Combining Transcranial Random Noise Stimulation and Functional Electrical Stimulation to Enhance Hand Function in Individuals With Chronic Stroke
Phase: NA
Conditions: Stroke
Sponsor: Amit Sethi

 
 
             
 
 
 
 
    Protocol approved: July 16, 2020 
 
 
Study Title: Transcranial random noise stimulation (t-RNS) After Hand Recovery in 
Chronic Stroke 
 
Clinical Trials.gov ID: NCT05489146 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
             
 
 
 
 
    Protocol approved: July 16, 2020 
 
 
STUDY PROTOCOL 
This is a double-blind pilot randomized control study. Individuals with moderate-to-severe stroke 
were randomly allocated to two groups:  
Screening procedures 
After obtaining the informed consent, potential participants were screened in more detail using a 
medical chart review and standardized clinical assessments. 
 
Participants were recruited through referrals from the UPMC Rehabilitation Institute, UPMC 
Centers for Rehab Services, and the University of Pittsburgh Stroke Rehabilitation Research 
Network.  
 
The following procedures were administered to screen potential participants: 
 
1) We reviewed potential participants' medical charts after obtaining informed consent to confirm 
they have a primary diagnosis of unilateral hemiparesis due to a single episode of stroke, are 18 
years or older, and that their onset of stroke is at least 6 months prior to study screening, have 
no history of schizophrenia, other neurological or medical conditions that would confound 
results.  
 
2) We conducted a brief screen of upper extremity range of motion using a goniometer to 
determine if individuals are able to actively flex and extend the more-affected shoulder and 
elbow at least 30°.  
 
3) We asked participants to follow directions to determine whether they have the ability to follow 
3-step commands. 
 
4) We conducted a brief cognitive screen using Mini Mental Status Examination to screen for 
cognitive impairments which may confound the results of the study. 
 
5) We also conducted a brief mood screen using Patient Health Questionnaire-9 to screen for 
more than mild depression and question 16 and items of the (hypo) maniac module of the Mini-
International Neuropsychiatric Interview Hybrid Assessment to screen for bipolar disorders. 
 
6) We screened for one side neglect or hemispatial neglect using the Line Bisection Test, which 
is a quick paper-pencil test. 
 
7) We also screened participants who do not show a motor evoked potential response of the 
wrist flexor and extensor muscle with the transcranial magnetic stimulation. This is important to 
determine whether there some pathways from the damaged motor brain areas, which control 
the movement of the affected hand are intact. This will help to determine the responsiveness of 
the treatment, because it is futile to give to include and provide intervention to individuals who 
do not have any pathways (connectivity) intact between the damaged motor brain areas and the 
affected hand. 
 
DETAILS OF THE SCREENING ASSESSMENTS (total participant time: 1 hour and 30 

 
 
             
 
 
 
 
    Protocol approved: July 16, 2020 
 
 
minutes): 
 
1) Amount scale of Motor Activity Log (MAL): 
 
The Amount scale of the Motor Activity Log measures the amount of use of the more-affected 
hand during activities of daily living. Items are scored on a 5-point ordinal scale with 0 
representing the inability to use the more-affected upper extremity in daily living tasks in the last 
two weeks and 5 representing as much use of the more-affected hand in the last two weeks as 
compared to before the stroke. The MAL has been shown to have good reliability and validity. 
Date: July 16, 2020 
 
 
2). Visual Analog Scale (VAS): 
 
The VAS quantifies the pain in the more-affected upper extremity using a 10-centimeter scale, 
with 0 representing no pain and 10 representing extreme pain. A cut-off score of 5 or greater will 
be used. The VAS has been shown to have good reliability and validity. 
 
3). Modified Ashworth Scale (MAS): 
 
The MAS is a clinical measure of muscle tone and involves the passive movement of the more 
affected should, elbow, forearm, wrist, and fingers. The MAS has been shown to have good 
reliability and validity. 
 
4) Mini-Mental State Examination (MMSE): 
 
The MMSE is a clinical measure to examine the cognitive status and the ability to follow 
commands and ranges from 0-30. A cut-off score of more than 24 will be used. MMSE has good 
reliability and validity. 
 
5) Patient Health Questionnaire (PHQ-9): 
 
The PHQ-9 rates the severity of 9 symptoms of depression on a scale of 0 to 3. A cut-off score 
of more than 10 will be used. PHQ-9 has good reliability and validity. 
 
6) Mini-International Neuropsychiatric Interview Hybrid Assessment (MINI): 
Question 16 and items on the (hypo) maniac module will be used to screen bipolar disorders. 
An answer to "yes" to the questions and items will indicate bipolar disorders. 
 
7) Line Bisection Test (LBT): 
Allows screening of patients with hemispatial neglect of the body. 
 
        Assessment procedures 
All individuals with severe impairments in the weak hand who provided informed consent, 
completed screening procedures, and meet study criteria will participate in the study. The PI or 
personnel trained and supervised by the PI will perform the procedures. 

 
 
             
 
 
 
 
    Protocol approved: July 16, 2020 
 
 
 
Eligible participants were assessed at 3-time points in the study (pre-intervention, post-
intervention, and 3 months after completion of treatment). The pre-intervention, post-
intervention, 3 months follow-up assessments were conducted at the Neuromotor Recovery and 
Rehabilitation Laboratory located in the Keystone building of the University of Pittsburgh.  
All the pre-intervention, post-intervention, and 3 months follow-up research assessments were 
videotaped and later reviewed by personnel trained by the PI to re-examine the scores of the 
assessments. 
 
These assessments were videotaped to monitor assessment procedures and fidelity. After the 
video recording was completed, the videos will be downloaded to a password-protected 
(encrypted) hard disk and stored in a locked cabinet in the PI's office. We obscured the faces in 
the videos to examine facial responses (such as fatigue) to intervention to modify intervention 
for future sessions.  
 
PRE-INTERVENTION ASSESSMENT: (total participant time: 7 hours) 
Descriptive Measures: Medical Record Review: We collected demographic (age, gender, race, 
ethnicity, education, vocation, pre-stroke residential status, and social support), medical (stroke 
etiology and onset, co-morbidities, medications) and rehabilitation history (type and duration) 
data from the medical record. Stroke location and volume were gleaned from neurological 
images in the medical record. The pre-intervention assessment will be completed over 2 days. 
  
The following assessments were administered: 
 
1) Wolf motor function test (WMFT): to measure functional recovery in the upper extremity 
 
The WMFT is a 15-item test in which participants are given 2 minutes to complete each item. 
The items increase in difficulty from simple UE movements requiring few degrees of freedom to 
tasks requiring the coordination of many degrees of freedom of movement. Faster performance 
is indicative of better UE motor control. The WMFT is a valid and reliable test of UE function 
post-stroke. 
 
2) Fugl Meyer Upper Extremity Assessment (FMUE): to measure motor recovery in the upper 
extremity 
 
This scale is considered the gold standard in upper extremity rehabilitation trials and measures 
motor impairment by asking the participant to perform various arm and hand motions. Items are 
scored on a 3-point ordinal scale with 0 representing the inability to complete the item and 2 
representing the ability to complete the item as asked. The FMUE has been shown to have 
good reliability and validity. 
 
3) Stroke Impact Scale (SIS): to measure participation in daily life 
 
The Stroke Impact Scale 3.0 (SIS) will be used to measure the impact of stroke on the 
participant’s health and daily life. The SIS is a stroke-specific health outcome measure. It is a 
self-report measure and each item is scored on a 5-item Likert scale. We will complete items 

 
 
             
 
 
 
 
    Protocol approved: July 16, 2020 
 
 
from the hand subscale of SIS. 
 
4) Action Research Arm Test (ARAT): to measure arm and hand recovery 
The ARAT is a 19-item measure divided into 4 sub-tests (grasp, grip, pinch, and gross arm 
movement). The test takes 10 minutes to administer and has good reliability and validity. 
 
Performance on each item is rated on a 4-point ordinal scale ranging from: 
3: Performs test normally 
2: Completes test, but takes abnormally long or has great difficulty 
1: Performs test partially 
0: Can perform no part of the test 
 
4) Kinematic Measures of the upper extremity (UE) reaching (motion analysis procedures): to 
measure arm recovery 
 
The data were collected using the Vicon Nexus three-dimensional motion analysis system. The 
Vicon is a passive infrared video-based motion analysis system. This system is capable of 
resolving motion in Cartesian space with an error of fewer than .5 millimeters. Calibration was 
completed both statistically and dynamically prior to each subject evaluation using standardized 
static and dynamic references. All data were collected and analyzed at 100 Hertz. Fourteen 
cameras were placed around the participant to obtain multiple views to construct 3D motion. 
 
Participants were seated on a height-adjustable bench with feet flat on the floor. The weak UE 
was rested, palm down, on a low table placed alongside the weak lower extremity. The UE was 
in neutral shoulder flexion/extension and rotation and was adducted. Participants reached, 
pointed to a target, or grasped an object in front of them. Targets were placed at 80% of each 
participant’s arm’s length on a height-adjustable table. Participants reached each target five 
times first with their less-affected UE and then with their weak UE. In addition, participants also 
performed a table-wiping task for 1 minute. To minimize fatigue, a 1-minute rest break was 
provided between reaches. 
 
Kinematics of reaches were also videotaped using a digital camera. Adhesive reflective markers 
(or spheres) were placed on various joints of the upper body including C7 and T10 vertebrae, 
the acromion process, clavicle, sternum, upper arm, lateral epicondyle of the elbow, forearm, 
wrist (VICON wrist band), dorsum of the hand, thumb fingertip, index fingertip, and the top of the 
target. These reflective markers were used to identify all targets and motion vectors of interest. 
 
5) Electroencephalography (EEG) was used to record brain activity. EEG was recorded while 
the participant is attempting to perform movements of the weak UE, or while they are at rest. 
EEG uses sensors attached to the scalp (with tape or adhesive) to measure brain activity. We 
may use audio or visual cues to prompt the movements. 
 
6) Basic Electromyography (EMG) was used to record muscle activity from a few muscles of the 
forearm. EMG sensors were attached to the forearm (with tape or adhesive) to measure muscle 
activity.  
 
7) Transcranial magnetic stimulation (TMS) was used to record brain excitability. Participants 

 
 
             
 
 
 
 
    Protocol approved: July 16, 2020 
 
 
were seated comfortably in a chair with armrests in which they can keep their arms and hands 
in a constantly relaxed position. We placed 9mm Ag/AgCl surface electrodes over the flexor 
carpii radialis (FCR) and extensor carpii radilias (ECR) muscles. We delivered single pulse TMS 
using the Magstim system. The TMS coil was placed tangentially to the scalp with the handle 
pointing posteriorly. The stimulation was applied over the wrist/hand area of the affected motor 
cortex and individually localized for each participant based on the optimal position for eliciting 
MEPs. In order to keep the brain target constant throughout the stimulation session, we will use 
a frameless stereotactic neuronavigation system. 
 
8) H-reflex (spastic reflex) testing was used to record the spastic reflex in the FCR muscle. H-
reflex is the reflex reaction of the muscles after electrical stimulation of the peripheral nerves 
supplying the muscle. Elicitation of the FCR H-reflex itself is a common, harmless, minimally 
discomforting neurophysiological testing procedure performed in many laboratories and clinics 
worldwide. In order to elicit the FCR muscle H-reflex, we stimulated the median nerve on the 
volar surface of the forearm near the medial epicondyle using the surface Ag-AgCl electrodes 
and isolated constant current stimulation. We used the Digitimer DS7A system to stimulate the 
median nerve. The Digitimer DS7A system is an FDA-approved system to stimulate peripheral 
nerves. The response of the median nerve stimulation produces an H-reflex after 25-35 
milliseconds, which were recorded by the EMG response from the 9mm Ag/AgCl surface 
electrodes placed over the FCR muscle. The EMG response from the FCR muscle were used to 
determine the H-reflex of the FCR muscle. In addition, to normalize EMG values of the FCR 
muscle, we recorded the M-wave from the EMG electrode of the FCR muscle, which is a 
response produced at 3-6 milliseconds after the median nerve stimulation. Similarly, in order to 
normalize the EMG value of the ECR muscle, we recorded the M-wave from the EMG electrode 
of the ECR muscle. In order to elicit an M-wave response for the ECR muscle, we stimulated 
the radial nerve on the dorsal surface of the forearm near the lateral epicondyle using the 
surface Ag-AgCl electrodes and the Digitimer DS7A. 
 
     Intervention procedures 
Participants were randomized to one of the two intervention groups [transcranial random-noise 
stimulation (tRNS) and functional electrical stimulation (FES) or FES with sham tRNS] before 
pre-intervention testing. After randomization, participants underwent pre-intervention testing, 
followed by intervention 3 times per week for 6 weeks. Participants were enrolled for a total 
duration of approximately 5 months from pre-intervention to the follow-up phase. The 
intervention is described in the following paragraphs. 
 
Experimental Group: Transcranial random-noise stimulation and functional training with FES. 
 
The intervention was divided into two procedures: 
 
1). Transcranial random-noise stimulation (tRNS): 
 
The tRNS was applied with the StarStim device from Neuroelectrics Barcelona SL. The 
StartStim is battery-operated and has 8 channels that can provide low current brain stimulation. 
The maximum total current the device can output is 2mA (with a current precision of ~1micoA) 
using a maximum voltage of +/-15V. Participants received low-intensity current, which will not 
exceed 1.5mA for the first 30 minutes of the intervention while undergoing the 1st block (first 30 

 
 
             
 
 
 
 
    Protocol approved: July 16, 2020 
 
 
minutes) of functional training with FES. The Starstim was programmed such that the Starstim 
safely shuts off automatically after the first 30 minutes. 
 
We used PiStim electrodes throughout the treatment, which have an area of 3.14 square cm. 
The Starstim system has a built-in function to adapt the current density to each type of 
electrode, such that no more than 1.5mA goes to every single electrode. This feature allowed us 
to safely administer the recommended current intensity throughout the treatment. 
 
We applied electrodes (filled with the conductive gel) to the cleaned sites on the scalp and 
informed the participants that they might experience a slight tingling sensation during the 
inspection for scalp impedance. We began the Starstim stimulation protocol after determining 
that the scalp impedance for each electrode is less than 20 kOhm. 
 
Before delivering the tRNS stimulation for 30 minutes, participants were provided a brief period 
of stimulation (less than 1 minute) and were asked if they can sustain this stimulation for the 
next 30 minutes. We immediately terminated the treatment if the participant was not willing to 
receive the treatment or if the participant reported any adverse events during the treatment.  
The Starstim initially gradually ramped up the low-intensity current stimulation for the 1st minute, 
which is followed by continuous stimulation for the rest of the session. 
 
2). Functional training with FES: Participants performed functional training with FES for one 
hour, three times a week for 6 weeks during each session of tRNS. Each one-hour session was 
divided into two-30 minutes blocks of functional training with FES. During the first 15 minutes of 
the 1st block, Neuromove, an FDA-approved device was used to facilitate wrist and finger 
flexion (wrist and finger flexor muscles) to practice grasping functional objects by closing the 
fingers with the Neuromove attached to their weak hand. During the next 15 minutes of the 1st 
block, the wrist and finger extension (wrist and finger extensor muscles) was facilitated using 
the same Neuromove device to practice releasing functional objects by opening the fingers with 
the Neuromove attached to their weak hand. 
 
We repeated the 1st block, which now constituted the 2nd block. Similar to the 1st block, during 
the first 15 minutes of the 2nd block, we used Neuromove to facilitate wrist and finger flexion 
(wrist and finger flexor muscles) to practice grasping functional objects by closing the fingers 
with the Neuromove attached to their more-affected hand. During the next 15 minutes of the 2nd 
block, the wrist and finger extension (wrist and finger extensor muscles) was facilitated using 
the same Neuromove device to practice releasing functional objects by opening the fingers with 
the Neuromove attached to their weak hand. 
 
A list of sample functional tasks is shown below. Participants chose 3 tasks and practice each 
task for 2 weeks. 
 
Tasks 
Reach and Grasp a can/cup, bring to mouth and then release on a surface 
Picking and transferring small objects into container 
Eating finger foods 
Eating with spoon/fork 

 
 
             
 
 
 
 
    Protocol approved: July 16, 2020 
 
 
Picking thin books/note pads and placing them on a shelf 
Placing coins 
Picking the phone receiver, dialing with the less-affected hand, and placing the receiver. 
Placing checkers in a game of connect 4 
Opening pill boxes 
 
We provided adequate rest breaks during the treatment if the patients feel tired during the 
treatment. Participants will only use the FES during research treatment. The Neuromove and 
the Starstim devices were not given to participants for their in-home use between the 
investigator’s interventions. Participants also completed a tRNS and FES side effects 
questionnaire immediately after each treatment session. 
 
Control Group: Functional training with FES with sham tRNS 
The control group underwent similar functional training with FES but received sham tRNS. 
Sham tRNS was delivered using the Starstim device. All the procedures of applying the 
electrodes and checking the impedance were the same for sham stimulation as well. During the 
stimulation, participants experienced a gradual ramp-up of the low-intensity current stimulation 
for the 1st minute, which gradually faded away after the 1st minute and participants did not 
receive any stimulation for the rest of the session. 
 
We provided adequate rest breaks during the treatment if the patients felt tired during the 
treatment. Participants only used the FES during research treatment. The FES was not given to 
participants for their in-home use between the investigator’s interventions. 
 
All intervention sessions in both the experimental and control groups were videotaped. We 
randomly examine 15% of sessions in both groups and assess fidelity based on pre-defined 
principles. 
 
Procedures to prevent interference between the devices: 
In addition, all cables from the electrodes of the Starstim device are encased in a small unit that 
securely attaches to the participant's back of the head. This small unit then wirelessly 
communicated with the software on the computer. Thus, there were no hanging cables from the 
Starstim device. 
Also, the electrodes of the Neuromove device are directly connected to the Neuromove device 
and are securely attached to the forearm muscles. Therefore, the two devices are never in 
direct contact, which will prevent any interference including leakage of current from the portable 
devices or leads during active treatment. 
 
Procedures to monitor and recognize excessive cortical excitability: 
During the treatment: The starstim has an in-built feature, which shuts automatically shuts off if 
the skin impedance is more than 2 kOhm. 
Immediately after treatment: We will ask the participants to complete a tCS side effects 
questionnaire (attached) to document any side effects and provide adequate treatment if 
required. 
 

 
 
             
 
 
 
 
    Protocol approved: July 16, 2020 
 
 
POST-INTERVENTION ASSESSMENT  
The assessments, which were administered pre-intervention were administered within one week 
after the completion of the intervention.  
POST-2 (FOLLOW-UP) INTERVENTION ASSESSMENT 
We administered the assessments again three months after the completion of the intervention.  
 
STATISTICAL ANALYSIS 
Linear mixed model analyses were used to test the added benefits of tRNS on upper-extremity 
function after stroke. This analysis was performed both for the primary (Fugl Meyer Upper 
Extremity Assessment) and secondary (grip strength, Wolf Motor Function Test, and hand 
subscale of stroke impact scale) outcome measures. The participant’s group (tRNS, sham-
tRNS), time (PRE, POST, POST-2), and group x time interaction were entered as the fixed 
independent variables along with baseline scores on the respective outcome measures as 
covariates in the model. Subject was included as a random effect in the model. A significant 
main or interaction effect was followed by post-hoc analyses using the Sidak multiple 
comparison procedure. An alpha level of P<0.05 was considered significant for all tests.