Evaluating the Use of Transcutaneous Vagus Nerve Stimulation (tVNS) and Robotic Training to Improve Upper Limb Motor Recovery After Stroke
Phase: PHASE2
Conditions: Stroke, Cerebrovascular Accident (CVA), Hemiparesis
Sponsor: Northwell Health

 
Protocol Title:  Evaluating the use of transcutaneous vagus nerve stimulation (tVNS) to improve 
upper limb motor recovery after stroke 
 
NCT #:  NCT03592745 
 
Protocol Version Date:  1.23.20

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RESEARCH PROTOCOL 
 
 
Protocol Title: 
Evaluating the use of transcutaneous vagus nerve stimulation 
(tVNS) to improve upper limb motor recovery after stroke 
Principal Investigator: 
 
Bruce T. Volpe 
Primary Contact Name: 
Johanna Chang 
Primary Contact Phone: 
(516)562-3646 
Primary Contact E-mail: 
Jchang14@northwell.edu 
IRB Number: 
18-0404 
 
 
Guidelines for Preparing a Research Protocol 
 
Instructions: 
 
• You do not need to complete this document if you are submitting an Application for 
Exemption or Application for a Chart Review.   
• Do not use this template if: 
o  Your study involves an FDA regulated product.  In this case, use the Clinical 
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• If a section of this protocol is not applicable, please indicate such. 
• Do not delete any of the text contained within this document. 
• Please make sure to keep an electronic copy of this document.  You will need to use it, if 
you make modifications in the future.   
• Start by entering study information into the table above, according to these rules: 
o Protocol Title:  Include the full protocol title as listed on the application. 
o Investigator:  include the principal investigator’s name as listed on the application 
form 
o IRB Number:  Indicate the assigned IRB number, when known.  At initial 
submission, this row will be left blank.   
• Once the table information in entered, proceed to page 2 and complete the rest of the 
form. 
 
 
 
 Continue to next page to begin entering information about this study  

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1.  PREVIOUS STUDY HISTORY 
 
Has this study ever been reviewed and rejected/disapproved by another IRB prior to 
submission to this IRB? 
 
 No  
 Yes −  if yes, please explain:  
 
 
2. BRIEF SUMMARY OF RESEARCH 
• The summary should be written in language intelligible to a moderately educated, 
non-scientific layperson.  
• It should contain a clear statement of the rationale and hypothesis of your study, a 
concise description of the methodology, with an emphasis on what will happen to the 
subjects, and a discussion of the results.  
• This section should be ½ page 
 
 
Stroke is the fifth leading cause of death and the leading cause of serious long-term 
disability in the U.S. [1].  Post-stroke impairment is often characterized by 
hemiparesis or weakness of the upper and lower limbs, rendering the individual 
dependent for most activities of daily living.  Traditional stroke rehabilitation 
medicine consists of a combination of one-on-one treatment and group therapy 
with physical, occupational and speech therapists, focusing on both labor-intensive 
motor training of the affected limbs, as well as compensatory training of the 
unaffected side of the body.  Even with aggressive standard rehabilitation, 65 
percent of patients cannot incorporate their affected hand in functional activities six 
months after stroke, and only 25 percent of patients return to the level of life 
participation equivalent to that of community-matched healthy controls [2]. 
 
 
We have previously demonstrated that robotic therapy provides functionally and 
clinically significant benefits to upper limb motor recovery after stroke, and has been 
consequently acknowledged by the American Heart Association as an effective form 
of stroke rehabilitation [3-5].  Robotic intervention operates through a series of 
interactive motors with low impedance which move a patient’s limb when the patient 
cannot move and progressively intervene less as the patient improves. The advantage 
of this technology is to deliver reproducible movement without tiring, increasing the 
level of training intensity and potentially decreasing the level of impairment.  Though 
the clinical benefit of robotic interventions to reduce motor impairment after stroke 
is well established, the results are generally not curative.  
 
Promising new animal research suggests that vagus nerve stimulation paired with 
motor intervention induces movement-specific plasticity in the motor cortex and 
improves limb function after stroke [6-7].  These results were recently extended to 
the first clinical trial, in which patients with stroke demonstrated significant 
improvements in upper limb function following rehabilitation paired with implanted 

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VNS [8].  Currently, vagus nerve stimulation is being used clinically to treat a 
number of human diseases including migraine headaches, epilepsy, and depression 
[9-11].  Many of these treatments are non-invasive, activating the auricular branch 
of the vagus nerve transcutaneously through the cymba concha at the pinna of the 
ear [9-10, 23, 40]. We propose here a pilot study combining non-invasive stimulation 
of the vagus nerve with upper limb robotic therapy to investigate the potential of 
tVNS to augment improvements gained with robotic therapy in patients with chronic 
hemiparesis after stroke. 
 
 
3. INTRODUCTION/BACKGROUND MATERIAL/PRELIMINARY STUDIES AND 
SIGNIFICANCE 
• Describe and provide the results of previous work by yourself or others, including 
animal studies, laboratory studies, pilot studies, pre-clinical and/or clinical studies 
involving the compound or device to be studied.  
• Include information as to why you are conducting the study and how the study differs 
from what has been previously researched, including what the knowledge gaps are. 
• Describe the importance of the knowledge expected to result 
 
Vagus nerve stimulation (VNS) is an FDA approved form of therapy to treat 
refractory epilepsy, depression, and cluster headaches.  Because VNS is believed to 
drive activation of neuromodulatory nuclei associated with plasticity (e.g. 
cholinergic basal forebrain and noradrenergic locus coeruleus), it has also been 
recently investigated for use in the treatment of neurological diseases and injuries.  
Animal models of tinnitus, ischemic stroke, intracerebral hemorrhage, and traumatic 
brain injury benefitted from repetitive bursts of VNS during rehabilitative 
interventions [12-15].  Khondaparast et al (2013) reported that VNS paired with 
intensive forelimb motor rehabilitation improved force generation recovery in rats 
with chronic motor impairment following ischemic infarction of the primary motor 
cortex.  Specifically, rats who received VNS during motor rehabilitation tasks 
improved twice as much as those who received rehabilitation alone, and returned to 
near pre-lesion levels of motor performance [7].  These results were also replicated 
in animal models of cerebral hemorrhage and TBI [12-13].  Taken together, these 
pre-clinical studies suggest VNS may be a viable additive rehabilitation intervention 
to deliver greater functional outcomes following neurological injury.   
 
However, these previous rehabilitation trials have shown that such improvements are 
often selective only to the task which has been paired with VNS.  Specifically, in 
rats, motor behaviors paired with implanted VNS following stroke demonstrated 
selective increases in the size of the motor representations within the motor cortex 
for trained behaviors, while motor representations for untrained tasks or tasks 
performed without VNS remained relatively unchanged [19].  Human and animal 
models of tinnitus rehabilitation involving selective pairing of VNS with tones 
outside of the tinnitus white noise perceptual range resulted in significant reductions 
in the perception of tinnitus for up to three months [20-21].  In stroke rehabilitation, 
one of the most notable hindrances to motor recovery is the persistence of 

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maladaptive upper and lower limb flexor synergy patterns.  Upper extremity flexor 
synergy is characterized by a fixed pattern of scapular retraction, shoulder 
abduction/external rotation, elbow/wrist/finger flexion, and wrist supination, 
resulting a ‘curling in’ of the arm towards the body with a rigid, closed hand. It is 
caused by damage to the corticospinal tract (CST), and subsequent upregulation of 
interneuron spinal networks and other descending spinal pathways, ultimately 
resulting in movement limitations, which are greatest for extensor movements [22].  
Given the apparent task-selectivity of VNS training, current delivered only during 
extensor movements of a motor therapy task might lead to more efficient recovery 
of arm function after stroke.  
 
 
Preliminary clinical evidence suggests that implanted VNS augments the benefits 
of upper limb rehabilitation for individuals with chronic upper limb hemiparesis 
post-stroke.  Dawson et al (2015) randomized twenty-one patients who were 
greater than 6 months from an ischemic stroke to receive either VNS plus 
rehabilitation (N=9) or upper limb rehabilitation alone (N=11).  Rehabilitation 
intervention was intensity matched across groups, and consisted of three 2hr 
treatment sessions per week for 6 weeks.  VNS was delivered manually by the 
therapist via button press while the patient completed all prescribed motor tasks.  
Results from the per-protocol analysis demonstrated a significant improvement in 
upper limb Fugl Meyer scores for the VNS plus rehabilitation group as compared 
with the rehabilitation group alone (between group difference= 6.5 points). There 
were no serious adverse device effects, though side effects included transient 
dysphagia and vocal fold paralysis following implantation, and temporary naseau 
and taste disturbances following stimulation [8]. Overall, this first clinical trial of 
stimulator implanted VNS suggests a promising augmentative tool may become 
available to enhance post-stroke motor rehabilitation.  However, given that vagus 
nerve stimulation appears to be task-selective and dose-sensitive, refinement of 
stimulation parameters is still needed. Thus, we propose an investigation of specific 
vagus nerve stimulation timing parameters via a transcutaneous route to potentially 
improve intervention efficacy and decrease side effects.  
 
 
For this study, investigators in the Laboratory of Rehabilitation Robotics are 
collaborating with investigators in the Center for Bioelectronic Medicine (CBEM) 
to test the hypothesis that vagus nerve stimulation via an external electrode placed 
on the ear and timed to deliver stimulation during upper limb extensor movements 
will improve the outcome in patients after stroke. Currently, CBEM investigators 
have experience with 8 healthy controls and 8 patients with lupus delivering 
transcutaneous auricular vagus nerve stimulation (tVNS) without any serious 
adverse events.  The advantages of non-invasive tVNS device for use in stroke 
rehabilitation are to eliminate the need for surgical implantation, reducing 
untoward side effects in an already vulnerable population, and to potentially 
develop a clinical tool for better and more efficient functional recovery.   

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In our previous research, the Laboratory for Rehabilitation Robotics employed 
robotic devices to train movement in paralyzed limbs with well over 300 patients, 
and have established robotic intervention as a recommended standard of care [3]. We 
have demonstrated that robotic interventions alone provide safe, targeted, 
impairment altering upper and lower limb motor rehabilitation in the chronic phase 
of stroke recovery [3-5]. We have subsequently investigated the combination of 
robotic training with two bioelectronic interventions, transcranial direct current 
stimulation (tDCS) and trans-spinal direct current stimulation (tsDCS), and 
specifically examined the optimal timing parameters for administration of non-
invasive brain and spinal stimulation devices during upper limb recovery. To that 
end, we demonstrated that tDCS improves robotic kinematic scores in patients with 
post-stroke hemiparesis, but only when it is used prior to robotic training, and not 
when applied during or after robotic therapy [14]. These results suggest tDCS 
increases cortical excitability and neural plasticity for a time period, and that robotic 
therapy is more effective when applied at that time.  In another group of experiments, 
we are testing the efficacy of tsDCS in order to pair it with robotic intervention.  We 
have demonstrated that tsDCS significantly reduces both objective measures of the 
spastic catch response (e.g. changes in peak amplitudes measured with force 
transducer and EMG) as well as clinical measures (Tardieu/MAS) of upper extremity 
spasticity in twenty-one patients in the chronic phase after stroke.  Importantly, these 
improvements are seen immediately following 5 days of stimulation compared to the 
sham condition, and are maintained for three weeks or greater.  While these studies 
have been crucial in characterizing optimal treatment windows and sensitively 
measuring kinematic profiles of motor recovery, the stimulation interventions were 
delivered in an “open loop,” which is to say the stimulation was not interactively 
timed with a motor task.  Recent evidence suggests that delivery of closed loop 
stimulation, in which stimulation is provided precisely online during a motor therapy 
task, may yield greater recovery of function [16-18].  However, better understanding 
of task-selectivity and the timing of tVNS stimulation parameters is still needed.   
 
Our experience treating patients in post-stroke condition, and with robotics 
combined with non-invasive stimulation, and also with tVNS will facilitate the 
experiment we propose.  Specifically, we will deliver tVNS in a closed loop 
approach during only extensor movements for consecutive upper limb robotic 
therapy training sessions in order to test whether task-specific closed loop tVNS 
combined with upper limb robotic intervention can significantly improve arm 
function compared to a sham condition.    
 
 
4. OBJECTIVE(S)/SPECIFIC AIMS AND HYPOTHESES 
• A concise statement of the goal(s) of the current study.  
• The rationale for and specific objectives of the study.  
• The goals and the hypothesis to be tested should be stated. 
 
Specific Aim 1: To evaluate whether 3 weeks of robotic therapy paired with 
tVNS delivered only during extensor movements will significantly change 

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EMG activation patterns of up the upper extremity during unassisted gravity-
eliminated movements in approximately 18 patients with chronic post-stroke 
hemiparesis compared to sham condition. 
 
In patients with chronic upper-limb hemiparesis post-stroke, we will use a within-
subjects repeated measure design to determine if 9 sessions of active tVNS during 
only extensor movements significantly alters EMG activation of the biceps brachii 
and triceps as compared to a sham condition. 
   
Specific Aim 2:  To determine whether 3 weeks of robotic therapy paired with 
tVNS will significantly improve clinical measures of upper extremity motor 
function in approximately 18 patients with chronic hemiparesis after stroke 
compared to a sham condition.  
 
We will use a within-subjects repeated measures design to determine if 9 sessions 
of robotic therapy paired with active tVNS during only extensor movements 
significantly improves upper extremity motor function in patients with chronic 
post-stroke hemiparesis as compared to sham tVNS paired with robotic therapy. 
 
 
5.  RESOURCES AVAILABLE TO CONDUCT THE HUMAN RESEARCH 
• Explain the feasibility of meeting recruitment goals of this project and demonstrate a 
potential for recruiting the required number of suitable subjects within the agreed 
recruitment period 
o How many potential subjects do you have access to? 
• Describe your process to ensure that all persons assisting with the trial are 
adequately informed about the protocol and their trial related duties and functions 
 
The study will involve approximately 36 subjects with chronic hemiparesis 
following stroke.  The research team will be led by Dr. Bruce Volpe, who has 
extensive experience recruiting for clinical trials related to stroke.  Additionally, 
the Northwell Health System treats over 1000 patients with stroke annually, and 
provides an excellent recruitment population eligible for participation in this study.  
 
The team in the Laboratory of Rehabilitation Robotics has substantial experience in 
the field of stroke rehabilitation.  Dr. Volpe is a treating neurologist, investigator, 
and lecturer with over 30 years of clinical and research experience with 
neurological recovery.  Dr. Maira Saul is a Physiatrist and Research Coordinator 
with over ten years of clinical experience in the treatment of neurological injuries 
and neurodegenerative impairment.  Johanna Chang is a Research Coordinator and 
Speech-Language Pathologist with extensive clinical and research experience 
related to neurological injury.  Alexandra Paget-Blanc is a Research Assistant with 
a background in neuroscience, and an expertise in EMG spike analysis.   
 
Additionally, the team in the Center for Bioelectronic Medicine has extensive 
experience in engineering, programming, and clinical administration of vagus 

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nerve stimulation via tVNS devices.  The team has developed a wireless all-in-one 
tVNS stimulator, the device was co-designed with an ISO 13485 certified company 
(MIDI), and fabricated by MIDI, and supplied to the CBEM team. 
 
In order to ensure everyone assisting on the study is well versed in the protocol 
requirements, there will be a study team meeting after institutional approval is 
obtained. At this meeting, everyone will be reminded of the study design and all of 
the study processes. In addition, there will be a delegation of responsibly log 
created to outline the specific tasks of each study member during the course of the 
study. The study team will also routinely meet to discuss study progress and 
address any questions that arise. 
 
 
6.  RECRUITMENT METHODS 
• Describe the source of potential subjects 
• Describe the methods that will be used to identify potential subjects 
• Describe any materials that will be used to recruit subjects.  A copy of any 
advertisements (flyers, radio scripts, etc.) should be submitted along with the 
protocol.  
• If monetary compensation is to be offered, this should be indicated in the protocol 
 
Stroke subjects who meet inclusion criteria will be recruited by consenting 
professionals through the Departments of Physical Medicine and Rehabilitation, 
Neurology, and Outpatient Stroke Rehabilitation at NSUH, LIJMC, GCH, SSH, 
Transitions of Long Island, and STARs Outpatient Rehabilitation Center.  
Recruitment will be done with direct contact and flyers. 
 
Northwell Health physicians and clinicians who have appropriate patient 
populations will be made aware of the research study protocol and procedures, and 
given an overview of the study through contacts with the study personnel.  These 
clinicians will identify potential study participants, and either: 1.) provide the 
patient with the study coordinator’s contact information or 2.) provide the patient’s 
contact information to study personnel. 
 
Investigators may contact (or be contacted by) a potential subject or subject’s 
LAR/next-of-kin by telephone or email to discuss participation in this research 
protocol. The investigator will provide the subject/LAR/next-of-kin with all the 
information contained in the written consent form.  The investigator will answer 
any questions regarding the research and give the subject/LAR/next-of-kin ample 
time to consider participation in the study which may require a follow-up phone 
conversation or an in-person appointment at the Feinstein for a brief study 
enrollment screening visit. 
 
 
 
 

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7.  ELIGIBILITY CRITERIA 
• Describe the characteristics of the subject population, including their anticipated 
number, age, ranges, sex, ethnic background, and health status. Identify the criteria 
for inclusion or exclusion of any subpopulation.  
• Explain the rationale for the involvement of special classes of subjects, such as 
fetuses, pregnant women, children, prisoners or other institutionalized individuals, or 
others who are likely to be vulnerable.   You cannot include these populations in your 
research, unless you indicate such in the protocol 
• Similarly, detail exclusionary criteria: age limits, special populations (minors, 
pregnant women, decisionally impaired), use of concomitant medications, subjects 
with other diseases, severity of illness, etc. 
 
Inclusion Criteria: 
• Individuals between 18 and 85 years of age 
• First single focal unilateral supratentorial ischemic stroke  with diagnosis 
verified by brain imaging (MRI or  CT  scans)  that  occurred  at  least  6  
months  prior   
• Cognitive  function sufficient  to  understand  the experiments  and  follow  
instructions  (per interview with Speech Pathologist or PI) 
• Fugl-Meyer assessment 12 to 44 out of 66 (neither hemiplegic nor fully 
recovered motor function in the muscles of the shoulder, elbow, and wrist).   
 
Exclusion Criteria: 
• Botox treatment within 3 months of enrollment 
• Fixed contraction deformity in the affected limb 
• Complete and total flaccid paralysis of all shoulder and elbow motor 
performance  
• Prior injury to the vagus nerve 
• Severe dysphagia 
• Introduction of any new rehabilitation interventions during study 
• 
Individuals with scar tissue, broken skin, or irremovable metal piercings 
that may interfere with the stimulation or the stimulation device 
• 
Highly conductive metal in any part of the body, including metal injury to 
the eye; this will be reviewed on a case by case basis for PI to make a 
determination  
• Pregnant or plan on becoming pregnant or breastfeeding during the study 
period 
• Significant arrhythmias, including but not limited to, atrial fibrillation, atrial 
flutter, sick sinus syndrome, and A-V blocks (enrollment to be determined 
by PI review) 
• Presence of an electrically, magnetically or mechanically activated implant  
(including cardiac pacemaker), an intracerebral vascular clip, or any other 
electrically sensitive support system; Loop recorders will be reviewed on a 
case by case basis by PI and the treating Cardiologist to make a 
determination  

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8.  NUMBER OF SUBJECTS 
• Indicate the total number of subjects to be accrued locally.  If applicable, distinguish 
between the number of subjects who are expected to be pre-screened, enrolled 
(consent obtained), randomized and complete the research procedures. 
• If your study includes different cohorts, include the total number of subjects in each 
cohort. 
• If this is multisite study, include total number of subjects across all sites.   
 
This is a double-blind, sham-controlled pilot study.   The total target enrollment is 
36 subjects with post-stroke hemiparesis.  Only patients who meet inclusion criteria 
following screening will be enrolled.  We have anticipated a 10-15% drop-out rate 
in determining target enrollment. 
 
This study will use a randomized controlled study design to determine whether nine 
repeated treatments of upper extremity robotic therapy paired with tVNS delivered 
only during extensor movements significantly changes objective EMG activation 
patterns and significantly improves clinical measures of upper extremity motor 
function in patients with chronic post-stroke hemiparesis as compared to a sham 
condition. 
 
 
9. STUDY TIMELINES 
• Describe the duration of an individuals participation in the study 
• Describe the duration anticipated to enroll all study subjects 
• The estimated date of study completion 
 
The duration of an individual’s participation in the study is approximately 4 months 
from providing consent to completing the study procedures. It is anticipated that 
enrollment will be completed within 20 months from receiving institutional 
approval, with all study procedures completed within 2 years.  After the completion 
of data analysis and any subsequent presentations or publications, the study will be 
closed. It is estimated that the study will be completed by December 2020. 
 
 
10.  ENDPOINTS 
• Describe the primary and secondary study endpoints 
• Describe any primary or secondary safety endpoints  
 
The primary measure of treatment efficacy will be an increase in EMG activation 
peak amplitude for upper extremity extensor muscles of at least 10%.  The 
secondary measure of treatment efficacy will be an improvement in Upper 
Extremity Fugl Meyer score of at least 3 points (out of 66).   
 

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The primary safety endpoint will be any serious adverse events of suspected 
relationship with the tVNS investigational device.  Any serious adverse events will 
be reported to the PI, research team, and IRB immediately for determination if the 
study should be discontinued.  However, given that there were no serious adverse 
device effects of implanted VNS in individuals with stroke [8], it is anticipated that 
transcutaneous auricular vagus nerve stimulation will pose an even lower risk. 
 
 
11.  RESEARCH PROCEDURES 
• Include a detailed description of all procedures to be performed on the research 
subject and the schedule for each procedure. 
• Include any screening procedures for eligibility and/or baseline diagnostic tests 
• Include procedures being performed to monitor subjects for safety or minimize risks 
• Include information about drug washout periods 
• If drugs or biologics are being administered provide information on dosing and route 
of administration 
• Clearly indicate which procedures are only being conducted for research purposes. 
• If any specimens will be used for this research, explain whether they are being 
collected specifically for research purposes.   
• Describe any source records that will be used to collect data about subjects 
• Indicate the data to be collected, including long term follow-up 
 
Consecutive Sessions of tVNS during robotic therapy intervention 
Thirty-six patients with chronic, post-stroke upper extremity hemiparesis will be 
accepted into this study, and randomized to receive either sham or active tVNS 
treatment coupled with robotic therapy.  There will be 2-3 baseline measurement 
periods prior to treatment.  Following the lead-in period, subjects will participate in 
a training period consisting of approximately 1 hour sessions robotic therapy paired 
with tVNS 3x/week for 3 weeks, for a total of 9 sessions.  Following the training 
period, subjects will complete clinical and objective measures both immediately at 
discharge and again a 3-month follow-up visit. 
 
Lead-in Period 
• Week 1, Visit 1  (approximately 90 minutes)  
• Baseline clinical outcome measures 
• Instrumental measures with EMG 
• Medical screening 
• Consent  
• Week 1, Visits 2-3  (approximately 60 minutes each) 
• Baseline clinical outcome measures 
• Instrumental measures with EMG 
Training Period  
• Weeks 2-4, Visits 4-12 (approximately 60 minutes) 
• robotic therapy +  tVNS  

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• Device tolerance questionnaires (every session) 
Discharge Evaluation 
• Week 4, Visit 13 (approximately 60 minutes) 
• Clinical outcome measures 
• Instrumental measures with EMG  
Follow-Up Evaluation 
• Week 16, Visit 14 (approximately 60 minutes) 
• Clinical outcome measures 
• Instrumental measures with EMG  
Phase II 
Schedule 
  
Screen 
1 
Screen 
2 
Screen 
3 
taVNS 
Tx +  
robotics  
DC 
eval 
3 
mo 
FU 
  
Visit 1 
Visit 2 
Visit 3 
Visit  
4-12 
Visit 
13 
Visi
t 14 
Informed 
Consent 
X 
  
  
  
  
  
  
Medical Hx 
X 
  
  
  
  
  
  
Demographic 
Info 
X 
  
  
  
  
  
  
Inclusion 
Criteria 
X 
  
  
  
  
  
  
Neurological 
Exam 
X 
  
  
  
  
  
  
Medication 
check 
X 
  
  
  
  
  
  
Outcome 
Measures 
X 
X 
X 
  
 
X 
X 
Instrumental  
Assessment 
X 
X 
X 
X 
X 
tVNS (sham 
or real) + 
robotics  
 
  
  
  
 
X 
  
  
Clinical Outcome Measures 
Fugl-Meyer (Primary):  The  Fugl-Meyer  scale  is  a  valid  and  reliable  
evaluation  instrument  used for measuring performance-based impairment in 
stroke patients [4, 24-25].  
 

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Medical Research Council  motor  power  score  (MRC): The MCR is a valid and 
reliable score that measures strength in isolated  muscle  groups  of  the involved  
shoulder  and elbow on an ordinal scale (scale range: 0, no muscle contraction;  5, 
normal strength) [5, 26]. 
 
Wolf Motor Function:  The Wolf Motor Function Test is a valid and reliable 
assessment of upper extremity function by asking the patient to complete 15 motor-
based tasks and two strength-based tasks [27].   
 
Robotic Therapy 
The MIT-MANUS (the planar robot) was developed in the Newman Laboratory of 
Biomechanics and Human Rehabilitation at the Massachusetts Institute of 
Technology and provides customized, goal-directed, robot assisted arm therapy.  The 
hallmark of this system is an impedance controller that modulates the way the robot 
reacts to mechanical perturbation from a patient or clinician and ensures a gentle 
compliant behavior. The stability of most robot controllers is vulnerable when 
contacting objects with unknown dynamics. In contrast, dynamic interaction with 
highly variable and poorly characterized objects (e.g. neurologically impaired 
patients) will not de-stabilize the impedance controller, as its stability is extremely 
robust to the uncertainties due to physical contact [28-32].  Impedance control has 
been the central contribution of Dr. Hogan’s engineering research since the early 
eighties and has been extensively adopted by other robotics researchers concerned 
with human-machine interaction [29]. At present the MIT-MANUS impedance 
controller is implemented using coupled nonlinear position and velocity feedback 
structured to produce a constant isotropic end-point stiffness and damping. High-
bandwidth current-controlled amplifiers produce motor output torques directly 
proportional to commanded input. These facts make the robot a stable device for 
operation in a clinical context [28, 30-32].   
 
During planar robot therapy, the patient’s hand and wrist are held in a rigid support 
affixed to the robotic arm, and the patient must reach towards points in space that 
correspond to the positions of the targets on a screen.  Throughout each therapy 
session, the participant completes a series of flexions, extensions, and rotational 
movements across the elbow and shoulder joints.  If a limb is initially paralyzed, the 
robot will move it passively, but as motor function returns, the robot will require the 
patient to initiate progressively more voluntary movement.  In this way, the robot 
safely delivers reproducible movement without tiring and can render the level of 
training intensity required to alter impairment.  
 
Robotic therapy has been established as a safe and effective tool for upper limb motor 
recovery after stroke, and is presently a recommended intervention by the American 
Heart Association [1].   
 
Transcutaneous auricular vagus nerve stimulation (tVNS) 
Electrical auricular stimulation will be accomplished using either the Roscoe 
Medical Transcutaneous Electrical Nerve Stimulation (TENS) 7000 device paired 

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with ear clip electrodes available from Lhasa Ohms or an Auricular Branch Vagus 
Nerve Stimulation device co-designed by the CBEM team and fabricated by the 
MIDI Product Development Corporation. The study will only use one device 
throughout its conduct for all study participants since using multiple devices will 
create unnecessary variability. If the Auricular Branch Vagus Nerve Stimulation 
device from the MIDI Product Development Corporation is received prior to the 
anticipated study start date and passes internal reviews for design, comfort, and 
performance, the study will use the Auricular Branch Vagus Nerve Stimulation 
device from the MIDI Product Development Corporation for the entirety of the 
study for all subjects. If it is not received by the anticipated start date of this study, 
the study will utilize only the Roscoe TENS 7000 unit for the entirety of the study 
for all subjects.  
 
Study Procedure:  
tVNS will target the left VNS in order to avoid cardiac side effects associated with 
right VNS stimulation.  The tVNS device will be applied to the left ear using a pair 
of conductive silicone electrodes, with one electrode contacting the back of the ear 
and the other electrode on a spring loaded arm, contacting the cymba conchae.  
Patients will wear the tVNS device for the duration of each 1 hour robotic therapy 
session.  During each session, patients will perform approximately 1000 
shoulder/elbow flexion and extension movements and will receive stimulation 
during only the extensor movements, for a total of 300 stimulations per session.  
The tVNS current will be delivered during each extensor movement in single 
500msec bursts with a frequency of 30Hz and a pulse width of 0.3msec.  The 
current intensity will be individually adjusted to a level just below the patient’s 
reported pain threshold, with amplitudes ranging from 0.1-5.0mA in steps of 100 
µA.  The FDA guidance for document for powered muscle stimulators (FDA 
document 2246) specifies a maximum power density at the electrode site of 250 
mW/cm2. The MIDI fabricated stimulator has a maximum power density of less 
than 100 mW/cm2, which falls well below the guidance limit for thermal burns.  A 
portable, battery-powered oscilloscope will be used to confirm peak current (for the 
Roscoe device).  These stimulation parameters are similar to parameters that have 
been demonstrated to be safe in several other tVNS clinical trials [8, 23, 34, 41]. 
 
To ensure participant tolerance of stimulation, current will be introduced at the 
lowest 0.1mA intensity and gradually increased to a level at which the patient just 
begins to report discomfort, or a maximum of 5mA.  The device will then be 
immediately adjusted to an intensity just below the reported discomfort level, and 
will remain at this intensity for 10 seconds to confirm patient tolerance.  This will 
be considered the maximum tolerated stimulation intensity threshold for the 
patient, and stimulation bursts during robotic therapy will then be administered at 
this level. This tolerability dose will be determined prior to every treatment session 
for all patients, and recorded in the stimulation tolerance monitoring log. Sham 
tVNS will have a comparable set-up to active tVNS, with 10 seconds of real 
current ramping to the maximally tolerated current intensity at commencement, 

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followed by a slow decrease to no current for the duration of the robotic therapy 
session.   
 
 
About the devices: 
The Auricular Branch Vagus Nerve Stimulation device fabricated by the MIDI 
Product Development Corporation is designed to deliver low levels of current to 
the cymba conchae region of the ear using a pair of conductive silicone electrodes. 
The electrodes are designed to fit over the left ear and are adjustable in both 
rotation and location, relative to the rest of the housing, in order to accommodate 
subjects with different ear sizes. The device has a power switch and USB port for 
charging. The device is controlled using wireless Bluetooth technology via an 
application run on a PC that allows control over the amplitude of stimulation, 
onset, and timing parameters, including pulse width, frequency, and burst patterns.  
 
The Roscoe Medical Transcutaneous Electrical Nerve Stimulation (TENS) 7000 
device (www.roscoemedical.com) delivers a programmable electrical current, 
which can be adjusted for varying frequencies. The device may be modified to 
include an additional switch allowing the investigator to have precise control of the 
timing of stimulation. The modification will not change the manner in which the 
stimulation pulses are generated or delivered. The TENS 7000 will be connected to 
ear using clip electrodes available from Lhasa Ohms 
(http://www.lhasaoms.com/Ear-Clip-Electrodes.html) to transcutaneously stimulate 
the cymba conchae region of the ear, targeting the auricular branch of the vagus 
nerve (e.g. Arnold’s nerve).  This device does not allow for precise amplitude 
changes, and will thus be adjusted from its lowest setting gradually to a maximum 
tolerated threshold by individual patient report as described above in the study 
procedure.  To confirm peak current at this level and ensure patient safety, a 
portable, battery-powered oscilloscope will be used during the initial adjustment of 
this device for each patient during each session. 
 
Both the Auricular Branch Vagus Nerve Stimulation device fabricated by the MIDI 
Product Development Corporation and the Roscoe Medical Transcutaneous 
Electrical Nerve Stimulation (TENS) 7000 device are considered non-significant 
risk investigational devices.  The Roscoe TENS 7000 was classified as a Class II 
device by the FDA in 2011 and is FDA cleared (K110390) for over-the-counter 
sale, with an indication to provide symptomatic relief of chronic intractable pain, 
relief of acute post-surgical pain, and post-traumatic pain. However, since it will be 
used on this study to provide transcutaneous electrical stimulation to the auricular 
branch of the vagus nerve, it is being used off-label as an investigational device for 
this study. For both devices, the non-significant risk determination was made since 
they are not intended as an implant, are not purported to be for use in supporting or 
sustaining life, and do not present a potential for serious risk to the health, safety, 
or welfare of a subject.   
 

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Moreover vagus nerve stimulation, which requires invasive implantation of a 
stimulator directly to the vagus nerve, has been approved by the FDA for the past 
two decades for the treatment of seizures, and has been demonstrated to be safe, 
without any related serious adverse events, and of clinical benefit across several 
clinical trials for the treatment of tinnitus (n=10), chronic depression (n=494), and 
more recently chronic, post-stroke hemiparesis (n=9) [8, 11, 21].  Transcutaneous 
electrical auricular stimulation in which the electrical current is delivered more 
safely and non-invasively via a transcutaneous route at the cymba concha of the 
ear, is also currently approved in Europe for the treatment of seizures.  tVNS has 
been similarly demonstrated to be safe and without any related serious adverse 
events across several clinical trials in the treatment of tinnitus (n=24), treatment 
resistant epilepsy (n=30), and chronic post-stroke hemiparesis (n=7) [23, 34, 41].  
Additionally, the tVNS device which we propose to use in this study has been 
approved by the Northwell IRB in an investigation involving healthy controls 
(IRB# HS16-0530) and patients with Lupus (IRB# HS16-0171).  These 
investigations have also been conducted without any related serious adverse events. 
 
Electromyography (EMG)  
Electrical activity of the muscle will be differentially recorded during tVNS 
sessions using a bipolar electrode montage placed on the belly of the muscle. 
Recordings will be made from the biceps and triceps brachii, pectoralis major, 
rhomboideus, and/or the deltoids, which are some of the important muscles 
responsible for flexion and extension of the shoulder and elbow.   
 
Randomization  
Subjects will be stratified by established clinical impairment levels based upon 
admission Upper Extremity Fugl Meyer scores (low function <23 & moderate 
function 23-44) such that there are an equal number of low and high functioning 
patients in each treatment group. Subjects will then be randomized to either the 
active or sham tVNS group [28].  Assignment will be predetermined by a 
randomized assignment list, created prior to the enrollment of the first subject by an 
investigator from the CBEM team who is not directly involved in subject treatment.  
There will be concealed allocation of treatment assignment such that investigators 
involved in subject screening, consent, and clinical scoring will be blinded to 
treatment condition. 
 
Blinding  
This will be a double-blind pilot study in which subjects will be randomly assigned 
to either the sham or active tVNS conditions.  Subjects will be told that they have a 
50-50 chance of receiving either active or sham stimulation, but they will not be 
told which condition they receive.  Additionally, the assigned clinical evaluators 
will remain blinded to condition.  For each study session, stimulation condition will 
be programmed into the device by the RA or members of the CBEM team who are 
not performing clinical measures.   
 
 

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12.  STATISTICAL ANALYSIS 
• Describe how your data will be used to test the hypotheses.  
• State clearly what variables will be tested and what statistical tests will be used. 
• Include sample size calculations.  
• If this is a pilot study, state which variables will be examined for hypothesis 
generation in later studies.  
 
For our primary outcome measure, we will investigate whether tVNS paired in a 
closed loop with robotic therapy changes peak amplitude EMG activation in 
muscle groups along the shoulder and elbow.  We hypothesize that upper extremity 
flexor synergy will be significantly improved when active tVNS is applied during 
extensor movements as compared to a sham condition, and will lead to an increase 
in EMG peak activation at the triceps brachii (elbow extensor muscle).  This will 
be examined with a 2x3 ANOVA with condition (active stimulation vs. sham) and 
time (peak amplitude of EMG activation during extensor movements at admission, 
discharge, and follow-up) as factors.   
 
For our secondary outcome measure, we will test whether active tVNS during 
extensor movements paired in a closed loop with intensive robotic intervention (9 
sessions) significantly improves upper extremity motor function as compared to 
sham tVNS paired with intensity-matched robotics.  This will be examined with a 
2x3 Friedman ANOVA with condition (active vs. sham tVNS) and time (upper 
extremity fugl meyer score at admission, discharge, and 3 month FU) as factors.      
 
Since this is a pilot study, there are presently no data from which we can derive a 
power calculation.  However, we propose to enroll 36 subjects, in order to achieve 
a target of at least fifteen subjects per treatment group and also allow for a 10-15% 
drop out rate.  In our extensive past experience with upper limb hemiparesis 
rehabilitation studies, 10-15 subjects per treatment group is required at minimum to 
capture a measurable treatment response.  Additionally, two other early pilot 
studies investigating post-stroke upper limb motor rehabilitation combined with 
VNS found a significant improvement in motor performance with nine and 
fourteen subjects per treatment group (e.g. sham and active VNS), respectively [8 
& 41].             
 
 
13. SPECIMEN BANKING 
• If specimens will be banked for future research, describe where the specimens will be 
stored, how long they will be stored, how they will be accessed and who will have 
access to the specimens 
• List the information that will be stored with each specimen, including how specimens 
are labeled/coded 
• Describe the procedures to release the specimens, including:  the process to request 
release, approvals required for release, who can obtain the specimens, and the 
information to be provided with the specimens. 
 

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n/a 
 
 
14.  DATA MANAGEMENT AND CONFIDENTIALITY 
• Describe the data and specimens to be sent out or received.  As applicable, describe: 
o What information will be included in that data or associated with the 
specimens? 
o Where and how data and specimens will be stored? 
o How long the data will be stored? 
o Who will have access to the data? 
o Who is responsible for receipt or transmission of data and specimens? 
• Describe the steps that will be taken to secure the data during storage, use and 
transmission. 
 
The information collected on participants will be derived from self-report, brain 
MRI/CT scans, and data from study procedures.  Brain MRI/CT scans will be 
obtained either directly from the subject, from the subject’s treating physician, or 
from the subject’s file in the health system EMR database with verbal consent from 
the subject/LAR.  After an individual is enrolled into the study, the signed consent 
form and case report forms will be securely maintained in password protected 
databases behind the health system firewall and/or in a locked drawer within the 
locked Feinstein robotics suite, which is only accessible to study investigators. 
Study data and participant PHI (e.g. demographics, contact info, medical history) 
will be collected and stored in the HIPAA-compliant system, REDCap. To protect 
subjects’ confidentiality, each subject will be assigned an ID number, and all data 
will be stored with the subject ID number only and not the subject’s name. Any 
study data containing PHI that is transferred between investigators at Feinstein will 
be shared via encrypted email, through Syncplicity (health system approved 
encrypted cloud system server), or through encrypted storage drives.  All study data 
will be stored for at least seven years following closure.   
 
 
15.  DATA AND SAFETY MONITORING PLAN 
 
A specific data and safety monitoring plan is only required for greater than minimal risk 
research.  For guidance on creating this plan, please see the Guidance Document on the 
HRPP website. 
 
Part I – this part should be completed for all studies that require a DSMP.   
Part II – This part should be completed when your study needs a Data and 
Safety Monitoring Board or Committee (DSMB/C) as part of your Data and 
Safety Monitoring Plan.   
 
Part I:  Elements of the Data and Safety Monitoring Plan 

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•  Indicate who will perform the data and safety monitoring for this study.   
• Justify your choice of monitor, in terms of assessed risk to the research subject’s 
health and well being.  In studies where the monitor is independent of the study staff, 
indicate the individual’s credentials, relationship to the PI, and rationale for selection 
• List the specific items that will be monitored for safety (e.g. adverse events, protocol 
compliance, etc) 
• Indicate the frequency at which accumulated safety and data information (items listed 
in # above) will be reviewed by the monitor (s) or the DSMB/C.   
• Where applicable, describe rules which will guide interruption or alteration of the 
study design.   
• Where applicable, indicate dose selection procedures that will be used to minimize 
toxicity. 
• Should a temporary or permanent suspension of your study occur, in addition to the 
IRB, indicate to whom will you report the occurrence.   
 
Although this is a minimal risk study, to protect both the integrity of the data and 
the safety of all study participants, study data review in aggregate will occur every 
4 months by the Principal Investigator.  Additionally, if a subject experiences an 
adverse event during the course of the study, the PI will be notified immediately 
and the IRB will be contacted within 5 days if the PI determines that the event is or 
may be related to the study intervention.  If it is determined that the study 
intervention caused or may have caused the adverse event, the participant may be 
removed from the study and the study protocol will either be modified or ceased.  
However serious adverse events are unanticipated as tVNS is a nonsignificant risk 
device.  Additionally, there were no serious adverse device effects of implanted 
VNS or tVNS in individuals with stroke [8, 41]. 
 
 
Part II:  Data and Safety Monitoring Board or Committee 
 
 
•  When appropriate, attach a description of the DSMB.   
• Provide the number of members and area of professional expertise.   
• Provide confirmation that the members of the board are all independent of the study. 
 
n/a 
 
 
16. WITHDRAWAL OF SUBJECTS 
• Describe anticipated circumstances under which subjects will be withdrawn from the 
research without their consent 
• Describe procedures for orderly termination 
• Describe procedures that will be followed when subjects withdraw from the research, 
including partial withdrawal from procedures with continued data collection.   
 

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Study participation is voluntary, and a subject can withdraw at any time by 
notifying a member of the research team.  It is also possible that a subject may be 
withdrawn from a study without his or her consent.  Reasons for such withdrawal 
may include failure to keep study appointments, changes in medications or medical 
history such that the subject no longer meets inclusion criteria, experiencing an 
adverse event that is related or potentially related to the study intervention, or study 
cessation.  Once a subject is withdrawn from the study, no new data will be 
collected, but previously collected data will be kept and may be used. 
 
 
17. RISKS TO SUBJECTS 
• Describe any potential risks and discomforts to the subject (physical, psychological, 
social, legal, or other) and assess their likelihood and seriousness and whether side 
effects are reversible. Where appropriate, describe alternative treatments and 
procedures that might be advantageous to the subjects.  
• Include risks to others , like sexual partners (if appropriate) 
• Discuss why the risks to subjects are reasonable in relation to the anticipated benefits 
and in relation to the importance of the knowledge that may reasonably be expected 
to result.  
• Describe the procedures for protecting against or minimizing any potential risks, 
including risks to confidentiality, and assess their likely effectiveness.   
 
Transcutaneous vagus nerve stimulation by the ear has the potential to cause 
temporary changes in hearing, pain at the site of stimulation, skin irritation or 
burns, and in rare occurrences, increases or decreases in heart rate as a result of 
activating the cervical vagus nerve via transcutaneous electrical stimulation of the 
ear.  However, serious adverse events are unanticipated with tVNS, as there were 
no serious adverse device effects of implanted VNS or transcutaneous VNS in 
individuals with chronic stroke [8, 41]. 
 
Ear pain/discomfort occurs from stimulation of the sensory nerves innervating the 
ear. Activation of the sensory nerves correlates with the peak charge density 
applied to the innervated area. Consequently, during the stimulation period, we will 
monitor for discomfort and can adjust the charge intensity in real time to rapidly 
reduce the stimulation intensity and reduce the physical discomfort. This physical 
discomfort is not serious and the side effects are reversible.   
 
Thermal burns at the stimulation site are due to excess power density through the 
electrode area. The FDA guidance for document for powered muscle stimulators 
(FDA document 2246) specifies a maximum power density at the electrode site of 
250 mW/cm2. The MIDI fabricated stimulator has a maximum power density of 
less than 100 mW/cm2, which falls well below the guidance limit for thermal burns. 
A portable, battery-powered oscilloscope will be used to confirm peak current for 
the Roscoe device, and ensure that power density does not exceed this level.  
 

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Given the rare risk of heart rate changes occurring with tVNS, patients with known 
cardiac arrhythmias have been excluded from this study.  Additionally, subjects 
will be continuously monitored during therapy.  Any patient report of dizziness, 
lightheadedness, or nausea, which are associated symptoms with arrhythmia will 
result in immediate reduction in the stimulation intensity and/or cessation of 
stimulation and robotic intervention. A medical professional trained in basic life 
support (BLS) and will be present at the time of stimulation and afterwards.  
Additionally, appropriate medical equipment is available on site and the PI and 
other trained physicians are available on-call in the case of an emergency to further 
safeguard against risks. 
 
There are no known risks associated with the use of robotic training for stroke 
rehabilitation. Some patients have pain in the shoulder after a stroke. Our 
experience has demonstrated a comparable incidence of shoulder pain in groups 
that were or were not treated by the robot. 
 
There is also a risk of a breach of confidentiality if unauthorized individuals obtain 
access to protected health information. This risk will be minimized by securely 
storing all collected information and limiting access to study investigators only. 
 
 
 
18. RESEARCH RELATED HARM/INJURY 
• Describe the availability of medical or psychological resources that subjects might 
need as a result of anticipated problems that may be known to be associated with the 
research. 
• If the research is greater than minimal risk, explain any medical treatments that are 
available if research-related injury occurs, who will provide it, what will be provided, 
and who will pay for it.   
 
Since this study is considered minimal risk, physical injuries are not expected. 
However, if participants are injured from study participation, they will be provided 
treatment by Northwell Health. However, they or their insurance company will be 
responsible for the associated costs. No money will be given to participants.    
 
Subjects will be continually monitored during the stimulation period, and will be in 
constant contact with a member of the research staff.  The study can be 
immediately stopped at the subject’s request.  
 
In the case of a medical emergency, the PI and or other licensed physicians on site 
will be immediately summoned, and EMS may be contacted.  Additionally, the 
Feinstein is equipped with necessary resuscitation equipment, including a code box, 
cardiac defibrillator, intravenous fluids, and supplemental oxygen. An EKG 
machine is also available at the CRC if needed.  The PI or other licensed medical 
professional will be available to provide any and all medical treatments deemed 
necessary. 

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19. POTENTIAL BENEFIT TO SUBJECTS 
 
• Explain what benefits might be derived from participation in the study, noting in 
particular the benefit over standard treatment (e.g. a once-a-day administration 
instead of four times a day, an oral formulation over an IV administration).  
• Also state if there are no known benefits to subjects, but detail the value of knowledge 
to be gained 
 
The potential benefit of the proposed study is to develop a tool to augment 
conventional rehabilitation methods and improve motor recovery after stroke. 
 
 
20. PROVISIONS TO PROTECT PRIVACY INTERESTS OF SUBJECTS 
 
• Describe the methods used to identify potential research subjects, obtain consent and 
gather information about subjects to ensure that their privacy is not invaded.  
• In addition consider privacy protections that may be needed due to communications 
with subjects (such as phone messages or mail).   
 
Eligible participants will be recruited by Northwell Health clinician’s in the 
Departments of Physical Medicine and Rehabilitation, Neurology, and Outpatient 
Stroke Rehabilitation at NSUH, LIJMC, GCH, SSH, Transitions of Long Island, 
and STARs Outpatient Rehabilitation Center. These clinicians will identify 
potential study participants, and either: 1.) provide the patient with the study 
coordinator’s contact information or 2.) provide the patient’s contact information to 
study personnel. 
 
Investigators may contact (or be contacted by) a potential subject or subject’s 
LAR/next-of-kin by telephone or email to discuss participation in this research 
protocol. The investigator will explain the goals and the risks of participating in 
this research study and the requirements of participation.  If the subject/LAR/next-
of-kin expresses interest in the study, the investigator will also review a pre-
screening checklist, and schedule a meeting with the patient-subject.  We will 
inform the patient that it is possible if they come in for the meeting, s/he may not 
be eligible for this study. If the subject is interested in participating in the study and 
has obtained a brain scan within the health system that is accessible through EMR, 
we can review that scan prior to the meeting if the subject provides verbal consent.  
Review of brain scans will occur in the interest of expediting determination of 
study candidacy, as many of our study participants have significant mobility 
impairments and prescreening brain scans may prevent excess hardship/travel to 
study site for ineligible subjects.     
 
During the initial evaluation or screening visit, the investigator will verify the 
patient’s candidacy and provide the subject/LAR/next-of-kin with all the 

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information contained in the written consent form, including a discussion of the 
risks/benefits of the study and the study schedule.  The investigator will answer any 
questions regarding the research and give the subject/LAR/next-of-kin ample time 
to consider participation in the study.  Following this discussion, the potential 
participant and/or their LAR/next-of-kin will be asked to provide consent to 
participation.  Upon signing, the subject/LAR/next-of-kin will be provided with a 
copy of the consent. 
 
In the event that a subject and/or LAR/next of kin arrives for the first evaluation 
and then requests to take the consent form home for review prior to signing it, 
minimal risk clinical measures of the subject’s upper extremity function may still 
be collected during the initial study visit, prior to the signing of the consent, in 
order to reduce the burden on the disabled subject and their family who would 
otherwise be required to come for an additional study visit.  If that subject and/or 
their LAR/next of kin then decline further participation in the study, the data for 
that subject’s first evaluation will be destroyed. 
   
In order to protect their confidentiality, subjects will be assigned a study ID 
number. The participant will then be referenced by that number. This identifiable 
information will be located on the HIPAA-compliant database, REDCap, and in 
hard-copy paper charts, which will be stored in a locked file cabinet. The study’s 
de-identified data may be shared to facilitate study conduct such as data analysis. In 
addition, all study data will be securely maintained with access limited to 
investigators and authorized individuals only. 
 
 
 
21.  COSTS TO SUBJECTS 
 
• Describe any foreseeable costs that subjects may incur through participation in the 
research 
• Indicate whether research procedures will be billed to insurance or paid for by the 
research study.   
 
There will be no direct costs to the subject for any study procedures or 
rehabilitation interventions.  However, subjects are required to provide their own 
transportation.   
 
 
 
22. PAYMENT TO SUBJECTS  
 
• Describe the amount of payment to subjects, in what form payment will be received 
and the timing of the payments.   
 
Subjects will receive no payment for participation in this study. 
 

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23.  CONSENT PROCESS 
 
If obtaining consent for this study, describe: 
• Who will be obtaining consent 
• Where consent will be obtained 
• Any waiting period available between informing the prospective participant and 
obtaining consent 
• Steps that will be taken to assure the participants’ understanding 
• Any tools that will be utilized during the consent process 
•   Information about how the consent will be documented in writing.  If using a  
standard consent form, indicate such.   
• Procedures for maintaining informed consent.   
 
The consent process will take place in the robotics suite at the Feinstein.  The 
investigator will provide the subject/LAR/next-of-kin with all the information 
contained in the written consent form.  The investigator will then encourage the 
subject/LAR/next-of-kin to “teach back” the risks and benefits of the study to 
ensure their comprehension.  The investigator will answer any questions 
regarding the research and give the subject/LAR/next-of-kin ample time to 
consider participation in the study.  If so desired, those interested will be given 
a copy of the consent form so that they may have the opportunity to discuss 
participation further with family and/or advisors. If an individual joins the study 
by providing informed consent, the subject will receive a signed copy of the 
consent form.    
 
Written consents will be maintained in a locked file cabinet within the locked 
Feinstein robotics suite for up to 7 years. 
 
 
In the state of NY, any participants under the age of 18 are considered children.  If your 
study involves children, additional information should be provided to describe: 
• How parental permission will be obtained 
• From how many parents will parental permission be obtained 
• Whether permission will be obtained from individuals other than parents, and if 
so, who will be allowed to provide permission.  The process used to determine 
these individual’s authority to consent for the child should be provided 
• Whether or not assent will be obtained from the child 
• How will assent be documented 
• Whether child subjects may be expected to attain legal age to consent to the 
procedures for research prior to the completion of their participation in the 
research.  If so, describe the process that will be used to obtain their legal 
consent to continue participation in the study.  Indicate what will occur if consent 
is not obtained from the now-adult subjects.   
 
n/a 

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If the study involves cognitively impaired adults, additional information should be 
provided to describe: 
• The process to determine whether an individual is capable of consent 
• Indicate who will make this assessment 
• The plan should indicate that documentation of the determination  and 
assessment will be placed in the medical record, when applicable, in addition to 
the research record. 
• If permission of a legally authorized representative will be obtained, 
o  list the individuals from who permission will be obtained in order of priority 
o Describe the process for assent of subjects; indicate whether assent will be 
required of all, some or none of the subjects.  If some, which subjects will be 
required to assent and which will not. 
o If assent will not be obtained from some or all subjects, provide an 
explanation as to why not 
o Describe whether assent will be documented and the process to document 
assent 
o Indicate if the subject could regain capacity and at what point you would 
obtain their consent for continued participation in the study 
 
If the patient is awake, alert, and oriented to person, place, and time, and 
demonstrates appropriate cognitive and communicative abilities as 
determined by the study coordinator or PI, the patient will be deemed to 
have the appropriate capacity to consent; however, given that borderline 
cognitive dysfunction and/or aphasia may not be easily distinguishable, the 
patient’s LAR/next of kin will be routinely included when consent to 
participate is being obtained for all subjects. 
 
If it is determined that a patient is unable to consent for him/herself, due to 
a lack of capacity or lack of comprehension, consent will be sought from 
the patient’s LAR/next of kin.  Assent of the adult subject with LAR/next-
of-kin will be obtained as appropriate.  If such a subject regains his/her 
ability to make healthcare decisions, he/she will be given the opportunity to 
provide consent.   This consent will be documented using the Addendum to 
Consent by Research Proxy for Continuing Participation in a Research 
Study form. 
 
If the patient provides the consent delegate with assent to participate in the 
research but, due to a physical disability, is unable to sign the consent form, 
the patient will provide verbal consent and one witness/a and the patient’s 
LAR/next of kin will sign the document affirming their presence during the 
consent process and the patient’s physical disability as reason for an absent 
signature. 
 
 

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If the study will enroll non-English speaking subjects: 
• Indicate what language(s) other than English are understood by prospective 
subjects or representatives 
• Indicate whether or not consent forms will be translated into a language other 
than English 
• Describe the process to ensure that the oral and written information provided 
to those subjects will be in that language 
• If non-English speaking subjects will be excluded, provide a justification for 
doing so 
 
Subjects with limited English proficiency are not the target of this study, 
but it is possible that subject’s with LEP may qualify for the study and seek 
enrollment. In such cases, the study will seek consent as per Northwell 
Health policy. 
 
 
24.  WAIVER OR ALTERATION OF THE CONSENT PROCESS       n N/A          
 
Complete this section if you are seeking an alteration or complete waiver of the consent   
process. 
• Describe the possible risks of harm to the subjects involved in this study and 
explain why the study involves no more than minimal risk to the subject:   
• Explain why the waiver/ alteration will not adversely affect the rights and welfare 
of subjects 
• Explain why it is impracticable to conduct this research if informed consent is 
required   
• If appropriate, explain how the subjects will be provided with additional pertinent 
information after participation.   If not appropriate to do so, explain why.  
 
n/a 
 
Complete this section if you are obtaining informed consent but you are requesting a 
waiver of the documentation of consent (i.e., verbal consent will be obtained). To 
proceed with a waiver based on these criteria, each subject must be asked whether they 
wish to have documentation linking them to this study.  Only complete subsection 1 OR 
subsection 2.  
 
  SUBSECTION 1 
 
• Explain how the only record linking the subject to the research would be the 
consent document. 
• Explain how the principal risk of this study would be the potential harm resulting 
from a breach in the confidentiality 
• Indicate whether or not subjects will be provided with a written statement 
regarding the research. 
 
n/a 

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SUBSECTION 2 
•  Describe the possible risks of harm to the subjects involved in this study and 
explain why the study involves no more than minimal risk.   
• Confirm that the research only involves procedure for which consent is not 
normally required outside the research context.  
• Indicate whether or not subjects will be provided with a written statement 
regarding the research. 
 
n/a 
 
. 
 
25. WAIVER OF HIPAA AUTHORIZATION  
 
 
 
 N/A       
 
Complete this section if you seek to obtain a full waiver of HIPAA authorization to use 
and/or disclose protected health information.  
• Describe the risks to privacy involved in this study and explain why the study 
involves no more than minimal risk to privacy:   
• Describe your plan to protect identifiers from improper use or disclosure and to 
destroy them at the earliest time. 
•  Indicate why it is not possible to seek subjects’ authorization for use or 
disclosure of PHI. 
• Indicate why it is not possible to conduct this research without use or disclosure 
of the PHI.   
• Indicate if PHI will be disclosed outside NSLIJ Health System, and if so, to whom.   
Note:  PHI disclosed outside NSLIJ Health System, without HIPAA authorization 
needs to be tracked. Please see guidance at www.nslij.com/irb for information 
about tracking disclosures. 
 
n/a 
 
Complete this section if you seek to obtain a partial waiver of the patient’s 
authorization for screening/recruitment purposes (i.e., the researcher does not have 
access to patient records as s/he is not part of the covered entity) 
Note: Information collected through a partial waiver for recruitment cannot be shared 
or disclosed to any other person or entity. 
• Describe how data will be collected and used:  
• Indicate why you need the PHI (e.g.PHI is required to determine eligibility, 
identifiers are necessary to contact the individual to discuss participation, other) 
• Indicate why  the research cannot practicably be conducted without the partial 
waiver (e.g. no access to medical records or contact information of the targeted 
population, no treating clinician to assist in recruitment of the study population, 
other) 

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If the subject is interested in participating in the study and has obtained a brain 
scan within the health system that is accessible through EMR, investigators can 
review that scan prior to the meeting if the subject provides verbal consent.  
Additionally, if a subject only has a brain scan from a health system outside of 
Northwell, the subject/LAR can provide investigators with a copy of that scan, 
if willing, prior to meeting.  Review of brain scans will occur in the interest of 
expediting determination of study candidacy, as many of our study participants 
have significant mobility impairments and prescreening brain scans may 
prevent excess hardship/travel to study site for ineligible subjects.   
 
 
26.  VULNERABLE POPULATIONS: 
 
Indicate whether you will include any of these vulnerable populations. If indicated, 
submit the appropriate appendix to the IRB for review: 
 
  Children or viable neonate 
  Cognitively impaired 
  Pregnant Women, Fetuses or neonates of uncertain viability or nonviable  
  Prisoners 
  NSLIJ Employees, residents, fellows, etc 
  poor/uninsured 
  Students 
  Minorities 
  Elderly 
  Healthy Controls 
 
If any of these populations are included in the study, describe additional safeguards that 
will be used to protect their rights and welfare. 
 
Given that the goal of this study is to treat motor impairments following stroke, it is 
necessary that our study enroll subjects who may have cognitive impairments from the 
associated neurological injury, are often elderly, and may be from minority and/or 
uninsured/poor populations.  In all cases, the risks/benefits of the study and the 
commitment of the study schedule will be discussed at length with the subject.  The 
subject’s LAR/next-of-kin will also be routinely included in these discussions.  
Subjects will be informed that their enrollment decision will not affect their medical 
access/care through Northwell Health, and that they can drop out of the study at any 
time, though they will be encouraged to maintain good attendance while enrolled.  
Additionally, the consent form will clearly state that participation is voluntary. 
 
 
27.  MULTI-SITE HUMAN RESEARCH (COORDINATING CENTER) 
 

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If this is a multi-site study where you are the lead investigator, describe the management 
of information (e.g. results, new information, unanticipated problems involving risks to 
subjects or others, or protocol modifications) among sites to protect subjects. 
n/a 
 
 
 
28.  REFERENCES/BIBIOGRAPHY 
 
Provide a reasonable list of references directly related to the study. Any diagrams for 
new medical devices or brief reprints from journals might also prove useful. 
 
 
1. A.H.A. American Heart Association (2017). Heart Disease and Stroke Statistics- 2017 
Update: a Report from the American Heart Association. 
2. Dobkin, B. H. (2005). Rehabilitation after Stroke. The New England Journal of 
Medicine, 352(16), 1677–1684. http://doi.org/10.1056/NEJMcp043511 
3. A.H.A. 
American 
Heart 
Association 
(2016). 
Guidelines for Adult Stroke 
Rehabilitation and Recovery: A Guideline for Healthcare Professionals From the 
American Heart Association/American Stroke Association. Stroke, 47(6), e98-e169.  
4. Lo A.C., et al. (2010). Robot-assisted therapy for long-term upper-limb impairment after 
stroke. N Engl J Med,362(19), 1772-83. 
5. Volpe BT, et al. (2009). Robotic devices as therapeutic and diagnostic tools for stroke 
recovery. Archives of neurology, 66: 1086-1090. 
6. Khodaparast N, Hays SA, Sloan AM, et al. (2014). Vagus nerve stimulation delivered 
during motor rehabilitation improves recovery in a rat model of stroke. Neurorehabil 
Neural Repair, 28:698-706. 
7. Khodaparast N, Hays SA, Sloan AM, et al. (2013). Vagus nerve stimulation during 
rehabilitative training improves forelimb strength following ischemic stroke. Neurobiol. 
Dis, 60:80-88. 
8. Dawson J, Dixit A, Pierce D, et al. (2016) Safety, feasibility and efficacy of vagus nerve 
stimulation paired with upper limb rehabilitation following ischaemic stroke. Stroke, 47(1), 
143-50. 
9. Bauer S, et al. (2016). Transcutaneous Vagus Nerve Stimulation (tVNS) for Treatment of 
Drug-Resistant Epilepsy: A Randomized, Double-Blind Clinical Trial (cMPsE02). Brain 
Stimul,9(3), 356-63.  
10. Tso AR, Marin J, Goadsby PJ. (2017). Noninvasive vagus nerve stimulation for the 
treatment of indomethacin-sensitive headaches. JAMA Neurol, 74(10): 1266-1267. 
 

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11. Aaronson ST, et al. (2017). A 5Year Observational Study of Patients With Treatment-
Resistant Depression Treated With Vagus Nerve Stimulation or Treatment as Usual:       
Comparison of Response, Remission, and Suicidality. Am J Psychiatry, 174(7):640-648. 
12. Hays SA, Khodaparast N, Hulsey DR, Ruiz A, Sloan AM, Rennaker RL 2nd, Kilgard 
MP. (2014). Vagus nerve stimulation during rehabilitative training improves functional 
recovery after intracerebral hemorrhage. Stroke, 45(10):3097-100. 
13. Hays, SA. (2016). Enhancing rehabilitative therapies with vagus nerve stimulation. 
Neurotherapeutics, 13(2):382-94. 
14. Giacobbe, V., H.I. Krebs, B.T. Volpe, A. Pascual-Leone, A. Rykman, G. Zeiarati, F. 
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stimulation (tDCS) and robotic practice in chronic stroke: The dimension of timing. 
NeuroRehabilitation, 2013. 33(1): p.49-56. 
http://www.ncbi.nlm.nih.gov/pubmed/23949028.  
15. Ahmed, Z., Trans-spinal direct current stimulation alters muscle tone in mice with and 
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16. Hays SA, Khodaparast N, Ruiz A, Sloan AM, Hulsey DR, Rennaker RL 2nd, Kilgard MP 
(2014). The timing and amount of vagus nerve stimulation during rehabilitative training 
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17. Isaković M, Belić M, Štrbac M, Popović I, Došen S, Farina D, Keller T (2016). 
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19. Porter BA, Khodaparast N, Fayyaz T, et al. (2011). Repeatedly pairing vagus nerve 
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20. Engineer ND, Riley JR, Seale JD, et al. (2011). Reversing pathological neural activity 
using targeted plasticity. Nature, 470:101-104. 
21. De Ridder D, Vanneste S, Engineer ND, Kilgard MP (2014). Safety and efficacy of vagus 
nerve stimulation paired with tones for the treatment of tinnitus: a case series. 
Neuromodulation,17:170-179. 
22. McMorland AJ, Runnalls KD, Byblow WD (2015). A neuroanatomical framework for 
upper limb synergies after stroke. Front Hum Neurosc, 9:82.  
23. Aihua L, Lu S, Liping L, Xiuru W, Hua L, Yuping W (2014). A controlled trial of 
transcutaneous vagus nerve stimulation for the treatment of pharmacoresistant epilepsy. 
Epilepsy Behav, 39:105-10.  
24. Bosecker C, Dipietro L, Volpe B, Krebs HI. Kinematic robot-based evaluation scales and 
clinical counterparts to measure upper limb motor performance in patients with chronic 
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34. Kreuzer PM, Landgrebe M, Husser O, Resch M, Schecklmann M, Geisreiter F, Poeppl 
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