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Treatment-resistant major depressive disorder is common; repetitive transcranial magnetic stimulation (rTMS) by use of high-frequency (10 Hz) left-side dorsolateral prefrontal cortex stimulation is an evidence-based treatment for this disorder. Intermittent theta burst stimulation (iTBS) is a newer form of rTMS that can be delivered in 3 min, versus 37·5 min for a standard 10 Hz treatment session. We aimed to establish the clinical effectiveness, safety, and tolerability of iTBS compared with standard 10 Hz rTMS in adults with treatment-resistant depression. In this randomised, multicentre, non-inferiority clinical trial, we recruited patients who were referred to specialty neurostimulation centres based at three Canadian university hospitals (Centre for Addiction and Mental Health and Toronto Western Hospital, Toronto, ON, and University of British Columbia Hospital, Vancouver, BC). Participants were aged 18–65 years, were diagnosed with a current treatment-resistant major depressive episode or could not tolerate at least two antidepressants in the current episode, were receiving stable antidepressant medication doses for at least 4 weeks before baseline, and had an HRSD-17 score of at least 18. Participants were randomly allocated (1:1) to treatment groups (10 Hz rTMS or iTBS) by use of a random permuted block method, with stratification by site and number of adequate trials in which the antidepressants were unsuccessful. Treatment was delivered open-label but investigators and outcome assessors were masked to treatment groups. Participants were treated with 10 Hz rTMS or iTBS to the left dorsolateral prefrontal cortex, administered on 5 days a week for 4–6 weeks. The primary outcome measure was change in 17-item Hamilton Rating Scale for Depression (HRSD-17) score, with a non-inferiority margin of 2·25 points. For the primary outcome measure, we did a per-protocol analysis of all participants who were randomly allocated to groups and who attained the primary completion point of 4 weeks. This trial is registered with ClinicalTrials.gov, number NCT01887782. Between Sept 3, 2013, and Oct 3, 2016, we randomly allocated 205 participants to receive 10 Hz rTMS and 209 participants to receive iTBS. 192 (94%) participants in the 10 Hz rTMS group and 193 (92%) in the iTBS group were assessed for the primary outcome after 4–6 weeks of treatment. HRSD-17 scores improved from 23·5 (SD 4·4) to 13·4 (7·8) in the 10 Hz rTMS group and from 23·6 (4·3) to 13·4 (7·9) in the iTBS group (adjusted difference 0·103, lower 95% CI −1·16; p=0·0011), which indicated non-inferiority of iTBS. Self-rated intensity of pain associated with treatment was greater in the iTBS group than in the 10 Hz rTMS group (mean score on verbal analogue scale 3·8 [SD 2·0] vs 3·4 [2·0] out of 10; p=0·011). Dropout rates did not differ between groups (10 Hz rTMS: 13 [6%] of 205 participants; iTBS: 16 [8%] of 209 participants); p=0·6004). The most common treatment-related adverse event was headache in both groups (10 Hz rTMS: 131 [64%] of 204; iTBS: 136 [65%] of 208). In patients with treatment-resistant depression, iTBS was non-inferior to 10 Hz rTMS for the treatment of depression. Both treatments had low numbers of dropouts and similar side-effects, safety, and tolerability profiles. By use of iTBS, the number of patients treated per day with current rTMS devices can be increased several times without compromising clinical effectiveness. Canadian Institutes of Health Research.

Background: Virtual reality (VR) has been shown to reduce pain, however outcome parameters of previous studies have primarily been of a subjective nature and susceptible to bias. This study investigated the effect of VR on cortical processing of evoked potentials (EPs) and subjectively reported pain. Additionally, we explored whether subjects’ demographic and personal characteristics modulated the effect of VR analgesia. Methods: Three VR conditions were compared in a randomized cross-over study of 30 healthy volunteers: Passive VR (i.e. no interaction possible with the virtual world), active VR (interactive virtual environment) and no VR (black screen). Subjects received noxious electrical stimuli at random intervals during all conditions. EPs, recorded at Cz, were extracted time locked to stimuli. Pain scores were reported after each condition. Results: Active VR significantly decreased pain scores and amplitudes of N1 and P3. Passive VR had no analgesic effect. Age was significantly correlated to pain scores, with older subjects demonstrating larger effects of VR. Gender, game experience, and susceptibility for immersion, did not influence VR analgesia. Conclusion: Active VR decreases pre-perceptual and perceptual brain activity following painful electrical stimuli, corresponding with reduced pain experience. VR has potential to serve as a non-pharmacologic treatment for pain, particularly in elderly patients.

Pain is closely linked to alpha oscillations (8 < 13 Hz) which are thought to represent a supra-modal, top-down mediated gating mechanism that shapes sensory processing. Consequently, alpha oscillations might also shape the cerebral processing of nociceptive input and eventually the perception of pain. To test this mechanistic hypothesis, we designed a sham-controlled and double-blind electroencephalography (EEG)-based neurofeedback study. In a short-term neurofeedback training protocol, healthy participants learned to up- and down-regulate somatosensory alpha oscillations using attention. Subsequently, we investigated how this manipulation impacts experimental pain applied during neurofeedback. Using Bayesian statistics and mediation analysis, we aimed to test whether alpha oscillations mediate attention effects on pain perception. The results showed that attention and neurofeedback successfully up- and down-regulated the asymmetry of somatosensory alpha oscillations. However, attention and neurofeedback did not modulate pain ratings or related brain responses. Accordingly, somatosensory alpha oscillations did not mediate attention effects on pain perception. Thus, our results challenge the hypothesis that somatosensory alpha oscillations shape pain perception. A causal relationship between alpha oscillations and pain perception might not exist or be more complex than hypothesized. Trial registration: Following Stage 1 acceptance, the study was registered at ClinicalTrials.gov NCT05570695 .

Abstract Objective The purpose of this study was to examine the interaction between the endogenous opioid and endocannabinoid (eCB) systems in a pain modulatory process known as exercise-induced hypoalgesia (EIH). Design Randomized controlled trial. Setting Clinical research unit in a hospital. Subjects Fifty-eight healthy men and women (mean age = 21 ± 3 years) participated in this study. Methods Participants were administered (randomized, double-blind, counterbalanced procedure) an opioid antagonist (i.e., naltrexone) and a placebo prior to performing pain testing and isometric exercise. Results Results indicated that 2-arachidonoylglycerol (2-AG) and 2-oleoylglycerol (2-OG) increased significantly (P < 0.05) following exercise in both placebo and naltrexone conditions. In comparison, N-arachidonylethanolamine (AEA) and oleoylethanolamine (OEA) increased significantly (P < 0.05) following exercise in the placebo condition but not the naltrexone condition. There were no significant (P > 0.05) differences in palmitolethanolamine (PEA) between the placebo and naltrexone conditions. Conclusions As reductions in pain (i.e., EIH) were observed following both conditions, these results suggest that the opioid system may not be the primary system involved in exercise-induced hypoalgesia and that 2-AG and 2-OG could contribute to nonopioid exercise-induced hypoalgesia. Moreover, as exercise-induced increases in AEA and OEA were blocked by naltrexone pretreatment, this suggests that the opioid system may be involved in the increase of AEA and OEA following exercise.

Abstract Objective Physically active individuals show greater conditioned pain modulation (CPM) compared with less active individuals. Understanding the effects of acute exercise on CPM may allow for a more targeted use of exercise in the management of pain. This study investigated the effects of acute isometric exercise on CPM. In addition, the between-session and within-session reliability of CPM was investigated. Design Experimental, randomized crossover study. Setting Laboratory at Marquette University. Subjects Thirty healthy adults (19.3±1.5 years, 15 males). Methods Subjects underwent CPM testing before and after isometric exercise (knee extension, 30% maximum voluntary contraction for three minutes) and quiet rest in two separate experimental sessions. Pressure pain thresholds (PPTs) at the quadriceps and upper trapezius muscles were assessed before, during, and after ice water immersions. Results PPTs increased during ice water immersion (i.e., CPM), and quadriceps PPT increased after exercise (P < 0.05). CPM decreased similarly following exercise and quiet rest (P > 0.05). CPM within-session reliability was fair to good (intraclass correlation coefficient [ICC] = 0.43–0.70), and the between-session reliability was poor (ICC = 0.20–0.35). Due to the variability in the systemic exercise-induced hypoalgesia (EIH) response, participants were divided into systemic EIH responders (N = 9) and nonresponders (N = 21). EIH responders experienced attenuated CPM following exercise (P = 0.03), whereas the nonresponders showed no significant change (P > 0.05). Conclusions Isometric exercise decreased CPM in individuals who reported systemic EIH, suggesting activation of shared mechanisms between CPM and systemic EIH responses. These results may improve the understanding of increased pain after exercise in patients with chronic pain and potentially attenuated CPM.

Exercise produces an immediate lessening of pain sensitivity (Exercise-Induced Hypoalgesia (EIH)) in healthy individuals at local and distant sites, possibly through a shared mechanism with conditioned pain modulation (CPM). Dynamic resistance exercise is a recommended type of exercise to reduce pain, yet limited research has examined the effects of intensity on EIH during this type of exercise. Therefore, the primary purpose of this study is to compare changes in PPT at a local and distant site during a leg extension exercise at a high intensity, a low intensity, or a quiet rest condition. A secondary purpose is to examine if CPM changes after each intervention. The final purpose is to examine if baseline pain sensitivity measures are correlated with response to each intervention. In a randomized controlled trial of 60 healthy participants, participants completed baseline pain sensitivity testing (heat pain threshold, temporal summation, a cold pressor test as measure of CPM) and were randomly assigned to complete a knee extension exercise at: 1) high intensity (75% of a 1 Repetition Maximum (RM), 2) low intensity (30% 1RM), or 3) Quiet Rest. PPT was measured between each set at a local (quadriceps) and distant (trapezius) site during the intervention. CPM was then repeated after the intervention. To test the first purpose of the study, a three-way ANOVA examined for time x site x intervention interaction effects. To examine for changes in CPM by group, a mixed-model ANOVA was performed. Finally, a Pearson Correlation examined the association between baseline pain sensitivity and response to each intervention. Time x site x intervention interaction effects were not significant (F(5.3, 150.97) = 0.87, p = 0.51, partial eta2 = 0.03). CPM did not significantly change after the interventions (time x intervention F(1,38) = 0.81, p = 0.37, partial eta2 = 0.02. EIH effects at the quadriceps displayed a significant, positive moderate association with baseline HPT applied over the trapezius (r = 0.61, p<0.01) and TS (r = 0.46, p = 0.04). In healthy participants, PPT and CPM did not significantly differ after a leg extension exercise performed at a high intensity, low intensity, or quiet rest condition. It is possible pre-intervention CPM testing with a noxious stimuli may have impaired inhibitory effects frequently observed during exercise but future research would need to examine this hypothesis.

Introduction Although there is clear evidence for the serotonergic regulation of descending control of pain in animals, little direct evidence exists in humans. The majority of our knowledge comes from the use of serotonin (5-HT)-modulating antidepressants as analgesics in the clinical management of chronic pain. Objectives Here, we have used an acute tryptophan depletion (ATD) to manipulate 5-HT function and examine its effects of ATD on heat pain threshold and tolerance, attentional manipulation of nociceptive processing and mood in human volunteers. Methods Fifteen healthy participants received both ATD and balanced amino acid (BAL) drinks on two separate sessions in a double-blind cross-over design. Pain threshold and tolerance were determined 4 h post-drink via a heat thermode. Additional attention, distraction and temperature discrimination paradigms were completed using a laser-induced heat pain stimulus. Mood was assessed prior and throughout each session. Results Our investigation reported that the ATD lowered plasma TRP levels by 65.05 ± 7.29% and significantly reduced pain threshold and tolerance in response to the heat thermode. There was a direct correlation between the reduction in total plasma TRP levels and reduction in thermode temperature. In contrast, ATD showed no effect on laser-induced pain nor significant impact of the distraction-induced analgesia on pain perception but did reduce performance of the painful temperature discrimination task. Importantly, all findings were independent of any effects of ATD on mood. Conclusion As far as we are aware, it is the first demonstration of 5-HT effects on pain perception which are not confounded by mood changes.

The aim of this study was to assess if ischaemic preconditioning (IPC) can reduce pain perception and enhance corticospinal excitability during voluntary contractions. In a randomised, within-subject design, healthy participants took part in three experimental visits after a familiarisation session. Measures of pressure pain threshold (PPT), maximum voluntary isometric force, voluntary activation, resting twitch force, corticospinal excitability and corticospinal inhibition were performed before and ≥10 min after either, unilateral IPC on the right leg (3 × 5 min); a sham protocol (3 × 1 min); or a control (no occlusion). Pain perception was then assessed in response to a hypertonic saline injection into the vastus lateralis muscle. In the right (occluded) leg, PPT was 10% greater after IPC compared to sham ( P  = 0.004). PPTs were also 9.5% greater in the contralateral leg for IPC compared to sham ( P  = 0.031). Maximum voluntary force, voluntary activation and resting twitch force were not different between conditions (all P  ≥ 0.133). Measures of corticospinal excitability and inhibition also revealed no significant differences between conditions (all P  ≥ 0.240). Hypertonic saline evoked pain revealed no difference in reported intensity or duration between conditions ( P  ≥ 0.082). IPC can reduce pain sensitivity in local and remote areas but does not subsequently impact neurophysiological measures of excitability or inhibition.

Background Exercise-induced hypoalgesia (EIH) is characterized by a reduction in pain perception and sensitivity across both exercising and non-exercising body parts during and after a single bout of exercise. EIH is mediated through central and peripheral mechanisms; however, the specific effect of muscle contraction alone on EIH remains unclear. Moreover, previous studies on electrical muscle stimulation (EMS) have primarily focused on local analgesic effects, often relying on subjective pain reports. This study investigated the contribution of EMS-induced muscle contractions to systemic analgesia, independent of motor cortex activity. We aimed to explore the underlying mechanisms of EIH by analyzing the influence of skeletal muscle mass (SMM), skeletal muscle mass index (SMI), and conditioned pain modulation (CPM). Methods In this crossover study, 27 healthy young adults participated in EMS and sham interventions, separated by a washout period of 2 to 3 days. SMM, SMI, and CPM were measured before the first intervention. Pressure pain thresholds (PPT) were evaluated before and after each intervention. EMS was applied to the non-dominant quadriceps at a frequency of 30 Hz, a pulse duration of 300 μs, and a duty cycle of 5 s on and 10 s off, without inducing joint movement, for 20 min. The sham intervention used the same settings, but the stimulation amplitude was insufficient to induce muscle contraction in the quadriceps. The average current intensity was 16.0 ± 3.2 mA and 11.3 ± 2.3 mA in the EMS and sham condition, respectively. Results In the EMS condition, PPT significantly increased in the stimulated quadriceps but not in non-contracted sites. There were strong positive correlations between changes in PPT and both SMM and SMI, but not CPM. The sham condition showed no significant effects at any assessment sites. Conclusions These findings suggest that the analgesic effects of EMS-induced muscle contractions are primarily localized to the stimulated muscle tissues, rather than mediated by the central pain modulatory mechanisms. Trial registration This study was enrolled in the UMIN-CTR Clinical Trial Registry (registration number: UMIN000051951; date of approval: August 19, 2023).

We aimed to compare the effects between non-vibration foam rolling (NVFR) and vibration foam rolling (VFR) on visual analogic scale (VAS), pressure pain threshold (PPT), oxygen saturation (SmO2), countermovement jump (CMJ) and hip and knee range of movement (ROM) after eliciting muscle damage through eccentric acute exercise using an inertial flywheel. Thirty-eight healthy volunteers (32 men, 6 women; aged 22.2±3.2 years) were randomly assigned in a counter-balanced fashion to either a VFR or NVFR protocol group. All participants performed a 10x10 (sets x repetitions) eccentric squat protocol to induce muscle damage. The protocols were administered 48-h post-exercise, measuring VAS, PPT, SmO2, CMJ and ROM, before and immediately post-treatment. The treatment technique was repeated on both legs for 1 minute for a total of five sets, with a 30-s rest between sets. The VFR group showed substantially greater improvements (likely to very likely) in the passive VAS (VFR -30.2%, 90% CI -66.2 to -12.8) with chances for lower, similar or greater VAS compared with the NVFR group of 82%, 14% and 4%, respectively and passive extension hip joint ROM (VFR 9.3%, 90% CI 0.2-19.2) with chances for lower, similar or greater ROM compared with the NVFR group of 78%, 21% and 1%, respectively. For intragroup changes, we observed substantial improvements in VAS (p=.05), lateral vastus, rectus femoris and medial vastus PPT. The results suggest that the VFR group achieved greater short-term benefits in pain perception and passive extension hip joint ROM. Both protocols were effective in improving PPT, SmO2, CMJ and knee joint ROM. The enhanced improvement in VAS and hip ROM measures could have significant implications for VFR treatment.