Combined Brain and Peripheral Nerve Stimulation for Stroke

Study Overview
=================
Brief Summary
-----------------
Cerebrovascular disease is a major cause of disability worldwide. The catastrophic burden of stroke is more dramatic in low- and middle- income countries, and the scarcity of evidence-based rehabilitation interventions represents a major challenge to global health care. Upper limb weakness is frequent after stroke, but there is no universally accepted treatment to effectively improve hand function in patients with moderate and severe motor impairment. These are the patients in deepest need of rehabilitative interventions. This project addresses this important issue, by testing effects of a novel approach. We will non-invasively stimulate the brain and peripheral nerves in order to enhance effects of motor training aided by an electrical stimulation device in patients with moderate to severe hand weakness. Our hypothesis is that brain stimulation, when added to peripheral nerve stimulation, will enhance effects of motor training to a greater extent than brain stimulation alone, peripheral stimulation alone, or no stimulation.

Detailed Description
-----------------
The goal of this study is to compare the effects of FES in close association with either transcranial direct current stimulation (tDCS) alone, peripheral nerve stimulation (PNS)alone, tDCS + PNS or sham tDCS + sham PNS, in patients with moderate to severe upper limb weakness, in a cross-over design. The working hypothesis of this proof-of-principle study is that either tDCS or PNS will enhance effects of functional electrical stimulation (FES) to a greater extent than placebo tDCS and PNS, and that the combination of tDCS and PNS will further improve motor outcomes than either tDCS or PNS alone. The interventions will consist of outpatient motor training of the paretic wrist with FES in four experimental sessions separated by two weeks. In each session, either active tDCS + sham PNS, active PNS + sham tDCS,active tDCS + active PNS or sham tDCS + sham PNS will be applied. PNS will be applied for 2 hours and tDCS will be applied in the last 20 minutes before completion of PNS. The order of the sessions will be randomized across patients. Before the first session, patients will be familiarized with the FES device.

Official Title
-----------------
Combined Brain and Peripheral Nerve Stimulation to Enhance Beneficial Effects of Functional Electrical Stimulation on Hand Motor Function After Stroke

Conditions
-----------------
Stroke

Intervention / Treatment
-----------------
* Other: Active tDCS
* Other: Active PNS
* Other: Sham tDCS
* Other: Sham PNS


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age, 18 years or older; First-ever, ischemic or hemorrhagic stroke at least six months before, confirmed by computed tomography or magnetic resonance imaging; Moderate to severe motor impairment of an upper limb, defined as a score between 7 and 50 on the Fugl-Meyer Assessment of Sensorimotor Recovery after stroke, a scale with scores for upper limb ranging from 0 (no function) to 66 (normal function; Ability to provide written Informed Consent (patient or legal representative); Ability to comply with the schedule of interventions and evaluations in the protocol. Exclusion Criteria: Lack of ability to voluntarily activate any active range of wrist extension; Anesthesia of the paretic hand; Stroke lesions affecting entirely the hand knob area of the motor cortex120; Stroke lesions affecting the cerebellum or the brain stem; Severe spasticity at the paretic elbow, wrist, or fingers, defined as a score of >3 on the Modified Ashworth Spasticity Scale; Active joint deformity; Uncontrolled medical problems such as end-stage cancer or renal disease; Pregnancy; Seizures; Pacemakers; Other neurological disorders such as Parkinson's disease; Psychiatric illness including severe depression; Aphasia or serious cognitive deficits that preclude comprehension of the experimental protocol or ability to provide consent. A score in the Minimental State Examination lower than 23/30 points will be used for patients with higher than 1 year of education, and a score lower than 19/30 will be used for patients with 1 year of education or less.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active tDCS and active PNS<br>1 session of active transcranial direct current stimulation (TDCS) of the hemisphere affected by the stroke and active peripheral nerve stimulation (PNS) | Other: Active tDCS<br>* Active tDCS will be applied with the anode positioned over the ipsilesional M1 and the cathode over the contralateral supraorbital region for 20 minutes (1mA).<br>Other: Active PNS<br>* Active PNS will be administered by 2 pairs of surface electrodes (cathode proximal). One pair will overly the median and ulnar nerves at the wrist, and the other pair will overly the radial nerve. Trains of electric stimulation will be delivered at 1 Hz by using isolation units connected to a square pulse stimulator.<br>|
| Other: Active tDCS and sham PNS<br>1 session of active transcranial direct current stimulation (TDCS) of the hemisphere affected by the stroke and sham peripheral nerve stimulation (PNS) | Other: Active tDCS<br>* Active tDCS will be applied with the anode positioned over the ipsilesional M1 and the cathode over the contralateral supraorbital region for 20 minutes (1mA).<br>Other: Sham PNS<br>* No current will be delivered to the radial, ulnar and median nerves.<br>|
| Other: Sham tDCS and active PNS<br>1 session of sham transcranial direct current stimulation (TDCS) of the hemisphere affected by the stroke and active peripheral nerve stimulation (PNS) | Other: Active PNS<br>* Active PNS will be administered by 2 pairs of surface electrodes (cathode proximal). One pair will overly the median and ulnar nerves at the wrist, and the other pair will overly the radial nerve. Trains of electric stimulation will be delivered at 1 Hz by using isolation units connected to a square pulse stimulator.<br>Other: Sham tDCS<br>* In sham tDCS, no current will be delivered through the tDCS device.<br>|
| Sham Comparator: Sham tDCS and sham PNS<br>1 session of sham transcranial direct current stimulation (TDCS) of the hemisphere affected by the stroke and sham peripheral nerve stimulation (PNS) | Other: Sham tDCS<br>* In sham tDCS, no current will be delivered through the tDCS device.<br>Other: Sham PNS<br>* No current will be delivered to the radial, ulnar and median nerves.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Active Range of Motion of Wrist Extension in the Paretic Side | In this cross-over study, the primary outcome was measured immediately before and after each session of treatment. In each session, one of the four possible interventions was administered. | Pre- and post-intervention on each intervention day |