Motor Cortex Reorganization in Limb Amputation: A Systematic Review of TMS Motor Mapping Studies.

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.

Recruitment challenges in stroke neurorecovery clinical trials.

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.

Combining Fluoxetine and rTMS in Poststroke Motor Recovery: A Placebo-Controlled Double-Blind Randomized Phase 2 Clinical Trial.

Background. Although recent evidence has shown a new role of fluoxetine in motor rehabilitation, results are mixed. We conducted a randomized clinical trial to evaluate whether combining repetitive transcranial magnetic stimulation (rTMS) with fluoxetine increases upper limb motor function in stroke. Methods. Twenty-seven hemiparetic patients within 2 years of ischemic stroke were randomized into 3 groups: Combined (active rTMS + fluoxetine), Fluoxetine (sham rTMS + fluoxetine), or Placebo (sham rTMS + placebo fluoxetine). Participants received 18 sessions of 1-Hz rTMS in the unaffected primary motor cortex and 90 days of fluoxetine (20 mg/d). Motor function was assessed using Jebsen-Taylor Hand Function (JTHF) and Fugl-Meyer Assessment (FMA) scales. Corticospinal excitability was assessed with TMS. Results. After adjusting for time since stroke, there was significantly greater improvement in JTHF in the combined rTMS + fluoxetine group (mean improvement: -214.33 seconds) than in the placebo (-177.98 seconds, P = 0.005) and fluoxetine (-50.16 seconds, P < 0.001) groups. The fluoxetine group had less improvement than placebo on both scales (respectively, JTHF: -50.16 vs -117.98 seconds, P = 0.038; and FMA: 6.72 vs 15.55 points, P = 0.039), suggesting that fluoxetine possibly had detrimental effects. The unaffected hemisphere showed decreased intracortical inhibition in the combined and fluoxetine groups, and increased intracortical facilitation in the fluoxetine group. This facilitation was negatively correlated with motor function improvement (FMA, r2 = -0.398, P = 0.0395). Conclusion. Combined fluoxetine and rTMS treatment leads to better motor function in stroke than fluoxetine alone and placebo. Moreover, fluoxetine leads to smaller improvements than placebo, and fluoxetine's effects on intracortical facilitation suggest a potential diffuse mechanism that may hinder beneficial plasticity on motor recovery.

Transcranial direct current stimulation in individuals with spinal cord injury: Assessment of autonomic nervous system activity.

BACKGROUND: We hypothesized in this study that transcranial direct current stimulation (tDCS) of primary motor cortex could exert top-down modulation over subcortical systems associated with autonomic control and thus be useful to revert some of the dysfunctional changes found in the autonomic nervous system (ANS) of subjects with spinal cord injuries (SCI). OBJECTIVE: To explore the acute effect of tDCS on ANS indexed by Heart Rate Variability (HRV) in individuals with SCI and analyze whether this effect depends on the gender, degree, level and time of injury. METHODS: In this randomized, placebo-controlled, crossover, double-blinded study, 18 adults with SCI (32.9±7.9 years old) were included; the intervention consisted of a single 12-minute session of active tDCS (anodal, 2 mA) and a control session of sham tDCS applied over Cz (bihemispheric motor cortex). HRV was calculated using spectral analysis. Low-frequency (LF), high-frequency (HF), and LF/HF ratio variables were evaluated before, during, and post tDCS. RESULTS: A two-way repeated measures ANOVA showed that after active (anodal) stimulation, LF/HF ratio was significantly increased (P = 0.013). There was a trend for an interaction between time and stimulation for both LF and HF (P = 0.052). Paired exploratory t-tests reported effects on the difference of time [post-pre] between stimulation conditions for LF (P = 0.052), HF (P = 0.052) and LF/HF (P = 0.003). CONCLUSION: Anodal tDCS of the motor cortex modulated ANS activity in individuals with SCI independent of gender, type and time of lesion. These changes were in the direction of normalization of ANS parameters, thus confirming our initial hypothesis that an enhancement of cortical excitability by tDCS could at least partially restore some of the dysfunctional activity in the ANS system of subjects with SCI.

Optimizing Rehabilitation for Phantom Limb Pain Using Mirror Therapy and Transcranial Direct Current Stimulation: A Randomized, Double-Blind Clinical Trial Study Protocol.

BACKGROUND: Despite 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. OBJECTIVE: The 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. METHODS: A 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. RESULTS: This 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. CONCLUSIONS: This 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 REGISTRATION: Clinicaltrials.gov NCT02487966; https://clinicaltrials.gov/ct2/show/NCT02487966 (Archived by WebCite at http://www.webcitation.org/6i3GrKMyf).