40% 60% 80% 100% VAS_Control – active MNS Z=-0.181 ; p = 0.856 Z = 1.477 ; p = 0.139 Z = 2.190 ; p = 0.036 Z = 1.061 ; p = 0.289 Z = 0.194 ; p = 0.846 Z = 0.612 ; p = 0.541 VAS_Sham – active MNS Z = 0.222 ; p = 0.824 Z = 1.709 ; p = 0.086 Z = 1.793 ; p = 0.094 Z = 0.352 ; p = 0.725 Z = 1.433 ; p = 0.152 Z = 1.331 ; p = 0.183 RPE_Control – active MNS Z=-0.656 ; p = 0.512 Z=-0.693 ; p = 0.488 Z=-0.121 ; p = 0.904 Z=-0.203 ; p = 0.839 Z = 0.882 ; p = 0.378 Z=-1.18 ; p = 0.236 RPE_Sham – active MNS Z = 1.213 ;p = 0.225 Z = 0.785 ; p = 0.433 Z = 1.46 ; p = 0.144 Z = 1.124 ; p = 0.213 Z = 1.6 ; p = 0.109 Z = 1.18 ; p = 0.235 Table III. Time to fatigue and pain local during physical exercise followed control, sham and anodal MNS. CONDITION CONTROL SHAM ACTIVE p value TIME TO FATIGUE 13.0 ± 7.84 13.0 ± 5.99 13.2 ± 7.10 p = 0.364 Values are represented as mean (± standard deviation). 5. Discussion This is an exploratory randomized, cross-over and double-blind trial, which shows a synergic effect of MNS plus physical exercise on pain in sedentary people both at rest and during physical exercise. We found that PPT of the left hand increased after physical exercise with active MNS (-0.05 KGS) when compared to the sham (0.08 KGS) and control conditions (0.05 KGS). We found no changes in PPT on the right hand, CPM and VAS at rest. MNS decreased the pain sensation during physical exercise when analyzing for the percentage of time showing the reduction of pain (33.4% less than control) in a specific time point (40% of total time equivalent to 5.28 minutes of physical exercise). Although we show significant differences, the effects were limited to a few outcomes only. In the descriptive statistic, the frequency and pain locations in lower limbs reported during physical exercise were lower in the active condition when compared with control and sham, and these effects did not change the time to fatigue and perceived exertion. This study explored the effects of MNS combined with physical exercise on the hypoalgesic effects. Our data suggest that combining two treatments which activated the endogenous pain inhibitory systems can lead to a summing analgesic effect when compared with just one treatment alone or physical exercise plus MNS placebo. Our results are in line with previous studies (22,23) , which combined two treatments, such as transcranial Direct Current Stimulation (tDCS) and TENS; and neuromuscular electrical stimulation and TENS which activate the endogenous pain inhibitory systems showing higher in analgesic effects. These results may be explained by several factors: 1) Physical exercise and MNS mechanisms at the cortical, subcortical, and brainstem levels. The cortical related effects of MNS and exercise are likely mainly driven by spinoreticular component connected to the neurons of the ascending reticular activating system (ARAS), which can activate various regions in the cortex through ventromedial part of the thalamus (31) which is characterized by its extensive neocortical projection (32) . Therefore our results show that MNS combined with physical exercise effects may not be side dependent, due to the wide cortical projection (33) and the part of descendent inhibitory pain pathway has bilateral fibers distribution (34) ; 2) The first stimulation could have primed the effect with physical exercise and/or the second stimulation applied during warming period (i.e., first 10 minutes on the treadmill), may have induced a synergistic (summation effect) effect of MNS. These two effects (prime and synergistic) are due of the increased brainstem and brain activity linked to MNS and walking (here warming period) which activate similar areas such as M1, sensorimotor areas, parietal, cingulated anterior cortex and periaqueductal gray (PAG) (35,36) , leading to a reinforcement of MNS effects. Such effects could only be seen on the left side due a) this non-dominant side has a lower threshold (37,38) , and b) this side is less stimulated during the protocol and may not have reached inhibitory systems exhaustion (39,40) . 3) Bienenstock-Cooper-Munro (BCM) (41) theory shows that synaptic plasticity depends on the previous level of postsynaptic neuronal activity in which the threshold for LTP induction increases if the previous level of postsynaptic neuronal activity was high. In this present study, the dominant side (right) was stimulated once prior to the physical exercise session, which maybe may have increased the pathway´s excitability leading to more difficulty in generating LTP. MNS induced pain reduction during physical exercise (33.4% compared to control) after 5.28 minutes of exercise (40% of total time) which is in line with a previous study (42) evaluating the effect of TENS (continuous pattern of stimulation with the frequency of 100 Hz) on pain. They found a reduction of pain perception (1) during isometric contractions (pain decreased by 12%) and (2) during a cycling exercise (i.e. bike 16.1km on a cycle ergometer as fast as possible; pain decreased between 19,4% and 32,6%. These results support the beneficial effect of MNS during physical exercise on pain perception, which could have a positive impact on sedentary subjects and patients required to perform the physical exercise as well as limit the number of drop-outs in researches. Interestingly we did not find differences in the PPT to among the conditions to the delta T0-T1 what may reflect no MNS stimulation effects when applied alone or MNS effect was masked by CPM test applied before MNS due the endogenous pain inhibitory systems has a plateau which when it is reached reaches exhaustion and its effects on the pain may not be increased, or it is reduced when another stimulus is applied as explained in prior studies (39,40) . The same results we found to CPM, which we did not find an effect of MNS alone (delta T0-T1) and combined with physical exercise (T1-T2) on CPM. These results are similar to the previous studies that investigated whether the simultaneous application of TENS and CPM (40) and physical exercise after CPM(39)will enhance the analgesic effect compared to each treatment when applied alone. In our study, the CPM test prior MNS, may have masked the MNS effects on the second CPM. Similarly, CPM tested prior to physical exercise may have masked the effects on the third CPM. The masking´s hypotheses may be explained due studies showed that PPT changes during CPM are positively correlated with PPT changes during TENS application (40) , and CPM is also positively correlated with physical exercise hypoalgesic effects (43) , in our study we cannot prove the effect of PPT with just MNS and just Physical exercise due the CPM was did prior the intervention. Study limitations This study had some limitations, such as the small sample size, and the p-value was not adjusted for multiple comparisons, which may have led to type I or II errors. However, it should be noted that our study has a crossover design, indicating that 24 subjects in our study are equivalent to 72 patients in a parallel study. In addition, within-subjects variability is smaller than between-subjects variability; therefore, this study has more power compared with 24 subjects in a parallel design. In addition, we used CPM, which activates pain inhibitory systems and may have biased the pain-related measures in our study. Therefore, future studies should take into account this issue and design protocols to test CPM without interfering with other measures (e.g., longer washout periods after the CPM and the next test). Finally, we only tested the effects of a single MNS session, while multiple sessions may be needed to induce clinically relevant effects. 6. Conclusions In conclusion, reducing pain using complementary non-pharmacological techniques could be extremely useful, especially for sedentary people. Although our results show a modest and limited effect, our findings bring a new way to overcome some issues linked to sedentary behaviors which have been shown to be related to higher pain perception and a decreased activity of the endogenous inhibitory system of pain when compared to active and athletes behavior ( 5 – 7 ) . Therefore, reducing pain sensation during physical exercise and increase pain threshold could improve the adherence to protocols or training of sedentary people and reduce the risks of health problems such as cardiovascular events, stroke, obesity, and chronic pain. However, a deeper understanding of the mechanisms and physiological responses of interaction between the simultaneous application of neuromodulation interventions on pain is still needed. More studies are necessary to clarify this mechanism and understand its responses in a larger population. Declarations 7. Acknowledgements Fundação de Amparo à pesquisa do Estado de São Paulo (FAPESP), Instituto de Medicina Física e Reabilitação do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo IMREA (HC FMUSP) and all the volunteers who participated this research. Conflicts of interest: The authors declare no conflict of interest. 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A utilização do questionário internacional de atividade física (IPAQ) como ferramenta diagnóstica do nível de aptidão física: uma revisão no Brasil. Saúde em Revista. 2012;12(32):49–54. MacAuley D. Oxford handbook of sport and exercise medicine. Oxford University Press; 2012. Bijur PE, Silver W, Gallagher EJ. Reliability of the visual analog scale for measurement of acute pain. Academic emergency medicine. 2001;8(12):1153–1157. Reidler JS, Mendonca ME, Santana MB, Wang X, Lenkinski R, Motta AF, et al. Effects of motor cortex modulation and descending inhibitory systems on pain thresholds in healthy subjects. The Journal of Pain. 2012;13(5):450–458. Rubin M. Do p values lose their meaning in exploratory analyses? It depends how you define the familywise error rate. Review of General Psychology. 2017;21(3):269–275. Starzl TE, Taylor CW, Magoun HW. Ascending conduction in reticular activating system, with special reference to the diencephalon. Journal of neurophysiology. 1951;14(6):461–477. Klockgether T, Schwarz M, Turski L, Sontag K-H. The rat ventromedial thalamic nucleus and motor control: role of N-methyl-D-aspartate-mediated excitation, GABAergic inhibition, and muscarinic transmission. Journal of Neuroscience. 1986;6(6):1702–1711. Edlow BL, Takahashi E, Wu O, Benner T, Dai G, Bu L, et al. Neuroanatomic connectivity of the human ascending arousal system critical to consciousness and its disorders. Journal of Neuropathology & Experimental Neurology. 2012;71(6):531–546. Llorca-Torralba M, Borges G, Neto F, Mico JA, Berrocoso E. Noradrenergic Locus Coeruleus pathways in pain modulation. Neuroscience. 2016;338:93–113. Hamacher D, Herold F, Wiegel P, Hamacher D, Schega L. Brain activity during walking: a systematic review. Neuroscience & Biobehavioral Reviews. 2015;57:310–327. Scheef L, Jankowski J, Daamen M, Weyer G, Klingenberg M, Renner J, et al. An fMRI study on the acute effects of exercise on pain processing in trained athletes. PAIN®. 2012;153(8):1702–1714. Pauli P, Wiedemann G, Nickola M. Pressure pain thresholds asymmetry in left-and right-handers: associations with behavioural measures of cerebral laterality. European Journal of Pain. 1999;3(2):151–156. Özcan A, Tulum Z, Pınar L, Başkurt F. Comparison of pressure pain threshold, grip strength, dexterity and touch pressure of dominant and non-dominant hands within and between right-and left-handed subjects. Journal of Korean medical science. 2004;19(6):874–878. Gajsar H, Nahrwold K, Titze C, Hasenbring MI, Vaegter HB. Exercise does not produce hypoalgesia when performed immediately after a painful stimulus. Scandinavian Journal of Pain. 2018;18(2):311–320. Liebano RE, Vance CG, Rakel BA, Lee JE, Cooper NA, Marchand S, et al. Transcutaneous electrical nerve stimulation and conditioned pain modulation influence the perception of pain in humans. European Journal of Pain. 2013;17(10):1539–1546. Bienenstock EL, Cooper LN, Munro PW. Theory for the development of neuron selectivity: orientation specificity and binocular interaction in visual cortex. Journal of Neuroscience. 1982;2(1):32–48. Astokorki AH, Mauger AR. Transcutaneous electrical nerve stimulation reduces exercise-induced perceived pain and improves endurance exercise performance. European journal of applied physiology. 2017;117(3):483–492. Lemley K, Hunter S, Bement M. Conditioned Pain Modulation Predicts Exercise-Induced Hypoalgesia in Healthy Adults. Medicine & Science in Sports & Exercise.2015. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 19 Apr, 2026 Read the published version in Sport Sciences for Health → Version 1 posted Editorial decision: Revision requested 26 May, 2025 Editor assigned by journal 19 Sep, 2024 Submission checks completed at journal 19 Sep, 2024 First submitted to journal 18 Sep, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5112792","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":461824193,"identity":"1e509423-64dc-4be2-be26-f691cad3ce42","order_by":0,"name":"Fabiana Tenório Gomes Silva","email":"","orcid":"","institution":"University of São Paulo (USP)","correspondingAuthor":false,"prefix":"","firstName":"Fabiana","middleName":"Tenório Gomes","lastName":"Silva","suffix":""},{"id":461824194,"identity":"c0e3033f-bc9d-494c-83a8-d231aca207b8","order_by":1,"name":"Marcel Simis","email":"","orcid":"","institution":"University of São Paulo (USP)","correspondingAuthor":false,"prefix":"","firstName":"Marcel","middleName":"","lastName":"Simis","suffix":""},{"id":461824195,"identity":"cb180ef7-29d9-4f72-8e69-1c2dd749cb2e","order_by":2,"name":"Aurore Thibaut","email":"","orcid":"","institution":"University and Univerisity Hospital of Liège","correspondingAuthor":false,"prefix":"","firstName":"Aurore","middleName":"","lastName":"Thibaut","suffix":""},{"id":461824196,"identity":"0b126066-270d-4860-aff6-18e3f1acf3ba","order_by":3,"name":"Felipe Fregni","email":"data:image/png;base64,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","orcid":"","institution":"Harvard Medical School","correspondingAuthor":true,"prefix":"","firstName":"Felipe","middleName":"","lastName":"Fregni","suffix":""}],"badges":[],"createdAt":"2024-09-18 23:54:45","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5112792/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5112792/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11332-026-01718-5","type":"published","date":"2026-04-19T15:58:05+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":90013680,"identity":"04bf01ef-90ed-41d3-940e-8894fe1397c1","added_by":"auto","created_at":"2025-08-27 11:20:29","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":42797,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic illustration of the experimental protocol performed during the control and two experimental sessions (placebo and real stimulation). The pain tests were: PPT, DNIC, and VAS, which were assessed on three times before and immediately after MNS and after physical exercise.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5112792/v1/178238561a69497be9d29d74.png"},{"id":90013681,"identity":"285c96b4-880e-443a-b55f-5ae275335dbf","added_by":"auto","created_at":"2025-08-27 11:20:29","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":19706,"visible":true,"origin":"","legend":"\u003cp\u003ePPT variation (PPT post stimulation (T1) minus PPT post exercise (T2) for control, sham and active conditions. A significant difference was found between the active and both sham and control conditions (*)\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5112792/v1/7ad4d2a72bac5f56f0bf9231.png"},{"id":90013682,"identity":"77bc4909-438c-499b-b4dd-32fa6f6c6d08","added_by":"auto","created_at":"2025-08-27 11:20:29","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":15682,"visible":true,"origin":"","legend":"\u003cp\u003eGraph Visual Analogic Scale (VAS – median scores).\u003cstrong\u003e \u003c/strong\u003eA significant difference was found between active MNS and control condition at 40% of the total time of physical exercise (*)\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5112792/v1/ac41fc6bbd9cba1d657ad78f.png"},{"id":107350749,"identity":"40a5905e-9c99-4a29-806c-7d9a420b2283","added_by":"auto","created_at":"2026-04-20 16:02:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":594980,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5112792/v1/55ba0b4c-1716-4663-a972-63922d7b6eb1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eEffects of Median Nerve Stimulation (Mns) Coupled With Physical Exercise on Pain Modulation: Double-blinded,randomized, Cross-over Exploratory Clinical Study\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eSedentary behavior is identified as the fourth risk factor for global mortality\u003csup\u003e(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/sup\u003e and is associated with the development of diseases such as diabetes, obesity, stroke, hypertension, cancer, bone and joint disease (osteoporosis and osteoarthritis), depression, peripheral artery disease, and chronic pain, some of which are listed in the top 10 causes of death, according to the World Health Organization\u003csup\u003e(\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/sup\u003e. Physical inactivity also causes physiological changes such as the reduced activity of the endogenous pain inhibitory system\u003csup\u003e(\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/sup\u003e. Although the exact mechanism for pain relief in sedentary individuals is not yet well understood, it is proposed that there is less opioid tone in the brainstem, resulting in pain facilitation after nociceptive entry due to increases in NR1 subunit phosphorylation of the NMDA receptor and increased expression of serotonin transporter\u003csup\u003e(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/sup\u003e which is associated with more recurrent pain complaints as well as chronic pain development\u003csup\u003e(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/sup\u003e. Therefore, strategies that modulate the endogenous pain inhibitory system may reduce the chances of developing chronic pain diseases.\u003c/p\u003e \u003cp\u003eExercise is a powerful non-pharmacological tool to manage pain. Experimental pain studies in healthy and patients with various conditions have shown that physical exercise may modulate descending pain inhibition pathways modulating the pain\u003csup\u003e(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/sup\u003e. While the underlying mechanisms of the analgesic effects of physical excise have been widely studied, they still remained to be fully uncovered. According to previous studies\u003csup\u003e(\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/sup\u003e, exercise-induced hypoalgesia (EIH) involves a complex series of phenomena and is likely caused by a combination of several factors such as activation of the endogenous opioid, cannabinoids, noradrenergics, serotoninergic and cardiovascular systems leading to activation of descending pain inhibition pathways. In relation to the activation of central inhibitory pathways, the main relay for pain modulation centrally in the rostral ventromedial medulla (RVM). There is recent evidence for the involvement of the RVM in the analgesia induced by exercise due to the increase opioid release (generated by physical exercise) leading to a reduction of phosphorylation of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor in the RVM, which would result in decreased facilitation of pain\u003csup\u003e(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMedian Nerve Stimulation (MNS), may be considered as a type of Transcutaneous electrical nerve stimulation (TENS) which has been tested to modulate pain in different conditions including healthy and patients with chronic and acute pain\u003csup\u003e(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/sup\u003e. Although the exact mechanism of pain relief linked to the application of transcutaneous electrical stimulation is not yet fully understood, it has been postulated that it acts via the gate-control theory of pain as described by Melzack and Wall\u003csup\u003e(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/sup\u003e which reduces the passage of the pain stimulus to the central nervous system and activates \u0026micro;-opioid receptors in the spinal cord and the brainstem\u003csup\u003e(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/sup\u003e which lead to an increase of the descending pain-inhibitory activity, thus reducing pain sensation. However, it is essential to note that the effects of peripheral electrical stimulation are likely dependent on the parameters of stimulation. Current research has tried to find the best stimulation patterns that are associated with optimal analgesic effects\u003csup\u003e(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/sup\u003e. One interesting option is to use a variation of the parameters of stimulation, especially the intensity and frequency of stimulation. In this present study, we developed an algorithm to vary current intensities and frequencies to optimize MNS effects. We used these parameters in another study showing that this method has a significant effect on motor learning\u003csup\u003e(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e)\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCurrently, studies have shown that the combination of two modalities of treatment, which can modulate pain inhibition pathways systems lead to greater effects on pain relief than one or the other alone\u003csup\u003e(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/sup\u003e. However, the impact of concurrent (simultaneous) methods has not been explored well. In this context, the main goal of our study is to analyze whether MNS (with parameters variation) combined with physical exercise will enhance the analgesic effect compared to physical exercise applied alone or physical exercise combining with sham MNS. Our secondary outcome is to explore the effects of MNS on time to fatigue, ratio perceiver exertion (RPE), and pain perception during physical exercise. Our hypothesis is that MNS combined with physical exercise will increase the PPT and CPM, and the MNS will reduce pain sensation during physical exercise, improving time to fatigue, increasing, thus its analgesic effect.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003e2.1 Subjects\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwenty-four healthy right-hand dominant adults (12 women and 12 men; 25 mean age ±5.53 years; 68.7±16.2kg; 23.7±5 BMI) volunteered to participate in this study. All subjects completed a medical history questionnaire (PAR-Q) and the International physical activity questionnaire (IPAQ) before being enrolled in the study. \u003cstrong\u003eInclusion criteria were:\u003c/strong\u003e i) able to provide informed consent to participate in the study, ii) able to perform physical activities such as treadmill, iii)18-40 years old iv) Body mass index (BMI) \u0026lt;27, v) to be insufficiently active (i.e., categories A or B in the International Physical Activity Questionnaire (IPAQ)). \u003cstrong\u003eExclusion criteria were:\u003c/strong\u003e i) hypertension, diabetes, cardiovascular disease, ii) subjects with pacemakers, and/or implantable cardioverter-defibrillators, iii) history of asthma with active symptomatology in the past year, pulmonary disease or use of inhalers, active smoker, or history of smoking in the last 6 months, iv) physical disability, neurological and/or psychological disorder that precludes safe and adequate testing, v) conditions that may impair the ability to feel pain, vi) mental impairment with limited ability to cooperate, vii) suffering from severe depression (with a score \u0026gt;30 in the Beck Depression Inventory - BECK), viii) history of alcohol or drug abuse within the past 6 months as self-reported, ix) use of antiepileptic and/or hypnotic medications like carbamazepine, valproate acid, gabapentin, zolpidem, etc., x) use of medication with potential cardiovascular influence, xi) history of unexplained fainting spells as self-reported, head injury resulting in more than a momentary loss of consciousness, xii) history of neurosurgery as self-reported, epilepsy, xiv) skin lesion or open wounds around or in area of electrode application, tattoos in upper limb or along the nerve tract, xv) untreated medical conditions, such as significant anemia, important electrolyte imbalance, or hyperthyroidism and xvi) pregnancy or trying to become pregnant in the next 6 months. Subjects were informed about all procedures of the study and gave written informed consent prior to the experiment. This study was approved by the Human Ethics Committee of Psychology Institute of São Paulo University (CAAE: 54812416.7.0000.5561) conducted in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2. Study design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is a double-blinded, randomized, cross-over trial where subjects received control (i.e., no intervention), sham and active sensorial stimulation on different days (time of washout between the three sessions: 1 to 2 weeks). Subjects were asked to avoid strenuous physical activity and alcohol consumption 48 hours and caffeinated products and exhaustive cognitive activity 24 hours prior to each study session, as well as to maintain a good sleeping pattern and normal dietary habits during the entire duration of the protocol.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study was performed at the Institute of Physical Medicine and Rehabilitation of Hospital of Clinics of the Medical School of University of São Paulo (IMREA-HC-FM-USP). Each subject completed a total of 4 visits: visit 1: screening and baseline evaluations; visits 2 to 4: interventional visits.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEach subject undertook the following procedures:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ea) Initial screening (exclusion and inclusion criteria) and baseline evaluation: Answer questionnaires (for medical history, depression, anxiety, and physical activity) and physical evaluation (maximal exercise test); On the same day, body weight (kg) and height (m) were measured. Body mass index was calculated as weight (kg) divided by the square of height in meters (kg/m\u003csup\u003e2\u003c/sup\u003e). The subjects performed the maximal exercise test (to find the maximal speed).\u003c/p\u003e\n\u003cp\u003eb) Interventional visits: The first interventional visit was made with a minimum interval of one week between one and the initial screening. Pain Pressure Thresholds (PPT), Conditioned pain modulation (CPM), and Time To Fatigue (TTF). Interventional visit - control, sham and active.\u003c/p\u003e\n\u003cp\u003eThe study protocol is presented in figure 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3\u0026nbsp;Procedures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAnxiety assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe anxiety status was\u0026nbsp;based on the State-Trait Anxiety Inventory that is a common and important construct in the study of the human experience\u003csup\u003e(24)\u003c/sup\u003e. This is a sensitive scale for evaluation of the severity of anxiety.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDepression assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe depression was evaluated with the screening Beck Depression Inventory (BDI) score\u003csup\u003e(25)\u003c/sup\u003e. For this study, a BDI score \u0026gt; 30 was considered as an exclusion criterion.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePhysical activity level assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe International Physical Activity Questionnaire (IPAQ)\u003csup\u003e(26)\u003c/sup\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003ewas used to assess physical activity level. For this study, insufficient activity (inclusion criteria) were considered for subjects that performed less than 150 minutes of activity per week or less than five days per week.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaximal exercise test\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEach participant underwent an incremental exercise \u0026nbsp;test to determine the maximal treadmill velocity. Firstly, there was a warm-up of five minutes\u003cbr\u003ewalking at 4km.h\u003csup\u003e-1\u003c/sup\u003e on a motorized treadmill (EMBRAMED\u003cstrong\u003e\u003csup\u003e®\u003c/sup\u003e\u003c/strong\u003e 10200). The test consisted of an increase of 1km/h per minute until volitional exhaustion\u003csup\u003e(27)\u003c/sup\u003e. The maximal treadmill velocity was defined as the velocity achieved during the last full stage before volitional exhaustion. There was no verbal stimulation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePressure Pain Threshold (PPT)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePPT was evaluated with an algometer (Baseline\u003cstrong\u003e\u003csup\u003e®\u003c/sup\u003e\u003c/strong\u003e 12-0304), with 1-cm\u003csup\u003e2\u003c/sup\u003e application surface and recordings displayed in kilograms of force (kgf) to establish the minimum pressure that triggered the pain at the thenar region of both hands. Recordings were taken with pressure applied at a rate of 1 kg.cm-\u003csup\u003e2\u003c/sup\u003e.s-\u003csup\u003e1\u003c/sup\u003e.\u0026nbsp;PPT was performed three times for each side (right and left hand) with an interval of 10 seconds between them. The participants verbally reported the first point when pain (distinct from pressure or discomfort) occurred, then, the algometry was immediately removed, and the corresponding measurement recorded as PPT\u003csup\u003e(20)\u003c/sup\u003e.\u0026nbsp;For each PPT, the pain intensity of pressure was also collected using the visual analog scale (VAS)\u003csup\u003e(28)\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConditioned pain modulation (CPM)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCPM was induced approximately for 1 min by having subjects immerse their right hand into a water bath maintained at 10-12˚C. After 30 seconds, the participant's pain intensity was collected using the VAS. During the following 30 seconds, the PPT procedure was repeated three times on the left hand (with an interval of 10 seconds between them). At the end of the procedure, the participant's pain intensity (VAS) of the hand into the water was asked one more time. CPM was evaluated as the mean difference in pain rating of the test stimulus applied before and during the conditioning stimulus and between the mean difference of the VAS during and in the end of CPM. We used the same protocol before in another study\u003csup\u003e(29)\u003c/sup\u003e except that we tested the left hand.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;Median Nerve Stimulation (MNS)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEach session consisted of 20 minutes of electrical stimulation (active or sham) delivered by standard electrodes to the right wrist (median nerve) with the participant sitting on a comfortable chair. The shape of the wave was a constant rectangular wave with a random frequency range (1-4 Hz, 8-12Hz and 60-90 Hz) and intensity levels (2 to 6 mA)\u0026nbsp;that changed every 2 minutes throughout of 20 minutes of stimulation. In the sham procedure, the device was turned on and only applied stimulation for the first and last 30 seconds. To control the condition, the participant stayed sited during the duration of the stimulation time (20 minutes). There was a second application of MNS, which was administered during the warm-up period on the treadmill; the duration was ten minutes prior to exercise with 70% of maximal velocity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTime To Fatigue (TTF)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEach experimental visit consisted of a warm-up of ten minutes on the treadmill with the velocity of 4km/h (depending on the randomization, the MNS (sham and active condition) was applied during this warm-up time (10 minutes). After that, the velocity was changed to 70% of the maximal velocity and kept until exhaustion (without MNS). During the second part of the exercise (70% of the maximal speed), the individuals were asked (each 1 minute) about perceived exertion (Borg scale), pain sensation (VAS), and where they feel the pain (subjective question). The test was kept until the individual asked to stop.\u003c/p\u003e\n\n\n\n"},{"header":"3. Statistical analysis ","content":"\u003cp\u003eThe normality of data variance was tested with the Shapiro-Wilk’s test, skewness, and kurtosis. In order to compare the values of PPT at rest (right and left side), PPT during CPM and pain sensation our primary outcome, we conducted a Friedman´s test to compare between the three conditions (control, sham and active rMNS) and Wilcoxon signed-rank test (two analyses (control x active and sham x active)) when the differences among the groups were found. We used the difference (i.e., delta) between post-stimulation minus post-exercise ((T1-T2) main outcome), before-stimulation minus post-stimulation ((T0-T1) exploratory analysis about MNS effects) where positive values represent hyperalgesia and negative values represent hyporalgesia.\u003c/p\u003e\u003cp\u003eWe also used a Friedman´s test to compare the values of pain sensation during total time physical exercise at different time points (i.e., 10%, 20%, 40%, 60%, 80% and 100% of total exercise time), between the three conditions (control, sham and active MNS). For posthoc analyses, we used Wilcoxon signed-rank as.\u003c/p\u003e\u003cp\u003eWe considered the p-value as \u0026lt; 0.05 for all the primary outcomes. We did not correct for multiple comparisons given this is an initial exploratory study\u003csup\u003e(30)\u003c/sup\u003e.\u003c/p\u003e"},{"header":"4. Results","content":"\u003cp\u003e \u003cb\u003ePopulation\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAll volunteers had a body mass index (BMI)\u0026thinsp;\u0026lt;\u0026thinsp;27 and were sedentary or insufficiently active, according to the IPAQ. At baseline, participants had a score of 6.95\u0026thinsp;\u0026plusmn;\u0026thinsp;5.32 (normal) at the Beck depression inventory, a State-Trait Anxiety Inventory score of 36.45\u0026thinsp;\u0026plusmn;\u0026thinsp;10 (state), and 37.62\u0026thinsp;\u0026plusmn;\u0026thinsp;9.44 (trait) (scale ranges from 20 to 80).\u003c/p\u003e \u003cp\u003e \u003cb\u003ePrimary Outcomes: PPT, CPM and VAS at rest\u003c/b\u003e \u003c/p\u003e \u003cp\u003eWe did not find a baseline difference for the PPT, VAS and CPM delta between the three conditions. We found a significant difference in PPT left between active and sham (p\u0026thinsp;=\u0026thinsp;0.039) and between active and control groups (p\u0026thinsp;=\u0026thinsp;0.041) when looking at the difference (i.e., delta) between PPT post-stimulation and post-exercise which show PPT increasing (meaning less pain) in the active group \u003cb\u003e(See\u003c/b\u003e Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e No other comparisons reached significance level for PPT neither for CPM and VAS at rest (\u003cb\u003eSee table 1)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eTable I. PPT and VAS (right and left hands) and CPM\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT0-T1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eT1-T2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eT0-T1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eT1-T2\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003ePPT left\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003ePPT right\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eControl \u0026ndash; active rMNS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eZ\u0026thinsp;=\u0026thinsp;0.300\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.764\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eZ=-2.115\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.041\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eControl \u0026ndash; active rMNS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eZ=-1.358\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.175\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eZ=-0.614\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.539\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSham \u0026ndash; active rMNS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eZ=-0.314\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.753\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eZ=-2.115\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.039\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSham \u0026ndash; active rMNS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eZ=-1.257\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.209\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eZ=-1.300\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.194\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVAS PPT left\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e\u003cb\u003eVAS PPT right\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eControl \u0026ndash; active rMNS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eZ=-0.246\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.805\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eZ\u0026thinsp;=\u0026thinsp;0.263\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.793\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eControl \u0026ndash; active rMNS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eZ=-0.157\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.875\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eZ=-0.908\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.364\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSham \u0026ndash; active rMNS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eZ=-0.145\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.885\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eZ\u0026thinsp;=\u0026thinsp;1.011\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.312\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSham \u0026ndash; active rMNS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eZ=-0.072\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.943\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eZ=-0.610\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.542\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePPT CPM left\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e\u003cb\u003eVAS CPM left\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eControl \u0026ndash; active rMNS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eZ\u0026thinsp;=\u0026thinsp;0.071\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.943\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eZ=-0.486\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.627\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eControl \u0026ndash; active rMNS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eZ\u0026thinsp;=\u0026thinsp;0.880\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.379\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eZ=-0.351\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.726\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSham \u0026ndash; active rMNS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eZ\u0026thinsp;=\u0026thinsp;0.257\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.797\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eZ=-1.115\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.265\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSham \u0026ndash; active rMNS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eZ=-0.233\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.816\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eZ\u0026thinsp;=\u0026thinsp;0.207\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.836\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eSecondary Outcome: Pain sensation during physical exercise, Time to fatigue, perceived exertion, frequency and pain locations in lower limbs.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eRegarding pain sensation (VAS) during physical exercise, we found a significant difference between the active MNS and the control condition at 40% of maximal time of exercise (p\u0026thinsp;=\u0026thinsp;0.036) \u003cb\u003e(see\u003c/b\u003e Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e (the comparison of active vs. sham reached a trend for significance (p\u0026thinsp;=\u0026thinsp;0.09) \u003cb\u003e(see table 2)\u003c/b\u003e. The time to fatigue and perceived exertion were not significantly different between the conditions \u003cb\u003e(See Table\u0026nbsp;3)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eTable II. VAS and Perceived exertion during physical exercise.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabb\" border=\"1\"\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10%\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20%\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40%\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e60%\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e80%\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e100%\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVAS_Control \u0026ndash; active MNS\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eZ=-0.181\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.856\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eZ\u0026thinsp;=\u0026thinsp;1.477\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.139\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eZ\u0026thinsp;=\u0026thinsp;2.190\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.036\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eZ\u0026thinsp;=\u0026thinsp;1.061\u0026nbsp;;\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.289\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eZ\u0026thinsp;=\u0026thinsp;0.194\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.846\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eZ\u0026thinsp;=\u0026thinsp;0.612\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.541\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVAS_Sham \u0026ndash; active MNS\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eZ\u0026thinsp;=\u0026thinsp;0.222\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.824\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eZ\u0026thinsp;=\u0026thinsp;1.709\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.086\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eZ\u0026thinsp;=\u0026thinsp;1.793\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.094\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eZ\u0026thinsp;=\u0026thinsp;0.352\u0026nbsp;;\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.725\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eZ\u0026thinsp;=\u0026thinsp;1.433\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.152\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eZ\u0026thinsp;=\u0026thinsp;1.331\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.183\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRPE_Control \u0026ndash; active MNS\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eZ=-0.656\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.512\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eZ=-0.693\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.488\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eZ=-0.121\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.904\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eZ=-0.203\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.839\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eZ\u0026thinsp;=\u0026thinsp;0.882\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.378\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eZ=-1.18\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.236\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRPE_Sham \u0026ndash;\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eactive MNS\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eZ\u0026thinsp;=\u0026thinsp;1.213\u0026nbsp;;p\u0026thinsp;=\u0026thinsp;0.225\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eZ\u0026thinsp;=\u0026thinsp;0.785\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.433\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eZ\u0026thinsp;=\u0026thinsp;1.46\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.144\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eZ\u0026thinsp;=\u0026thinsp;1.124\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.213\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eZ\u0026thinsp;=\u0026thinsp;1.6\u0026nbsp;;\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eZ\u0026thinsp;=\u0026thinsp;1.18\u0026nbsp;; p\u0026thinsp;=\u0026thinsp;0.235\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTable III. Time to fatigue and pain local during physical exercise followed control, sham and anodal MNS.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabc\" border=\"1\"\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCONDITION\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eCONTROL\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eSHAM\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eACTIVE\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTIME TO FATIGUE\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e13.0\u0026thinsp;\u0026plusmn;\u0026thinsp;7.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e13.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e13.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.364\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eValues are represented as mean (\u0026plusmn;\u0026thinsp;standard deviation).\u003c/p\u003e"},{"header":"5. Discussion","content":"\u003cp\u003eThis is an exploratory randomized, cross-over and double-blind trial, which shows a synergic effect of MNS plus physical exercise on pain in sedentary people both at rest and during physical exercise. We found that PPT of the left hand increased after physical exercise with active MNS (-0.05 KGS) when compared to the sham (0.08 KGS) and control conditions (0.05 KGS). We found no changes in PPT on the right hand, CPM and VAS at rest. MNS\u0026nbsp;decreased the pain sensation during physical exercise when analyzing for the percentage of time showing the reduction of pain (33.4% less than control) in a specific time point (40% of total time equivalent to 5.28 minutes of physical exercise). Although we show significant differences, the effects were limited to a few outcomes only.\u0026nbsp;In\u0026nbsp;the descriptive statistic, the frequency and pain locations in lower limbs reported during physical exercise were lower in the active condition when compared with control and sham, and these effects did not change the time to fatigue and perceived exertion.\u003c/p\u003e\n\u003cp\u003eThis study explored the effects of MNS combined with physical exercise on the hypoalgesic effects. Our data suggest that\u0026nbsp;combining two treatments which activated the endogenous pain inhibitory systems can lead to a summing analgesic effect when compared with just one treatment alone or physical exercise plus MNS placebo. Our results are in line with previous studies\u003csup\u003e(22,23)\u003c/sup\u003e, which combined two treatments, such as transcranial Direct Current Stimulation (tDCS) and TENS; and neuromuscular electrical stimulation and TENS which activate the endogenous pain inhibitory systems showing higher in analgesic effects. These results may be explained by several factors:\u003c/p\u003e\n\u003cp\u003e1)\u0026nbsp; \u0026nbsp;Physical exercise and MNS mechanisms at the cortical, subcortical, and brainstem levels. The cortical related effects of MNS and exercise are likely mainly driven by spinoreticular component connected to the neurons of the ascending reticular activating system (ARAS), which can activate various regions in the cortex through ventromedial part of the thalamus\u003csup\u003e(31)\u003c/sup\u003e which is characterized by its extensive neocortical projection\u003csup\u003e(32)\u003c/sup\u003e.\u0026nbsp;Therefore our results show that\u0026nbsp;MNS combined with physical exercise effects may not be side dependent, due to the wide cortical projection\u003csup\u003e(33)\u003c/sup\u003e and the part of descendent inhibitory pain pathway\u0026nbsp;has bilateral fibers distribution\u003csup\u003e(34)\u003c/sup\u003e;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2) The first stimulation could have primed the effect with physical exercise and/or the second stimulation applied during warming period (i.e., first 10 minutes on the treadmill), may have induced a synergistic (summation effect) effect of MNS. These two effects (prime and synergistic) are due of the increased brainstem and brain activity linked to MNS and walking (here warming period) which activate similar areas such as M1, sensorimotor areas, parietal, cingulated anterior cortex and periaqueductal gray (PAG)\u003csup\u003e(35,36)\u003c/sup\u003e, leading to a \u0026nbsp;reinforcement of MNS effects. Such effects could only be seen on the left side due a) this non-dominant side has a lower threshold\u003csup\u003e(37,38)\u003c/sup\u003e, and b) this side is less stimulated during the protocol and may not have reached\u0026nbsp;inhibitory systems exhaustion\u003csup\u003e(39,40)\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3) Bienenstock-Cooper-Munro (BCM)\u003csup\u003e(41)\u003c/sup\u003e theory shows that synaptic plasticity depends on the previous level of postsynaptic neuronal activity in which the threshold for LTP induction increases if the previous level of postsynaptic neuronal activity was high. In this present study, the dominant side (right) was stimulated once prior to the physical exercise session, which maybe may have increased the pathway\u0026acute;s excitability leading to more difficulty in generating LTP.\u003c/p\u003e\n\u003cp\u003eMNS\u0026nbsp;induced pain reduction during physical exercise (33.4% compared to control) after 5.28 minutes of exercise (40% of total time) which is in line with a previous study\u003csup\u003e(42)\u003c/sup\u003e evaluating the effect of TENS (continuous pattern of stimulation with the frequency of 100 Hz) on pain. They found a reduction of pain perception (1) during isometric contractions (pain decreased by 12%) and (2) during a cycling exercise (i.e. bike 16.1km on a cycle ergometer as fast as possible; pain decreased between 19,4% and 32,6%. These results support the beneficial effect of MNS during physical exercise on pain perception, which\u0026nbsp;could have a positive impact on sedentary subjects and patients required to perform the physical exercise as well as limit the number of drop-outs in researches.\u003c/p\u003e\n\u003cp\u003eInterestingly we did not find differences in the PPT to among the conditions to the delta T0-T1 what may reflect no MNS stimulation effects when applied alone or MNS effect was masked by CPM test applied\u0026nbsp;before MNS due the endogenous pain inhibitory systems has a plateau which when it is reached reaches exhaustion and its effects on the pain may not be increased, or it is reduced when another stimulus is applied\u003csup\u003e\u0026nbsp;\u003c/sup\u003eas explained in prior studies\u003csup\u003e(39,40)\u003c/sup\u003e. The same results we found to CPM, which we did not find an effect of MNS alone (delta T0-T1) and combined with physical exercise (T1-T2) on CPM. These results are similar to the previous studies\u003csup\u003e\u0026nbsp;\u003c/sup\u003ethat investigated whether the simultaneous application of TENS and CPM\u003csup\u003e(40)\u003c/sup\u003e and physical exercise after CPM(39)will enhance the analgesic effect compared to each treatment when applied alone.\u0026nbsp;In our study, the CPM test prior MNS, may have masked the MNS effects on the second CPM. Similarly, CPM tested prior to physical exercise may have masked the effects on the third CPM. The masking\u0026acute;s hypotheses may be explained due studies showed that PPT changes during CPM are positively correlated with PPT changes during TENS application\u003csup\u003e(40)\u003c/sup\u003e, and CPM is also positively correlated with physical exercise hypoalgesic effects\u003csup\u003e(43)\u003c/sup\u003e, in our study we cannot prove the effect of PPT with just MNS and just Physical exercise due the CPM was did prior the intervention.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy limitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study had some limitations, such as the small sample size, and the p-value was not adjusted for multiple comparisons, which may have led to type I or II errors. However, it should be noted that our study has a crossover design, indicating that 24 subjects in our study are equivalent to 72 patients in a parallel study. In addition, within-subjects variability is smaller than between-subjects variability; therefore, this study has more power compared with 24 subjects in a parallel design. In addition, we used CPM, which activates pain inhibitory systems and may have biased the pain-related measures in our study. Therefore, future studies should take into account this issue and design protocols to test CPM without interfering with other measures (e.g., longer washout periods after the CPM and the next test). Finally, we only tested the effects of a single MNS session, while multiple sessions may be needed to induce clinically relevant effects.\u003c/p\u003e"},{"header":"6. Conclusions","content":"\u003cp\u003eIn conclusion, reducing pain using complementary non-pharmacological techniques could be extremely useful, especially for sedentary people. Although our results show a modest and limited effect, our findings bring a new way to overcome some issues linked to sedentary behaviors which have been shown to be related to higher pain perception and a decreased activity of the endogenous inhibitory system of pain when compared to active and athletes behavior\u003csup\u003e(\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/sup\u003e. Therefore, reducing pain sensation during physical exercise and increase pain threshold could improve the adherence to protocols or training of sedentary people and reduce the risks of health problems such as cardiovascular events, stroke, obesity, and chronic pain. However, a deeper understanding of the mechanisms and physiological responses of interaction between the simultaneous application of neuromodulation interventions on pain is still needed. More studies are necessary to clarify this mechanism and understand its responses in a larger population.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e7. \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFunda\u0026ccedil;\u0026atilde;o de Amparo \u0026agrave; pesquisa do Estado de S\u0026atilde;o Paulo (FAPESP), Instituto de Medicina F\u0026iacute;sica e Reabilita\u0026ccedil;\u0026atilde;o do Hospital das Cl\u0026iacute;nicas da Faculdade de Medicina da Universidade de S\u0026atilde;o Paulo IMREA (HC FMUSP) and all the volunteers who participated this research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest:\u003c/strong\u003e The authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval:\u003c/strong\u003e This study was approved by the Human Ethics Committee of Psychology Institute of S\u0026atilde;o Paulo University (CAAE: 54812416.7.0000.5561) conducted in accordance with the Declaration of Helsinki. Informed consent Informed consent was obtained from all subjects involved in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eOrganization, World Health. (2010). Global recommendations on physical activity for health: World Health Organization.\u003c/li\u003e\n \u003cli\u003eBooth, Frank W, Roberts, Christian K, \u0026amp; Laye, Matthew J. (2012). Lack of exercise is a major cause of chronic diseases. Comprehensive Physiology, 2(2), 1143.\u003c/li\u003e\n \u003cli\u003eSluka KA, O\u0026rsquo;Donnell JM, Danielson J, Rasmussen LA. Regular physical activity prevents development of chronic pain and activation of central neurons. Journal of applied physiology. 2012;114(6):725\u0026ndash;733.\u003c/li\u003e\n \u003cli\u003eWarburton DE, Nicol CW, Bredin SS. Health benefits of physical activity: the evidence. Cmaj. 2006;174(6):801\u0026ndash;809.\u003c/li\u003e\n \u003cli\u003eFlood A, Waddington G, Thompson K, Cathcart S. Increased conditioned pain modulation in athletes. Journal of sports sciences. 2017;35(11):1066\u0026ndash;1072.\u003c/li\u003e\n \u003cli\u003eGeva N, Defrin R. Enhanced pain modulation among triathletes: a possible explanation for their exceptional capabilities. PAIN\u0026reg;. 2013;154(11):2317\u0026ndash;2323.\u003c/li\u003e\n \u003cli\u003eTesarz J, Schuster AK, Hartmann M, Gerhardt A, Eich W. Pain perception in athletes compared to normally active controls: a systematic review with meta-analysis. Pain. 2012;153(6):1253\u0026ndash;1262.\u003c/li\u003e\n \u003cli\u003eSluka KA, Frey-Law L, Bement MH. Exercise-induced pain and analgesia? Underlying mechanisms and clinical translation. Pain. 2018;159:S91\u0026ndash;S97.\u003c/li\u003e\n \u003cli\u003eLandmark T, Romundstad P, Borchgrevink PC, Kaasa S, Dale O. Associations between recreational exercise and chronic pain in the general population: evidence from the HUNT 3 study. 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Exercise-Induced Hypoalgesia in Pain-Free and Chronic Pain Populations: State of the Art and Future Directions. The Journal of Pain. 2019;\u003c/li\u003e\n \u003cli\u003eGibson W, Wand BM, O\u0026rsquo;Connell NE. Transcutaneous electrical nerve stimulation (TENS) for neuropathic pain in adults. Cochrane Database of Systematic Reviews. 2017;(9).\u003c/li\u003e\n \u003cli\u003eJohnson MI, Paley CA, Howe TE, Sluka KA. Transcutaneous electrical nerve stimulation for acute pain. Cochrane database of systematic reviews. 2015;(6).\u003c/li\u003e\n \u003cli\u003eMelzack R, Wall PD. Pain mechanisms: a new theory. Science. 1965;150(3699):971\u0026ndash;979.\u003c/li\u003e\n \u003cli\u003eDeSantana JM, Walsh DM, Vance C, Rakel BA, Sluka KA. Effectiveness of transcutaneous electrical nerve stimulation for treatment of hyperalgesia and pain. Current rheumatology reports. 2008;10(6):492.\u003c/li\u003e\n \u003cli\u003ePantaleao MA, Laurino MF, Gallego NL, Cabral CM, Rakel B, Vance C, et al. Adjusting pulse amplitude during transcutaneous electrical nerve stimulation (TENS) application produces greater hypoalgesia. The journal of pain. 2011;12(5):581\u0026ndash;590.\u003c/li\u003e\n \u003cli\u003eMoran F, Leonard T, Hawthorne S, Hughes CM, McCrum-Gardner E, Johnson MI, et al. Hypoalgesia in response to transcutaneous electrical nerve stimulation (TENS) depends on stimulation intensity. The Journal of Pain. 2011;12(8):929\u0026ndash;935.\u003c/li\u003e\n \u003cli\u003eCarvalho S, French M, Thibaut A, Lima W, Simis M, Leite J, et al. Median nerve stimulation induced motor learning in healthy adults: A study of timing of stimulation and type of learning. European Journal of Neuroscience. 2018;48(1):1667\u0026ndash;1679.\u003c/li\u003e\n \u003cli\u003eBoggio PS, Amancio EJ, Correa CF, Cecilio S, Valasek C, Bajwa Z, et al. Transcranial DC stimulation coupled with TENS for the treatment of chronic pain: a preliminary study. The Clinical journal of pain. 2009;25(8):691\u0026ndash;695.\u003c/li\u003e\n \u003cli\u003eMoore SR, Shurman J. Combined neuromuscular electrical stimulation and transcutaneous electrical nerve stimulation for treatment of chronic back pain: a double-blind, repeated measures comparison. Archives of physical medicine and rehabilitation. 1997;78(1):55\u0026ndash;60.\u003c/li\u003e\n \u003cli\u003eSpielberger CD, Gorsuch RL, Lushene R, Vagg PR, Jacobs GA. Manual for the State-trait anxiety inventory (form Y self-evaluation questionnaire) consulting psychologists press: Palo Alto. CA; 1983.\u003c/li\u003e\n \u003cli\u003eGomes-Oliveira MH, Gorenstein C, Neto FL, Andrade LH, Wang YP. Validation of the Brazilian Portuguese version of the Beck Depression Inventory-II in a community sample. Revista Brasileira de Psiquiatria. 2012;34(4):389\u0026ndash;394.\u003c/li\u003e\n \u003cli\u003ede Souza Vespasiano B, Dias R, Correa DA. A utiliza\u0026ccedil;\u0026atilde;o do question\u0026aacute;rio internacional de atividade f\u0026iacute;sica (IPAQ) como ferramenta diagn\u0026oacute;stica do n\u0026iacute;vel de aptid\u0026atilde;o f\u0026iacute;sica: uma revis\u0026atilde;o no Brasil. Sa\u0026uacute;de em Revista. 2012;12(32):49\u0026ndash;54.\u003c/li\u003e\n \u003cli\u003eMacAuley D. Oxford handbook of sport and exercise medicine. Oxford University Press; 2012.\u003c/li\u003e\n \u003cli\u003eBijur PE, Silver W, Gallagher EJ. Reliability of the visual analog scale for measurement of acute pain. Academic emergency medicine. 2001;8(12):1153\u0026ndash;1157.\u003c/li\u003e\n \u003cli\u003eReidler JS, Mendonca ME, Santana MB, Wang X, Lenkinski R, Motta AF, et al. Effects of motor cortex modulation and descending inhibitory systems on pain thresholds in healthy subjects. The Journal of Pain. 2012;13(5):450\u0026ndash;458.\u003c/li\u003e\n \u003cli\u003eRubin M. Do p values lose their meaning in exploratory analyses? It depends how you define the familywise error rate. Review of General Psychology. 2017;21(3):269\u0026ndash;275.\u003c/li\u003e\n \u003cli\u003eStarzl TE, Taylor CW, Magoun HW. Ascending conduction in reticular activating system, with special reference to the diencephalon. Journal of neurophysiology. 1951;14(6):461\u0026ndash;477.\u003c/li\u003e\n \u003cli\u003eKlockgether T, Schwarz M, Turski L, Sontag K-H. The rat ventromedial thalamic nucleus and motor control: role of N-methyl-D-aspartate-mediated excitation, GABAergic inhibition, and muscarinic transmission. Journal of Neuroscience. 1986;6(6):1702\u0026ndash;1711.\u003c/li\u003e\n \u003cli\u003eEdlow BL, Takahashi E, Wu O, Benner T, Dai G, Bu L, et al. Neuroanatomic connectivity of the human ascending arousal system critical to consciousness and its disorders. Journal of Neuropathology \u0026amp; Experimental Neurology. 2012;71(6):531\u0026ndash;546.\u003c/li\u003e\n \u003cli\u003eLlorca-Torralba M, Borges G, Neto F, Mico JA, Berrocoso E. Noradrenergic Locus Coeruleus pathways in pain modulation. Neuroscience. 2016;338:93\u0026ndash;113.\u003c/li\u003e\n \u003cli\u003eHamacher D, Herold F, Wiegel P, Hamacher D, Schega L. Brain activity during walking: a systematic review. Neuroscience \u0026amp; Biobehavioral Reviews. 2015;57:310\u0026ndash;327.\u003c/li\u003e\n \u003cli\u003eScheef L, Jankowski J, Daamen M, Weyer G, Klingenberg M, Renner J, et al. An fMRI study on the acute effects of exercise on pain processing in trained athletes. PAIN\u0026reg;. 2012;153(8):1702\u0026ndash;1714.\u003c/li\u003e\n \u003cli\u003ePauli P, Wiedemann G, Nickola M. Pressure pain thresholds asymmetry in left-and right-handers: associations with behavioural measures of cerebral laterality. European Journal of Pain. 1999;3(2):151\u0026ndash;156.\u003c/li\u003e\n \u003cli\u003e\u0026Ouml;zcan A, Tulum Z, Pınar L, Başkurt F. Comparison of pressure pain threshold, grip strength, dexterity and touch pressure of dominant and non-dominant hands within and between right-and left-handed subjects. Journal of Korean medical science. 2004;19(6):874\u0026ndash;878.\u003c/li\u003e\n \u003cli\u003eGajsar H, Nahrwold K, Titze C, Hasenbring MI, Vaegter HB. Exercise does not produce hypoalgesia when performed immediately after a painful stimulus. Scandinavian Journal of Pain. 2018;18(2):311\u0026ndash;320.\u003c/li\u003e\n \u003cli\u003eLiebano RE, Vance CG, Rakel BA, Lee JE, Cooper NA, Marchand S, et al. Transcutaneous electrical nerve stimulation and conditioned pain modulation influence the perception of pain in humans. European Journal of Pain. 2013;17(10):1539\u0026ndash;1546.\u003c/li\u003e\n \u003cli\u003eBienenstock EL, Cooper LN, Munro PW. Theory for the development of neuron selectivity: orientation specificity and binocular interaction in visual cortex. Journal of Neuroscience. 1982;2(1):32\u0026ndash;48.\u003c/li\u003e\n \u003cli\u003eAstokorki AH, Mauger AR. Transcutaneous electrical nerve stimulation reduces exercise-induced perceived pain and improves endurance exercise performance. European journal of applied physiology. 2017;117(3):483\u0026ndash;492.\u003c/li\u003e\n \u003cli\u003eLemley K, Hunter S, Bement M. Conditioned Pain Modulation Predicts Exercise-Induced Hypoalgesia in Healthy Adults. Medicine \u0026amp; Science in Sports \u0026amp; Exercise.2015.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"sport-sciences-for-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ssfh","sideBox":"Learn more about [Sport Sciences for Health](http://link.springer.com/journal/11332)","snPcode":"11332","submissionUrl":"https://submission.nature.com/new-submission/11332/3","title":"Sport Sciences for Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Median Nerve Stimulation, Pain Threshold, Conditioned pain modulation (CPM), Physical exercise","lastPublishedDoi":"10.21203/rs.3.rs-5112792/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5112792/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePhysical exercise (PE) and median nerve stimulation (MNS) are powerful non-pharmacological tools to control pain. However, the effects of concurrent use of these two techniques have not been explored. Therefore, combining the two treatments could increase their respective effects on pain control. We aim to test whether MNS, using a novel algorithm that varies intensity and frequency of stimulation, combined with PE modulates pain and physical activity performance.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eTwenty-four healthy adults participated in this double-blinded, randomized, cross-over trial. Each subject underwent a control, sham and active MNS. MNS was applied for 20 minutes at rest and then for 10minutes during the warm-up period on the treadmill. Pain tests were performed at three time-points; at baseline (T0), after stimulation (T1) and after the PE (T2). In addition, during PE, the perceived exertion and pain sensation were assessed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eWe found a significant difference in the delta (T1 minus T2) between the active and the sham (p\u0026thinsp;=\u0026thinsp;0.039) and between the active and the control (p\u0026thinsp;=\u0026thinsp;0.041) for pressure pain threshold (PPT) on the left hand; pain thresholds being higher in the active group. Pain sensation during PE was lower for the active compared to the control group (p\u0026thinsp;=\u0026thinsp;0.036). No other differences were identified.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eOur findings suggest a modest effect of MNS on pain perception during PE and a supplementary effect of MNS combined with PE on PPT. Although the results are limited, this study investigates a novel approach to analyze the concurrent effect of two techniques that modulate the pain.\u003c/p\u003e","manuscriptTitle":"Effects of Median Nerve Stimulation (Mns) Coupled With Physical Exercise on Pain Modulation: Double-blinded,randomized, Cross-over Exploratory Clinical Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-27 11:20:24","doi":"10.21203/rs.3.rs-5112792/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-05-26T08:22:53+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-19T11:01:09+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-09-19T10:59:50+00:00","index":"","fulltext":""},{"type":"submitted","content":"Sport Sciences for Health","date":"2024-09-18T23:53:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"sport-sciences-for-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ssfh","sideBox":"Learn more about [Sport Sciences for Health](http://link.springer.com/journal/11332)","snPcode":"11332","submissionUrl":"https://submission.nature.com/new-submission/11332/3","title":"Sport Sciences for Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"96d53292-a86e-4fb8-abd7-4da18e4b84c8","owner":[],"postedDate":"August 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-04-20T16:01:08+00:00","versionOfRecord":{"articleIdentity":"rs-5112792","link":"https://doi.org/10.1007/s11332-026-01718-5","journal":{"identity":"sport-sciences-for-health","isVorOnly":false,"title":"Sport Sciences for Health"},"publishedOn":"2026-04-19 15:58:05","publishedOnDateReadable":"April 19th, 2026"},"versionCreatedAt":"2025-08-27 11:20:24","video":"","vorDoi":"10.1007/s11332-026-01718-5","vorDoiUrl":"https://doi.org/10.1007/s11332-026-01718-5","workflowStages":[]},"version":"v1","identity":"rs-5112792","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5112792","identity":"rs-5112792","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}