Transcutaneous Electrical Nerve Stimulation for Fibromyalgia-like Syndrome in Patients with Post-Acute Sequelae of Sars-Cov-2: A Pilot Randomized Clinical Trial

Transcutaneous Electrical Nerve Stimulation for Fibromyalgia-like Syndrome in Patients with Post-Acute Sequelae of Sars-Cov-2: A Pilot Randomized Clinical Trial | 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 Article Transcutaneous Electrical Nerve Stimulation for Fibromyalgia-like Syndrome in Patients with Post-Acute Sequelae of Sars-Cov-2: A Pilot Randomized Clinical Trial Alejandro Zulbaran-Rojas, Rasha Bara, Myeounggon Lee, Miguel Bargas-Ochoa, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4391458/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 08 Nov, 2024 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract This study investigated the effect of Transcutaneous Electrical Nerve Stimulation (TENS) for fibromyalgia-like symptoms including chronic widespread pain, fatigue, and gait impairment in twenty-five individuals with Post-Acute Sequelae of Sars-Cov-2 (PASC). Participants were randomized to a high dose (intervention group, IG) or low dose (placebo group, PG) TENS device. Both groups received daily 3–5 hours of TENS therapy for 4-weeks. The Brief Pain Inventory assessed functional interference from pain (BPI-I), and pain severity (BPI-S). The global fatigue index (GFI) assessed functional interference from fatigue. Wearable technology measured gait parameters during three 30-feet consecutive walking tasks. At 4-weeks, the IG exhibited a greater decrease in BPI-I compared to the PG (mean difference = 2.61, p = 0.008), and improved in gait parameters including stride time (4%-8%, test condition dependent), cadence (4%-10%, depending on condition), and double-support phase (12% in dual-task) when compared to baseline. A sub-group meeting the American College of Rheumatology Fibromyalgia diagnostic criteria undergoing high-dose TENS showed GFI improvement at 4-weeks from baseline (mean change = 6.08, p = 0.005). Daily TENS therapy showed potential in reducing functional interference from pain, fatigue, and gait alterations in PASC individuals. The study's limited power could affect the confirmation of certain observations. Extending the intervention period may improve treatment effectiveness. Health sciences/Medical research/Study design/Randomized controlled trials Health sciences/Neurology/Neurological disorders/Neuromuscular disease Figures Figure 1 Figure 2 Introduction Post-Acute Sequelae of Sars-Cov-2 (PASC) is a multisystemic condition characterized by persistent symptoms in one or more organs after acute COVID-19 clearance 1 . Approximately 1 in 13 adults recovering from COVID-19 experience PASC 2 , with the musculoskeletal system particularly affected 3 . Persistent symptoms include long-lasting widespread pain, fatigue and weakness varying in frequency, duration, and intensity 4,5 , which can lead to functional interference affecting gait and daily activities 6–8 . The mechanism of musculoskeletal damage in PASC remains unknown, and whether widespread pain is associated with the nervous system is uncertain. Currently, there are no diagnostic criteria for PASC, but some symptoms resemble those of fibromyalgia (FM), a chronic disorder characterized by hyperalgesia and muscle weakness without a specific location 9 . FM is listed by the CDC as one of the conditions sharing symptoms with PASC 10 and recent studies showed that 30–40% of individuals with PASC meet the American College of Rheumatology (ACR) FM diagnostic criteria 11,12 . FM's underlying cause has not been proven, but it is hypothesized to involve sensory sensitization of the spinothalamic tract, possibly attributed to microglial overactivation by numerous factors, including viral infections 13–15 . Some researchers postulate that Sars-Cov-2 may induce central pain by interacting with ACE2 receptors in the microglia or via Spike proteins activating microglial apoptotic pathways 16–18 . Microglial overactivation can result in excessive release of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6) in the spinal cord’s dorsal horn, potentially increasing neural excitability and pain sensitivity 19,20 . Phetsouphanh et al. 21 found elevated levels of these cytokines in PASC patients exhibiting pain and fatigue even after 8 months, mirroring findings in patients with FM 22 . The unknown origins and atypical pain patterns associated with FM in PASC individuals make its approach challenging 12 . Current therapies, including anti-inflammatory 23 and central pain-targeted agents have shown limited efficacy 24 , with few drug-based randomized clinical trial (RCTs) demonstrating pain relief in individuals with PASC and FM 25 . This highlights the need for effective therapies in this population. Transcutaneous electrical nerve stimulation (TENS) is a supportive intervention believed to alleviate pain by stimulating peripheral nerves and modulating central pain processing 26,27 , reaching the CNS through a sequenced stimulation of non-painful 1st -order neurons (Alpha-beta fibers) leading to the activation of pain inhibitory interneurons in the dorsal horn (referred as “nerve gate”) 28 . This hypothesized effect blocks pain signals between painful 1st -order neurons (A-delta and C-fibers) and 2nd -order neurons (spinothalamic tract) 29,30 . A recent meta-analysis encasing 11 randomized controlled trials (RCT) involving patients with FM undergoing TENS therapy reported a large mean reduction in pain influenced by higher number of sessions, frequency, and intensity 31 . However, this technology’s effect on pain has not been explored in individuals with PASC developing FM-like symptoms. This pilot study investigated wearable TENS therapy as a potential treatment for FM-like symptoms in individuals with PASC. We hypothesize that 4-weeks of daily home-based wearable TENS therapy will reduce pain and fatigue interference with functional outcomes, and gait alterations among this population. In addition, we anticipate this regimen will be feasible and acceptable. Methods Study population A pilot RCT of individuals with PASC was conducted between April 2022 and August 2023. Participants were referred by a pulmonologist and critical care specialist from the post-COVID-19 Care Clinic or Internal Medicine Clinic at Baylor College of Medicine (Houston, TX), or self-referred by meeting the criteria in our public ClinicalTrials.gov registered protocol (Identifier: NCT05200858, 01/21/2022). All participants signed an informed consent approved by the local Institutional Review Board (IRB number: H-50753) before study enrollment. The study followed the Consolidated Standards of Reporting Trials (CONSORT) guidelines for RCTs. The methods used were in accordance with the relevant guidelines and regulations, and the Helsinki Declaration. Inclusion criteria were: 18–64 years old; reported persistent muscle and joint pain, fatigue, and weakness in one or more body sections that were not present before acute COVID-19 infection; had access to a personal smartphone and willing to install a smartphone application; and able to attend in-person visits. Exclusion criteria were patients with demand-type cardiac pacemaker; implanted defibrillator; major lower extremity wounds; and previous neuromuscular diseases (i.e., Guillan-Barre, Myasthenia Gravis, multiple sclerosis) or hearing weakness. Baseline demographics, comorbidities, and current PASC symptoms were gathered from participants' medical records. Neurovascular baseline characteristics, including bilateral sural nerve conduction velocity and amplitude, and plantar tissue oxygenation (SatO2), were assessed using the DPNCheck (NeuroMetrix Inc., MA, US) and SnapShot NIRS (Kent Imaging, Al, CAN) devices, respectively. Randomization, group allocation, and intervention Participants were randomized (ratio: 1:1) to intervention (IG) and placebo (PG) groups through a computer-generated list followed by sequential allocation. Participants and care providers were blinded to the group allocation. Investigators collecting and analyzing data were not blinded. The IG received high-dose (1-hour) TENS therapy utilizing an FDA-cleared wearable device (Quell, NeuroMetrix Inc., MA, US). The device was unilaterally attached around the patients’ upper calf via four hydrogel pads containing an electrode array, secured to a stretchable band strap (Fig. 1 ). The device consists of a one-channel electrical stimulator that communicates with a smartphone application through Bluetooth. The PG was provided with an identical device that elicited 10% dose (6-minutes per hour) of TENS therapy. [Insert Fig. 1 here] Participants self-administered therapy daily, each session lasting 1 hour. They were instructed to complete 3–5 sessions per day, alternating device placement contralaterally weekly. After the initial 4 weeks, participants were unblinded, with the IG continuing TENS therapy for an additional 4 weeks (total of 8 weeks), while the PG switched to a high-dose TENS device for the subsequent 4 weeks. Weekly support phone calls addressed device-related queries. No lifestyle/dietary modifications to pain medication were enforced during the study. Device and smartphone app characteristics The system around the upper calf provides a total stimulation surface area of 60 cm 2 , stimulating sensory dermatomes S2 through L4, commonly targeted for lower body pain 32 . The stimulator generates bipolar, current-regulated pulses with a duration of 290 microseconds and alternating leading phase polarity. Stimulation frequency uniform distribution between 60 and 100 Hz 33 . These device’s characteristics were proven safe in a recent study of patients with FM 34 . The mobile application serves as a remote control for stimulator functions. Procedures and measurements Participants attended three in-person visits at our facility during regular work hours. Assessments for both groups occurred at baseline, 4 weeks, and 8 weeks. At each visit, pain, fatigue, and gait were evaluated. Outcomes The primary outcome included functional interference from pain, assessed via the Brief Pain Index questionnaire interference composite score (BPI-I) 35 . Secondary outcomes included: 1) pain severity, assessed via the BPI questionnaire severity composite score (BPI-S) 35 ; 2) fatigue, via the Multi-dimensional Assessment of Fatigue (MAF) questionnaire, and calculating the Global Fatigue Index (GFI) 36 ; and 3) gait measured using five inertial measurement units (IMUs, LEGSys BioSensics, MA, USA) on participants’ ankles, thighs, and waist. Parameters included stride time 37 , cadence 38 , and double-support phase 39 , and were measured during three consecutive tasks: 1) simple-task (30-feet walk at normal pace); 2) dual-task (30-feet walk at normal pace while counting aloud backwards by 2); and 3) fast-walking-task (30-feet walk at a faster pace without jogging/running) 40 . In case of marked fatigue during the walking tasks, patients completed questionnaires via RedCap at home. Feasibility metrics Compliance to the TENS device was linked to a cloud system. The median therapy sessions per day and the median days of device use were quantified. Completers were those adherent to the TENS device for ≥ 3 sessions per day. High compliance was set to 70% 41 of the maximum possible number of sessions per day (3.5 out of 5) and days in 4-weeks (21 out of 30). Adverse events and therapy discontinuation were reported. Acceptability to the TENS device was assessed using a Technology Acceptance Model (TAM) questionnaire 42 ( Supplemental Table 1 ), that measured: perceived usefulness (PU), perceived ease of use (PEOU), and attitude towards use (ATU). Power analysis G*Power software (version 3.1.6) calculated the minimum sample size based on a similar study 34 . The following parameters were used: ( 1 ) effect size d = 1.168 43 , ( 2 ) 80% power, ( 3 ) 5% alpha, ( 4 ) two groups, and ( 5 ) equal number of participants per group. A minimum of 13 subjects per group, totaling 26 subjects, is required. A sample size of n = 12 per group is expected to yield 95% power for detecting a time-effect difference. To accommodate an anticipated 10% dropout rate, we aimed to enroll 30 subjects (15 per group) in this study. Statistical analysis Categorical data was presented as number and percentage (%). Shapiro–Wilk test determined normality of continuous data (p > 0.05). Normally distributed data was presented with mean ± standard deviation; non-normally distributed data with median (interquartile range, IQR). Baseline characteristics between groups were compared using t-test, Chi-square, and Mann-Whitney U test, with Cohen's d for effect size. Interaction effect between group and time was analyzed using generalized estimation equations (GEE) representing estimated means and standard errors [SE] at baseline and 4-weeks. No covariates adjustments were made due to low sample size. TAM % agreement per item was calculated using our prior medical technology acceptability studies’ Eq. 4 4–46 , then compared between groups using t-test. SPSS 29.0 (IBM) was utilized forall statistical analyses with a significance set at p < 0.05. Results Thirty participants met the criteria, but five discontinued intervention during the blinded study phase (4-weeks), as detailed in Fig. 2 . Thus, 25 patients were included for analysis (IG, n = 12; PG, n = 13). Twenty-three patients were referred from our post-COVID-19 Care/Internal Medicine Clinic; two patients were self-referred. The unblinded phase of the study (week 4 to 8) was not analyzed due to the increase in lost to follow-ups (n = 4) and missed final visits (n = 7). Patient characteristics Baseline clinical characteristics revealed a higher incidence of cancer history (41.7% vs 0, p = 0.03) and osteoarthritis (33.3% vs 0, p = 0.01) in the IG compared to the PG. Other baseline characteristics did not significantly differ between groups (Table 1 ). Table 1 Baseline clinical characteristics. Placebo Group (n = 13) Intervention Group (n = 12) P-value Effect-size (Cohen's d) Demographics Age, years 43.4 ± 11.8 51 ± 12.3 0.12 0.64 BMI, kg/m 2 27.7 ± 7.9 27.8 ± 6 0.98 0.01 Sex, female 9 (69.2) 10 (83.3) 0.41 0.33 Race, no. African American 1 (7.7) 2 (16.7) 0.36 1.06 Hispanic 2 (15.4) 3 ( 25 ) Asian 2 (15.4) 0 White 6 (46.2) 6 ( 50 ) Other 2 (15.4) 1 (8.3) Comorbidities High blood pressure, no. 3 (23.1) 3 ( 25 ) 0.91 0.05 Heart disease 3 (23.1) 5 (41.7) 0.32 0.41 Depression 3 (23.1) 3 ( 25 ) 0.91 0.05 Osteoarthritis 0 4 (33.3) 0.03 0.98 Cancer 0 5 (41.7) 0.01 1.22 Brain Fog 7 (53.9) 9 ( 75 ) 0.27 0.45 Hospitalization due to COVID-19 5 (38.5) 4 (33.3) 0.79 0.11 Admitted to ICU 2 (15.4) 0 0.16 0.59 Supplemental oxygen hospital 4 (30.8) 1 (8.3) 0.16 0.58 Current physical therapy 2 (15.4) 3 ( 25 ) 0.61 0.21 Neurovascular lower extremity features Sural Nerve conduction velocity, m/s 58.1 ± 6.6 55.9 ± 4 0.19 0.39 Sural Nerve amplitude, µV 14.1 ± 9.5 13.9 ± 5.8 0.91 0.02 Plantar SatO2, % 66.6 ± 3.9 67 ± 6.2 0.72 0.08 Current PASC symptoms Days of persistent symptoms 335.5 ± 175.6 377.7 ± 249.1 0.63 0.28 Memory difficulty, no. 10 (80) 11 (91.7) 0.59 0.43 Shortness of breath 7 (53.9) 5 (41.7) 0.70 0.51 Fatigue 13 (100) 11 (91.7) 0.31 0.43 Insomnia 6 (46.1) 7 (58.3) 0.78 0.43 Weakness 11 (84.6) 9 ( 75 ) 0.33 0.64 Muscle pain 11 (84.6) 8 (66.7) 0.42 0.72 Unsteady gait 7 (53.9) 6 ( 50 ) 0.76 0.45 Atrophy 8 (61.5) 5 (41.7) 0.27 0.71 Numbness 11 (84.6) 6 ( 50 ) 0.07 1.08 Reported as mean ± standard deviation or n (%). Reported symptoms were not present before acute COVID-19 infection. Kg, kilograms; m, meters; no., number; µV, microvolts; m, meters; s, seconds; PASC, post-acute sequelae of Sars-Cov-2 Outcomes Baseline BPI-I was significantly higher in the PG than the IG (Table 2 ). At 4-weeks, the IG showed a significantly greater decrease in BPI-I scores compared to the PG (mean difference = 2.61, p = 0.008, d = 1.12 ) . However, within-group comparison did not show significant improvement (Table 3 ). Baseline BPI-S and GFI did not significantly differ between groups (Table 2 ), nor did they show significant differences at 4 weeks (Table 3 ). Table 2 Baseline score comparison for pain and fatigue between groups/sub-groups Placebo Group (n = 13) Intervention Group (n = 12) P-value Effect-size (Cohen's d) All cohort BPI-I, score 5.54 ± 0.62 3.17 ± 0.81 0.021 3.3 BPI-S 4.79 ± 0.43 3.60 ± 0.69 0.15 2.09 GFI 37.89 ± 3.32 37.75 ± 2.65 0.98 0.05 Fibromyalgia sub-group Control (n = 9) Intervention (n = 5) P-value Effect-size (Cohen's d) BPI-I, score 6.48 ± 0.65 6.06 ± 0.66 0.65 0.64 BPI-S 5.28 ± 0.47 5.35 ± 1.01 0.95 0.1 GFI 42.63 ± 2.54 43.16 ± 2.38 0.88 0.21 Reported as mean ± standard deviation. BPI-I, functional interference from pain via Brief Pain Inventory; BPI-S, pain severity via Brief Pain Inventory; GFI, global fatigue index via the Multi-dimensional Assessment of Fatigue. Table 3 Pain and fatigue score comparison between groups/sub-groups at 4-weeks Variable N Mean Change SE Treatment Comparison at 4-weeks (IG vs PG) Mean Difference 95% CI p-value All cohort BPI-I, score PG 12 0.198 0.407 -2.616 -4.543, 0.689 0.008 IG 11 0.454 0.503 BPI-S PG 11 0.289 0.255 -1.305 -2.894, 0.284 0.107 IG 10 1.184 0.815 GFI PG 11 2.231 3.207 -0.732 -9.298, 7.834 0.867 IG 10 2.821 1.504 Fibromyalgia sub-group BPI-I, score PG 9 0.079 0.327 -1.397 -3.183, 0.39 0.08 IG 5 1.057 0.603 BPI-S PG 9 0.028 0.164 -0.456 -2.097, 1.186 0.587 IG 5 0.5 0.604 GFI PG 8 1.747 1.503 -3.806 -9.132, 1.52 0.161 IG 5 6.08* 2.188 *Significant within group improvement. PG, placebo group; IG, intervention group; BPI-I, functional interference from pain via Brief Pain Inventory; BPI-S, pain severity via Brief Pain Inventory; GFI, global fatigue index via the Multi-dimensional Assessment of Fatigue. Objective assessment of gait parameters showed no significant differences in baseline stride time, cadence, and double support phase between groups ( Table 4 ). At 4-weeks from baseline, there was a significant improvement for stride time during the three walking tasks in the IG (single: 5.83%; dual: 8; fast-walking: 3.96%, all p < 0.05). Similarly, cadence significantly improved at 4-weeks from baseline during the three waking tasks in the IG (single: 5.57%; dual: 9.5%; fast-walking-task: 3.89%, all p < 0.05). A significant time x group effect was seen for cadence and stride time ( Supplemental Table 2 ). In addition, double-support phase significantly improved during the dual-task at 4-weeks from baseline in the IG (11.57%, p = 0.017). Fibromyalgia sub-group Participants meeting the 2010 ACR FM diagnostic criteria 47 were labeled as the FM sub-group (PG-FM, n = 9; IG-FM, n = 5). At 4-weeks from baseline, the IG-FM showed a decreased trend for BPI-I scores (mean change = 1.057 [SE = 0.6], p = 0.080). Comparison between sub-groups at 4-weeks showed a trend in favor of the IG-FM compared to the PG-FM (mean difference = 1.39, p = 0.125, d = 2.257, Table 3 ). Moreover, the IG-FM showed a significant improvement in GFI scores at 4-weeks from baseline (mean change = 6.08 [SE = 10.61], p = 0.005). Feasibility metrics At 4-weeks, median TENS therapy sessions per day were 4 (IQR = 3-4.9) in the IG and 3.5 (IQR = 3–5) in the PG. The median days of device use at 4-weeks were 27 (IQR = 25-27.5) in the IG, and 26 (IQR = 20–27) in the PG. Completers (≥ 3 sessions per day) rate in the IG was 100%, while 92.3% in the PG. High compliance (≥ 3.5 sessions per day) rate in the IG was 54.5%, while 61.5% in the PG ( Supplemental Table 3 ). No severe adverse events requiring discontinuation were reported. However, two patients (CG, n = 1; IG, n = 1) experienced mild pain and itchiness, respectively, when TENS was delivered immediately after shaving their lower extremities. After using TENS daily for 5 hours, one patient (CG, n = 1) reported mild fatigue, and one patient (IG, n = 1) reported skin irritation. Two patients (IG, n = 1; PG, n = 1) complained of pain and skin spots, respectively, from the hydrogel pads when not weekly alternating the device to the contralateral calf. The TAM questionnaire showed overall acceptability above 70% in all categories, with no significant differences between groups: PEOU (IG = 94.2 ± 10.8% vs PG = 91.5 ± 9.9%, p = 0.42), ATU (IG = 89.2 ± 10% vs PG = 83 ± 14.4%, p = 0.283), and PU (IG = 71.2 ± 11.6% vs PG = 61.4 ± 14.9%, p = 0.13). Discussion This pilot RCT examined the effectiveness of daily wearable TENS therapy in alleviating pain, fatigue, and gait alterations in individuals with PASC. High-dose TENS participants experienced greater reduction in functional interference due to pain compared to low-dose TENS participants. Additionally, objective assessment of gait parameters revealed significant improvement in stride time and cadence at 4 weeks from baseline in the high-dose TENS group across various walking tasks. Moreover, both groups exhibited high compliance rates (≥ 3 hours per day) and reported device acceptability above 70% during the blinded study phase. Previous RCTs utilizing FDA-approved pharmacological treatment for FM (i.e., duloxetine 48 , milnacipran 49 ) have shown improvement in functional interference from pain when compared to placebo, with a BPI-I between-group mean difference ranging from 0.58–1.74 in a 12-week timeframe; however, accompanied by notable side effects including nausea (> 36%), constipation (> 14.7%), and dizziness (> 10.5%), amongst others 48,49 . The present study explored TENS as a safer pain management intervention with known minimal side effects 50 . We acknowledge the IG had less severe functional baseline pain scores than the PG, thus, evidence suggests this cohort would have had lesser improvement post-intervention 51 . However, after 4-weeks of TENS therapy, the IG showed significantly greater reduction of BPI-I scores compared to the PG (mean difference = 2.61 points, p = 0.008, Table 2 ). The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) suggests a 1-point mean change from baseline to the targeted endpoint as a meaningful clinically significant difference (MCID) 52 . In our study, the FM subgroup undergoing high-dose TENS showed a trend for reaching this MCID as early as 4-weeks (mean change = 1.06 points, p = 0.080). This magnitude of reduction in BPI-I scores with high-dose TENS mirrors the improvements noted by Kong et al. 53 and Jamison et al. 34 in non-PASC patients with FM after 60-days and 3-months therapy, respectively. Our study uniquely demonstrates the benefit of high-dose TENS over low-dose in individuals with PASC and FM-like symptoms within a short timeframe. Despite a small sample size, the substantial effect size compared to low-dose TENS at 4-weeks (d = 2.26) indicates the potential of high-dose TENS for larger, longer-term studies. Functional interference from fatigue is crucial to assess in PASC patients given its prolonged and severe nature 54 . Similarly to FM, the origin of fatigue in PASC patients has been linked to persistent inflammatory biomarkers 55 .Therefore, we used the GFI to assess functional interference from fatigue, a reliable tool that has shown significant fatigue reduction (1.4 to 1.6 points) in FM patients taking mild-moderate pregabalin doses (300mg to 450mg) over 14-weeks 56 , with further improvement when increasing doses (600mg) over 32 weeks 57 . Interestingly, other pregabalin trials identified that substantial fatigue reduction, such as 10-point GFI decrease, was only seen in FM patients experiencing a 30% of pain reduction 58 . This trend was echoed in a recent study employing 4-week TENS therapy in women with FM 59 , which demonstrated a significant GFI improvement of 4.6-points correlated with reduced pain evoked by movement. Similarly, our study showed a significant 6.08-point GFI improvement in the sub-group of FM patients receiving high-dose TENS at 4-weeks from baseline. However, this mean change did not correlate with the observed changes in BPI-I scores, suggesting that PASC patients with FM may experience significant functional improvement from fatigue without necessarily needing concurrent pain relief. In a recent systematic review, significant gait alterations were found in FM patients 60 . Utilizing instrumented walkway systems, observational studies revealed FM patients have significantly shorter cadence and longer double support phases compared to healthy individuals in 61 . The present study exhibited that PASC patients with widespread pain undergoing 4-week high-dose TENS significantly improved their cadence by 5.6% and 9.5% in the single- and dual-tasks, respectively, and 3.9% in the fast-walking task. Moreover, studies have incorporated cognitive elements (dual-task) in walking assessments to predict risk-of-fall caused by fatigue in FM patients 62 , showing a notable impact on double-support phase during such tasks 63 . In the present study, the double-support phase of PASC patients undergoing 4-weeks high-dose TENS significantly improved by 11.6% in the dual-task. While no MCID is established for gait via wearables in FM patients, Kaleth et al. 64 established an anchor-based MCID for walking distance, indicating clinically meaningful fatigue improvement. Our findings suggest that reducing functional interference from fatigue may aid fall prevention in PASC patients with chronic pain; however, further risk-of-fall assessment is needed for confirmation. To date, the objective assessment of gait improvement in FM patients has been limited to studies focusing on interventions like aerobic exercise and physical therapy 65–67 . Moreover, the effectiveness of TENS in enhancing gait has only been investigated in stroke patients, however incorporating exercise therapy into the treatment regimen therapy as well 68 . This modality is often unsuitable for PASC patients given their high-risk for post-exertional malaise 69 . Consequently, they are generally advised to refrain from moderate physical exertion 70 . In this context, high-dose TENS offers a promising alternative for improving gait parameters in PASC patients with FM-like symptoms. Nevertheless, further research with a larger sample size is essential to substantiate this potential benefit. The adherence to analgesic drugs among FM patients can be influenced by intermittent pain and adverse events 71 . In a duloxetine 12-week trial, up to 21% participants discontinued therapy due to adverse events 72 . The present study showed no discontinuations at 4-weeks, despite 6 patients reporting mild fatigue, pain, and skin irritation. These issues were resolved with advice from the research team. Compliance resulted in a median of > 3.5 therapy sessions per day and > 26 days of device usage. High compliant (≥ 21 of days used) patients’ rate was 100% in the IG and 81.8% in the CG. However, compliance decreased in the unblinded study phase (week-4 to 8). We attribute this to disengagement from placebo devices, depression, brain fog, and multiple hospital visits encountered by our patients during the study 73 . A key factor contributing to high compliance may be high acceptability and perceived benefit of the wearable TENS device. The high-dose TENS group showed slightly higher perceived usefulness compared to the low-dose group (~ 71.2% vs ~ 61.4%), consistent with a previous RCT in FM patients undergoing TENS therapy for 3 weeks 74 . Moreover, all other acceptability items were similar to our previous trial involving PASC individuals undergoing electrical stimulation for musculoskeletal sequelae 75 . Limitations This study encountered limitations, including a small sample size and substantial missing data in the second/unblinded phase (weeks 4 to 8) due to challenges such as patients managing in-person clinic visits and coordinating appointments with specialists in pulmonology, cardiology, and rheumatology. The prevalent 'brain fog' hindered participants from remembering study-related tasks, impacting questionnaire completion and appointment tracking. The short TENS therapy duration and unanalyzed adjuvant medications effects for pain and fatigue added complexity. While five patients (PG, n = 4; IG, n = 1) received concurrent physical therapy, detailed session information was not collected. Unblinding at the 4-week visit may have increased loss to follow-up and decreased therapy adherence. Conclusion High-dose daily TENS therapy in individuals with PASC experiencing persistent pain, fatigue, and weakness for an average of ~ 356 days post-acute COVID-19 infection was feasible, and acceptable, with a greater improvement in functional interference from pain when compared to low-dose TENS therapy. Additionally, using high-dose TENS led to an improvement in gait characteristics such as cadence, stride time, and double-support phase as early as 4-weeks. Lastly, those individuals with PASC meeting the 2010 ACR FM diagnostic criteria showed improvement in functional interference due to fatigue at 4-weeks from baseline. Future studies, with larger sample sizes and extended follow-up periods, are needed to confirm these findings. Declarations Data availability: The data that support the findings of this study are not publicly available but are available from the corresponding author BN, [email protected] upon reasonable request. Ethics statement: The studies involving human participants were reviewed and approved by the Institutional Review Board for Human Subject Research for Baylor College of Medicine and Affiliated Hospitals (BCM IRB: #H-50753; Initial submit date: 10/27/2021). The patients/participants provided their written informed consent to participate in this study. The informed consent was obtained from all participants and/or their legal guardians. Author contributions : Concept and design: AZ, BN; Data Acquisition: AZ, RB, MB, AF, MP, TP; Data analysis: ML, MR; Preparing tables and figures: ML, AZ, TP; Interpretation of data: AZ, MB, AF, BN; Drafting the manuscript: AZ, RB, MB, TP, SM; Critical revision of the manuscript: BN, RB, AZ, DM, FS. All authors contributed to the article and approved the submitted version. Funding: This study was supported by a grant from the National Science Foundation's Industry-University Cooperative Research Centers (IUCRC), specifically from the Center to Stream HealthCare in Place (C2SHIP), with award numbers NSF 2052514 and C2SHIP Y01-BCM-008. Additionally, there was in-kind support provided by Neurometrix Inc., based in Massachusetts, USA, which is the manufacturer of the Quell® TENS device. Competing interests : BN is a consultant for BioSensics LLC (MA, USA) a manufacturer of the IMUs used in this study, who declares potential conflicts of interest regarding the research, authorship, and/or publication of this article. Although his consultation does not relate to the scope of this study, he was not involved in the analysis of data for this study. No additional potential conflicts of interest were reported. The disclosure for other authors is none. Acknowledgments: We thank Elissa Love, MS, PA-C, Dana Gross, MD, and Isabel Valdez, PA-C for patient referral. Additional information: Correspondence and requests for materials should be addressed to B.N References Raveendran, A., Jayadevan, R. & Sashidharan, S. Long COVID: an overview. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 15, 869–875 (2021). Control, C. f. D. & Prevention. Nearly one in five American adults who have had COVID-19 still have “long COVID”. National Center for Health Statistics. https://www.cdc.gov/nchs/pressroom/nchs _ press_ relea ses/ 2022 /20220 622 (2022). Sojka, A., Machniak, M., Andrzejewski, W., Kosendiak, A. & Chwałczyńska, A. Changes in physical activity and the occurrence of specific symptoms of “long-COVID syndrome” in men aged 18–25. International Journal of Environmental Research and Public Health 19, 1199 (2022). Khoja, O. et al. Clinical characteristics and mechanisms of musculoskeletal pain in long COVID. Journal of Pain Research, 1729–1748 (2022). Parker, A. M. et al. Addressing the post-acute sequelae of SARS-CoV-2 infection: a multidisciplinary model of care. The Lancet Respiratory Medicine 9, 1328–1341 (2021). Keklicek, H., Selçuk, H., Kurt, İ., Ulukaya, S. & Öztürk, G. Individuals with a COVID-19 history exhibit asymmetric gait patterns despite full recovery. Journal of Biomechanics 137, 111098 (2022). Mitrović-Ajtić, O. et al. in Healthcare. 1666 (MDPI). Gil, S. et al. Post-acute sequelae of SARS-CoV-2 associates with physical inactivity in a cohort of COVID-19 survivors. Sci Rep 13, 215 (2023). https://doi.org:10.1038/s41598-022-26888-3 Burgmer, M. et al. Cerebral mechanisms of experimental hyperalgesia in fibromyalgia. European journal of pain 16, 636–647 (2012). Control, C. f. D. & Prevention. Post-COVID Conditions: Information for Healthcare Providers. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-conditions.html (2024). Plaut, S. “Long COVID-19” and viral “fibromyalgia-ness”: Suggesting a mechanistic role for fascial myofibroblasts (Nineveh, the shadow is in the fascia). Frontiers in Medicine 10, 952278 (2023). Ursini, F. et al. Fibromyalgia: a new facet of the post-COVID-19 syndrome spectrum? Results from a web-based survey. RMD open 7, e001735 (2021). Cordero, M. D. The inflammasome in fibromyalgia and CRPS: a microglial hypothesis? Nature Reviews Rheumatology 11, 630–630 (2015). O'Brien, A. T., Deitos, A., Pego, Y. T., Fregni, F. & Carrillo-de-la-Peña, M. T. Defective endogenous pain modulation in fibromyalgia: a meta-analysis of temporal summation and conditioned pain modulation paradigms. The Journal of Pain 19, 819–836 (2018). Williams, D. A. & Gracely, R. H. Biology and therapy of fibromyalgia. Functional magnetic resonance imaging findings in fibromyalgia. Arthritis research & therapy 8, 1–8 (2007). Clough, E. et al. Mitochondrial dynamics in SARS-COV2 spike protein treated human microglia: implications for neuro-COVID. Journal of Neuroimmune Pharmacology, 1–15 (2021). Li, S. et al. SARS-CoV-2 triggers inflammatory responses and cell death through caspase-8 activation. Signal transduction and targeted therapy 5, 235 (2020). Panariello, F., Cellini, L., Speciani, M., De Ronchi, D. & Atti, A. R. How does SARS-CoV-2 affect the central nervous system? A working hypothesis. Frontiers in Psychiatry 11, 582345 (2020). Mahmudpour, M., Roozbeh, J., Keshavarz, M., Farrokhi, S. & Nabipour, I. COVID-19 cytokine storm: The anger of inflammation. Cytokine 133, 155151 (2020). Pottorf, T. S., Rotterman, T. M., McCallum, W. M., Haley-Johnson, Z. A. & Alvarez, F. J. The role of microglia in neuroinflammation of the spinal cord after peripheral nerve injury. Cells 11, 2083 (2022). Phetsouphanh, C. et al. Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection. Nature immunology 23, 210–216 (2022). Littlejohn, G. & Guymer, E. in Seminars in immunopathology. 291–300 (Springer). Fialho, M. F. P., Brum, E. S. & Oliveira, S. M. Could the fibromyalgia syndrome be triggered or enhanced by COVID-19? Inflammopharmacology 31, 633–651 (2023). A Phase 2 Study to Evaluate the Efficacy and Safety of TNX-102 SL in Patients With Multi-Site Pain Associated With Post-Acute Sequelae of SARS-CoV-2 Infection (PREVAIL) (2023). Fernández-de‐las‐Peñas, C., Nijs, J., Giordano, R. & Arendt‐Nielsen, L. Precision management of post‐COVID pain: An evidence and clinical‐based approach. European Journal of Pain 27, 1107–1125 (2023). DeSantana, J. M., Walsh, D. M., Vance, C., Rakel, B. A. & Sluka, K. A. Effectiveness of transcutaneous electrical nerve stimulation for treatment of hyperalgesia and pain. Current rheumatology reports 10, 492–499 (2008). Vance, C. G., Dailey, D. L., Rakel, B. A. & Sluka, K. A. Using TENS for pain control: the state of the evidence. Pain management 4, 197–209 (2014). Gozani, S. N. Remote analgesic effects of conventional transcutaneous electrical nerve stimulation: a scientific and clinical review with a focus on chronic pain. Journal of pain research, 3185–3201 (2019). Lin, T., Gargya, A., Singh, H., Sivanesan, E. & Gulati, A. Mechanism of peripheral nerve stimulation in chronic pain. Pain Medicine 21, S6-S12 (2020). Moayedi, M. & Davis, K. D. Theories of pain: from specificity to gate control. Journal of neurophysiology (2013). Amer-Cuenca, J. J. et al. The dose-dependent effects of transcutaneous electrical nerve stimulation for pain relief in individuals with fibromyalgia: a systematic review and meta-analysis. Pain, 10.1097 (2022). Johnson, M. I., Claydon, L. S., Herbison, G. P., Jones, G. & Paley, C. A. Transcutaneous electrical nerve stimulation (TENS) for fibromyalgia in adults. Cochrane Database Syst Rev 10, Cd012172 (2017). https://doi.org:10.1002/14651858.CD012172.pub2 Quell 2.0. Wearable pain relief technology TM User Manual. 2018. http://www.quellrelief.com/wp-content/uploads/2018/09/Quell-2.0-User-Manual-PN2204823-Rev-A.pdf Jamison, R. N. et al. Effects of wearable transcutaneous electrical nerve stimulation on fibromyalgia: a randomized controlled trial. Journal of Pain Research, 2265–2282 (2021). Cleeland, C. & Ryan, K. Pain assessment: global use of the Brief Pain Inventory. Annals of the Academy of Medicine, Singapore 23, 129–138 (1994). Hewlett, S., Dures, E. & Almeida, C. Measures of fatigue: Bristol rheumatoid arthritis fatigue multi-dimensional questionnaire (BRAF MDQ), Bristol rheumatoid arthritis fatigue numerical rating scales (BRAF NRS) for severity, effect, and coping, chalder fatigue questionnaire (CFQ), checklist individual strength (CIS20R and CIS8R), fatigue severity scale (FSS), functional assessment chronic illness therapy (fatigue)(FACIT‐F), multi‐dimensional assessment of fatigue (MAF), multi‐dimensional fatigue inventory (MFI), pediatric quality of life (PedsQL) multi‐dimensional fatigue scale, profile of fatigue (ProF), short form 36 vitality subscale (SF‐36 VT), and visual analog scales (VAS). Arthritis care & research 63, S263-S286 (2011). Beauchet, O. et al. Walking speed-related changes in stride time variability: effects of decreased speed. Journal of neuroengineering and rehabilitation 6, 1–6 (2009). Deusen, J. V. Temporal and Distance Parameters, in Assessment in Occupational Therapy and Physical Therapy Chap. 17 . (1996). Lee, T., Lee, M., Youm, C., Noh, B. & Park, H. Association between gait variability and gait-ability decline in elderly women with subthreshold insomnia stage. International journal of environmental research and public health 17, 5181 (2020). Kang, G. E., Zahiri, M., Lepow, B., Saleem, N. & Najafi, B. The effect of daily use of plantar mechanical stimulation through micro-mobile foot compression device installed in shoe insoles on vibration perception, gait, and balance in people with diabetic peripheral neuropathy. Journal of diabetes science and technology 13, 847–856 (2019). Gewandter, J. S. et al. Wireless Transcutaneous Electrical Nerve Stimulation (TENS) for Chronic Chemotherapy-Induced Peripheral Neuropathy (CIPN): A Proof-of-Concept Randomized Clinical Trial. The journal of pain (2023). Venkatesh, V. & Davis, F. D. A theoretical extension of the technology acceptance model: Four longitudinal field studies. Management science 46, 186–204 (2000). Jamison, R. N. et al. Effects of Wearable Transcutaneous Electrical Nerve Stimulation on Fibromyalgia: A Randomized Controlled Trial. J Pain Res 14, 2265–2282 (2021). https://doi.org:10.2147/jpr.S316371 Zulbaran-Rojas, A. et al. Optimizing Tissue Oxygenation in Reduction Mammoplasty: The Role of Continuous Diffusion of Oxygen: A Feasibility Pilot Randomized Controlled Trial. journal of surgical research 292, 113–122 (2023). Zulbaran-Rojas, A., Mishra, R., Pham, A., Suliburk, J. & Najafi, B. Continuous Diffusion of Oxygen Adjunct Therapy to Improve Scar Reduction After Cervicotomy–A Proof of Concept Randomized Controlled Trial. Journal of Surgical Research 268, 585–594 (2021). Zulbaran-Rojas, A., Park, C., El-Refaei, N., Lepow, B. & Najafi, B. Home-based electrical stimulation to accelerate wound healing—a double-blinded randomized control trial. Journal of Diabetes Science and Technology 17, 15–24 (2023). Wolfe, F. et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis care & research 62, 600–610 (2010). Arnold, L. M. et al. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain 119, 5–15 (2005). Arnold, L. M., Gendreau, R. M., Palmer, R. H., Gendreau, J. F. & Wang, Y. Efficacy and safety of milnacipran 100 mg/day in patients with fibromyalgia: Results of a randomized, double-blind, placebo‐controlled trial. Arthritis & Rheumatism 62, 2745–2756 (2010). Coskun Benlidayi, I. The effectiveness and safety of electrotherapy in the management of fibromyalgia. Rheumatology international 40, 1571–1580 (2020). Salaffi, F., Stancati, A., Silvestri, C. A., Ciapetti, A. & Grassi, W. Minimal clinically important changes in chronic musculoskeletal pain intensity measured on a numerical rating scale. European journal of pain 8, 283–291 (2004). Ahmed, M., Aamir, R., Jishi, Z. & Scharf, M. B. The Effects of Milnacipran on Sleep Disturbance in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled, Two-Way Crossover Study. J Clin Sleep Med 12, 79–86 (2016). https://doi.org:10.5664/jcsm.5400 Kong, X. & Gozani, S. N. Effectiveness of fixed-site high-frequency transcutaneous electrical nerve stimulation in chronic pain: a large-scale, observational study. Journal of pain research, 703–714 (2018). Azadvari, M., Haghparast, A., Nakhostin-Ansari, A., Razavi, S. Z. E. & Hosseini, M. Musculoskeletal symptoms in patients with long COVID: A cross-sectional study on Iranian patients. Heliyon 8 (2022). Kedor, C. et al. A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity. Nature communications 13, 5104 (2022). Straube, S., Derry, S., Moore, R. A. & McQuay, H. J. Pregabalin in fibromyalgia: meta-analysis of efficacy and safety from company clinical trial reports. Rheumatology 49, 706–715 (2010). Crofford, L. J. et al. Fibromyalgia relapse evaluation and efficacy for durability of meaningful relief (FREEDOM): a 6-month, double-blind, placebo-controlled trial with pregabalin. Pain 136, 419–431 (2008). Moore, A. R. et al. Fibromyalgia: moderate and substantial pain intensity reduction predicts improvement in other outcomes and substantial quality of life gain. Pain 149, 360–364 (2010). Dailey, D. L. et al. A randomized controlled trial of tens for movement-evoked pain in women with fibromyalgia. Arthritis & rheumatology (hoboken, NJ) 72, 824 (2020). Carrasco-Vega, E., Ruiz-Muñoz, M., Cuesta-Vargas, A., Romero-Galisteo, R. P. & González-Sánchez, M. Individuals with fibromyalgia have a different gait pattern and a reduced walk functional capacity: a systematic review with meta-analysis. PeerJ 10, e12908 (2022). Heredia-Jimenez, J., Latorre-Roman, P., Santos-Campos, M., Orantes-Gonzalez, E. & Soto-Hermoso, V. M. Spatio-temporal gait disorder and gait fatigue index in a six-minute walk test in women with fibromyalgia. Clinical Biomechanics 33, 1–6 (2016). Martín-Martínez, J. P. et al. Impact of cognitive tasks on biomechanical and kinematic parameters of gait in women with fibromyalgia: a cross-sectional study. Physiology & behavior 227, 113171 (2020). Radunović, G. et al. Assessment of gait in patients with fibromyalgia during motor and cognitive dual task walking: A cross-sectional study. Advances in Rheumatology 61, 53 (2021). Kaleth, A. S., Slaven, J. E. & Ang, D. C. Determining the minimal clinically important difference for 6-minute walk distance in fibromyalgia. American journal of physical medicine & rehabilitation 95, 738–745 (2016). Salvat, I. et al. Functional status, physical activity level, and exercise regularity in patients with fibromyalgia after Multidisciplinary treatment: retrospective analysis of a randomized controlled trial. Rheumatology international 37, 377–387 (2017). Tiidus, P. M., Pierrynowski, M. & Dawson, K. A. Influence of moderate training on gait and work capacity of fibromyalgia patients: a preliminary field study. Journal of Sports Science & Medicine 1, 122 (2002). Tran, S. T. et al. A pilot study of biomechanical assessment before and after an integrative training program for adolescents with juvenile fibromyalgia. Pediatr Rheumatol Online J 14, 43 (2016). https://doi.org:10.1186/s12969-016-0103-7 Lin, S., Sun, Q., Wang, H. & Xie, G. Influence of transcutaneous electrical nerve stimulation on spasticity, balance, and walking speed in stroke patients: A systematic review and meta-analysis. Journal of rehabilitation medicine 50, 3–7 (2018). Appelman, B. et al. Muscle abnormalities worsen after post-exertional malaise in long COVID. Nature communications 15, 1–15 (2024). Singh, I. et al. Persistent exertional intolerance after COVID-19: insights from invasive cardiopulmonary exercise testing. Chest 161, 54–63 (2022). Roskell, N. S., Beard, S. M., Zhao, Y. & Le, T. K. A meta-analysis of pain response in the treatment of fibromyalgia. Pain practice 11, 516–527 (2011). Arnold, L. M. et al. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology 50, 2974–2984 (2004). Orfei, M. D. et al. A new look on long-COVID effects: the functional brain fog syndrome. Journal of Clinical Medicine 11, 5529 (2022). Dailey, D. L. et al. Transcutaneous electrical nerve stimulation reduces pain, fatigue and hyperalgesia while restoring central inhibition in primary fibromyalgia. Pain® 154, 2554–2562 (2013). Zulbaran-Rojas, A. et al. Electrical stimulation to regain lower extremity muscle perfusion and endurance in patients with post‐acute sequelae of SARS CoV‐2: A randomized controlled trial. Physiological reports 11, e15636 (2023). Table 4 Table 4 is not available with this version. Additional Declarations Competing interest reported. Funding: This study was supported by a grant from the National Science Foundation's Industry-University Cooperative Research Centers (IUCRC), specifically from the Center to Stream HealthCare in Place (C2SHIP), with award numbers NSF 2052514 and C2SHIP Y01-BCM-008. Additionally, there was in-kind support provided by Neurometrix Inc., based in Massachusetts, USA, which is the manufacturer of the Quell® TENS device. Competing interests: BN is a consultant for BioSensics LLC (MA, USA) a manufacturer of the IMUs used in this study, who declares potential conflicts of interest regarding the research, authorship, and/or publication of this article. Although his consultation does not relate to the scope of this study, he was not involved in the analysis of data for this study. No additional potential conflicts of interest were reported. The disclosure for other authors is none. Supplementary Files SupplementarymaterialNMXNature5.8.24.docx Cite Share Download PDF Status: Published Journal Publication published 08 Nov, 2024 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 22 Aug, 2024 Reviews received at journal 14 Aug, 2024 Reviews received at journal 06 Aug, 2024 Reviewers agreed at journal 04 Aug, 2024 Reviewers agreed at journal 03 Aug, 2024 Reviewers invited by journal 03 Aug, 2024 Editor assigned by journal 03 Aug, 2024 Editor invited by journal 18 May, 2024 Submission checks completed at journal 17 May, 2024 First submitted to journal 08 May, 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-4391458","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":307139998,"identity":"de84ed16-34ae-499e-8d71-4fbf5731d79b","order_by":0,"name":"Alejandro Zulbaran-Rojas","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Alejandro","middleName":"","lastName":"Zulbaran-Rojas","suffix":""},{"id":307139999,"identity":"4da7ff35-447f-47fd-b8f6-199fd911e548","order_by":1,"name":"Rasha Bara","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Rasha","middleName":"","lastName":"Bara","suffix":""},{"id":307140000,"identity":"1baae6f7-1d08-4fd1-b23c-a7fd96c917fe","order_by":2,"name":"Myeounggon Lee","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Myeounggon","middleName":"","lastName":"Lee","suffix":""},{"id":307140001,"identity":"78da2d30-bc05-4425-aaa2-496f0905ed50","order_by":3,"name":"Miguel Bargas-Ochoa","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Miguel","middleName":"","lastName":"Bargas-Ochoa","suffix":""},{"id":307140002,"identity":"d9b48c97-2bc5-4dbc-86ad-da9364b78e6f","order_by":4,"name":"Tina Phan","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Tina","middleName":"","lastName":"Phan","suffix":""},{"id":307140003,"identity":"feeeb5f9-986e-42d8-9789-5d9ab1c9c75a","order_by":5,"name":"Manuel Pacheco","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Manuel","middleName":"","lastName":"Pacheco","suffix":""},{"id":307140004,"identity":"fdff08ec-04dc-4e9d-a762-4516972ac913","order_by":6,"name":"Areli Flores Camargo","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Areli","middleName":"Flores","lastName":"Camargo","suffix":""},{"id":307140005,"identity":"222e0d3e-70e4-4013-a5cb-a478e5335529","order_by":7,"name":"Syed Murtaza Kazmi","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Syed","middleName":"Murtaza","lastName":"Kazmi","suffix":""},{"id":307140006,"identity":"8ee47f67-06ef-4a38-a270-e81474993256","order_by":8,"name":"Mohammad Dehghan Rouzi","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Mohammad","middleName":"Dehghan","lastName":"Rouzi","suffix":""},{"id":307140007,"identity":"16926049-b99c-4633-82fe-b8959f7940e3","order_by":9,"name":"Dipaben Modi","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Dipaben","middleName":"","lastName":"Modi","suffix":""},{"id":307140008,"identity":"20c90925-dac0-4682-a6c8-893334af4c70","order_by":10,"name":"Fidaa Shaib","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Fidaa","middleName":"","lastName":"Shaib","suffix":""},{"id":307140009,"identity":"5c67158e-02ca-4809-8580-d091d0a86461","order_by":11,"name":"Bijan Najafi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIiWNgGAWjYBACA2aGBDCDsYHxwYGPDRBBYrUwGxycSZQWBJPZgJmXGC3m7AwPPxcw3JFnbj/MeNh2h100A3vzNgl8WiybGZKlZzA8M2zsSWY4nHsmObeB51gZXi0GhxkSpHkYDjM2NuQfOJzbdiC3QSLHjJCW5N9ALfaN/Y8ZDluCtMi/IaglDWRLYuMMoMMYwbbw4NcC9EuaNY/B4eTGGY8ZDvYC/dLGk1ZsgU+LOf+Z5Ns8FYdtN/YnM3/4ucMut5/98MYb+LQwMPAkgCPCsAHKZ8OvHATYD4ApecIqR8EoGAWjYKQCAM7NS3Oc7RXPAAAAAElFTkSuQmCC","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Bijan","middleName":"","lastName":"Najafi","suffix":""}],"badges":[],"createdAt":"2024-05-08 21:23:45","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4391458/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4391458/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-78651-5","type":"published","date":"2024-11-08T15:57:12+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":57626246,"identity":"d705dae4-6a87-4d0d-afed-33a3638a68ff","added_by":"auto","created_at":"2024-06-03 14:02:56","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1824474,"visible":true,"origin":"","legend":"\u003cp\u003eTranscutaneous Nerve Electrical Stimulation device set up and placement.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4391458/v1/fc614b7d9af3e02ea4d97d29.png"},{"id":57626244,"identity":"f578e9e7-9bf1-42f0-bc38-15d296c1c43d","added_by":"auto","created_at":"2024-06-03 14:02:56","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":88347,"visible":true,"origin":"","legend":"\u003cp\u003ePatient flow chart.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4391458/v1/d6601f4c84bd5fb16b7ac70b.png"},{"id":68750153,"identity":"676cd79c-e563-49a0-a249-f1d04bc31232","added_by":"auto","created_at":"2024-11-11 16:11:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2744916,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4391458/v1/87004ab5-04e1-451a-af19-0be3a199b4f6.pdf"},{"id":57626245,"identity":"0d180bab-e81f-42db-9ed1-58bbdf1e655b","added_by":"auto","created_at":"2024-06-03 14:02:56","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":24581,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementarymaterialNMXNature5.8.24.docx","url":"https://assets-eu.researchsquare.com/files/rs-4391458/v1/4a0829a883ab72c16d15d2c1.docx"}],"financialInterests":"Competing interest reported. Funding: This study was supported by a grant from the National Science Foundation's Industry-University Cooperative Research Centers (IUCRC), specifically from the Center to Stream HealthCare in Place (C2SHIP), with award numbers NSF 2052514 and C2SHIP Y01-BCM-008. Additionally, there was in-kind support provided by Neurometrix Inc., based in Massachusetts, USA, which is the manufacturer of the Quell® TENS device. \n\nCompeting interests: BN is a consultant for BioSensics LLC (MA, USA) a manufacturer of the IMUs used in this study, who declares potential conflicts of interest regarding the research, authorship, and/or publication of this article. Although his consultation does not relate to the scope of this study, he was not involved in the analysis of data for this study. No additional potential conflicts of interest were reported. The disclosure for other authors is none.","formattedTitle":"Transcutaneous Electrical Nerve Stimulation for Fibromyalgia-like Syndrome in Patients with Post-Acute Sequelae of Sars-Cov-2: A Pilot Randomized Clinical Trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePost-Acute Sequelae of Sars-Cov-2 (PASC) is a multisystemic condition characterized by persistent symptoms in one or more organs after acute COVID-19 clearance\u003csup\u003e1\u003c/sup\u003e. Approximately 1 in 13 adults recovering from COVID-19 experience PASC\u003csup\u003e2\u003c/sup\u003e, with the musculoskeletal system particularly affected\u003csup\u003e3\u003c/sup\u003e. Persistent symptoms include long-lasting widespread pain, fatigue and weakness varying in frequency, duration, and intensity\u003csup\u003e4,5\u003c/sup\u003e, which can lead to functional interference affecting gait and daily activities\u003csup\u003e6\u0026ndash;8\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe mechanism of musculoskeletal damage in PASC remains unknown, and whether widespread pain is associated with the nervous system is uncertain. Currently, there are no diagnostic criteria for PASC, but some symptoms resemble those of fibromyalgia (FM), a chronic disorder characterized by hyperalgesia and muscle weakness without a specific location\u003csup\u003e9\u003c/sup\u003e. FM is listed by the CDC as one of the conditions sharing symptoms with PASC\u003csup\u003e10\u003c/sup\u003e and recent studies showed that 30\u0026ndash;40% of individuals with PASC meet the American College of Rheumatology (ACR) FM diagnostic criteria\u003csup\u003e11,12\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFM's underlying cause has not been proven, but it is hypothesized to involve sensory sensitization of the spinothalamic tract, possibly attributed to microglial overactivation by numerous factors, including viral infections\u003csup\u003e13\u0026ndash;15\u003c/sup\u003e. Some researchers postulate that Sars-Cov-2 may induce central pain by interacting with ACE2 receptors in the microglia or via Spike proteins activating microglial apoptotic pathways\u003csup\u003e16\u0026ndash;18\u003c/sup\u003e. Microglial overactivation can result in excessive release of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6) in the spinal cord\u0026rsquo;s dorsal horn, potentially increasing neural excitability and pain sensitivity\u003csup\u003e19,20\u003c/sup\u003e. Phetsouphanh et al.\u003csup\u003e21\u003c/sup\u003e found elevated levels of these cytokines in PASC patients exhibiting pain and fatigue even after 8 months, mirroring findings in patients with FM\u003csup\u003e22\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe unknown origins and atypical pain patterns associated with FM in PASC individuals make its approach challenging\u003csup\u003e12\u003c/sup\u003e. Current therapies, including anti-inflammatory\u003csup\u003e23\u003c/sup\u003e and central pain-targeted agents have shown limited efficacy\u003csup\u003e24\u003c/sup\u003e, with few drug-based randomized clinical trial (RCTs) demonstrating pain relief in individuals with PASC and FM\u003csup\u003e25\u003c/sup\u003e. This highlights the need for effective therapies in this population.\u003c/p\u003e \u003cp\u003eTranscutaneous electrical nerve stimulation (TENS) is a supportive intervention believed to alleviate pain by stimulating peripheral nerves and modulating central pain processing\u003csup\u003e26,27\u003c/sup\u003e, reaching the CNS through a sequenced stimulation of non-painful 1st -order neurons (Alpha-beta fibers) leading to the activation of pain inhibitory interneurons in the dorsal horn (referred as \u0026ldquo;nerve gate\u0026rdquo;)\u003csup\u003e28\u003c/sup\u003e. This hypothesized effect blocks pain signals between painful 1st -order neurons (A-delta and C-fibers) and 2nd -order neurons (spinothalamic tract)\u003csup\u003e29,30\u003c/sup\u003e. A recent meta-analysis encasing 11 randomized controlled trials (RCT) involving patients with FM undergoing TENS therapy reported a large mean reduction in pain influenced by higher number of sessions, frequency, and intensity\u003csup\u003e31\u003c/sup\u003e. However, this technology\u0026rsquo;s effect on pain has not been explored in individuals with PASC developing FM-like symptoms.\u003c/p\u003e \u003cp\u003eThis pilot study investigated wearable TENS therapy as a potential treatment for FM-like symptoms in individuals with PASC. We hypothesize that 4-weeks of daily home-based wearable TENS therapy will reduce pain and fatigue interference with functional outcomes, and gait alterations among this population. In addition, we anticipate this regimen will be feasible and acceptable.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eA pilot RCT of individuals with PASC was conducted between April 2022 and August 2023. Participants were referred by a pulmonologist and critical care specialist from the post-COVID-19 Care Clinic or Internal Medicine Clinic at Baylor College of Medicine (Houston, TX), or self-referred by meeting the criteria in our public ClinicalTrials.gov registered protocol (Identifier: NCT05200858, 01/21/2022). All participants signed an informed consent approved by the local Institutional Review Board (IRB number: H-50753) before study enrollment. The study followed the Consolidated Standards of Reporting Trials (CONSORT) guidelines for RCTs. The methods used were in accordance with the relevant guidelines and regulations, and the Helsinki Declaration.\u003c/p\u003e \u003cp\u003eInclusion criteria were: 18\u0026ndash;64 years old; reported persistent muscle and joint pain, fatigue, and weakness in one or more body sections that were not present before acute COVID-19 infection; had access to a personal smartphone and willing to install a smartphone application; and able to attend in-person visits. Exclusion criteria were patients with demand-type cardiac pacemaker; implanted defibrillator; major lower extremity wounds; and previous neuromuscular diseases (i.e., Guillan-Barre, Myasthenia Gravis, multiple sclerosis) or hearing weakness.\u003c/p\u003e \u003cp\u003eBaseline demographics, comorbidities, and current PASC symptoms were gathered from participants' medical records. Neurovascular baseline characteristics, including bilateral sural nerve conduction velocity and amplitude, and plantar tissue oxygenation (SatO2), were assessed using the DPNCheck (NeuroMetrix Inc., MA, US) and SnapShot NIRS (Kent Imaging, Al, CAN) devices, respectively.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eRandomization, group allocation, and intervention\u003c/h2\u003e \u003cp\u003eParticipants were randomized (ratio: 1:1) to intervention (IG) and placebo (PG) groups through a computer-generated list followed by sequential allocation. Participants and care providers were blinded to the group allocation. Investigators collecting and analyzing data were not blinded. The IG received high-dose (1-hour) TENS therapy utilizing an FDA-cleared wearable device (Quell, NeuroMetrix Inc., MA, US). The device was unilaterally attached around the patients\u0026rsquo; upper calf via four hydrogel pads containing an electrode array, secured to a stretchable band strap (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The device consists of a one-channel electrical stimulator that communicates with a smartphone application through Bluetooth. The PG was provided with an identical device that elicited 10% dose (6-minutes per hour) of TENS therapy.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003e[Insert\u003c/b\u003e Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e \u003cb\u003ehere]\u003c/b\u003e\u003c/p\u003e \u003cp\u003eParticipants self-administered therapy daily, each session lasting 1 hour. They were instructed to complete 3\u0026ndash;5 sessions per day, alternating device placement contralaterally weekly. After the initial 4 weeks, participants were unblinded, with the IG continuing TENS therapy for an additional 4 weeks (total of 8 weeks), while the PG switched to a high-dose TENS device for the subsequent 4 weeks. Weekly support phone calls addressed device-related queries. No lifestyle/dietary modifications to pain medication were enforced during the study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eDevice and smartphone app characteristics\u003c/h2\u003e \u003cp\u003eThe system around the upper calf provides a total stimulation surface area of 60 cm\u003csup\u003e2\u003c/sup\u003e, stimulating sensory dermatomes S2 through L4, commonly targeted for lower body pain\u003csup\u003e32\u003c/sup\u003e. The stimulator generates bipolar, current-regulated pulses with a duration of 290 microseconds and alternating leading phase polarity. Stimulation frequency uniform distribution between 60 and 100 Hz\u003csup\u003e33\u003c/sup\u003e. These device\u0026rsquo;s characteristics were proven safe in a recent study of patients with FM\u003csup\u003e34\u003c/sup\u003e. The mobile application serves as a remote control for stimulator functions.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eProcedures and measurements\u003c/h2\u003e \u003cp\u003eParticipants attended three in-person visits at our facility during regular work hours. Assessments for both groups occurred at baseline, 4 weeks, and 8 weeks. At each visit, pain, fatigue, and gait were evaluated.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes\u003c/h2\u003e \u003cp\u003eThe primary outcome included functional interference from pain, assessed via the Brief Pain Index questionnaire interference composite score (BPI-I)\u003csup\u003e35\u003c/sup\u003e. Secondary outcomes included: 1) pain severity, assessed via the BPI questionnaire severity composite score (BPI-S)\u003csup\u003e35\u003c/sup\u003e; 2) fatigue, via the Multi-dimensional Assessment of Fatigue (MAF) questionnaire, and calculating the Global Fatigue Index (GFI)\u003csup\u003e36\u003c/sup\u003e ; and 3) gait measured using five inertial measurement units (IMUs, LEGSys BioSensics, MA, USA) on participants\u0026rsquo; ankles, thighs, and waist. Parameters included stride time\u003csup\u003e37\u003c/sup\u003e, cadence\u003csup\u003e38\u003c/sup\u003e, and double-support phase\u003csup\u003e39\u003c/sup\u003e, and were measured during three consecutive tasks: 1) simple-task (30-feet walk at normal pace); 2) dual-task (30-feet walk at normal pace while counting aloud backwards by 2); and 3) fast-walking-task (30-feet walk at a faster pace without jogging/running)\u003csup\u003e40\u003c/sup\u003e. In case of marked fatigue during the walking tasks, patients completed questionnaires via RedCap at home.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section3\"\u003e \u003ch2\u003eFeasibility metrics\u003c/h2\u003e \u003cp\u003eCompliance to the TENS device was linked to a cloud system. The median therapy sessions per day and the median days of device use were quantified. Completers were those adherent to the TENS device for \u0026ge;\u0026thinsp;3 sessions per day. High compliance was set to 70%\u003csup\u003e41\u003c/sup\u003e of the maximum possible number of sessions per day (3.5 out of 5) and days in 4-weeks (21 out of 30). Adverse events and therapy discontinuation were reported.\u003c/p\u003e \u003cp\u003eAcceptability to the TENS device was assessed using a Technology Acceptance Model (TAM) questionnaire\u003csup\u003e42\u003c/sup\u003e (\u003cb\u003eSupplemental Table\u0026nbsp;1\u003c/b\u003e), that measured: perceived usefulness (PU), perceived ease of use (PEOU), and attitude towards use (ATU).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003ePower analysis\u003c/h2\u003e \u003cp\u003eG*Power software (version 3.1.6) calculated the minimum sample size based on a similar study\u003csup\u003e34\u003c/sup\u003e. The following parameters were used: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) effect size d\u0026thinsp;=\u0026thinsp;1.168\u003csup\u003e43\u003c/sup\u003e, (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) 80% power, (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) 5% alpha, (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) two groups, and (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) equal number of participants per group. A minimum of 13 subjects per group, totaling 26 subjects, is required. A sample size of n\u0026thinsp;=\u0026thinsp;12 per group is expected to yield 95% power for detecting a time-effect difference. To accommodate an anticipated 10% dropout rate, we aimed to enroll 30 subjects (15 per group) in this study.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eCategorical data was presented as number and percentage (%). Shapiro\u0026ndash;Wilk test determined normality of continuous data (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Normally distributed data was presented with mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation; non-normally distributed data with median (interquartile range, IQR). Baseline characteristics between groups were compared using t-test, Chi-square, and Mann-Whitney U test, with Cohen's d for effect size. Interaction effect between group and time was analyzed using generalized estimation equations (GEE) representing estimated means and standard errors [SE] at baseline and 4-weeks. No covariates adjustments were made due to low sample size. TAM % agreement per item was calculated using our prior medical technology acceptability studies\u0026rsquo; Eq.\u0026nbsp;4\u003csup\u003e4\u0026ndash;46\u003c/sup\u003e, then compared between groups using t-test. SPSS 29.0 (IBM) was utilized forall statistical analyses with a significance set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThirty participants met the criteria, but five discontinued intervention during the blinded study phase (4-weeks), as detailed in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. Thus, 25 patients were included for analysis (IG, n\u0026thinsp;=\u0026thinsp;12; PG, n\u0026thinsp;=\u0026thinsp;13). Twenty-three patients were referred from our post-COVID-19 Care/Internal Medicine Clinic; two patients were self-referred. The unblinded phase of the study (week 4 to 8) was not analyzed due to the increase in lost to follow-ups (n\u0026thinsp;=\u0026thinsp;4) and missed final visits (n\u0026thinsp;=\u0026thinsp;7).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003ch2\u003ePatient characteristics\u003c/h2\u003e\n\u003cp\u003eBaseline clinical characteristics revealed a higher incidence of cancer history (41.7% vs 0, p\u0026thinsp;=\u0026thinsp;0.03) and osteoarthritis (33.3% vs 0, p\u0026thinsp;=\u0026thinsp;0.01) in the IG compared to the PG. Other baseline characteristics did not significantly differ between groups (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eBaseline clinical characteristics.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePlacebo\u003c/p\u003e\n\u003cp\u003eGroup (n\u0026thinsp;=\u0026thinsp;13)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eIntervention Group (n\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eP-value\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eEffect-size\u003c/p\u003e\n\u003cp\u003e(Cohen's d)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eDemographics\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge, years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e43.4\u0026thinsp;\u0026plusmn;\u0026thinsp;11.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e51\u0026thinsp;\u0026plusmn;\u0026thinsp;12.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.64\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27.7\u0026thinsp;\u0026plusmn;\u0026thinsp;7.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27.8\u0026thinsp;\u0026plusmn;\u0026thinsp;6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.98\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.01\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSex, female\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (69.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (83.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.41\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.33\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRace, no.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAfrican American\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (7.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (16.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"5\" align=\"left\"\u003e\n\u003cp\u003e0.36\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"5\" align=\"left\"\u003e\n\u003cp\u003e1.06\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHispanic\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (15.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAsian\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (15.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWhite\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (46.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (\u003cspan class=\"CitationRef\"\u003e50\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOther\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (15.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (8.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eComorbidities\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHigh blood pressure, no.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (23.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.91\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.05\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHeart disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (23.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (41.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.32\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.41\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDepression\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (23.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.91\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.05\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOsteoarthritis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (33.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.03\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.98\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (41.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.01\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.22\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBrain Fog\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (53.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (\u003cspan class=\"CitationRef\"\u003e75\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.45\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHospitalization due to COVID-19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (38.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (33.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.79\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.11\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAdmitted to ICU\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (15.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.59\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSupplemental oxygen hospital\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (30.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (8.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.58\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCurrent physical therapy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (15.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.61\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.21\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNeurovascular lower extremity features\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSural Nerve conduction velocity, m/s\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e58.1\u0026thinsp;\u0026plusmn;\u0026thinsp;6.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e55.9\u0026thinsp;\u0026plusmn;\u0026thinsp;4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.39\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSural Nerve amplitude, \u0026micro;V\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14.1\u0026thinsp;\u0026plusmn;\u0026thinsp;9.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13.9\u0026thinsp;\u0026plusmn;\u0026thinsp;5.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.91\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.02\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePlantar SatO2, %\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e66.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e67\u0026thinsp;\u0026plusmn;\u0026thinsp;6.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.72\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.08\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCurrent PASC symptoms\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDays of persistent symptoms\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e335.5\u0026thinsp;\u0026plusmn;\u0026thinsp;175.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e377.7\u0026thinsp;\u0026plusmn;\u0026thinsp;249.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.63\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.28\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMemory difficulty, no.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (80)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (91.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.59\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.43\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eShortness of breath\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (53.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (41.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.70\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.51\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFatigue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (100)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (91.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.43\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInsomnia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (46.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (58.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.78\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.43\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWeakness\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (84.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (\u003cspan class=\"CitationRef\"\u003e75\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.33\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.64\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMuscle pain\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (84.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (66.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.42\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.72\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnsteady gait\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (53.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (\u003cspan class=\"CitationRef\"\u003e50\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.76\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.45\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAtrophy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (61.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (41.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.71\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNumbness\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (84.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (\u003cspan class=\"CitationRef\"\u003e50\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.07\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.08\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eReported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or n (%). Reported symptoms were not present before acute COVID-19 infection. Kg, kilograms; m, meters; no., number; \u0026micro;V, microvolts; m, meters; s, seconds; PASC, post-acute sequelae of Sars-Cov-2\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n\u003ch2\u003eOutcomes\u003c/h2\u003e\n\u003cp\u003eBaseline BPI-I was significantly higher in the PG than the IG (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). At 4-weeks, the IG showed a significantly greater decrease in BPI-I scores compared to the PG (mean difference\u0026thinsp;=\u0026thinsp;2.61, p\u0026thinsp;=\u0026thinsp;0.008, d\u0026thinsp;=\u0026thinsp;1.12\u003cstrong\u003e)\u003c/strong\u003e. However, within-group comparison did not show significant improvement (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Baseline BPI-S and GFI did not significantly differ between groups (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e), nor did they show significant differences at 4 weeks (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eBaseline score comparison for pain and fatigue between groups/sub-groups\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePlacebo Group\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;13)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eIntervention Group (n\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eP-value\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eEffect-size (Cohen's d)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAll cohort\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBPI-I, score\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.54\u0026thinsp;\u0026plusmn;\u0026thinsp;0.62\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.81\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.021\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBPI-S\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.79\u0026thinsp;\u0026plusmn;\u0026thinsp;0.43\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.60\u0026thinsp;\u0026plusmn;\u0026thinsp;0.69\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.09\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGFI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37.89\u0026thinsp;\u0026plusmn;\u0026thinsp;3.32\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37.75\u0026thinsp;\u0026plusmn;\u0026thinsp;2.65\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.98\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.05\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eFibromyalgia sub-group\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eControl\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(n\u0026thinsp;=\u0026thinsp;9)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention (n\u0026thinsp;=\u0026thinsp;5)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eEffect-size (Cohen's d)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBPI-I, score\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.48\u0026thinsp;\u0026plusmn;\u0026thinsp;0.65\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.06\u0026thinsp;\u0026plusmn;\u0026thinsp;0.66\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.65\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.64\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBPI-S\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.28\u0026thinsp;\u0026plusmn;\u0026thinsp;0.47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.35\u0026thinsp;\u0026plusmn;\u0026thinsp;1.01\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.95\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGFI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e42.63\u0026thinsp;\u0026plusmn;\u0026thinsp;2.54\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e43.16\u0026thinsp;\u0026plusmn;\u0026thinsp;2.38\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.88\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.21\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eReported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. BPI-I, functional interference from pain via Brief Pain Inventory; BPI-S, pain severity via Brief Pain Inventory; GFI, global fatigue index via the Multi-dimensional Assessment of Fatigue.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003ePain and fatigue score comparison between groups/sub-groups at 4-weeks\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr style=\"height: 59px;\"\u003e\n\u003cth style=\"height: 94px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eVariable\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 94px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eN\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 94px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMean\u003c/p\u003e\n\u003cp\u003eChange\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 94px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eSE\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 59px;\" colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eTreatment Comparison at 4-weeks\u003c/p\u003e\n\u003cp\u003e(IG vs PG)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003cth style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eMean Difference\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e95% CI\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003ep-value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003cth style=\"height: 35px;\" colspan=\"7\" align=\"left\"\u003e\n\u003cp\u003eAll cohort\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eBPI-I, score\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003ePG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e0.198\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e0.407\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 70px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-2.616\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 70px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-4.543, 0.689\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 70px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.008\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eIG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e0.454\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e0.503\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eBPI-S\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003ePG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e0.289\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e0.255\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 70px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-1.305\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 70px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-2.894, 0.284\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 70px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.107\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eIG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e1.184\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e0.815\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eGFI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003ePG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e2.231\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e3.207\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 70px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-0.732\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 70px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-9.298, 7.834\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 70px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.867\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eIG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e2.821\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e1.504\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" colspan=\"7\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eFibromyalgia sub-group\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eBPI-I, score\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003ePG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e0.079\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e0.327\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 70px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-1.397\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 70px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-3.183, 0.39\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 70px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.08\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eIG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e1.057\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e0.603\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eBPI-S\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003ePG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e0.028\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e0.164\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 70px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-0.456\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 70px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-2.097, 1.186\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 70px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.587\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eIG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e0.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e0.604\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eGFI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003ePG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e1.747\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e1.503\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 70px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-3.806\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 70px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-9.132, 1.52\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 70px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.161\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eIG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e6.08*\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e2.188\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr style=\"height: 26px;\"\u003e\n\u003ctd style=\"height: 26px;\" colspan=\"7\"\u003e*Significant within group improvement. PG, placebo group; IG, intervention group; BPI-I, functional interference from pain via Brief Pain Inventory; BPI-S, pain severity via Brief Pain Inventory; GFI, global fatigue index via the Multi-dimensional Assessment of Fatigue.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n\u003cp\u003eObjective assessment of gait parameters showed no significant differences in baseline stride time, cadence, and double support phase between groups (\u003cstrong\u003eTable\u0026nbsp;4\u003c/strong\u003e). At 4-weeks from baseline, there was a significant improvement for stride time during the three walking tasks in the IG (single: 5.83%; dual: 8; fast-walking: 3.96%, all p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Similarly, cadence significantly improved at 4-weeks from baseline during the three waking tasks in the IG (single: 5.57%; dual: 9.5%; fast-walking-task: 3.89%, all p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). A significant time x group effect was seen for cadence and stride time (\u003cstrong\u003eSupplemental Table\u0026nbsp;2\u003c/strong\u003e). In addition, double-support phase significantly improved during the dual-task at 4-weeks from baseline in the IG (11.57%, p\u0026thinsp;=\u0026thinsp;0.017).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n\u003ch2\u003eFibromyalgia sub-group\u003c/h2\u003e\n\u003cp\u003eParticipants meeting the 2010 ACR FM diagnostic criteria\u003csup\u003e47\u003c/sup\u003e were labeled as the FM sub-group (PG-FM, n\u0026thinsp;=\u0026thinsp;9; IG-FM, n\u0026thinsp;=\u0026thinsp;5). At 4-weeks from baseline, the IG-FM showed a decreased trend for BPI-I scores (mean change\u0026thinsp;=\u0026thinsp;1.057 [SE\u0026thinsp;=\u0026thinsp;0.6], p\u0026thinsp;=\u0026thinsp;0.080). Comparison between sub-groups at 4-weeks showed a trend in favor of the IG-FM compared to the PG-FM (mean difference\u0026thinsp;=\u0026thinsp;1.39, p\u0026thinsp;=\u0026thinsp;0.125, d\u0026thinsp;=\u0026thinsp;2.257, Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Moreover, the IG-FM showed a significant improvement in GFI scores at 4-weeks from baseline (mean change\u0026thinsp;=\u0026thinsp;6.08 [SE\u0026thinsp;=\u0026thinsp;10.61], p\u0026thinsp;=\u0026thinsp;0.005).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n\u003ch2\u003eFeasibility metrics\u003c/h2\u003e\n\u003cp\u003eAt 4-weeks, median TENS therapy sessions per day were 4 (IQR\u0026thinsp;=\u0026thinsp;3-4.9) in the IG and 3.5 (IQR\u0026thinsp;=\u0026thinsp;3\u0026ndash;5) in the PG. The median days of device use at 4-weeks were 27 (IQR\u0026thinsp;=\u0026thinsp;25-27.5) in the IG, and 26 (IQR\u0026thinsp;=\u0026thinsp;20\u0026ndash;27) in the PG. Completers (\u0026ge;\u0026thinsp;3 sessions per day) rate in the IG was 100%, while 92.3% in the PG. High compliance (\u0026ge;\u0026thinsp;3.5 sessions per day) rate in the IG was 54.5%, while 61.5% in the PG (\u003cstrong\u003eSupplemental Table\u0026nbsp;3\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eNo severe adverse events requiring discontinuation were reported. However, two patients (CG, n\u0026thinsp;=\u0026thinsp;1; IG, n\u0026thinsp;=\u0026thinsp;1) experienced mild pain and itchiness, respectively, when TENS was delivered immediately after shaving their lower extremities. After using TENS daily for 5 hours, one patient (CG, n\u0026thinsp;=\u0026thinsp;1) reported mild fatigue, and one patient (IG, n\u0026thinsp;=\u0026thinsp;1) reported skin irritation. Two patients (IG, n\u0026thinsp;=\u0026thinsp;1; PG, n\u0026thinsp;=\u0026thinsp;1) complained of pain and skin spots, respectively, from the hydrogel pads when not weekly alternating the device to the contralateral calf.\u003c/p\u003e\n\u003cp\u003eThe TAM questionnaire showed overall acceptability above 70% in all categories, with no significant differences between groups: PEOU (IG\u0026thinsp;=\u0026thinsp;94.2\u0026thinsp;\u0026plusmn;\u0026thinsp;10.8% vs PG\u0026thinsp;=\u0026thinsp;91.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.9%, p\u0026thinsp;=\u0026thinsp;0.42), ATU (IG\u0026thinsp;=\u0026thinsp;89.2\u0026thinsp;\u0026plusmn;\u0026thinsp;10% vs PG\u0026thinsp;=\u0026thinsp;83\u0026thinsp;\u0026plusmn;\u0026thinsp;14.4%, p\u0026thinsp;=\u0026thinsp;0.283), and PU (IG\u0026thinsp;=\u0026thinsp;71.2\u0026thinsp;\u0026plusmn;\u0026thinsp;11.6% vs PG\u0026thinsp;=\u0026thinsp;61.4\u0026thinsp;\u0026plusmn;\u0026thinsp;14.9%, p\u0026thinsp;=\u0026thinsp;0.13).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis pilot RCT examined the effectiveness of daily wearable TENS therapy in alleviating pain, fatigue, and gait alterations in individuals with PASC. High-dose TENS participants experienced greater reduction in functional interference due to pain compared to low-dose TENS participants. Additionally, objective assessment of gait parameters revealed significant improvement in stride time and cadence at 4 weeks from baseline in the high-dose TENS group across various walking tasks. Moreover, both groups exhibited high compliance rates (≥ 3 hours per day) and reported device acceptability above 70% during the blinded study phase.\u003c/p\u003e \u003cp\u003ePrevious RCTs utilizing FDA-approved pharmacological treatment for FM (i.e., duloxetine\u003csup\u003e48\u003c/sup\u003e, milnacipran\u003csup\u003e49\u003c/sup\u003e) have shown improvement in functional interference from pain when compared to placebo, with a BPI-I between-group mean difference ranging from 0.58–1.74 in a 12-week timeframe; however, accompanied by notable side effects including nausea (\u0026gt; 36%), constipation (\u0026gt; 14.7%), and dizziness (\u0026gt; 10.5%), amongst others\u003csup\u003e48,49\u003c/sup\u003e. The present study explored TENS as a safer pain management intervention with known minimal side effects\u003csup\u003e50\u003c/sup\u003e. We acknowledge the IG had less severe functional baseline pain scores than the PG, thus, evidence suggests this cohort would have had lesser improvement post-intervention \u003csup\u003e51\u003c/sup\u003e. However, after 4-weeks of TENS therapy, the IG showed significantly greater reduction of BPI-I scores compared to the PG (mean difference = 2.61 points, p = 0.008, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) suggests a 1-point mean change from baseline to the targeted endpoint as a meaningful clinically significant difference (MCID)\u003csup\u003e52\u003c/sup\u003e. In our study, the FM subgroup undergoing high-dose TENS showed a trend for reaching this MCID as early as 4-weeks (mean change = 1.06 points, p = 0.080). This magnitude of reduction in BPI-I scores with high-dose TENS mirrors the improvements noted by Kong et al.\u003csup\u003e53\u003c/sup\u003e and Jamison et al.\u003csup\u003e34\u003c/sup\u003e in non-PASC patients with FM after 60-days and 3-months therapy, respectively. Our study uniquely demonstrates the benefit of high-dose TENS over low-dose in individuals with PASC and FM-like symptoms within a short timeframe. Despite a small sample size, the substantial effect size compared to low-dose TENS at 4-weeks (d = 2.26) indicates the potential of high-dose TENS for larger, longer-term studies.\u003c/p\u003e \u003cp\u003eFunctional interference from fatigue is crucial to assess in PASC patients given its prolonged and severe nature\u003csup\u003e54\u003c/sup\u003e. Similarly to FM, the origin of fatigue in PASC patients has been linked to persistent inflammatory biomarkers\u003csup\u003e55\u003c/sup\u003e.Therefore, we used the GFI to assess functional interference from fatigue, a reliable tool that has shown significant fatigue reduction (1.4 to 1.6 points) in FM patients taking mild-moderate pregabalin doses (300mg to 450mg) over 14-weeks \u003csup\u003e56\u003c/sup\u003e, with further improvement when increasing doses (600mg) over 32 weeks\u003csup\u003e57\u003c/sup\u003e. Interestingly, other pregabalin trials identified that substantial fatigue reduction, such as 10-point GFI decrease, was only seen in FM patients experiencing a 30% of pain reduction\u003csup\u003e58\u003c/sup\u003e. This trend was echoed in a recent study employing 4-week TENS therapy in women with FM\u003csup\u003e59\u003c/sup\u003e, which demonstrated a significant GFI improvement of 4.6-points correlated with reduced pain evoked by movement. Similarly, our study showed a significant 6.08-point GFI improvement in the sub-group of FM patients receiving high-dose TENS at 4-weeks from baseline. However, this mean change did not correlate with the observed changes in BPI-I scores, suggesting that PASC patients with FM may experience significant functional improvement from fatigue without necessarily needing concurrent pain relief.\u003c/p\u003e \u003cp\u003eIn a recent systematic review, significant gait alterations were found in FM patients\u003csup\u003e60\u003c/sup\u003e. Utilizing instrumented walkway systems, observational studies revealed FM patients have significantly shorter cadence and longer double support phases compared to healthy individuals in \u003csup\u003e61\u003c/sup\u003e. The present study exhibited that PASC patients with widespread pain undergoing 4-week high-dose TENS significantly improved their cadence by 5.6% and 9.5% in the single- and dual-tasks, respectively, and 3.9% in the fast-walking task. Moreover, studies have incorporated cognitive elements (dual-task) in walking assessments to predict risk-of-fall caused by fatigue in FM patients\u003csup\u003e62\u003c/sup\u003e, showing a notable impact on double-support phase during such tasks\u003csup\u003e63\u003c/sup\u003e. In the present study, the double-support phase of PASC patients undergoing 4-weeks high-dose TENS significantly improved by 11.6% in the dual-task. While no MCID is established for gait via wearables in FM patients, Kaleth et al.\u003csup\u003e64\u003c/sup\u003e established an anchor-based MCID for walking distance, indicating clinically meaningful fatigue improvement. Our findings suggest that reducing functional interference from fatigue may aid fall prevention in PASC patients with chronic pain; however, further risk-of-fall assessment is needed for confirmation.\u003c/p\u003e \u003cp\u003eTo date, the objective assessment of gait improvement in FM patients has been limited to studies focusing on interventions like aerobic exercise and physical therapy\u003csup\u003e65–67\u003c/sup\u003e. Moreover, the effectiveness of TENS in enhancing gait has only been investigated in stroke patients, however incorporating exercise therapy into the treatment regimen therapy as well\u003csup\u003e68\u003c/sup\u003e. This modality is often unsuitable for PASC patients given their high-risk for post-exertional malaise\u003csup\u003e69\u003c/sup\u003e. Consequently, they are generally advised to refrain from moderate physical exertion\u003csup\u003e70\u003c/sup\u003e. In this context, high-dose TENS offers a promising alternative for improving gait parameters in PASC patients with FM-like symptoms. Nevertheless, further research with a larger sample size is essential to substantiate this potential benefit.\u003c/p\u003e \u003cp\u003eThe adherence to analgesic drugs among FM patients can be influenced by intermittent pain and adverse events\u003csup\u003e71\u003c/sup\u003e. In a duloxetine 12-week trial, up to 21% participants discontinued therapy due to adverse events\u003csup\u003e72\u003c/sup\u003e. The present study showed no discontinuations at 4-weeks, despite 6 patients reporting mild fatigue, pain, and skin irritation. These issues were resolved with advice from the research team. Compliance resulted in a median of \u0026gt; 3.5 therapy sessions per day and \u0026gt; 26 days of device usage. High compliant (≥ 21 of days used) patients’ rate was 100% in the IG and 81.8% in the CG. However, compliance decreased in the unblinded study phase (week-4 to 8). We attribute this to disengagement from placebo devices, depression, brain fog, and multiple hospital visits encountered by our patients during the study\u003csup\u003e73\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eA key factor contributing to high compliance may be high acceptability and perceived benefit of the wearable TENS device. The high-dose TENS group showed slightly higher perceived usefulness compared to the low-dose group (~ 71.2% vs ~ 61.4%), consistent with a previous RCT in FM patients undergoing TENS therapy for 3 weeks\u003csup\u003e74\u003c/sup\u003e. Moreover, all other acceptability items were similar to our previous trial involving PASC individuals undergoing electrical stimulation for musculoskeletal sequelae\u003csup\u003e75\u003c/sup\u003e.\u003c/p\u003e "},{"header":"Limitations","content":"\u003cp\u003eThis study encountered limitations, including a small sample size and substantial missing data in the second/unblinded phase (weeks 4 to 8) due to challenges such as patients managing in-person clinic visits and coordinating appointments with specialists in pulmonology, cardiology, and rheumatology. The prevalent 'brain fog' hindered participants from remembering study-related tasks, impacting questionnaire completion and appointment tracking. The short TENS therapy duration and unanalyzed adjuvant medications effects for pain and fatigue added complexity. While five patients (PG, n = 4; IG, n = 1) received concurrent physical therapy, detailed session information was not collected. Unblinding at the 4-week visit may have increased loss to follow-up and decreased therapy adherence.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eHigh-dose daily TENS therapy in individuals with PASC experiencing persistent pain, fatigue, and weakness for an average of ~\u0026thinsp;356 days post-acute COVID-19 infection was feasible, and acceptable, with a greater improvement in functional interference from pain when compared to low-dose TENS therapy. Additionally, using high-dose TENS led to an improvement in gait characteristics such as cadence, stride time, and double-support phase as early as 4-weeks. Lastly, those individuals with PASC meeting the 2010 ACR FM diagnostic criteria showed improvement in functional interference due to fatigue at 4-weeks from baseline. Future studies, with larger sample sizes and extended follow-up periods, are needed to confirm these findings.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability:\u0026nbsp;\u003c/strong\u003eThe data that support the findings of this study are not publicly available but are available from the corresponding author BN, [email protected] upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics statement:\u003c/strong\u003e The studies involving human participants were reviewed and approved by the Institutional Review Board for Human Subject Research for Baylor College of Medicine and Affiliated Hospitals (BCM IRB: #H-50753; Initial submit date: 10/27/2021). The patients/participants provided their written informed consent to participate in this study. The informed consent was obtained from all participants and/or their legal guardians.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e: Concept and design: AZ, BN; Data Acquisition: AZ, RB, MB, AF, MP, TP;\u0026nbsp;Data analysis: ML, MR; Preparing tables and figures: ML, AZ, TP; Interpretation of data: AZ, MB, AF, BN; Drafting the manuscript: AZ, RB, MB, TP, SM; Critical revision of the manuscript: BN, RB, AZ, DM, FS. All authors contributed to the article and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This study was supported by a grant from the National Science Foundation\u0026apos;s Industry-University Cooperative Research Centers (IUCRC), specifically from the Center to Stream HealthCare in Place (C2SHIP), with award numbers NSF 2052514 and C2SHIP Y01-BCM-008. Additionally, there was in-kind support provided by Neurometrix Inc., based in Massachusetts, USA, which is the manufacturer of the Quell\u0026reg; TENS device.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e:\u0026nbsp;BN is a consultant for BioSensics LLC (MA, USA) a manufacturer of the IMUs used in this study, who declares potential conflicts of interest regarding the research, authorship, and/or publication of this article. Although his consultation does not relate to the scope of this study, he was not involved in the analysis of data for this study. No additional potential conflicts of interest were reported. The disclosure for other authors is none.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e We thank Elissa Love, MS, PA-C, Dana Gross, MD, and Isabel Valdez, PA-C for patient referral.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional information:\u0026nbsp;\u003c/strong\u003eCorrespondence and requests for materials should be addressed to B.N\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRaveendran, A., Jayadevan, R. \u0026amp; Sashidharan, S. Long COVID: an overview. Diabetes \u0026amp; Metabolic Syndrome: Clinical Research \u0026amp; Reviews 15, 869\u0026ndash;875 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eControl, C. f. D. \u0026amp; Prevention. Nearly one in five American adults who have had COVID-19 still have \u0026ldquo;long COVID\u0026rdquo;. \u003cem\u003eNational Center for Health Statistics.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.cdc.gov/nchs/pressroom/nchs _\u003c/span\u003e\u003cspan address=\"https://www.cdc.gov/nchs/pressroom/nchs _\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e \u003cem\u003epress_ relea ses/\u003c/em\u003e2022\u003cem\u003e/20220\u003c/em\u003e 622 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSojka, A., Machniak, M., Andrzejewski, W., Kosendiak, A. \u0026amp; Chwałczyńska, A. Changes in physical activity and the occurrence of specific symptoms of \u0026ldquo;long-COVID syndrome\u0026rdquo; in men aged 18\u0026ndash;25. International Journal of Environmental Research and Public Health 19, 1199 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhoja, O. \u003cem\u003eet al.\u003c/em\u003e Clinical characteristics and mechanisms of musculoskeletal pain in long COVID. Journal of Pain Research, 1729\u0026ndash;1748 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eParker, A. M. \u003cem\u003eet al.\u003c/em\u003e Addressing the post-acute sequelae of SARS-CoV-2 infection: a multidisciplinary model of care. The Lancet Respiratory Medicine 9, 1328\u0026ndash;1341 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKeklicek, H., Sel\u0026ccedil;uk, H., Kurt, İ., Ulukaya, S. \u0026amp; \u0026Ouml;zt\u0026uuml;rk, G. Individuals with a COVID-19 history exhibit asymmetric gait patterns despite full recovery. Journal of Biomechanics 137, 111098 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMitrović-Ajtić, O. \u003cem\u003eet al.\u003c/em\u003e in \u003cem\u003eHealthcare.\u003c/em\u003e 1666 (MDPI).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGil, S. \u003cem\u003eet al.\u003c/em\u003e Post-acute sequelae of SARS-CoV-2 associates with physical inactivity in a cohort of COVID-19 survivors. Sci Rep 13, 215 (2023). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org:10.1038/s41598-022-26888-3\u003c/span\u003e\u003cspan address=\"https://doi.org:10.1038/s41598-022-26888-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBurgmer, M. \u003cem\u003eet al.\u003c/em\u003e Cerebral mechanisms of experimental hyperalgesia in fibromyalgia. European journal of pain 16, 636\u0026ndash;647 (2012).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eControl, C. f. D. \u0026amp; Prevention. Post-COVID Conditions: Information for Healthcare Providers. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-conditions.html\u003c/span\u003e\u003cspan address=\"https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-conditions.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePlaut, S. \u0026ldquo;Long COVID-19\u0026rdquo; and viral \u0026ldquo;fibromyalgia-ness\u0026rdquo;: Suggesting a mechanistic role for fascial myofibroblasts (Nineveh, the shadow is in the fascia). Frontiers in Medicine 10, 952278 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUrsini, F. \u003cem\u003eet al.\u003c/em\u003e Fibromyalgia: a new facet of the post-COVID-19 syndrome spectrum? Results from a web-based survey. RMD open 7, e001735 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCordero, M. D. The inflammasome in fibromyalgia and CRPS: a microglial hypothesis? Nature Reviews Rheumatology 11, 630\u0026ndash;630 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eO'Brien, A. T., Deitos, A., Pego, Y. T., Fregni, F. \u0026amp; Carrillo-de-la-Pe\u0026ntilde;a, M. T. Defective endogenous pain modulation in fibromyalgia: a meta-analysis of temporal summation and conditioned pain modulation paradigms. The Journal of Pain 19, 819\u0026ndash;836 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWilliams, D. A. \u0026amp; Gracely, R. H. Biology and therapy of fibromyalgia. Functional magnetic resonance imaging findings in fibromyalgia. Arthritis research \u0026amp; therapy 8, 1\u0026ndash;8 (2007).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eClough, E. \u003cem\u003eet al.\u003c/em\u003e Mitochondrial dynamics in SARS-COV2 spike protein treated human microglia: implications for neuro-COVID. Journal of Neuroimmune Pharmacology, 1\u0026ndash;15 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi, S. \u003cem\u003eet al.\u003c/em\u003e SARS-CoV-2 triggers inflammatory responses and cell death through caspase-8 activation. Signal transduction and targeted therapy 5, 235 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePanariello, F., Cellini, L., Speciani, M., De Ronchi, D. \u0026amp; Atti, A. R. How does SARS-CoV-2 affect the central nervous system? A working hypothesis. Frontiers in Psychiatry 11, 582345 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMahmudpour, M., Roozbeh, J., Keshavarz, M., Farrokhi, S. \u0026amp; Nabipour, I. COVID-19 cytokine storm: The anger of inflammation. Cytokine 133, 155151 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePottorf, T. S., Rotterman, T. M., McCallum, W. M., Haley-Johnson, Z. A. \u0026amp; Alvarez, F. J. The role of microglia in neuroinflammation of the spinal cord after peripheral nerve injury. Cells 11, 2083 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePhetsouphanh, C. \u003cem\u003eet al.\u003c/em\u003e Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection. Nature immunology 23, 210\u0026ndash;216 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLittlejohn, G. \u0026amp; Guymer, E. in \u003cem\u003eSeminars in immunopathology.\u003c/em\u003e 291\u0026ndash;300 (Springer).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFialho, M. F. P., Brum, E. S. \u0026amp; Oliveira, S. M. Could the fibromyalgia syndrome be triggered or enhanced by COVID-19? \u003cem\u003eInflammopharmacology\u003c/em\u003e 31, 633\u0026ndash;651 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eA Phase 2 Study to Evaluate the Efficacy and Safety of TNX-102 SL in Patients With Multi-Site Pain Associated With Post-Acute Sequelae of SARS-CoV-2 Infection (PREVAIL) (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFern\u0026aacute;ndez-de‐las‐Pe\u0026ntilde;as, C., Nijs, J., Giordano, R. \u0026amp; Arendt‐Nielsen, L. Precision management of post‐COVID pain: An evidence and clinical‐based approach. European Journal of Pain 27, 1107\u0026ndash;1125 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDeSantana, J. M., Walsh, D. M., Vance, C., Rakel, B. A. \u0026amp; Sluka, K. A. Effectiveness of transcutaneous electrical nerve stimulation for treatment of hyperalgesia and pain. Current rheumatology reports 10, 492\u0026ndash;499 (2008).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVance, C. G., Dailey, D. L., Rakel, B. A. \u0026amp; Sluka, K. A. Using TENS for pain control: the state of the evidence. Pain management 4, 197\u0026ndash;209 (2014).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGozani, S. N. Remote analgesic effects of conventional transcutaneous electrical nerve stimulation: a scientific and clinical review with a focus on chronic pain. Journal of pain research, 3185\u0026ndash;3201 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLin, T., Gargya, A., Singh, H., Sivanesan, E. \u0026amp; Gulati, A. Mechanism of peripheral nerve stimulation in chronic pain. Pain Medicine 21, S6-S12 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoayedi, M. \u0026amp; Davis, K. D. Theories of pain: from specificity to gate control. Journal of neurophysiology (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmer-Cuenca, J. J. \u003cem\u003eet al.\u003c/em\u003e The dose-dependent effects of transcutaneous electrical nerve stimulation for pain relief in individuals with fibromyalgia: a systematic review and meta-analysis. Pain, 10.1097 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJohnson, M. I., Claydon, L. S., Herbison, G. P., Jones, G. \u0026amp; Paley, C. A. Transcutaneous electrical nerve stimulation (TENS) for fibromyalgia in adults. Cochrane Database Syst Rev 10, Cd012172 (2017). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org:10.1002/14651858.CD012172.pub2\u003c/span\u003e\u003cspan address=\"https://doi.org:10.1002/14651858.CD012172.pub2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQuell 2.0. Wearable pain relief technology TM User Manual. 2018. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.quellrelief.com/wp-content/uploads/2018/09/Quell-2.0-User-Manual-PN2204823-Rev-A.pdf\u003c/span\u003e\u003cspan address=\"http://www.quellrelief.com/wp-content/uploads/2018/09/Quell-2.0-User-Manual-PN2204823-Rev-A.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJamison, R. N. \u003cem\u003eet al.\u003c/em\u003e Effects of wearable transcutaneous electrical nerve stimulation on fibromyalgia: a randomized controlled trial. Journal of Pain Research, 2265\u0026ndash;2282 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCleeland, C. \u0026amp; Ryan, K. Pain assessment: global use of the Brief Pain Inventory. Annals of the Academy of Medicine, Singapore 23, 129\u0026ndash;138 (1994).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHewlett, S., Dures, E. \u0026amp; Almeida, C. Measures of fatigue: Bristol rheumatoid arthritis fatigue multi-dimensional questionnaire (BRAF MDQ), Bristol rheumatoid arthritis fatigue numerical rating scales (BRAF NRS) for severity, effect, and coping, chalder fatigue questionnaire (CFQ), checklist individual strength (CIS20R and CIS8R), fatigue severity scale (FSS), functional assessment chronic illness therapy (fatigue)(FACIT‐F), multi‐dimensional assessment of fatigue (MAF), multi‐dimensional fatigue inventory (MFI), pediatric quality of life (PedsQL) multi‐dimensional fatigue scale, profile of fatigue (ProF), short form 36 vitality subscale (SF‐36 VT), and visual analog scales (VAS). \u003cem\u003eArthritis care \u0026amp; research\u003c/em\u003e 63, S263-S286 (2011).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeauchet, O. \u003cem\u003eet al.\u003c/em\u003e Walking speed-related changes in stride time variability: effects of decreased speed. Journal of neuroengineering and rehabilitation 6, 1\u0026ndash;6 (2009).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDeusen, J. V. \u003cem\u003eTemporal and Distance Parameters, in Assessment in Occupational Therapy and Physical Therapy Chap. 17\u003c/em\u003e. (1996).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee, T., Lee, M., Youm, C., Noh, B. \u0026amp; Park, H. Association between gait variability and gait-ability decline in elderly women with subthreshold insomnia stage. International journal of environmental research and public health 17, 5181 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKang, G. E., Zahiri, M., Lepow, B., Saleem, N. \u0026amp; Najafi, B. The effect of daily use of plantar mechanical stimulation through micro-mobile foot compression device installed in shoe insoles on vibration perception, gait, and balance in people with diabetic peripheral neuropathy. Journal of diabetes science and technology 13, 847\u0026ndash;856 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGewandter, J. S. \u003cem\u003eet al.\u003c/em\u003e Wireless Transcutaneous Electrical Nerve Stimulation (TENS) for Chronic Chemotherapy-Induced Peripheral Neuropathy (CIPN): A Proof-of-Concept Randomized Clinical Trial. The journal of pain (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVenkatesh, V. \u0026amp; Davis, F. D. A theoretical extension of the technology acceptance model: Four longitudinal field studies. Management science 46, 186\u0026ndash;204 (2000).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJamison, R. N. \u003cem\u003eet al.\u003c/em\u003e Effects of Wearable Transcutaneous Electrical Nerve Stimulation on Fibromyalgia: A Randomized Controlled Trial. J Pain Res 14, 2265\u0026ndash;2282 (2021). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org:10.2147/jpr.S316371\u003c/span\u003e\u003cspan address=\"https://doi.org:10.2147/jpr.S316371\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZulbaran-Rojas, A. \u003cem\u003eet al.\u003c/em\u003e Optimizing Tissue Oxygenation in Reduction Mammoplasty: The Role of Continuous Diffusion of Oxygen: A Feasibility Pilot Randomized Controlled Trial. journal of surgical research 292, 113\u0026ndash;122 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZulbaran-Rojas, A., Mishra, R., Pham, A., Suliburk, J. \u0026amp; Najafi, B. Continuous Diffusion of Oxygen Adjunct Therapy to Improve Scar Reduction After Cervicotomy\u0026ndash;A Proof of Concept Randomized Controlled Trial. Journal of Surgical Research 268, 585\u0026ndash;594 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZulbaran-Rojas, A., Park, C., El-Refaei, N., Lepow, B. \u0026amp; Najafi, B. Home-based electrical stimulation to accelerate wound healing\u0026mdash;a double-blinded randomized control trial. Journal of Diabetes Science and Technology 17, 15\u0026ndash;24 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWolfe, F. \u003cem\u003eet al.\u003c/em\u003e The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis care \u0026amp; research 62, 600\u0026ndash;610 (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArnold, L. M. \u003cem\u003eet al.\u003c/em\u003e A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain 119, 5\u0026ndash;15 (2005).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArnold, L. M., Gendreau, R. M., Palmer, R. H., Gendreau, J. F. \u0026amp; Wang, Y. Efficacy and safety of milnacipran 100 mg/day in patients with fibromyalgia: Results of a randomized, double-blind, placebo‐controlled trial. Arthritis \u0026amp; Rheumatism 62, 2745\u0026ndash;2756 (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCoskun Benlidayi, I. The effectiveness and safety of electrotherapy in the management of fibromyalgia. Rheumatology international 40, 1571\u0026ndash;1580 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSalaffi, F., Stancati, A., Silvestri, C. A., Ciapetti, A. \u0026amp; Grassi, W. Minimal clinically important changes in chronic musculoskeletal pain intensity measured on a numerical rating scale. European journal of pain 8, 283\u0026ndash;291 (2004).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAhmed, M., Aamir, R., Jishi, Z. \u0026amp; Scharf, M. B. The Effects of Milnacipran on Sleep Disturbance in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled, Two-Way Crossover Study. J Clin Sleep Med 12, 79\u0026ndash;86 (2016). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org:10.5664/jcsm.5400\u003c/span\u003e\u003cspan address=\"https://doi.org:10.5664/jcsm.5400\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKong, X. \u0026amp; Gozani, S. N. Effectiveness of fixed-site high-frequency transcutaneous electrical nerve stimulation in chronic pain: a large-scale, observational study. Journal of pain research, 703\u0026ndash;714 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAzadvari, M., Haghparast, A., Nakhostin-Ansari, A., Razavi, S. Z. E. \u0026amp; Hosseini, M. Musculoskeletal symptoms in patients with long COVID: A cross-sectional study on Iranian patients. Heliyon 8 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKedor, C. \u003cem\u003eet al.\u003c/em\u003e A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity. Nature communications 13, 5104 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStraube, S., Derry, S., Moore, R. A. \u0026amp; McQuay, H. J. Pregabalin in fibromyalgia: meta-analysis of efficacy and safety from company clinical trial reports. Rheumatology 49, 706\u0026ndash;715 (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCrofford, L. J. \u003cem\u003eet al.\u003c/em\u003e Fibromyalgia relapse evaluation and efficacy for durability of meaningful relief (FREEDOM): a 6-month, double-blind, placebo-controlled trial with pregabalin. Pain 136, 419\u0026ndash;431 (2008).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoore, A. R. \u003cem\u003eet al.\u003c/em\u003e Fibromyalgia: moderate and substantial pain intensity reduction predicts improvement in other outcomes and substantial quality of life gain. Pain 149, 360\u0026ndash;364 (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDailey, D. L. \u003cem\u003eet al.\u003c/em\u003e A randomized controlled trial of tens for movement-evoked pain in women with fibromyalgia. Arthritis \u0026amp; rheumatology (hoboken, NJ) 72, 824 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarrasco-Vega, E., Ruiz-Mu\u0026ntilde;oz, M., Cuesta-Vargas, A., Romero-Galisteo, R. P. \u0026amp; Gonz\u0026aacute;lez-S\u0026aacute;nchez, M. Individuals with fibromyalgia have a different gait pattern and a reduced walk functional capacity: a systematic review with meta-analysis. PeerJ 10, e12908 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHeredia-Jimenez, J., Latorre-Roman, P., Santos-Campos, M., Orantes-Gonzalez, E. \u0026amp; Soto-Hermoso, V. M. Spatio-temporal gait disorder and gait fatigue index in a six-minute walk test in women with fibromyalgia. Clinical Biomechanics 33, 1\u0026ndash;6 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMart\u0026iacute;n-Mart\u0026iacute;nez, J. P. \u003cem\u003eet al.\u003c/em\u003e Impact of cognitive tasks on biomechanical and kinematic parameters of gait in women with fibromyalgia: a cross-sectional study. Physiology \u0026amp; behavior 227, 113171 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRadunović, G. \u003cem\u003eet al.\u003c/em\u003e Assessment of gait in patients with fibromyalgia during motor and cognitive dual task walking: A cross-sectional study. Advances in Rheumatology 61, 53 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaleth, A. S., Slaven, J. E. \u0026amp; Ang, D. C. Determining the minimal clinically important difference for 6-minute walk distance in fibromyalgia. American journal of physical medicine \u0026amp; rehabilitation 95, 738\u0026ndash;745 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSalvat, I. \u003cem\u003eet al.\u003c/em\u003e Functional status, physical activity level, and exercise regularity in patients with fibromyalgia after Multidisciplinary treatment: retrospective analysis of a randomized controlled trial. Rheumatology international 37, 377\u0026ndash;387 (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTiidus, P. M., Pierrynowski, M. \u0026amp; Dawson, K. A. Influence of moderate training on gait and work capacity of fibromyalgia patients: a preliminary field study. Journal of Sports Science \u0026amp; Medicine 1, 122 (2002).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTran, S. T. \u003cem\u003eet al.\u003c/em\u003e A pilot study of biomechanical assessment before and after an integrative training program for adolescents with juvenile fibromyalgia. Pediatr Rheumatol Online J 14, 43 (2016). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org:10.1186/s12969-016-0103-7\u003c/span\u003e\u003cspan address=\"https://doi.org:10.1186/s12969-016-0103-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLin, S., Sun, Q., Wang, H. \u0026amp; Xie, G. Influence of transcutaneous electrical nerve stimulation on spasticity, balance, and walking speed in stroke patients: A systematic review and meta-analysis. Journal of rehabilitation medicine 50, 3\u0026ndash;7 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAppelman, B. \u003cem\u003eet al.\u003c/em\u003e Muscle abnormalities worsen after post-exertional malaise in long COVID. Nature communications 15, 1\u0026ndash;15 (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSingh, I. \u003cem\u003eet al.\u003c/em\u003e Persistent exertional intolerance after COVID-19: insights from invasive cardiopulmonary exercise testing. Chest 161, 54\u0026ndash;63 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoskell, N. S., Beard, S. M., Zhao, Y. \u0026amp; Le, T. K. A meta-analysis of pain response in the treatment of fibromyalgia. Pain practice 11, 516\u0026ndash;527 (2011).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArnold, L. M. \u003cem\u003eet al.\u003c/em\u003e A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis \u0026amp; Rheumatism: Official Journal of the American College of Rheumatology 50, 2974\u0026ndash;2984 (2004).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOrfei, M. D. \u003cem\u003eet al.\u003c/em\u003e A new look on long-COVID effects: the functional brain fog syndrome. Journal of Clinical Medicine 11, 5529 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDailey, D. L. \u003cem\u003eet al.\u003c/em\u003e Transcutaneous electrical nerve stimulation reduces pain, fatigue and hyperalgesia while restoring central inhibition in primary fibromyalgia. Pain\u0026reg; 154, 2554\u0026ndash;2562 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZulbaran-Rojas, A. \u003cem\u003eet al.\u003c/em\u003e Electrical stimulation to regain lower extremity muscle perfusion and endurance in patients with post‐acute sequelae of SARS CoV‐2: A randomized controlled trial. Physiological reports 11, e15636 (2023).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Table 4","content":"\u003cp\u003eTable 4 is not available with this version.\u003c/p\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":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4391458/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4391458/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThis study investigated the effect of Transcutaneous Electrical Nerve Stimulation (TENS) for fibromyalgia-like symptoms including chronic widespread pain, fatigue, and gait impairment in twenty-five individuals with Post-Acute Sequelae of Sars-Cov-2 (PASC). Participants were randomized to a high dose (intervention group, IG) or low dose (placebo group, PG) TENS device. Both groups received daily 3\u0026ndash;5 hours of TENS therapy for 4-weeks. The Brief Pain Inventory assessed functional interference from pain (BPI-I), and pain severity (BPI-S). The global fatigue index (GFI) assessed functional interference from fatigue. Wearable technology measured gait parameters during three 30-feet consecutive walking tasks. At 4-weeks, the IG exhibited a greater decrease in BPI-I compared to the PG (mean difference\u0026thinsp;=\u0026thinsp;2.61, p\u0026thinsp;=\u0026thinsp;0.008), and improved in gait parameters including stride time (4%-8%, test condition dependent), cadence (4%-10%, depending on condition), and double-support phase (12% in dual-task) when compared to baseline. A sub-group meeting the American College of Rheumatology Fibromyalgia diagnostic criteria undergoing high-dose TENS showed GFI improvement at 4-weeks from baseline (mean change\u0026thinsp;=\u0026thinsp;6.08, p\u0026thinsp;=\u0026thinsp;0.005). Daily TENS therapy showed potential in reducing functional interference from pain, fatigue, and gait alterations in PASC individuals. The study's limited power could affect the confirmation of certain observations. Extending the intervention period may improve treatment effectiveness.\u003c/p\u003e","manuscriptTitle":"Transcutaneous Electrical Nerve Stimulation for Fibromyalgia-like Syndrome in Patients with Post-Acute Sequelae of Sars-Cov-2: A Pilot Randomized Clinical Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-03 14:02:51","doi":"10.21203/rs.3.rs-4391458/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-22T07:09:07+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-14T08:06:49+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-07T00:12:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"167994538476952720426821393723829003405","date":"2024-08-04T06:39:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"326079766807792794510384135235116517820","date":"2024-08-03T14:05:31+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-08-03T11:24:47+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-08-03T11:15:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-05-18T08:25:26+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-17T05:14:05+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-05-08T21:18:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2cc820df-d37d-478a-b1c4-32508724f9f0","owner":[],"postedDate":"June 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":32438987,"name":"Health sciences/Medical research/Study design/Randomized controlled trials"},{"id":32438988,"name":"Health sciences/Neurology/Neurological disorders/Neuromuscular disease"}],"tags":[],"updatedAt":"2024-11-11T16:06:23+00:00","versionOfRecord":{"articleIdentity":"rs-4391458","link":"https://doi.org/10.1038/s41598-024-78651-5","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-11-08 15:57:12","publishedOnDateReadable":"November 8th, 2024"},"versionCreatedAt":"2024-06-03 14:02:51","video":"","vorDoi":"10.1038/s41598-024-78651-5","vorDoiUrl":"https://doi.org/10.1038/s41598-024-78651-5","workflowStages":[]},"version":"v1","identity":"rs-4391458","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4391458","identity":"rs-4391458","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}