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The study’s objective was to develop a clinical prediction rule that predicts a clinically significant analgesic effect on chronic knee osteoarthritis pain after transcranial direct current stimulation treatment. This is a secondary analysis from a double-blind randomized controlled trial. Data from 51 individuals with chronic knee osteoarthritis pain and an impaired descending pain inhibitory system were used. The intervention comprised a 15-session protocol of anodal primary motor cortex transcranial direct current stimulation. Treatment success was defined by the Western Ontario and McMaster Universities’ Osteoarthritis Index pain subscale. Accuracy statistics were calculated for each potential predictor and for the final model. The final logistic regression model was statistically significant (p < 0.01) and comprised five physical and psychosocial predictor variables that together yielded a positive likelihood ratio of 14.40 (95% CI: 3.66–56.69) and an 85% (95%CI: 60–96%) post-test probability of success. This is the first clinical prediction rule proposed for transcranial direct current stimulation in patients with chronic pain. The model underscores the importance of both physical and psychosocial factors as predictors of the analgesic response to transcranial direct current stimulation treatment. Validation of the proposed clinical prediction rule should be performed in other datasets.

Conditioned pain modulation (CPM) can discriminate between healthy and chronic pain patients. However, its relationship with neurophysiological pain mechanisms is poorly understood. Brain oscillations measured by electroencephalography (EEG) might help gain insight into this complex relationship. Objective To investigate the relationship between CPM response and self-reported pain intensity in non-specific chronic low back pain (NSCLBP) and explore respective EEG signatures associated to these mechanisms. Design Cross-sectional analysis. Participants Thirty NSCLBP patients participated. Methods Self-reported low back pain, questionnaires, mood scales, CPM (static and dynamic quantitative sensory tests), and resting surface EEG data were collected and analyzed. Linear regression models were used for statistical analysis. Results CPM was not significantly correlated with self-reported pain intensity scores. Relative power of EEG in the beta and high beta bands as recorded from the frontal, central, and parietal cortical areas were significantly associated with CPM. EEG relative power at delta and theta bands as recorded from the central area were significantly correlated with self-reported pain intensity scores while controlling for self-reported depression. Conclusions Faster EEG frequencies recorded from pain perception areas may provide a signature of a potential cortical compensation caused by chronic pain states. Slower EEG frequencies may have a critical role in abnormal pain processing.

Objectives To explore associations of intracortical excitability with clinical characteristics in a large sample of subjects with phantom limb pain (PLP). Methods Ancillary study using baseline and longitudinal data from a large multicenter randomized trial that investigated the effects of non-invasive brain stimulation combined with sensorimotor training on PLP. Multivariate regression modeling analyses were used to investigate the association of intracortical excitability, measured by percentages of intracortical inhibition (ICI) and facilitation (ICF) with clinical variables. Results Ninety-eight subjects were included. Phantom sensation of itching was positively associated with ICI changes and at baseline in the affected hemisphere (contralateral to PLP). However, in the non-affected hemisphere (ipsilateral to PLP), the phantom sensation of warmth and PLP intensity were negatively associated with ICI (both models). For the ICF, PLP intensity (baseline model only) and age (longitudinal model) were negatively associated, while time since amputation and amputation level (both for longitudinal model only) were positively associated in the affected hemisphere. Additionally, use of antidepressants led to lower ICF in the non-affected hemisphere for the baseline model while higher amputation level also led to less changes in the ICF. Conclusion Results revealed clear associations of clinical variables and cortical excitability in a large chronic pain sample. ICI and ICF changes appear not to be mainly explained by PLP intensity. Instead, other variables associated with duration of neuroplasticity changes (such as age and duration of amputation) and compensatory mechanisms (such as itching and phantom limb sensation) seem to be more important in explaining these variables.

Introduction: COVID-19 complications manifest with a disproportionately high rate of respiratory failure and Acute Respiratory Distress Syndrome (ARDS) overwhelming healthcare systems worldwide. In comparison with lung-protective mechanical ventilation, the mainstay treatment of ARDS ventilatory support, INTELLiVENT-ASV® (I-ASV) has shown higher efficiency with reduced weaning, ventilation times, and improved safety by eliminating human errors while providing automate and individually optimized respiratory support. Objective: This study aims to determine the efficacy and safety of I-ASV compared to conventional mechanical ventilation in the context of COVID-19 ARDS (CARDS). Methods: In this phase II trial protocol we describe a single-center, randomized, superiority, open-label, parallel two-arm (1:1 ratio) and active-controlled trial, comparing conventional mechanical ventilation with Volume Assist Mode (VAC) vs I-ASV, both following the lung-protective protocol in 463 adult patients diagnosed with CARDS requiring ventilation support. The primary outcome will be weaning time. Secondary outcomes will include total ventilation time, ICU time to discharge, extubation failure rate, and adverse events. We propose a competing risk analysis for improved accuracy by accounting for mortality in all time-to-event data analysis. Fisher’s exact test will be used to test the difference between trial arms in terms of binary secondary outcomes. Discussion: Given the limitations in conventional mechanical ventilation modes, automated closed-loop devices such as I-ASV could significantly benefit patients with CARDS while increasing resource efficiency thus extended care for the patients in need.

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.

Background The analgesic effects of transcranial Direct Current Stimulation (tDCS) combined with physical therapy remain unclear. Objective To systematically review available evidence comparing tDCS with any physical therapy modality (PTM) to PTM alone or PTM with sham tDCS on pain relief on common musculoskeletal (MSK) conditions, namely knee osteoarthritis (KOA), chronic low back pain (CLBP), myofascial pain syndrome (MPS) and fibromyalgia. Methods EMBASE and MEDLINE were searched from inception to April 2019 for randomized controlled trials. Reviewers independently assessed the studies quality and extracted data according to the PRISMA protocol. The GRADE approach was used to asses quality of evidence and a "Summary of Findings" table was created. The analyses used random-effects model. The primary outcome was pain reduction after treatment. Results Eight articles were included. Only one study had low risk of bias. Quality of evidence was considered low or very low. Significant reduction in pain scores were found for fibromyalgia and KOA (Standardized mean difference (SMD) = -1.94 [95% CI: -3.37 to -0.49; I 2=76.4%] and SMD = -2.35 [95% CI: -3.63 to -1.06; I 2=69.7%] respectively). Subgroup analysis considering the type of PTM despite MSK condition revealed significant reduction in pain scores for exercise, SMD = -1.20 [95% CI: -1.683 to -0.717; I 2=10.8%]. Conclusions Large heterogeneity and low quality of evidence and limited number of studies were found. Results suggest a potential analgesic effect of tDCS in combination with a PTM for fibromyalgia and KOA. Subgroup analysis suggests a stronger effect of tDCS when combined with an exercise based PTM.

Introduction Fibromyalgia is a complex pain condition that affects mostly women. Given the disease's lack of understanding, patients report poor adherence to medication and mistrust of medical services. This study aims to describe the recruitment characteristics and non-adherence associated factors of fibromyalgia patients to an RCT. Methods We performed a retrospective longitudinal analysis with data from our ongoing RCT. We investigated characteristics of subjects recruited, consented, and randomized. Adherence was studied using survival analysis techniques, and its associated factors were identified using Cox proportional hazards regression model. Results 524 subjects were contacted, 269 were eligible, 61 consented and 40 subjects were randomized. Thirty-eight percent were non-adherent to the protocol with a median of visits of five. The recruitment survey reported that 90% would likely participate in RCTs, 52% had previous participation, and 19% were aware of RCTs by their physicians. Some barriers were investigator-related (staff's friendliness and receiving the results of their trial participation) and center-related (privacy-confidentiality issues and the institution's reputation), without difference between adherent and non-adherent participants. We report significant factors for non-adherence as VAS anxiety score of 5 or more (5.3 HR, p = 0.01), Body Mass Index (BMI) (0.91 HR, p = 0.041) and Quality of Life (QoL) – Personal development subdomain (0.89 HR, p = 0.046). Conclusion Recruitment and adherence of fibromyalgia patients is a challenge; however, they seem eager to participate in RCTs. We recommend creating a comfortable, friendly and trusting environment to increase the recruitment rate. Higher anxiety, lower BMI and lower quality of life were associated with a higher attrition rate.

Introduction: Transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) are noninvasive neuromodulation techniques used as therapeutic and research tools for several neuropsychiatric conditions. Given the exponential scientific growth of this field, we aimed to systematically review the most cited clinical trials using TMS or tDCS. Areas covered: A de-novo keyword search strategy identified and characterized the 100 most-cited trials. Total citation count for the most cited trials was 13,204. Articles were published between 2008 and 2014 in 50 different journals with a median impact factor of 6.52 (IQR 3.37). Almost half of the top cited papers were investigating mechanisms of action in healthy subjects. Most studies were feasibility trials and only five were pivotal trials, including the ones used for recent FDA approval. Seven articles were interlinked with another article by at least 25 citations and eight authors had collaborated with at least one other author. Expert opinion: Although there has been a significant increase in interest for rTMS and tDCS, most of the cited clinical trials are still small feasibility studies, what reinforced the need for more robust clinical trials (larger samples sizes and effects sizes) to better define clinical effectiveness.