Transcranial direct current stimulation (tDCS) modulates spontaneous neuronal activity that can generate long-term neuroplastic changes. It has been used in numerous therapeutic trials showing significant clinical effects especially when combined with other behavioral therapies. One area of intensive tDCS research is chronic pain. Since the initial tDCS trials for chronic pain treatment using current parameters of stimulation, more than 60 clinical trials have been published testing its effects in different pain syndromes. However, as the field moves in the direction of clinical application, several aspects need to be taken into consideration regarding tDCS effectiveness and parameters of stimulation. In this article, we reviewed the evidence of tDCS effects for the treatment of chronic pain and critically analyzed the literature pertaining its safety and efficacy, and how to optimize tDCS clinical effects in a therapeutic setting. We discuss optimization of tDCS effects in 3 different domains: (i) parameters of stimulation, (ii) combination therapies, and (iii) subject selection. This article aims to provide insights for the development of future tDCS clinical trials.

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BackgroundDespite the multiple available pharmacological and behavioral therapies for the management of chronic phantom limb pain (PLP) in lower limb amputees, treatment for this condition is still a major challenge and the results are mixed. Given that PLP is associated with maladaptive brain plasticity, interventions that promote cortical reorganization such as non-invasive brain stimulation and behavioral methods including transcranial direct current stimulation (tDCS) and mirror therapy (MT), respectively, may prove to be beneficial to control pain in PLP. Due to its complementary effects, a combination of tDCS and MT may result in synergistic effects in PLP.ObjectiveThe objective of this study is to evaluate the efficacy of tDCS and MT as a rehabilitative tool for the management of PLP in unilateral lower limb amputees.MethodsA prospective, randomized, placebo-controlled, double-blind, factorial, superiority clinical trial will be carried out. Participants will be eligible if they meet the following inclusion criteria: lower limb unilateral traumatic amputees that present PLP for at least 3 months after the amputated limb has completely healed. Participants (N=132) will be randomly allocated to the following groups: (1) active tDCS and active MT, (2) sham tDCS and active MT, (3) active tDCS and sham MT, and (4) sham tDCS and sham MT. tDCS will be applied with the anodal electrode placed over the primary motor cortex (M1) contralateral to the amputation side and the cathode over the contralateral supraorbital area. Stimulation will be applied at the same time of the MT protocol with the parameters 2 mA for 20 minutes. Pain outcome assessments will be performed at baseline, before and after each intervention session, at the end of MT, and in 2 follow-up visits. In order to assess cortical reorganization and correlate with clinical outcomes, participants will undergo functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) before and after the intervention.ResultsThis clinical trial received institutional review board (IRB) approval in July of 2015 and enrollment started in December of 2015. To date 2 participants have been enrolled. The estimate enrollment rate is about 30 to 35 patients per year; thus we expect to complete enrollment in 4 years.ConclusionsThis factorial design will provide relevant data to evaluate whether tDCS combined with MT is more effective than each therapy alone, as well as with no intervention (sham/sham) in patients with chronic PLP after unilateral lower limb amputation. In addition, this randomized clinical trial will help to investigate the neurophysiological mechanisms underlying the disease, which could potentially provide relevant findings for further management of this chronic condition and also help to optimize the use of this novel intervention.Trial RegistrationClinicaltrials.gov NCT02487966; https://clinicaltrials.gov/ct2/show/NCT02487966 (Archived by WebCite at http://www.webcitation.org/6i3GrKMyf)

Phantom limb pain (PLP) is a frequent complication in amputees, which is often refractory to treatments. We aim to assess in a factorial trial the effects of transcranial direct current stimulation (tDCS) and mirror therapy (MT) in patients with traumatic lower limb amputation; and whether the motor cortex plasticity changes drive these results. In this large randomized, blinded, 2-site, sham-controlled, 2 × 2 factorial trial, 112 participants with traumatic lower limb amputation were randomized into treatment groups. The interventions were active or covered MT for 4 weeks (20 sessions, 15 minutes each) combined with 2 weeks of either active or sham tDCS (10 sessions, 20 minutes each) applied to the contralateral primary motor cortex. The primary outcome was PLP changes on the visual analogue scale at the end of interventions (4 weeks). Motor cortex excitability and cortical mapping were assessed by transcranial magnetic stimulation (TMS). We found no interaction between tDCS and MT groups ( F = 1.90, P = .13). In the adjusted models, there was a main effect of active tDCS compared to sham tDCS (beta coefficient = −0.99, P = .04) on phantom pain. The overall effect size was 1.19 (95% confidence interval: 0.90, 1.47). No changes in depression and anxiety were found. TDCS intervention was associated with increased intracortical inhibition (coefficient = 0.96, P = .02) and facilitation (coefficient = 2.03, P = .03) as well as a posterolateral shift of the center of gravity in the affected hemisphere. MT induced no motor cortex plasticity changes assessed by TMS. These findings indicate that transcranial motor cortex stimulation might be an affordable and beneficial PLP treatment modality.

Purpose: The purpose of this systematic review is to evaluate motor cortex reorganization in amputees as indexed by transcranial magnetic stimulation (TMS) cortical mapping and its relationship with phantom limb pain (PLP).Methods: Pubmed database were systematically searched. Three independent researchers screened the relevant articles, and the data of motor output maps, including the number of effective stimulation sites, center of gravity (CoG) shift, and their clinical correlations were extracted. We calculated a pooled CoG shift for motor cortex TMS mapping.Results: The search yielded 468 articles, 11 were included. Three studies performed correlation between the cortical changes and PLP intensity, and only one study compared cortical mapping changes between amputees with pain and without pain. Results showed (i) enlarged excitable area and a shift of CoG of neighboring areas toward the deafferented limb area; (ii) no correlation between motor cortex reorganization and level of pain and (iii) greater cortical reorganization in patients with PLP compared to amputation without pain.Conclusion: Our review supports the evidence for cortical reorganization in the affected hemisphere following an amputation. The motor cortex reorganization could be a potential clinical target for prevention and treatment response of PLP.

Selective serotonin reuptake inhibitors (SSRIs) are currently widely used in the field of the neuromodulation not only because of their anti-depressive effects but also due to their ability to promote plasticity and enhance motor recovery in patients with stroke. Recent studies showed that fluoxetine promotes motor recovery after stroke through its effects on the serotonergic system enhancing motor outputs and facilitating long term potentiation, key factors in motor neural plasticity. However, little is known in regards of the exact mechanisms underlying these effects and several aspects of it remain poorly understood. In this manuscript, we discuss evidence supporting the hypothesis that SSRIs, and in particular fluoxetine, modulate inhibitory pathways, and that this modulation enhances reorganization and reestablishment of excitatory-inhibitory control; these effects play a key role in learning induced plasticity in neural circuits involved in the promotion of motor recovery after stroke. This discussion aims to provide important insights and rationale for the development of novel strategies for stroke motor rehabilitation.

Introduction: The exact mechanisms underlying the development and maintenance of phantom limb pain (PLP) are still unclear. This study aimed to identify the factors affecting pain intensity in patients with chronic, lower limb, traumatic PLP. Methods: This is a cross-sectional analysis of patients with PLP. We assessed amputation-related and pain-related clinical and demographic variables. We used univariate and multivariate models to evaluate the associated factors modulating PLP and residual limb pain (RLP) intensity. Results: We included 71 unilateral traumatic lower limb amputees. Results showed that (1) amputation-related perceptions were experienced by a large majority of the patients with chronic PLP (sensations: 90.1%, n = 64; residual pain: 81.7%, n = 58); (2) PLP intensity has 2 significant protective factors (phantom limb movement and having effective treatment for PLP previously) and 2 significant risk factors (phantom limb sensation intensity and age); and (3) on the other hand, for RLP, risk factors are different: presence of pain before amputation and level of amputation (in addition to the same protective factors). Conclusion: These results suggest different neurobiological mechanisms to explain PLP and RLP intensity. While PLP risk factors seem to be related to maladaptive plasticity, since phantom sensation and older age are associated with more pain, RLP risk factors seem to have components leading to neuropathic pain, such as the amount of neural lesion and previous history of chronic pain. Interestingly, the phantom movement appears to be protective for both phenomena. &

There are multiple available treatments to enhance stroke rehabilitation, although few interventions have confirmed significant clinical improvements on motor function in pivotal Randomized Clinical Trials. Development of large Randomized Clinical Trials is limited by several barriers and low enrollment rate is considered an important factor. Consequently, most of the evidence comes from small sample size studies, often leading to limited conclusions. According to the National Institute of Health (NIH), about 80% of clinical trials in the United States do not achieve their timelines, increasing research costs and postponing regulatory approval of new therapies. Given that the success of a Randomized Clinical Trial is dependent on enrolling an adequate number of subjects, effective strategies to enhance recruitment rates are highly desirable. In addition, given the resources and time limitations, it is important to understand which strategies are most cost-effective. In this manuscript, we summarize and discuss nine recruitment strategies used in an NIH R21 sponsored clinical trial, including medical records review and online advertising, among others. In addition, we developed an index to compare the time spent benefit of each approach and guide the allocation of the recruitment efforts. For this trial, online advertising and referral from health care professionals other than physicians were the strategies with greater time-benefit, leading to the largest number of stroke subjects enrolled.