A Mechanistic Analysis of the Neural Modulation of the Inflammatory System Through Vagus Nerve Stimulation: A Systematic Review and Meta-analysis.

OBJECTIVE: We aimed to conduct a systematic review and meta-analysis assessing the antiinflammatory effects of various VNS methods while exploring multiple antiinflammatory pathways. MATERIALS AND METHODS: We included clinical trials that used electrical stimulation of the vagus nerve and assessed inflammatory markers up to October 2022. We excluded studies lacking control groups, those with combined interventions, or abstracts without full text. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and the Cochrane Handbook for Systematic Reviews. For each inflammatory marker, a random-effects meta-analysis using the inverse variance method was performed. Methods used include transcutaneous auricular VNS (taVNS), transcutaneous cervical VNS (tcVNS), invasive cervical VNS (iVNS), and electroacupuncture VNS (eaVNS). Main reported outcomes included tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1ß, C-reactive protein (CRP), and IL-10. Risk of bias was evaluated using the Cochrane Collaboration Tool (RoB 2.0). RESULTS: This review included 15 studies, involving 597 patients. No statistically significant general VNS effect was observed on TNF-α, IL-6, and IL-1ß. However, CRP, IL-10, and interferon (IFN)-γ were significantly modulated by VNS across all methods. Subgroup analysis revealed specific stimulation techniques producing significant results, such as taVNS effects in IL-1ß and IL-10, and iVNS in IL-6, whereas tcVNS and eaVNS did not convey significant pooled results individually. Cumulative exposure to VNS, higher risk of bias, study design, and pulse width were identified as effect size predictors in our meta-regression models. CONCLUSIONS: Pooling all VNS techniques indicated the ability of VNS to modulate inflammatory markers such as CRP, IL-10, and IFN-γ. Individually, methods such as taVNS were effective in modulating IL-1ß and IL-10, whereas iVNS modulated IL-6. However, different VNS techniques should be separately analyzed in larger, homogeneous, and powerful studies to achieve a clearer and more consistent understanding of the effect of each VNS method on the inflammatory system.

Factors associated with pain pressure threshold in both local and remote sites in knee osteoarthritis.

BACKGROUND: Knee osteoarthritis (KOA) is a prevalent condition, and its most frequent symptom is pain that often leads to disability. Pain sensitization is a core feature of KOA, and it can be measured through quantitative sensory testing protocols such as pain pressure threshold (PPT). However, there is a lack of understanding about the factors that may influence changes in PPTs in the KOA population. OBJECTIVE: To explore the clinical and functional factors associated with PPTs in a sample of people with chronic KOA pain and to compare models of local (knees) and remote (thenar regions) sites. DESIGN: Cross-sectional analysis of a prospective cohort. SETTING: Primary care in public institution. PARTICIPANTS: 113 adults with KOA. INTERVENTION: N/A. MAIN OUTCOME MEASURES: Multivariable regression analyses evaluating demographic, clinical, and functional variables that could be associated with local and remote PPTs (main outcomes) were performed. RESULTS: Both thenar region (adjusted-R2 : 0.29) and knee (adjusted-R2 : 0.45) models had the same significant negative association with being a female, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain levels (thenar: ß: -0.15, p = .002; knee: ß: -0.2, p < .001), and the 10-Meter Walking Test (thenar: ß: -0.05, p = .038; knee: ß: -0.08, p = .004). A small significant positive association with depressive symptoms was identified in both models, which acted as a confounder for WOMAC pain and was likely affected by unmeasured confounders. CONCLUSIONS: PPTs in KOA pain are associated with functional outcomes such as the 10-Meter Walking Test and activity-related pain intensity; thus more disability is associated with smaller pain thresholds. Similarity between models may suggest central sensitization.

Functional and Neural Correlates Associated with Conditioned Pain Modulation in Patients with Chronic Knee Osteoarthritis Pain: A Cross-Sectional Study.

Background: In this study, we aimed to assess the factors that predict a dysfunctional conditioned pain modulation (CPM) in chronic knee OA. Methods: This is a cross-sectional analysis of patients with chronic knee OA from a prospective cohort study in Brazil (n = 85). We performed linear and logistic multivariate regression models using the purposeful selection approach to test the relationship between the CPM in both knees (average) as a dependent variable and demographics, clinical, and neurophysiological as independent variables. Results: A significant negative association between WOMAC pain scores and CPM (ß: -0.13) was found. This association was modified by the subjects' race, being stronger in the non-white subjects. In our logistic regression models, pain intensity indexed with the WOMAC pain scale remained a significant association with dichotomized CPM. Furthermore, a significant CPM association with balance, indexed with the Berg Balance score, was evidenced (ß: 0.04). Neurophysiological variables showed a significant negative relationship with CPM, such as the relative power of delta oscillations in the frontal area (ß: -3.11) and central area (ß: -3.23). There was no significant relationship between CPM and the following domains: cognitive, emotion, sleep, opioid receptor polymorphisms, and intrinsic variables of OA disease. There was no association of CPM with TMS-indexed inhibitory markers. Conclusions: These results may indicate that less function of the pain descending inhibitory system in patients with OA is correlated with higher activity-related pain (WOMAC), less balance, and cortical plasticity especially with increased low-frequency (delta) brain oscillations. These associations seem modified by race.

Understanding the Neuroplastic Effects of Auricular Vagus Nerve Stimulation in Animal Models of Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND: Transauricular vagus nerve stimulation (taVNS) is being studied as a feasible intervention for stroke, but the mechanisms by which this non-invasive technique acts in the cortex are still broadly unknown. OBJECTIVES: This study aimed to systematically review the current pre-clinical evidence in the auricular vagus nerve stimulation (aVNS) neuroplastic effects in stroke. METHODS: We searched, in December of 2022, in Medline, Cochrane, Embase, and Lilacs databases. The authors executed the extraction of the data on Excel. The risk of bias was evaluated by adapted Cochrane Collaboration's tool for animal studies (SYRCLES's RoB tool). RESULTS: A total of 8 studies published between 2015 and 2022 were included in this review, including 391 animal models. In general, aVNS demonstrated a reduction in neurological deficits (SMD = -1.97, 95% CI -2.57 to -1.36, I2 = 44%), in time to perform the adhesive removal test (SMD = -2.26, 95% CI -4.45 to -0.08, I2 = 81%), and infarct size (SMD = -1.51, 95% CI -2.42 to -0.60, I2 = 58%). Regarding the neuroplasticity markers, aVNS showed to increase microcapillary density, CD31 proliferation, and BDNF protein levels and RNA expression. CONCLUSIONS: The studies analyzed show a trend of results that demonstrate a significant effect of the auricular vagal nerve stimulation in stroke animal models. Although the aggregated results show high heterogeneity and high risk of bias. More studies are needed to create solid conclusions.

The Analgesic Effect of Transcranial Direct Current Stimulation in Fibromyalgia: A Systematic Review, Meta-Analysis, and Meta-Regression of Potential Influencers of Clinical Effect.

BACKGROUND: There is tentative evidence to support the analgesic effect of transcranial direct current stimulation (tDCS) in fibromyalgia (FM), with large variability in the effect size (ES) encountered in different clinical trials. Understanding the source of the variability and exploring how it relates to the clinical results could characterize effective neuromodulation protocols and ultimately guide care in FM pain. The primary objective of this study was to determine the effect of tDCS in FM pain as compared with sham tDCS. The secondary objective was to explore the relationship of methodology, population, and intervention factors and the analgesic effect of tDCS in FM. MATERIALS AND METHODS: For the primary objective, a systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Randomized clinical trials (RCTs) investigating tDCS as an intervention for FM pain were searched in MEDLINE, Embase, and the Web Of Science. Studies were excluded if they used cross-over designs or if they did not use tDCS as an intervention for pain or did not measure clinical pain. Analysis for the main outcome was performed using a random-effects model. Risk of bias and evidence certainty were assessed for all studies using Cochrane Risk of Bias and Grading of Recommendations Assessment, Development, and Evaluation tools. For the secondary objective, a meta-regression was conducted to explore methodology, population, and intervention factors potentially related to the ES. RESULTS: Sixteen RCTs were included. Six studies presented a high risk of bias. Significant reduction in pain scores were found for FM (standardized mean difference = 1.22, 95% CI = 0.80-1.65, p < 0.001). Subgroup analysis considering tDCS as a neural target revealed no differences between common neural sites. Meta-regression revealed that the duration of the tDCS protocol in weeks was the only factor associated with the ES, in which protocols that lasted four weeks or longer reported larger ES than shorter protocols. CONCLUSIONS: Results suggest an analgesic effect of tDCS in FM. tDCS protocols that last four weeks or more may be associated with larger ESs. Definite conclusions are inadequate given the large heterogeneity and limited quality of evidence of the included studies.

Additive effect of transcranial direct current stimulation (tDCS) in combination with multicomponent training on elderly physical function capacity: a randomized, triple blind, controlled trial.

PURPOSE: To evaluate the additive effect of Transcranial Direct Current Stimulation (tDCS) associated with multi-component training (MT) on the functional capacity (FC) of older adults and to assess whether these effects remain after the end of training. The secondary objectives were to evaluate the locomotion capacity, balance, functional independence, and quality of life and correlate them with functional capacity. METHODOLOGY: Twenty-eight older adults were randomized into two groups: experimental (MT associated with active tDCS - a-tDCS) and control (MT associated with sham tDCS - s-tDCS). The FC was measured by the Glittre-ADL test, locomotion capacity by the 6-minute walk test, balance by the BESTest, functional independence by the FIM, and quality of life by the WHQOL. The assessments were performed pre-, post-intervention, and 30-day follow-up. RESULTS: There was a significant decrease in the time to the Glittre-ADL test when comparing the a-tDCS and s-tDCS groups after the interventions (139.77 ± 21.62, 205.10 ± 43.02, p < .001) and at the 30-day follow-up (142.74 ± 17.12, 219.55 ± 54.05, p < .001), respectively. There was a moderate correlation between FC and locomotion capacity and balance. CONCLUSIONS: The addition of tDCS potentiated the results of MT to impact FC, maintaining the positive results longer. Locomotion and balance influenced the improvement of functional capacity.

Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis.

Transcutaneous auricular vagus nerve stimulation (taVNS) has been investigated as a novel neuromodulation tool. Although taVNS is generally considered safe with only mild and transient adverse effects (AEs), those specifically caused by taVNS have not yet been investigated. This systematic review and meta-analysis on taVNS aimed to (1) systematically analyze study characteristics and AE assessment, (2) characterize and analyze possible AEs and their incidence, (3) search for predictable risk factors, (4) analyze the severity of AE, and (5) suggest an evidence-based taVNS adverse events questionnaire for safety monitoring. The articles searched were published through April 7, 2022, in Medline, Embase, Web of Science, Cochrane, and Lilacs databases. In general, we evaluated 177 studies that assessed 6322 subjects. From these, 55.37% of studies did not mention the presence or absence of any AEs; only 24.86% of the studies described that at least one adverse event occurred. In the 35 studies reporting the number of subjects with at least one adverse event, a meta-analytic approach to calculate the risk differences of developing an adverse event between active taVNS and controls was used. The meta-analytic overall adverse events incidence rate was calculated for the total number of adverse events reported on a 100,000 person-minutes-days scale. There were no differences in risk of developing an adverse event between active taVNS and controls. The incidence of AE, in general, was 12.84/100,000 person-minutes-days of stimulation, and the most frequently reported were ear pain, headache, and tingling. Almost half of the studies did not report the presence or absence of any AEs. We attribute this to the absence of AE in those studies. There was no causal relationship between taVNS and severe adverse events. This is the first systematic review and meta-analysis of transcutaneous auricular stimulation safety. Overall, taVNS is a safe and feasible option for clinical intervention.

Electroencephalographic Patterns in taVNS: A Systematic Review.

Transcutaneous auricular vagus nerve stimulation (taVNS) is a newer delivery system using a non-invasive stimulation device placed at the ear. taVNS research is focused on clinical trials showing potential therapeutic benefits, however the neurophysiological effects of this stimulation on brain activity are still unclear. We propose a systematic review that aims to describe the effects of taVNS on EEG measures and identify taVNS parameters that can potentially lead to consistent EEG-mediated biomarkers for this therapy. A systematic literature review was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) and the Cochrane handbook for systematic reviews. Clinical trials examining EEG parameters were considered, including absolute and relative power, coherence, degree of symmetry, evoked potentials, and peak frequency of all bands. According to our criteria, 18 studies (from 122 articles) were included. Our findings show a general trend towards increased EEG power spectrum activity in lower frequencies, and changes on early components of the ERP related to inhibitory tasks. This review suggests that quantitative electroencephalography can be used to assess the effects of taVNS on brain activity, however more studies are needed to systematically establish the specific effects and metrics that would reflect the non-invasive stimulation through the auricular branch of the vagus nerve.

Measuring Contralateral Silent Period Induced by Single-Pulse Transcranial Magnetic Stimulation to Investigate M1 Corticospinal Inhibition.

Contralateral silent period (cSP) is a period of suppression in the background electrical muscle activity captured by electromyography (EMG) after a motor evoked potential (MEP). To obtain this, an MEP is elicited by a suprathreshold transcranial magnetic stimulation (TMS) pulse delivered to the primary motor cortex (M1) of the target muscle selected, while the participant provides a standardized voluntary target muscle contraction. The cSP is a result of inhibitory mechanisms that occur after the MEP; it provides a broad temporal assessment of spinal inhibition in its initial ~50 ms, and cortical inhibition after. Researchers have tried to better understand the neurobiological mechanism behind the cSP to validate it as a potential diagnostic, surrogate, and predictive biomarker for different neuropsychiatric diseases. Therefore, this article describes a method to measure M1 cSP of lower and upper limbs, including a selection of target muscle, electrode placement, coil positioning, method of measuring voluntary contraction stimulation, intensity setup, and data analysis to obtain a representative result. It has the educational objective of giving a visual guideline in performing a feasible, reliable, and reproducible cSP protocol for lower and upper limbs and discussing practical challenges of this technique.

Temporal Summation in Fibromyalgia Patients: Comparing Phasic and Tonic Paradigms.

Introduction: Fibromyalgia (FM) is associated with dysfunctional pain modulation mechanisms, including central sensitization. Experimental pain measurements, such as temporal summation (TS), could serve as markers of central sensitization and have been previously studied in these patients, with conflicting results. Our objective in this study was to explore the relationships between two different protocols of TS (phasic and tonic) and test the associations between these measures and other clinical variables. Materials and Methods: In this cross-sectional analysis of a randomized clinical trial, patients were instructed to determine their pain-60 test temperature, then received one train of 15 repetitive heat stimuli and rated their pain after the 1st and 15th stimuli: TSPS-phasic was calculated as the difference between those. We also administered a tonic heat test stimulus at the same temperature continuously for 30 s and asked them to rate their pain levels after 10 s and 30 s, calculating TSPS-tonic as the difference between them. We also collected baseline demographic data and behavioral questionnaires assessing pain, depression, fatigue, anxiety, sleepiness, and quality of life. We performed univariable analyses of the relationship between TSPS-phasic and TSPS-tonic, and between each of those measures and the demographic and clinical variables collected at baseline. We then built multivariable linear regression models to find predictors for TSPS-phasic and TSPS-tonic, while including potential confounders and avoiding collinearity. Results: Fifty-two FM patients were analyzed. 28.85% developed summation during the TSPS-phasic protocol while 21.15% developed summation during the TSPS-tonic protocol. There were no variables associated TSPS phasic or tonic in the univariable analyses and both measures were not correlated. On the multivariate model for the TSPS-phasic protocol, we found a weak association with pain variables. BPI-pain subscale was associated with more temporal summation in the phasic protocol (ß = 0.38, p = 0.029), while VAS for pain was associated with less summation in the TSPS-tonic protocol (ß = -0.5, p = 0.009). Conclusion: Our results suggest that, using heat stimuli with pain-60 temperatures, a TSPS-phasic protocol and a TSPS-tonic protocol are not correlated and could index different neural responses in FM subjects. Further studies with larger sample sizes would be needed to elucidate whether such responses could help differentiating subjects with FM into specific phenotypes.

EEG theta and beta bands as brain oscillations for different knee osteoarthritis phenotypes according to disease severity.

This study aims to investigate the multivariate relationship between different sociodemographic, clinical, and neurophysiological variables with resting-state, high-definition, EEG spectral power in subjects with chronic knee osteoarthritis (OA) pain. This was a cross-sectional study. Sociodemographic and clinical data were collected from 66 knee OA subjects. To identify associated factors, we performed independent univariate and multivariate regression models by frequency bands (delta, theta, alpha, beta, low-beta, and high-beta) and by pre-defined regions (frontal, central, and parietal). From adjusted multivariate models, we found that: (1) increased frontocentral high-beta power and reduced central theta activity are positively correlated with pain intensity (ß = 0.012, 95% CI 0.004-0.020; and ß = - 0.008; 95% CI 0.014 to - 0.003; respectively); (2) delta and alpha oscillations have a direct relationship with higher cortical inhibition; (3) diffuse increased power at low frequencies (delta and theta) are associated with poor cognition, aging, and depressive symptoms; and (4) higher alpha and beta power over sensorimotor areas seem to be a maladaptive compensatory mechanism to poor motor function and severe joint degeneration. Subjects with higher pain intensity and higher OA severity (likely subjects with maladaptive compensatory mechanisms to severe OA) have higher frontocentral beta power and lower theta activity. On the other hand, subjects with less OA severity and less pain have higher theta oscillations power. These associations showed the potential role of brain oscillations as a marker of pain intensity and clinical phenotypes in chronic knee OA patients. Besides, they suggest a potential compensatory mechanism of these two brain oscillators according to OA severity.

Increased motor cortex inhibition as a marker of compensation to chronic pain in knee osteoarthritis.

This study aims to investigate the associative and multivariate relationship between different sociodemographic and clinical variables with cortical excitability as indexed by transcranial magnetic stimulation (TMS) markers in subjects with chronic pain caused by knee osteoarthritis (OA). This was a cross-sectional study. Sociodemographic and clinical data were extracted from 107 knee OA subjects. To identify associated factors, we performed independent univariate and multivariate regression models per TMS markers: motor threshold (MT), motor evoked potential (MEP), short intracortical inhibition (SICI), intracortical facilitation (ICF), and cortical silent period (CSP). In our multivariate models, the two markers of intracortical inhibition, SICI and CSP, had a similar signature. SICI was associated with age (ß: 0.01), WOMAC pain (ß: 0.023), OA severity (as indexed by Kellgren-Lawrence Classification) (ß: - 0.07), and anxiety (ß: - 0.015). Similarly, CSP was associated with age (ß: - 0.929), OA severity (ß: 6.755), and cognition (as indexed by the Montreal Cognitive Assessment) (ß: - 2.106). ICF and MT showed distinct signatures from SICI and CSP. ICF was associated with pain measured through the Visual Analogue Scale (ß: - 0.094) and WOMAC (ß: 0.062), and anxiety (ß: - 0.039). Likewise, MT was associated with WOMAC (ß: 1.029) and VAS (ß: - 2.003) pain scales, anxiety (ß: - 0.813), and age (ß: - 0.306). These associations showed the fundamental role of intracortical inhibition as a marker of adaptation to chronic pain. Subjects with higher intracortical inhibition (likely subjects with more compensation) are younger, have greater cartilage degeneration (as seen by radiographic severity), and have less pain in WOMAC scale. While it does seem that ICF and MT may indicate a more acute marker of adaptation, such as that higher ICF and MT in the motor cortex is associated with lesser pain and anxiety.

Deficit of Inhibition as a Marker of Neuroplasticity (DEFINE Study) in Rehabilitation: A Longitudinal Cohort Study Protocol.

Background: Brain plasticity is an intrinsic property of the nervous system, which is modified during its lifetime. This is one mechanism of recuperation after injuries with an important role in rehabilitation. Evidence suggests that injuries in the nervous system disturb the stability between inhibition and excitability essential for the recuperation process of neuroplasticity. However, the mechanisms involved in this balance are not completely understood and, besides the advancement in the field, the knowledge has had a low impact on the rehabilitation practice. Therefore, the understanding of the relationship between biomarkers and functional disability may help to optimize and individualize treatments and build consistent studies in the future. Methods: This cohort study, the deficit of inhibition as a marker of neuroplasticity study, will follow four groups (stroke, spinal cord injury, limb amputation, and osteoarthritis) to understand the neuroplasticity mechanisms involved in motor rehabilitation. We will recruit 500 subjects (including 100 age- and sex-matched controls). A battery of neurophysiological assessments, transcranial magnetic stimulation, electroencephalography, functional near-infrared spectroscopy, and magnetic resonance imaging, is going to be used to assess plasticity on the motor cortex before and after rehabilitation. One of the main hypotheses in this cohort is that the level of intracortical inhibition is related to functional deficits. We expect to develop a better understanding of the neuroplasticity mechanisms involved in the rehabilitation, and we expect to build neurophysiological "transdiagnostic" biomarkers, especially the markers of inhibition, which will have great relevance in the scientific and therapeutic improvement in rehabilitation. The relationship between neurophysiological and clinical outcomes will be analyzed using linear and logistic regression models. Discussion: By evaluating the reliability of electroencephalography, functional near-infrared spectroscopy, transcranial magnetic stimulation, and magnetic resonance imaging measures as possible biomarkers for neurologic rehabilitation in different neurologic disorders, this study will aid in the understanding of brain plasticity mechanisms in rehabilitation, allowing more effective approaches and screening methods to take place.

Home-based transcranial direct current stimulation (tDCS) and motor imagery for phantom limb pain using statistical learning to predict treatment response: an open-label study protocol.

Background: Phantom limb pain (PLP) management has been a challenge due to its response heterogeneity and lack of treatment access. This study will evaluate the feasibility of a remotely home-based M1 anodal tDCS combined with motor imagery in phantom limb patients and assess the preliminary efficacy, safety, and predictors of response of this therapy. Methods: This is a pilot, single-arm, open-label trial in which we will recruit 10 subjects with phantom limb pain. The study will include 20 sessions. All participants will receive active anodal M1 tDCS combined with phantom limb motor imagery training. Our primary outcome will be the acceptability and feasibility of this combined intervention. Moreover, we will assess preliminary clinical (pain intensity) and physiological (motor inhibition tasks and heart rate variability) changes after treatment. Finally, we will implement a supervised statistical learning (SL) model to identify predictors of treatment response (to tDCS and phantom limb motor imagery) in PLP patients. We will also use data from our previous clinical trial (total observations=224 [n=112 x timepoints = 2)) for our statistical learning algorithms. The new prospective data from this open-label study will be used as an independent test dataset. Discussion: This protocol proposes to assess the feasibility of a novel, neuromodulatory combined intervention that will allow the design of larger remote clinical trials, thus increasing access to safe and effective treatments for PLP patients. Moreover, this study will allow us to identify possible predictors of pain response and PLP clinical endotypes.

To Combine or Not to Combine Physical Therapy With tDCS for Stroke With Shoulder Pain? Analysis From a Combination Randomized Clinical Trial for Rehabilitation of Painful Shoulder in Stroke.

Purpose: Transcranial Direct Current Stimulation (tDCS) is an intervention that seems to be an ideal tool to enhance the effects of rehabilitation therapies given it facilitates generation of plasticity in the stimulated brain area. In stroke this strategy has been highly utilized; however, the results have been mixed. In this trial we have evaluated the analgesic and functional effects of Transcranial Direct Current Stimulation (tDCS) combined with physiotherapy in stroke survivors with shoulder pain. Methods: Twenty-six stroke surviving adults with shoulder pain received 10 sessions of passive mobilization and performed upper limb exercises using a cycle ergometer, combined with active or sham tDCS. The intensity of pain in the hemiplegic shoulder was measured using the Visual Analog Scale (VAS); secondary outcomes were the level of motor impairment, handgrip strength, range of motion, motor function of the upper limbs, and quality of life (QOL) assessed before and after 10 sessions and 1 month after the end of the treatment. Results: A clinically important pain reduction (3 points) was found in both groups and was maintained at follow-up; there was no significant difference between groups (p = 0.3). Similarly, the shoulder range of motion improved, motor function and quality of life improved showed no significant differences between groups. One result that needs to be underscored is that both groups had a significant effect size toward improvement in all of these outcomes. Conclusions: We discuss in this study that tDCS is not a useful combination strategy when the physical therapy has a large effect by itself and we also review other negative trials of combined therapy under this framework of ceiling effect of the main physical therapy. Trial registry: Trial registration: Brazilian Registry of Clinical Trials, RBR-8F5MNY (http://www.ensaiosclinicos.gov.br/rg/RBR-8f5mny/). Registered on June 2, 2017. Beginning of the recruitment of the volunteers: august, 2017.