title: Effectiveness and neural mechanisms associated with tDCS delivered to premotor cortex in stroke rehabilitation: study protocol for a randomized controlled trial.
abstract: BACKGROUND
  More than 60% of stroke survivors experience residual deficits of the paretic upper limb/hand. Standard rehabilitation generates modest gains. Stimulation delivered to the surviving Primary Motor Cortex in the stroke-affected hemisphere has been considered a promising adjunct. However, recent trials challenge its advantage. We discuss our pilot clinical trial that aims to address factors implicated in divergent success of the approach. We assess safety, feasibility and efficacy of targeting an alternate locus during rehabilitation- the premotor cortex. In anticipating variance across patients, we measure neural markers differentiating response from non-response.
  
  
  METHODS
  In a randomized, sham-controlled, double-blinded pilot clinical study, patients with chronic stroke (n = 20) are assigned to receive transcranial direct current stimulation delivered to the premotor cortex or sham during rehabilitation of the paretic arm/hand. Patients receive the designated intervention for 30 min, twice a day for 3 days a week for 5 weeks. We assess hand function and patients' reports of use of paretic hand. A general linear mixed methods model will analyze changes from pre- to post-intervention. Responders and non-responders will be compared upon baseline level of function, and neural substrates, including function and integrity of output tracts, bi-hemispheric balance, and lesion profile. Incidence of adverse events will be compared using Fisher's Exact test, while rigor of blinding will be assessed with Chi-square analysis to ascertain feasibility.
  
  
  CONCLUSIONS
  Variable success of cortical stimulation in rehabilitation can be related to gaps in theoretical basis and clinical investigation. Given that most patients with severe deficits have damage to the primary motor cortex or its output pathways, it would be futile to target stimulation to this site. We suggest targeting premotor cortex because it contributes substantially to descending output, a role that is amplified with greater damage to the motor cortex. With regards to clinical investigation, paired cortical stimulation in rehabilitation has been compared to rehabilitation alone in unblinded trials or to unconvincing sham conditions. Transcranial direct current stimulation, a noninvasive technique of brain stimulation, which offers a more effective placebo and has a favorable safety-feasibility profile, may improve scientific rigor. Neural markers of response would help inform patient selection for future clinical trials so we can address limitations of recent negative studies.
  
  
  BACKGROUND
  NCT01539096.
authors.affiliation: Department of Biomedical Engineering, Lerner Research Instt,, Cleveland Clinic, 9500 Euclid Avenue, ND20, Cleveland, OH, 44195, USA. plowe2@ccf.org.
authors.forename: Ela B
authors.initials: EB
authors.lastname: Plow
authors.forename: David A
authors.initials: DA
authors.lastname: Cunningham
authors.forename: Erik
authors.initials: E
authors.lastname: Beall
authors.forename: Stephen
authors.initials: S
authors.lastname: Jones
authors.forename: Alexandria
authors.initials: A
authors.lastname: Wyant
authors.forename: Corin
authors.initials: C
authors.lastname: Bonnett
authors.forename: Guang H
authors.initials: GH
authors.lastname: Yue
authors.forename: Mark
authors.initials: M
authors.lastname: Lowe
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Wang
authors.forename: Ken
authors.initials: K
authors.lastname: Sakaie
authors.forename: Andre
authors.initials: A
authors.lastname: Machado
mesh_terms: D002540:Cerebral Cortex / Q000503:physiopathology*; D016009:Chi-Square Distribution; D002985:Clinical Protocols; D004311:Double-Blind Method; D005240:Feasibility Studies; D006801:Humans; D016014:Linear Models; D008279:Magnetic Resonance Imaging; D009820:Ohio; D010808:Physical Examination; D010865:Pilot Projects; D020127:Recovery of Function; D012107:Research Design; D020521:Stroke / Q000175:diagnosis / Q000503:physiopathology; D000071939:Stroke Rehabilitation; D013997:Time Factors; D050781:Transcranial Magnetic Stimulation / Q000379:methods*; D016896:Treatment Outcome; D034941:Upper Extremity / Q000294:innervation*