The Combined Use of Transcranial Direct Current Stimulation and Robotic Therapy for the Upper Limb

Summary

The combined use of transcranial direct current stimulation and robotic therapy as an add-on for conventional rehabilitation therapy may result in improved therapeutic outcomes due to modulation of brain plasticity. In this article, we describe the combined methods used in our institute for improving motor performance after stroke.

Abstract

Neurologic disorders such as stroke and cerebral palsy are leading causes of long-term disability and can lead to severe incapacity and restriction of daily activities due to lower and upper limb impairments. Intensive physical and occupational therapy are still considered main treatments, but new adjunct therapies to standard rehabilitation that may optimize functional outcomes are being studied.

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that polarizes underlying brain regions through the application of weak direct currents through electrodes on the scalp, modulating cortical excitability. Increased interest in this technique can be attributed to its low cost, ease of use, and effects on human neural plasticity. Recent research has been performed to determine the clinical potential of tDCS in diverse conditions such as depression, Parkinson's disease, and motor rehabilitation after stroke. tDCS helps enhance brain plasticity and seems to be a promising technique in rehabilitation programs.

A number of robotic devices have been developed to assist in the rehabilitation of upper limb function after stroke. The rehabilitation of motor deficits is often a long process requiring multidisciplinary approaches for a patient to achieve maximum independence. These devices do not intend to replace manual rehabilitation therapy; instead, they were designed as an additional tool to rehabilitation programs, allowing immediate perception of results and tracking of improvements, thus helping patients to stay motivated.

Both tDSC and robot-assisted therapy are promising add-ons to stroke rehabilitation and target the modulation of brain plasticity, with several reports describing their use to be associated with conventional therapy and the improvement of therapeutic outcomes. However, more recently, some small clinical trials have been developed that describe the associated use of tDCS and robot-assisted therapy in stroke rehabilitation. In this article, we describe the combined methods used in our institute for improving motor performance after stroke.

Introduction

Neurological disorders such as stroke, cerebral palsy, and traumatic brain injury are leading causes of long-term disability, due to lesions and subsequent neurologic symptoms that can lead to severe incapacity and restriction of daily activities¹. Movement disorders significantly reduce a patient's quality of life. Motor recovery is fundamentally driven by neuroplasticity, the basic mechanism underlying the reacquisition of motor skills lost due to brain lesions^2,3. Thus, rehabilitation therapies are strongly based on high-dose intensive training and intense repetition of movements to recover strength and range of motion. These repetitive activities are based on daily life movements, and patients may become less motivated due to the slow motor recovery and repetitive exercises, which can impair the success of neurorehabilitation⁴. Intensive physical and occupational therapy are still considered main treatments, but newer adjunct therapies to standard rehabilitation are being studied to optimize functional outcomes¹.

The advent of robotic-assisted therapies has been shown to have great value in stroke rehabilitation, influencing processes of neuronal synaptic plasticity and reorganization. They have been investigated for the training of patients with damaged neurological functions and assisting people with disabilities⁵. One of the most important advantages of adding robot technology to rehabilitive interventions is its ability to deliver high-intensity and high-dosage training, which otherwise would be a very labor-intensive process⁶. The use of robotic therapies, along with virtual reality computer programs, allows for an immediate perception and evaluation of motor recovery and can change repetitive actions into meaningful, interactive functional tasks such as cleaning a stovetop⁷. This can elevate patients' motivation and adherence to the long rehabilitation process and allows, through the possibility of measuring and quantifying movements, tracking of their progress⁵. Integration of robotic therapy into current practices may increase the efficacy and effectiveness of rehabilitation and enable the development of novel modes of exercise⁸.

Therapeutic rehabilitation robots provide task-specific training and can be divided into end-effector-type devices and exoskeleton-type devices⁹. The difference between these classifications is related to how movement is transferred from the device to the patient. End-effector devices have simpler structures, contacting the patient's limb only at its most distal part, making it more difficult to isolate movement of one joint. Exoskeleton-based devices have more complex designs with a mechanical structure that mirrors the skeletal structure of the limb, so a movement of the device's joint will produce the same movement on the patient's limb^7,9.

The T-WREX is an exoskeleton-based robot that assists whole arm movements (shoulder, elbow, forearm, wrist, and finger movements). The adjustable mechanical arm allows variable levels of gravity support, enabling patients who have some residual upper limb function to achieve a larger active range of motion in a tridimensional spatial therapy^7,9. The MIT-MANUS is an end-effector-type robot that works in a single plan (x- and y-axis) and allows a two-dimensional gravity compensated therapy, assisting shoulder and elbow movements by moving the patient's hand in the horizontal or vertical plane^9,10. Both robots have built-in position sensors that can quantify upper extremity motor control and recovery and an interface for computer integration that allows 1) the training of meaningful functional tasks simulated in a virtual learning environment and 2) therapeutic exercise games, which help the practice of motor planning, eye-hand coordination, attention, and visual field defects or neglects^7,9. They also allow for the compensation of gravity effects on the upper limb and are capable of offering support and assistance to repetitive and stereotyped movements in severely impaired patients. This progressively reduces assistance as the subject improves and applies minimal assistance or resistance to movement for mildly impaired patients^9,11.

Another new technique for neurorehabilitation is transcranial direct current stimulation (tDCS). tDCS is a non-invasive brain stimulation technique that induces cortical excitability changes through the use of low amplitude direct currents applied via scalp electrodes^12,13. Depending on the polarity of the current flow, brain excitability can be increased by anodal stimulation or decreased by cathodal stimulation².

Recently, there has been increased interest in tDCS, as it has been shown to have beneficial effects on a wide range of diseases such as stroke, epilepsy, Parkinson's disease, Alzheimer's disease, fibromyalgia, psychiatric disorders such as depression, affective disorders, and schizophrenia². tDCS has some advantages, such as its relatively low cost, ease of use, safety, and rare side effects¹⁴. tDCS is also a painless method and can be reliably blinded in clinical trials, as it has a sham mode¹³. tDCS is likely not optimal for functional recovery on its own; however, it is showing increased promise as an associated therapy in rehabilitation, as it enhances brain plasticity¹⁵.

In this protocol, we demonstrate combined robot-assisted therapy (with two state-of-the-art robots) and non-invasive neuromodulation with tDCS as a method for improving rehabilitation outcomes, in addition to conventional physical therapy. Most studies involving robotic therapies or tDCS have used them as isolated techniques, and few have combined both, which may enhance the beneficial effects beyond each intervention alone. These smaller trials demonstrated a possible synergistic effect between the two procedures, with improved motor recovery and functional ability^{8,15,16,17,18,19}. Therefore, novel multi-modal therapies may enhance movement recovery beyond the current possibilities.

Protocol

This protocol follows the guidelines of our institution's human research ethics committee.

1. tDCS

1. Contraindications and Special Considerations
   Note: tDCS is a safe technique that sends constant and low direct current through the electrodes, inducing changes in neuronal excitability of the area being stimulated.
   1. Prior to device setup, confirm that the patient does not have any contraindications to tDCS, such as adverse reactions to previous tDCS treatment, implanted brain medical devices, or the presence of metal implants in the head.
   2. Use the following inclusion criteria: subacute and chronic stroke patients with light to moderate upper-extremity hemiparesis. Other contraindications include skull defects, which could alter intensity and location of current flow, and subjects must be free of unstable medical conditions such as uncontrolled epilepsy.
   3. Inspect the patient's scalp thoroughly for cutaneous lesions, such as acute or chronic skin disorders, cuts, or other inflammatory signs. Avoid placing the electrodes and stimulating areas with such lesions as a safety precaution.
2. Materials for tDCS
   1. Check if all the following listed materials are available (Figure 1) before starting the procedure: tDCS stimulator device, 9 V battery, 2 conductive electrodes, 2 sponge electrodes, cables, 2 rubber head bands (or Velcro straps, non-conductive straps), sodium chloride (NaCl) solution, measuring tape
3. Measurements
   1. Electrode sites are usually defined as 10/20 EEG positions, as described in a previous publication²⁰. Make sure the subject is comfortably seated.
   2. First, localize the vertex (Cz).
      1. Measure the distance from the nasion (bridge of the nose or intersection of the frontal bone and two nasal bones) to the inion (external occipital protuberance or most prominent projection of the protuberance), and mark 50% of this length. Mark this preliminary Cz location as a line, using either an oil pencil or nontoxic water-based marker.
      2. Measure the left and right pre-auricular points distance (i.e., the area anterior to the tragus). Divide this distance in half and mark the calculated point with a line.
      3. Connect both lines to create a cross. The intersection of both lines will correspond to the vertex (Cz) (Figure 2).
   3. Identify the target site on the head.
      NOTE: Anodal stimulation increases the cortical excitability in the stimulated brain tissue, while cathodal stimulation decreases it. Previous studies have used anodal stimulation in the lesioned hemisphere or cathodal stimulation in the contralesional hemisphere in order to decrease cortical excitability in the unaffected motor cortex and increase it in the affected motor cortex. In this protocol, we will describe both bihemispheric stimulation (with both anodal and cathodal stimulation in the same session) and anodal stimulation over the primary motor cortex.
      1. To locate the primary motor cortex (M1), use 20% of the distance from Cz to the left or right pre-auricular point (Figure 3). This area should correspond to the C3/C4 EEG location.
      2. Place the anode over the center of M1 motor cortex of the ipsilesional hemisphere and the cathode over the contralateral supraorbital region (Fp) (Figure 3).
      3. Alternatively, place the anode over the center of M1 motor cortex of the ipsilesional hemisphere and the cathode over the contralesional M1. The M1 positions for the tDCS electrodes are located at channels C3 and C4 (Figure 3).
4. Skin Preparation
   1. Inspect the skin and avoid stimulating over lesions or damaged skin.
   2. Move the hair away from the site of stimulation to improve conductance. Clean the surface of the skin, removing any signs of lotion and gel. For subjects with thicker hair, using conductive gel may be necessary.
5. Electrode positioning and device setup²⁰
   1. After preparing the skin and localizing the stimulation site, place one head strap under the inion, around the head circumference. Provide head straps made of non-conducting and non-absorbent material such as elastic, Velcro, or rubber straps.
   2. Soak the sponges with saline solution. For a 35 cm² sponge, approximately 6 mL of solution per side may suffice. Avoid oversoaking the sponge. Avoid producing fluid leaks over the subject. If necessary, use a syringe to add more solution.
   3. Connect the cables to the tDCS device. Make sure the polarity of the cables is correct, since the effects of tDCS are polarity-specific (as standardized: red corresponds to the anode electrode, and black or blue corresponds to the cathode electrode).
   4. Insert the connector cord pin securely into the conductive rubber inset.
   5. Insert the conductive rubber inset into the sponge. Ensure that the entire conductive rubber inset is covered by the sponge and that the connector cord pin is not visible.
   6. Place the first sponge electrode under the head strap and ensure that excessive fluid is not released from the sponge.
   7. Connect both elastic head straps, according to the electrode montage planned.
   8. Place the second sponge electrode on the head over the area being stimulated, under the second elastic head strap.
   9. If the overall electrical resistance of the electrodes and body is high, it may indicate inadequate electrode set-up. Some devices provide resistance measuring, which should be under 5 kΩ, ideally.
   10. Some devices provide a continuous indication of resistance during stimulation, which is a useful way to detect potentially hazardous situations (such as a dry electrode). In such cases, the device may finish or reduce the stimulation intensity if resistance increases beyond a certain threshold.
6. Stimulation
   1. Make sure that the patient is awake, relaxed, and seated comfortably during the procedure²¹.
   2. Adjust the tDCS stimulator settings (intensity, time, and sham condition, if applicable). In accordance with previous studies, apply direct current for 20 minutes at an intensity of 1 mA.
      NOTE: For sham intervention, the current is usually applied only for the first 30 s to give the subject the sensation of stimulation. This duration has been established in several studies as being effective in blinding them to the assigned intervention, without stimulating cortical excitability²².
   3. Initiate the tDCS stimulation. Start the current flow by ramping up the current to avoid the most adverse effects. Ramping up is automatically done on some devices, but if it is not, increase the current slowly during the initial 30 s to reach the maximum programmed current (in our protocol, up to 1 mA).
   4. After starting the electrical stimulation, some patients may perceive temporary slight itching sensations, dizziness, or vertigo. This can be avoided by ramping the current up and down at the start and end of each session.
   5. At the end of the procedure, gradually ramp off the current for 30 s.
7. After the procedure
   1. To record and evaluate the safety of the stimulation, ask the patient to fill out a questionnaire of common adverse effects and their intensities after the procedure is done. These may include skin irritation, nausea, headaches, burning sensations, dizziness, tingling, or other discomforts.
   2. Explain to the patient that any possible side effects are usually of mild or moderate intensity and usually temporary.
   3. After tDCS, refer the patients to undergo robotic therapy.
      NOTE: In the next sections of this protocol, we will describe the use of the commercial versions of the MIT-Manus and T-WREX.

2. Robotic Therapy with MIT-Manus

1. Positioning
   NOTE: This robot is an interactive robot for rehabilitation of the upper limb. The version utilized in our study allows training of wrist movement in the horizontal plane (planar).
   1. Make sure the subject is seated in a comfortable and ergonomic chair, secured by a four-point seatbelt, and facing the video screen.
   2. Make sure that a trained therapist is supervising the robotic training.
   3. Place the hand that will be subject to training into the grip of the robotic handle. Adjust both straps around the subject's arm. Adjust the support on the back of the arm so that it stays stable during training.
   4. Place the paretic upper extremity as indicated: shoulder in a 30° flexion, 90° elbow flexion, forearm in mid-prone position, wrist in neutral position.
   5. During machine operation, make sure movement of the shoulder joints and elbow range is limited to about 45°. Make sure that the arm is immobilized, and the wrist has freedom of movement. Movement is possible in the horizontal plane (in all possible directions).
2. Training
   1. The number of movements in a robotic training session is variable; however, it is common to perform about 320 repetitions in every possible direction of a plane within a same plane.
   2. The video screen shows cues of the tasks that the subject needs to perform and gives constant feedback of the position of the arm.
   3. The robot's software has several therapeutic exercise games for motor training. The visual feedback usually consists of a yellow ball that the patient must move between targets. Other training scenarios are available.
   4. The robot will only assist the patient if necessary; for example, if the subject cannot realize the intended movement within 2 s, the machine will help complete its movement. If the subject does not have enough motor coordination to carry out the intended movement, the robot will guide the subject's arm to perform the appropriate movement.

3. Training with MIT-Manus Arm

Note: This robotic arm allows training of elbow flexion and extension, shoulder protraction and retraction, and shoulder internal and external rotation on a horizontal plane.

1. Positioning
   1. For the MIT-MANUS Arm, make sure the subject is seated comfortably. Adjust the seat belts accordingly. Position the patient's right or left arm on the robot and adjust both straps.
   2. Adjust the robot's height as necessary. Adjust the table height as necessary.
   3. If there is any discomfort or pain, press the emergency stop button to turn off the robot immediately.
2. Training
   1. Calibrate the machine by asking the subject to move its arm along the lines.
   2. The robot will only assist the patient if necessary. For example, if the subject cannot realize the intended movement within 2 s, the machine will help complete its movement. If the subject does not have enough motor coordination to carry out the intended movement, the robot will guide the subject's arm to perform the appropriate movement.
      NOTE: The robot's software has several therapeutic exercise games for motor training. The visual feedback usually consists of a yellow ball that the patient must move between targets. Other training scenarios are available.

4. Training with T-WREX

1. Positioning
   NOTE: The T-WREX consists of an exoskeleton that fits the subject's arm and allows free movement of the shoulder, elbow, and wrist joints in a tridimensional setting.
   1. Ensure that the subject is seated in a comfortable and ergonomic chair facing the video screen, which provides visual and auditory feedback in a virtual reality setting, helping the patient achieve his or her goal.
   2. Place the patient seated in front of the robot's main module. Use the provided remote control to adjust the exoskeleton's height accordingly. Adjust the robot's exoskeleton arm to the corresponding side of the patient's limb that will be trained (either left or right).
   3. Leave about 4 fingers of height above the shoulder.
   4. Adjust the patient's limb into the exoskeleton, adjusting the straps on the arm and forearm.
   5. Adjust the length of the exoskeleton's arm and forearm accordingly, as well as the weight (gravity) compensation necessary for the arm (A to I) and forearm (A to E). It consists of a linear scale of gravity support, where A has no gravity support.
   6. Input these measurements to the computer.
   7. Before starting the training, adjust and calibrate the range of motion limits of the robot, according to the patient's capabilities.
   8. To test the calibrated range of motion, ask the patient to move the cube in all directions of the screen.
2. Training
   1. In each session, have the individual perform about 72 repetitions of the movement towards different functional targets (a T-WREX training session usually lasts about 60 min).
   2. Between each movement, allow a 10-second interval to prevent fatigue. The 72 repetitions are divided into 3 blocks of 24 movements each. Allow an interval of 5 min between each block of 24 movements.

Results

Non-invasive brain stimulation with tDCS has recently generated interest due to its potential neuroplastic effects, comparatively inexpensive equipment, ease of use, and few side effects²². Studies have shown that neuromodulation by tDCS has the potential to modulate cortical excitability and plasticity, thus promoting improvements in motor performance through synaptic plasticity by stimulating the primary motor cortex⁴. Anodal stimulation i...

Discussion

In this protocol, we describe a standard therapy protocol for combined tDCS stimulation associated and robotic therapy, used as a complement to conventional rehabilitation programs in patients with arm impairments. The protocol's goal is to improve motor function and mobility. It is important to observe the ramping-on and ramping-off of the tDCS machine to avoid any risk of adverse effects. tDCS is a safe technique with few side effects described in the literature².

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
tDCS device	Soterix Medical		Soterix Medical 1x1
9V Battery (2x)
Two rubber head bands
Two conductive rubber electrodes
Two sponge electrodes
Cables
NaCl solution
Measurement tape
Armeo Spring Robot	Hocoma
inMotion ARM	Interactive Motion Technologies