title: Optimizing Rehabilitation for Phantom Limb Pain Using Mirror Therapy and Transcranial Direct Current Stimulation: A Randomized, Double-Blind Clinical Trial Study Protocol.
abstract: 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.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT02487966; https://clinicaltrials.gov/ct2/show/NCT02487966 (Archived by WebCite at http://www.webcitation.org/6i3GrKMyf).
authors.affiliation: Laboratory of Neuromodulation & Center for Clinical Research Learning, Physics and Rehabilitation Department, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, United States.
authors.forename: Camila Bonin
authors.identifier: http://orcid.org/0000-0003-2820-8703
authors.initials: CB
authors.lastname: Pinto
authors.forename: Faddi Ghassan
authors.identifier: http://orcid.org/0000-0002-2626-6259
authors.initials: FG
authors.lastname: Saleh Velez
authors.forename: Nadia
authors.identifier: http://orcid.org/0000-0002-2921-8658
authors.initials: N
authors.lastname: Bolognini
authors.forename: David
authors.identifier: http://orcid.org/0000-0002-4832-4587
authors.initials: D
authors.lastname: Crandell
authors.forename: Lotfi B
authors.identifier: http://orcid.org/0000-0002-8094-9536
authors.initials: LB
authors.lastname: Merabet
authors.forename: Felipe
authors.identifier: http://orcid.org/0000-0002-1703-7526
authors.initials: F
authors.lastname: Fregni
keywords: cerebral cortex; clinical trial; electric stimulation therapy; electrical stimulation; factorial design; mirror therapy; non-invasive brain stimulation; transcranial electrical stimulation