Effects of Transcranial Direct Current Stimulation Paired With Robotic Arm Therapy on Recovery of Upper Extremity Motor Function in Stroke Patients
Phase: PHASE2
Conditions: Stroke
Sponsor: Northwell Health

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Protocol Title: 
Robots Paired with Transcranial Direct Current Stimulation in 
Stroke Recovery 
 
Principal Investigator: 
Bruce T. Volpe, M.D.  
 
Sub-Investigators:      
 
 
 
 
 
Richard Libman, MD 
Hermano I Krebs, Ph.D (MIT) 
 
  
 
 
 
 
 
 
 
 
 
 
 

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Introduction 
 
Cerebral ischemia, stroke, is the third leading cause of death in the U.S. and the leading cause 
of permanent disability (1). Traditionally, rehabilitation medicine treatment for stroke patients 
consists of one-on-one treatment and group therapy with physical, occupational and speech 
therapists who focus their treatment on both compensatory strategies to regain independence 
and a variety of techniques that can be described as neuromuscular re-education. For example, 
one learns to brush one’s teeth with the non-preferred hand. There are also labor-intensive 
motor training exercise protocols that focus on the stroke-affected limb using hand-over-hand 
techniques to move the impaired limb. Prompted by work in non-human primates and other 
basic experiments, it has become routine in the rehabilitation medicine programs for stroke 
patients with paralyzed or weakened limb motor function to increase the intensity of activity-
based therapy (2-4).  
 
Two promising modern approaches to stroke rehabilitation are the highly reproducible and 
intense activity-based robotic training and the modulation of brain function by non-invasive brain 
stimulation (NBS); specifically, trans-cranial magnetic stimulation (TMS) and trans-cranial direct 
current stimulation (tDCS). This protocol will test whether the addition of the tDCS treatment to 
the standard robotic treatment protocol positively influences the motor outcome in patients with 
chronic hemiparesis after stroke. TMS will be used to enhance the characterization and 
measurement of the motor performance.  
 
Robotic Therapy 
Recently, the invention of robotic therapy has been investigated as a potentially superior 
technique to maximize motor recovery after stroke. Interactive motors with low impedance and 
driven by smart controllers has led to a revolution in treatment of motor impairment. These 
devices move a patient’s limb when the patient cannot move and then as a patient’s motor 
function improves, the device allows the patient to execute voluntary movement. A robot 
delivers reproducible movement without tiring and can render the level of training intensity 
required to alter impairment.  
 
It is important to know that the robot control 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. Impedance control has been the central contribution of Hogan’s 
engineering research since the early eighties and has been extensively adopted by other 
robotics researchers concerned with human-machine interaction (60). 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 this application, the most important feature of the controller above is that its stability is 
extremely robust to the uncertainties due to physical contact (61-63). 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 (to wit, neurologically impaired 
patients) will not de-stabilize the impedance controller above; even inadvertent contact with 
points other than the robot end-effector will not de-stabilize the controller. This is essential for 
safe operation in a clinical context. 
 

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The robot control architecture is implemented on a standard personal computer (presently a 66 
MHz 486CPU) with 16-bit A/D and D/A I/O cards, as well as a 32-line DIO card. Besides its 
primary control function, this computer displays the exercise to be performed to both the 
operator (clinician) and patient via a video-splitter with dedicated monitors. The neuro-
rehabilitation workstation also includes a second personal computer (presently a 25 MHz 
386CPU) to display on-line video and audio information. Communication between computers is 
through a serial port at transmission rates that allow video update above 30 frames/sec. Thus 
important aspects of the patient’s sensory and motor experience can be controlled at the same 
time. 
 
Transcranial Magnetic Stimulation (TMS) 
TMS as it is used today, was introduced by Barker et al in 1985 (7), and has been applied in 
numerous clinical and physiologic investigations using single and paired pulse techniques (8). 
The magnetic stimulator comprises an insulated coil wire connected to a large electrical 
capacitance, and induces electric  currents  in  brain  tissue  proportional  to  the  rate  of  
change  of  the  magnetic  field,  when  a  high  current (9) (peak  ~several  thousand  amps)  
runs  through  the  coil  extremely  briefly  (~200micro  sec) .  The induced currents are thought 
to activate corticospinal cells trans-synaptically in  the  relaxed  subject,  resulting  in  waves  of  
descending  corticospinal  volleys  which  recruit  a  portion  of  the spinal  motoneuron  pool  
(probably  monosynaptically)  and  are  detected  via  the  surface  EMG  response,  the 
amplitude of which is one measure of the corticospinal excitability. Motor threshold represents 
the stimulus intensity needed to activate the most excitable corticospinal elements and 
motoneurons.  A motor-evoked potential (MEP) is evoked only when a cortical stimulus 
produces a volley of impulses in the corticospinal tract which is of sufficient size to bring the 
spinal motoneurons to their firing threshold (10). The threshold for producing a local effect in the 
brain is much lower. The probability of evoking a response is the most logical way of defining 
motor threshold, and one commonly used method is to increase the stimulus intensity in 5% 
increments until reaching a level which induces reliable responses in 50% of stimuli. Threshold 
curves may be used to detect small changes in motor threshold (11).  
 
Paired-pulse experiments are used for investigations into the nature of the cortical circuitry 
activated by TMS, and a variety of different methods exist to examine cortico-cortical  
connections,  or  connections  to  the  motor cortex from other parts of the nervous system (12, 
13). The precise mechanisms by which TMS elicits these effects are not yet fully understood, 
but the modulations are believed to occur in the cortex, as they are accompanied by  parallel  
changes  in  the  descending  corticospinal  volleys  recorded  over  the  cervical  cord (14).  
With  paired-stimuli  delivered  over  the  motor  cortex  target  muscle  area,  stimulus  intensity  
and  interval  parameters  can  be manipulated to preferentially activate inhibitory or facilitatory 
cortical circuits (13), although modulation of the test response  probably  reflects  the  balance  
between inhibitory and excitatory effects.  A small subthreshold conditioning stimulus is known 
to reduce the response to a suprathreshold test stimulus if the inter-stimulus interval is between 
1-6ms (15). The mechanism of this reduction is thought to be the activation of short-latency 
intracortical  inhibitory  networks  by  the  conditioning  stimulus  that inhibits  later  I-waves  (12, 
15, 16). The inhibition is thought to  be mediated  by GABAa,  with  the  observation  of inhibition 
with administration of GABA enhancing drugs, although other neurotransmitters such as 
dopamine and acetylcholine might  also  be  involved (12, 17-19). GABA and  glutamate  are  
considered  the  main  inhibitory  and  excitatory  neurotransmitters  in  the  cerebral cortex, and 
animal studies have shown that both types of neurons receive cholinergic inputs that are 
capable of modulating the efficacy of synaptic transmission (20). Refractoriness of pyramidal 
neurons is not considered to substantially contribute to short latency intracortical inhibition (21). 
A suprathreshold stimulus delivered 50-200ms before the same intensity test stimulus, can 

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reduce the amplitude of the second response, probably as a result of GABAb receptor activation 
due to activation of intracortical inhibitory networks at long latency (12). Intracortical facilitation 
may occur as a result of activation of cortico-cortical pyramidal cells and their axons, via 
excitatory glutamatergic synapses (22).  
 
The mechanism and interneuron pools may be different between intracortical facilitation and 
inhibition, between short and long latency intracortical inhibition, and between different latencies 
of inter-stimulus interval in the short-latency inhibition range (23, 24). Recent evidence has 
shown that brain stimulation might be beneficial in stroke recovery. Indeed epidural stimulation 
of the motor cortex induces an improvement in motor function in acute stroke (25). Although 
invasive brain stimulation has shown positive results, this technique is costly and associated 
with adverse effects. Therefore the field of non-invasive brain stimulation has developed rapidly.  
TMS  applied  repetitively  is  known to induce lasting effects and has  been studied more  
recently as a tool for neuromodulation, where the aim  is  to  promote  return of  normal  cortical 
excitability following  the disruption caused by neurological damage.  Long-term changes in 
corticomotor excitability can be induced using repetitive TMS that are largely dependent on the 
frequency, duration and intensity of stimulation (26, 27). We are aware of the gaps in the 
detailed and complete understanding of these mechanisms clinically available to influence 
motor performance, and we are equally aware of their current interest and possible usefulness 
(28). 
 
Transcranial Direct Current Stimulation (tDCS)  
tDCS  modulates  the  excitability  of  a  targeted  brain  region  non-invasively  by  altering  
neuronal  membrane potentials (29, 30). Hence this technique can be used to increase or 
decrease the excitability of neurons in a brain area, in order to determine if  that  region  plays  
an  integral  role  in  a  specific  motor  /  cognitive  function.  Unlike TMS, tDCS does not cause 
neurons to fire.  tDCS only alters the likelihood that neurons will fire by hyperpolarizing or 
depolarizing brain tissue. The prolonged effects of tDCS have been attributed to long-term 
potentiation (LTP) (59, 60) and long-term depression (LTD) (31, 32). Dextromethorphan, an 
NMDA antagonist suppressed post-tDCS  stimulation  effects  of  both anodal  and  cathodal  
stimulation strongly suggesting the involvement of NMDA  receptors  in  both  types  of  DC-
induced  neuroplasticity.  In contrast, Carbamazepine selectively eliminated anodal effects.  
Since Carbamazepine stabilizes the membrane potential voltage-dependently, the results reveal 
that after-effects of anodal tDCS require a depolarization of membrane potentials. This study by 
Liebetanz et al., provided pharmacological evidence that induction of the after-effects of tDCS 
requires a combination  of  glutamatergic  (excitatory)  and  membrane  mechanisms,  similar  to  
the  induction  of  established types of short- and long-term neuroplasticity (33). 
 
In animals, anodal cortical stimulation of 5-30 minutes has been shown to cause excitability 
increases lasting for hours after the stimulation, primarily through modulation of the resting  
membrane potential  (29, 30, 34-36).   
 
In humans, 13 minutes of tDCS resulted in an increase in excitability up to 150% and lasting 90 
minutes (37). Research with tDCS has revealed  that  anodal  stimulation can  induce  transient  
(on the order of 30 minutes)  improvements in performance on cognitive, motor and  linguistic  
tasks (38, 39). For example, Hummel et al. found that anodal tDCS delivered to the primary 
motor area in the lesion hemisphere elicited significant improvements in motor control of the 
paretic limb. The effect lasted for more than 25 minutes after stimulation. In a recent study, 
Fregni et al. also verified that anodal tDCS to the affected hemisphere and cathodal tDCS to the 
contralesional hemisphere improved motor function (40). Other examples highlighting the 
efficacy of anodal tDCS include: anodal tDCS to dorsolateral prefrontal cortex elicited an 

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improvement in working memory (41, 42); stimulation to primary motor cortex improved motor 
learning (43); tDCS  delivered  to  primary  motor  area  or  to visual  area  V5  induced  
improvements  in  visuo-motor  coordination (44);  anodal stimulation of fronto-polar  regions 
improved  probabilistic  classification  learning (45);  and left prefrontal  cortical  stimulation  lead  
to  increased  verbal fluency. Cathodal stimulation decreases cortical excitability in humans - 
i.e., affected neurons will be less likely to fire (46). The above studies attest to the efficacy and 
safety of tDCS in stroke patients, as well as its potential for therapeutic applications in stroke 
recovery. 
 
It remains to be determined if non-invasive brain stimulation could be used to further enhance 
the effects of behavioral training such as robotic therapy. Anodal tDCS, applied at rest over the 
primary motor cortex can raise corticomotor excitability and transiently improve motor function in 
healthy participants, and chronic stroke patients (38, 47). No reported studies of tDCS have 
investigated the physiological interactions of tDCS and highly controlled motor training, like 
robotic training, and additionally reported detailed kinematic changes.  Again we are aware of 
the flux in this field and of the scientific details that are not currently available, but the 
procedures with the appropriate constraints are safe and may be clinically effective (48). 
 
In this protocol we will test the effectiveness of adding tDCS to the standard robotic training. 
Despite the best efforts of current standard clinical rehabilitation, stroke survivors are left with 
significant and seemingly permanent motor impairments. New clinical data in the past decade 
supports the use of intensive re-training efforts to abet motor recovery. The rationale for 
intensive re-training, as in this robotic protocol, derives from experiments in pre-clinical and 
clinical work in which activity-dependent plasticity leads to improved motor outcome.  
 
Specific Aims 
 
SPECIFIC AIM 1: To evaluate whether multiple sessions of combined tDCS and robotic 
upper limb training in patients with chronic hemiplegia after stroke, leads to a sustained 
clinical improvement in upper limb motor function.   
In patients with  chronic  stroke (>6months  post-injury,  stable  unilateral  motor  deficit)  using  
a  within-subjects  repeated-measures design we will evaluate the effects of 12 weeks of robotic 
upper limb training (3x/week,  36 sessions, shoulder/elbow/wrist  in  alternating  sessions)  with  
real or sham tDCS before the robotic  training.  Functional improvement will be determined by a 
change in upper-limb Fugl-Meyer (primary), Wolf Motor Function Test, Barthel Index, and Stroke 
Impact Scale (secondary) outcome measures following the training, and assessed again six 
months later.   
  
SPECIFIC AIM 2: To identify and compare kinematic performance characteristics 
between   intervention groups.  
Quantitative measurements obtained from robotics are highly sensitive, precise and reliable. 
These data will provide important contributions to understanding the components of motor 
control that underlie improvements in clinical function. Previously published studies and new 
pilot data from our group support the hypothesis that a relationship may exist for five key 
parameters (mean speed, peak speed, smoothness, aim, deviation) (50), however confirmation 
in a larger number of patients needs to be established. This information may additionally be 
useful as a clinical predictor of motor recovery. Since movement smoothness was shown to 
improve with  just  one  session of  tDCS  and  robotics,  we  predict  that  there  will  be  a  
strong and sustained  effect on this parameter. Movement smoothness is associated with more 

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advanced stages of motor learning, and has high correlation with functional clinical scales, and 
as such should be mirrored with change in Fugl-Meyer score.   
  
SPECIFIC AIM 3: To identify and compare the neurophysiological characteristics 
between intervention groups.   
The relationship between clinical improvement and neurophysiological measures pertaining to 
robotic motor training following stroke are presently not described in the literature. By measuring 
accepted, quantitative and reliable EMG response (wrist and elbow flexor/extensor muscles) to 
TMS (cortical inhibition and excitation) we will establish: (i) the plasticity associated with training, 
and (ii) the neurophysiological characteristics of patients (and muscles within patients) who 
respond to training. By understanding how brain excitability changes underpin motor 
dysfunction, and motor recovery, interventions can be more effectively prescribed and 
prognoses established. 
 
SPECIFIC AIM 4: To evaluate whether multiple sessions of anodal tDCS to the motor 
cortex of the affected hemisphere in patients with chronic aphasia after stroke leads to 
sustained clinical improvements in verbal expression. 
In patients with  chronic aphasia after stroke (>6months  post-injury,  stable  expressive 
language deficit)  using  a  within-subjects  repeated-measures design we will evaluate change 
in verbal expression scores across 12 weeks of anodal stimulation to affected motor cortex with 
real or sham tDCS before the robotic  training.  Improvement in verbal expression will be 
determined by a change in verbal fluency as measured by the Apraxia Battery for Adults (ABA-
2, primary), Philadelphia Naming Test short form (PNT), Action vs. Non-action word naming 
task, generative naming task, “Repetition” subtest of the Aphasia Diagnostic Profiles (ADP), 
picture description and connected speech sample, the and “Symbol Cancellation” subtest of the 
Cognitive Linguistic Quick Test (CLQT) (secondary) following the training, and assessed again 
six months later.  The Western Aphasia Battery Revised (WAB-R) will additionally be given 
upon admission, discharge, and at follow up six months after training for a comprehensive 
profile of language function.   
 
SPECIFIC AIM 5: To identify and compare cytokine levels between stroke rehabilitation 
intervention groups. 
We hypothesize that persistent HMGB-1 serum levels in patients with stroke retard 
functional recovery. A first step in the test of this hypothesis is to gather serum data in study 
participants to longitudinally assess if cytokine levels correlate with responsiveness to the 
robotic rehab interventions, and to determine if that response is affected by intervention group 
(sham vs. real tDCS). 
 
Preliminary Data 
 
A recent multi-center study has demonstrated the effectiveness of robotic training in patients 
recovering from hemiparesis after stroke, and the robot training has become a standard of care 
(5, 6).   
 
We  recently  demonstrated  that  the  combination  of  the  NBS  technique  of  transcranial  
direct current  stimulation  (tDCS)  and  upper-arm  robotic  therapy  improves  motor  
performance  after  stroke,  but  only when tDCS is used to prime the therapy; that is, prior to 
robotic training (49). When tDCS is applied during or after robotic therapy it confers no 
additional advantage. The interpretation is that tDCS increases cortical excitability and neural 
plasticity for a time period, and that robotic therapy is more effective when applied at that time.  

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Having established that tDCS cortical excitability after-effects could be sustained during robotic 
upper-limb training, we tested if this combination  of  tDCS  and  robotic  training  applied over  
multiple  practice  sessions  might  translate  to improved   motor   function.   In six right-handed 
patients with chronic stroke (>6 mo since ictus), two with right hemiparesis and four with left 
hemiparesis (3/3 Male/Female, mean 4.7 yrs since stroke; and 67. 7± 12.7 years of age) 
received a full course of 36 weeks of robotic training on the shoulder-elbow and wrist devices. 
They were considered to be at a stable plateau for their upper limb function. They received 2 
weeks (6 sessions) of combined tDCS and robotic wrist training.  Four  patients  received  real 
tDCS  and  training,  while  2  patients  received  sham stimulation  and  training  (randomly  
assigned). The results demonstrated that  in  the  group that received tDCS and robot training,  
but  not  the  sham (no tDCS and robot training),  a  clinically  meaningful improvement   
occurred   over   this   short   training period. Motor power at the wrist improved to 112±6% pre-
training in the real-treatment group (pre-training = 19.5, to post training 22 points (out of 30) and 
no change in the sham group (pre training=19.5, post training=19.5). The wrist-hand Fugl-Meyer 
improved by 3 points (mean pre=16.83, post=19.83 out of 30) and improved 1 point in the sham 
condition (mean pre=18, post=19).  Preliminary analysis of the kinematic data also revealed that 
the group that received tDCS had smoother movements (fewer jerks) than controls receiving 
sham tDCS. While this preliminary study was in a small number of patients, the results suggest 
that tDCS followed by motor training may be advantageous over training alone.  
 
These studies support investigations aiming to understand the mechanisms and clinical benefit 
of combined tDCS and robotic motor training in chronic stroke.  
 
Research Design and Methods 
 
Inclusion/Exclusion Criteria 
Inclusion Criteria:  
1. ≥ 18 years of age 
2. First single focal unilateral lesion with diagnosis verified by brain imaging (MRI or  CT  
scans)  that  occurred  at  least  6  months  prior;   
3. Cognitive  function sufficient  to  understand  the experiments  and  follow  instructions  
(Mini-Mental Status Score of 24 or  higher  or  interview  for  aphasic subjects);   
4. Fugl-Meyer assessment 7 to 58 out of 66 (neither hemiplegic nor fully recovered motor 
function in the muscles of the shoulder and elbow and wrist).   
 
Exclusion Criteria:  
1. Botox treatment within 6-weeks of enrollment; 
2. Fixed contraction deformity in the affected limb;  
3. Complete and total flaccid paralysis of all shoulder and elbow motor performance;  
4. History of hemorrhagic stroke  
5. Ongoing use of CNS-active medications  
6. Ongoing use of psychoactive medications, such as stimulants, antidepressants, and  
anti-psychotic medications  
7. Presence of additional potential tDCS / TMS risk factors:  
 
Damaged skin at the site of stimulation (i.e., skin with ingrown hairs, acne, razor 
nicks, wounds that have not healed, recent scar tissue, broken skin, etc.)  
 
Presence of an electrically, magnetically or mechanically activated implant  (including 
cardiac pacemaker), an intracerebral vascular clip, or any other electrically sensitive 
support system  

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Fig 1: Diagram of study design showing the relationship between the robotic training program with or 
without tDCS and the evaluation schedule 
 
Metal in any part of the body, including metal injury to the eye (jewelry must be 
removed during stimulation)  
 
A history of medication-resistant epilepsy in the family  
 
Past history of seizures or unexplained spells of loss of consciousness 
 
 
 
Visit Schedule 
In this double-blind research study, 66 participants will be randomized to receive real or sham    
tDCS prior to receiving an established interactive upper limb (shoulder/elbow and wrist) robotic 
training regimen.  During the lead-in period, each subject will attend 3 weekly visits to complete 
TMS screening and have outcome measures (see below) assessed. Following the lead-in 
period, each subject will attend 36 90-minute sessions (3 visits/week) over a 12-week period (or 
up to 14-weeks to allow for missed appointments) comprising the training period. These visits 
will include further TMS screening and outcome measures, TMS, tDCS and robot training. 
Subjects will undergo further outcomes measures upon discharge and during a final 6-month 
follow-up visit. All study procedures will be administered and supervised by a therapist. All visits 
will be conducted in either the robot and TMS suites at the Feinstein Institute for Medical 
Research or at the Burke Medical Research Institute (Fig. 1).  Participants will additionally 
undergo five blood draws longitudinally during the study to determine if cytokine levels change 
over the course of rehabilitation intervention, and if those changes are correlated with improved 
functional outcomes and treatment group (sham vs. real tDCS). 
 
Lead-in Period 
 
Week 1, Visit 1 (approximately 30 minutes)  
 
TMS screening questionnaire 
 
Outcome measures 
 
Week 2 & 3, Visit 2 & 3 (approximately 60 minutes each) 
 
Outcome measures 
 
One time 10cc DNA sample and 2 separate 4cc baseline blood draws (2 total 
draws) 
 
Training Period 
 
Week 4-15, Visits 4-39 (approximately 90 minutes) 
 
TDCS risk questionnaire (visit 4 only) 
 
TMS 
 
tDCS 
 
Robotic training 
 
4cc blood draw at midpoint, session 18 (1 total) 
 
 
Weeks 16 Visit 40 (approximately 2.5 hours) 
 
tDCS 

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 
Robotic training 
 
Outcomes measures 
 
4cc discharge blood draw (1 total) 
 
 
Final Visit 
 
Week 40, Visit 41 (approximately 60 minutes) 
 
Outcome measures 
 
4cc follow up blood draw (1 total) 
 
Clinical Outcome Measures 
 
All outcome measures will be recorded three times prior to the training period separated by one 
week to ensure reliability and stability of measures, then again following the 12-week training 
program, and six months later.  In general, study visits will take place at the institution of 
recruitment (e.g. subjects recruited through Feinstein will be treated at Feinstein).  However, 
occasionally TMS and clinical assessments may take place at the other institute.  Individual 
patient assessments will always be performed by the same evaluator to ensure internal 
consistency.    
 
Fugl-Meyer (Primary):  The  Fugl-Meyer  scale  is  a  valid  and  reliable  evaluation  instrument  
used for measuring performance-based impairment in stroke patients (54, 55).  
 
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) .  
 
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 (56). 
 
 
Barthel Index (BI): The BI is a valid and reliable index of independence widely used in scoring 
improvement in the rehabilitation of stroke population (57). The BI consists of 10 items assigned 
various weightings: 15 points for the subcategories of walking and transfers; 10 points for the 
subcategories of feeding, bowel, bladder, toileting, dressing and stairs; 5 points for the 
subcategories of bathing and grooming.  The BI is a cumulative score achieved by summating 
the score for all sections. The BI scores are recorded in multiples of 5, ranging from 0 
(completely dependent) to 100 (independent in basic activities of daily living).  
 
Stroke Impact Scale (SIS): The SIS is a valid and reliable index that assesses changes in 
impairments, disabilities and handicaps following a stroke and has internal consistency and 
established test-retest reliability (58, 59).  We  have  chosen  the  Stroke Impact  Scale  (SIS)  
Version  3.0  to  measure  physical  abilities,  as  well  as  other  dimensions  that  contribute  to 
quality of life and participation in everyday life. This is a 59-item self-reported questionnaire that 
asks persons with stroke to rate perceived problems in eight domains using a 5-point scale: 
strength, hand function, mobility, activities of daily living, emotion, memory, communication and 
social participation. This self-report assessment is unique in that it addresses motor 
impairments of the paretic limbs in addition to other key variables that are important to patients 
and their caregivers.  This  assessment  will not only offer  data  concerning  perceived changes  
in  motor  abilities  following  involvement  in the  planned  study,  but will also help to identify 

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other incidental changes in emotional status, memory and thinking, or activities of daily living 
following participation in robot training. 
 
Verbal Expression Battery for Aphasia:  A set of brief subtests from larger aphasia batteries will 
be used to asses changes in verbal expression and fluency in subjects with chronic expressive 
aphasia.  Audio/Video recordings will be made of speech-language assessments for review and 
scoring by approved clinicians.   
“Diadochokinetic Rate,” “Increasing Word Length,” and “Inventory of Articulation 
Characteristics” subtests of the Apraxia Battery for Adults (ABA-2): The ABA-2 is a valid 
and reliable measure of changes in motor speech across isolated speech sounds, 
multisyllabic utterances, and connected speech samples.  Together, these subtests take 
approximately 5 minutes to administer and derive an apraxia impairment profile score 
(75, 78, 79). 
Generative Naming:  Generative Naming is a commonly used clinical measure of verbal 
fluency and semantic memory in individuals with aphasia.  It has been used frequently in 
the tDCS literature as a sensitive metric of changes in verbal fluency (71, 72, 76).  
Philadelphia Naming Test short form (PNT): The PNT is a valid and reliable measure of 
changes in expressive naming across time in stroke patients with expressive aphasia.  
Performance on the PNT short form has been statistically correlated to PNT long form 
performance for individuals with aphasia (73, 74, 75). 
 Verbal production of Action vs. Nonaction words:  Network models of language suppose 
that motor acts and the words used to describe them are a part of the same neural 
network.  tDCS stimulation of the motor cortex may produce enhanced verbal production 
of action vs. nonaction words (69, 70). 
Connected Speech Sample including the “Cookie Theft” or “Birthday Party” picture 
descriptions: Connected speech samples are frequently used metrics of changes in rate, 
fluency, and language formulation in individuals with aphasia.  Audio/visual recordings of 
naturalistic language samples allow for independent quantitative scoring of language 
function by clinicians (78, 79).   
“Repetition” subtest of the Aphasia Diagnostic Profile (ADP): The ADP is a valid and 
reliable measure of changes in repetition and verbal facility for simple sentences and 
basic reflexive speech (78, 79).    
 “Symbol Cancellation” subtest of the Cognitive Linguistic Quick Test (CLQT): is a valid 
and reliable non-verbal, visual cancellation task.  It is frequently used by clinicians in 
aphasia literature as a non-verbal control task of attention and visual memory (76).  
Western Aphasia Battery Revised (WAB-R):  The WAB-R provides an aphasia quotient 
for type and severity of aphasia, and is commonly used in the aphasia literature.  
Changes of >5 points are clinically significant (75, 77, 78).  
 
TMS Evaluation 
Screening: A questionnaire to screen for TMS risk factors, published for use with TMS research, 
will be completed by every participant prior to undergoing TMS (67). An  answer  of  “yes”  to  
any  of  the  listed  questions  will  necessitate  further  inquiry  by  the  investigator, but not 
necessarily exclusion from the TMS study.   
 
Motor cortex stimulation and electromyography: Patients will sit comfortably in a chair and the 
investigator will gently apply the TMS wand against the skull. There will be a clicking noise that 
indicates the stimulator is generating a magnetic field and the sound will be followed by a 
muscle twitch in the opposite arm, forearm or hand.  
 

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We will use BrainsightTM neuronavigation to deliver stimuli on a grid in 1-cm steps in the coronal 
and sagittal planes, over the region of the primary motor cortex in the affected hemisphere. TMS 
will be delivered using a MagPro  X100  stimulator  with  a  5  cm  diameter  figure-of-eight  coil,  
held  tangential  to  the  skull  and aligned  in  the  para-sagittal  plane  with  the  handle  rotated  
45°  lateral.  Surface electromyographic (sEMG) recordings will be made from electrodes 
positioned over the muscle belly of the right flexor carpi radialis (FCR) muscle. EMG signals will 
be amplified (x1000) and band-pass filtered between 20 and 1000 Hz, before being digitized at 
2000 Hz for 100 ms following each stimulation, using a Cambridge Electronic Design (CED) 
acquisition system. The optimal site of stimulation for FCR will be determined from initial 
exploration, and used throughout the experiment. 
 
Resting Motor Threshold (RMT): Motor evoked potentials (MEP) recorded via surface EMG 
during the torque recordings, will be analyzed for peak-to-peak amplitude. The lowest stimulus 
intensity evoking a MEP of 50 µV in at least five of ten trials in the relaxed muscle will be used. 
We will use 2% increments in stimulator output starting just below the intensity determined from 
initial exploration.  Motor threshold is considered to reflect membrane-related intrinsic neuronal 
excitability. Ten MEP responses with single stimuli delivered at 120% RMT intensity will be 
recorded, to determine if a change in amplitude is observed at each time point.  
 
Intracortical Inhibition: A single pulse TMS stimulus can be inhibited or facilitated if preceded by 
a subthreshold conditioning stimulus (Short Interval Cortical Inhibition SICI, 3msec inter-
stimulus interval) is an accepted measure to determine if changes in corticospinal output are 
related to altered intracortical excitability. We will record 10 test MEPs, and 10 conditioned 
MEPs (80%RMT conditioning TMS intensity, test intensity adjusted to give 1mV amplitude 
MEPs) for SICI. Conditioned and unconditioned pulses will be randomly presented.   
 
The frequency of TMS stimulation will not exceed 0.2 Hz, as this will avoid cumulative effects of 
the stimulation during assessment. 
 
Transcranial Direct Current Stimulation (tDCS) Application 
Patients will sit in a comfortable chair and a plastic band will encircle the skull. An electrode – a 
flat 6cm X 6cm plate – will be ensheathed in a disposable cotton sponge and held in place by 
the band. The electrode (cathode) covered by the pad will be placed above the eye and on the 
forehead contralateral to the affected limb and another electrode (anode) will be placed over the 
skull site that has been determined by TMS to produce a maximal motor contraction in the 
affected limb (33).  
 
A 2mA current will be delivered using the surface rubber-carbon electrodes (35cm2)  with  
surrounding  saline  soaked  sponges  (0.9%  NaCl)  by a battery  driven,  constant  current  
stimulator  (maximum  output  10mA) (51). Participants will receive stimulation for 20 minutes 
while seated (prior to robotic motor training), with the anode over  the  optimal  site  for  flexor  
carpi  radialis  (FCR)  as  identified  using  TMS,  and  the  cathode  on  the contralateral 
supraorbital area (37). Sham tDCS: comparable set-up to real tDCS, 30 seconds real current 
ramping to 2mA at commencement, then after 5 seconds a slow decrease but to no current 
sustained for 20 minutes.   
 
Robotic Training  
We will use existing robots at the Feinstein Institute which are FDA-approved robotic devices 
that move the shoulder-and-elbow or wrist-and-forearm (used in a previous IRB protocol 11-
121B). Following tDCS, the patient will be seated in a chair facing a video screen and the robot. 
The patient will hold onto the end of the robotic arm, and if this is not possible, then the patient’s 

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affected arm will be placed in a foam-lined trough attached to the robot handle. Their hand and 
forearm will be held in place by Velcro® straps. The patient will move the robot arm as best 
he/she can through a series of exercises guided by a visual display on the video screen. The 
patient will see their moving arm and hand and see their movements recorded on the video 
screen. If a patient cannot move within 1.5 seconds, the device will move his/her arm through 
the exercises.  These sessions will alternate the treatment of shoulder and elbow with wrist in 
successive sessions. 
 
The standard patient robot interaction involves visuomotor tasks, moving the robotic 
manipulandum  according  to  targets  on  a  computer  screen  mounted  at eye  level.  The  
force  required  to  move  the  robotic  arm  is minimal,  comparable  to  moving  unrestricted,  
and  if  a  patient cannot move  the  robot  arm,  it  will  guide the limb to provide an adaptive 
sensorimotor experience. The robot program will always be tuned to the so-called progressive 
algorithm which blends the features of aiming or path trajectory correction and speed of 
movement.  
 
Blood Sampling 
As we are interested in assay of HMGB-1 and other cytokines longitudinally for the duration of 
the rehabilitation intervention, we will collect two baseline admission samples during admission 
evaluations 2 and 3. We will then collect additional samples at midpoint, treatment 18 (end of 
week 6), discharge, treatment 36 (end of week 12), and follow up, 6 months following the end of 
the rehabilitation intervention.  Given the challenges of collecting samples within a specific 24 
hour time period, the collection window will be extended such that all samples collected during 
the intervention will be obtained plus or minus one treatment day of the target (e.g. between 
treatments 17-19, 35-36-final evaluation day, respectively), and follow up samples will be 
collected plus or minus 7 days of the 6 month follow up target.  Each of the 5 samples will be 4 
cc each (green top tube). We will also obtain a one-time DNA sample, via the collection of a 
10cc lavender tube (EDTA) at the time of the first sample collection.  If this is not possible we 
will collect this sample at the time of a subsequent research blood sample collection.  The total 
volume of blood drawn for each study subject will be no more than 30 cc over the duration of the 
study. All blood sampling will take place at the CRC during scheduled intervention and 
evaluation visits.  
 
The blood will be centrifuged and prepared for HMGB-1 analysis by NS-LIJ Biorepository staff. If 
we miss sample collection across the eight time points the available collected samples from a 
subject will be analyzed. We will measure HMGB-1 and if the levels are elevated (>20ng/ml) we 
will return to the banked samples in the bio-repository to repository to assay samples for IL-1, 
IL-6, IL-8, IL-10, TNF and BDNF, all molecules known to be stimulated by HMGB-1 secretion [4, 
5].  
 
Randomization  
Previous  studies  indicate  that  stroke  patients  may  differentially  respond  to  non-invasive  
motor  cortex stimulation  protocols  according  to  whether  the  lesion  includes  cortex,  or  is  
confined  to  white  matter (52). Accordingly,  we  will  use  blocked  stratified  randomization  to  
ensure  our  two  comparison  groups  are  balanced with  respect  to  this  known  prognostic  
factor  (cortical  versus  subcortical  classification).   Classification  of  this grouping will be 
assessed using CT or MRI with ‘subcortical’ defined as a stroke without involvement of  cortical  
motor  areas,  and  ‘cortical’  as  infarction  of  cortical  primary  or  secondary  sensorimotor  
areas  in addition to subcortical infarction.  
 

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Randomization of patients is performed by a statistician and epidemiologist, Dr. Jessica Elder. 
She will communicate the status to Dr. Volpe.  The switch is covered so that the therapist and 
the PI will not know the group assignment.  
  
Blinding  
The study is double-blind.  All  investigators  interacting  with  patients  will  be  unaware  which  
patients  are receiving  real  or  sham  stimulation.  This  includes  the  principal  investigator  
and  research  fellows  conducting robotic,  neurophysiology  or  clinical assessments.  The 
tDCS device has a coding option to program sham or real stimulation. Ms. Roseann Berlin, a 
histopathologist in Dr. Volpe’s lab who is not involved with the robot project and has agreed to 
perform this toggling task will set the tDCS device for any particular patient. She knows Dr. 
Elder and we will establish communication between Dr. Elder – who will determine the 
randomization and Ms. Berlin so that Dr. Volpe and the Research Associate to be named will 
not have the patient’s code. It is important to note that once the machine to deliver the trans 
cranial direct current stimulation is toggled no further manipulation of the device is needed. The 
tDCSM operates automatically to deliver current or not. We will receive the coding option from 
the collaborating institution, and will reveal this information after analysis, unless there is a need 
to inform the PI in case of an adverse event. Patients will be asked at visit 9 and visit 15 (mid-
point and end of the intervention period), whether they think they received real or sham 
stimulation.   
 
Statistical Considerations and Data Analysis 
 
Specific Aim 1 (Clinical): Determine if there is a statistically significant difference in the change 
in upper limb Fugl-Meyer and  Wolf  Motor  Function score  between  subjects  trained  with  and  
without  tDCS  prior  to  robotic training.   
 
Methods to address specific aim 1:  We will compare demographic, clinical, kinematic, and 
tDCS variables between  intervention  groups  using  t-tests  to  compare  means  and  chi-
squared  tests  to  compare  proportions; where continuous data is non-parametric as defined by 
Shapiro-Wilk or Q-Q plots, we will use Kruskall Wallis tests.    To  assess  the  univariate  
relationship  between  treatment  group  and  upper  limb  Fugl-Meyer  score, repeated 
measures ANOVA will be used in order to account for longitudinal evaluations.  Multivariate 
methods will  include  linear  mixed  models  and  ANCOVA  to  adjust  for  interactions  or  other  
covariates  potentially contributing to the association between treatment and outcome.  Further, 
Pearson correlation coefficients will be  assessed  to  identify  any  linear  association  between  
kinematic,  clinical  and  tDCS  data  points.  The Spearman Rank correlation coefficient will be 
used for non-normally distributed variables. Like the Fugl-Meyer, secondary  outcome  
measures,  Wolf  Motor  Function,  Barthel  Index  and  Stroke  Impact  Scale  are  scored  on  a 
continuous scale and thus, will be analyzed as above. The MRC is scored on a scale from 0-5; 
Fisher analyses will be used to look for differences in strength between groups. 
  
Specific  Aim  2  (Kinematic): Determine if there is a statistically significant difference in a) 
mean  speed,  b) peak speed, c) smoothness, d) aim, and e) deviation from the straight line 
between subjects trained with and without  tDCS  prior  to  robotic  training.  This will be 
determined for both the trained tasks, as well as for the untrained, circle-drawing task.    We  will  
also  include  a  static  and  dynamic  quantitative  measure  of  strength using the robotic 
device.  
                                                                      

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Methods to address specific aim 2:  To assess the univariate relationship between treatment 
group and outcome, repeated measures ANOVA will be used in order to account for longitudinal 
evaluations.  Multivariate methods will include linear mixed models and ANCOVA to adjust for 
interactions or other covariates potentially contributing to the association between treatment and 
outcome.  
   
Specific Aim 3 (Neurophysiology): Determine if there is a statistically significant difference in: 
a) RMT, (b) MEP amplitude at 120% RMT, and c) SICI between subjects trained with and 
without tDCS prior to robotic training, both immediately following the training regimen, and 6 
months later.  
 
Methods to address specific aim 3: To assess the univariate relationship between treatment 
group and outcome, repeated measures ANOVA will be used in order to account for longitudinal 
evaluations.  Multivariate methods will include linear mixed models and ANCOVA to adjust for 
interactions or other covariates potentially contributing to the association between treatment and 
outcome.    
 
POWER:   Based  on  the  previous  study  by  Lo et al., we  can  expect  twelve  weeks  of  
upper  limb  robotic training to result in a 2.88 change in the FM score (5).  We estimated that 
tDCS plus robotics would result in a FM change score of 4.33.  Using  a  two-sided  alpha  and  
a  standard  deviation  of  approximately 1.5, enrolling 56 subjects  (28  per  group)  would  give  
us  90%  power  to  detect  a  difference  in  Fugl-Myer  score  of  1.45  between the intervention 
groups.  To account for potential subject attrition, we aim to increase our sample size by 15% 
thus resulting in an enrollment goal to 66 (33 subjects per group). 
 
Specific Aim 4 (Clinical): Determine if there is a statistically significant difference in the change 
in verbal expression scores on the Apraxia Battery for Adults (ABA-2) and Philadelphia Naming 
Test Short Form (PNT short form)  between  subjects with aphasia trained  with  and  without  
tDCS  prior  to  robotic training.   
 
Methods to address specific aim 4:  We will compare demographic, clinical, and tDCS 
variables between intervention groups with aphasia  using  t-tests  to  compare  means  and  
chi-squared  tests  to  compare  proportions; where continuous data is non-parametric as 
defined by Shapiro-Wilk or Q-Q plots, we will use Kruskall Wallis tests.    To  assess  the  
univariate  relationship  between  treatment  group  and  ABA-2 score, repeated measures 
ANOVA will be used in order to account for longitudinal evaluations.  Multivariate methods will  
include  linear  mixed  models  and  ANCOVA  to  adjust  for  interactions  or  other  covariates  
potentially contributing to the association between treatment and outcome.  Further, Pearson 
correlation coefficients will be  assessed  to  identify  any  linear  association  between clinical  
and  tDCS  data  points.  The Spearman Rank correlation coefficient will be used for non-
normally distributed variables. Fisher analyses will be used to look for differences in strength 
between groups. 
  
Specific Aim 5 (Biological): Examine whether blood levels of HMGB-1, and TNF,IL-1, IL-6, IL-
8, IL-10, and BDNF change across rehabilitation intervention, and if those changes are 
correlated to functional recovery. 
 
Methods to address specific aim 5. The statistical analysis for this pilot study will be 
primarily descriptive in nature. The main statistical analysis will employ repeated 
measures analysis to describe the patterns of change in HMGB-1 and the cytokine values 
over time. Other techniques will be explored if the data warrant it; such as examining 

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pairs of outcome variables  (HMGB-1 and TNF, HMGB-1 and IL-1, or HMGB-1 and stroke 
severity; as pioneered at Feinstein by Dr. O Bloom and as in [57]).  
 
Protection of Human Subjects 
 
RISKS TO SUBJECTS 
 
Human Subject Involvement and Characteristics:  We anticipate enrolling 66 human 
subjects. Inclusion and exclusion criteria are stated above in the Research Design and Methods 
section.  Subjects will be enrolled into one of two sites: the Feinstein Institute for Medical 
Research or the Burke Medical Research Institute. 
 
Sources of Material:  Sources  of  research  material  for participants from Feinstein will  be  
the  hospital  records  providing  demographic  and  medical information  including  CT  or  MRI  
imaging  studies,  and  clinical  examinations  performed  at  outpatient facilities run by the 
Department of Physical Medicine and Rehabilitation of the North Shore University Hospital 
(NSUH) and LIJ Medical Center (LIJMC).  Sources of research material for study participants at 
Burke Medical Research Institute will be obtained through hospital records at the Burke 
Rehabilitation Hospital in White Plains, NY, and overseen by the Burke IRB. 
 
Potential Risks:   
TMS Risks: TMS  is  a  technique  that  has  been  used  widely  and  in  a  growing number of 
laboratories since 1985. A consensus was reached at the International Safety Conference on  
Transcranial  Magnetic  Stimulation,  held  at  the  National  Institutes  of  Health  in  June  of  
1996,  that single-pulse  TMS  and  slow  rTMS  (with  rates  of  stimulation  less  than  one  Hz)  
are  safe.  Subjects may experience mild headaches or neck pain, which are believed to be due 
to muscle tension and from the straight posture of the head and neck during the application of 
TMS. A rare possibility of activating a seizure in susceptible subjects has been documented. 
 
tDCS Risks: tDCS is a safe technique that poses a non-significant risk to participants. The 
safety of this technique has been addressed and tested by multiple researchers (38, 40-42, 45, 
46) who have concluded that tDCS, as applied in a manner similar to our proposed protocol has 
no long-term negative side effects.  More than 30 research studies involving hundreds of 
participants have been published using tDCS. Hundreds more participants have undergone 
tDCS for unpublished pilot research (46).  No undesirable or long-lasting effects have been 
reported, nor have any participants reportedly abandoned a study due to discomfort.   
 
Researchers at the National Institute of Neurological Disorders and  Stroke  (NINDS) conducted 
a safety study on tDCS, investigating 20-minute sessions of 1 mA and 2 mA current stimulation  
with healthy controls (n=103) (45). No negative effects were identified.  Nitsche  and  colleagues 
(2004)  found  no  measurable  structural  changes  in  brain  tissue  due  to  tDCS (64).  
Additionally, studies have shown that tDCS can be used safely in stroke patients (38, 40, 41, 
47). Thus, a growing body of research from different laboratories has shown that tDCS is a safe, 
non-invasive  and  painless  technique  for  modulating  neural  excitability,  with  measurable  
but only transient effects. The protocol described here uses stimulation levels that fall well within 
safety limits established  by  basic  research  investigating  neural  tissue  damage,  as  well  as  
numerous  studies applying  tDCS  with  human  participants (64-66). tDCS  has  the  potential  
to  cause  erythema –  redness  of  the  skin  that  is  uniform  or  mottled  around the  area of 
stimulation.  The reddening has been found to be transient for levels of stimulation proposed in 
this protocol (45). 2005).  

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Nitsche and colleagues (2003) reported that, in unpublished research, stimulation at electrical 
current levels above 1 mA can be uncomfortable for subjects. No such discomfort was reported 
in the NINDS safety study conducted by Iyer and colleagues (2005), in which 103 participants 
were stimulated at levels higher than those used by Nitsche and colleagues (2003).  
 
Robot 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.  
 
Blood Draw Risk: Minimal risks of blood withdrawal include pain from the needle being inserted 
through the skin into the vein, bruising, clot formation under the skin, lightheadedness, possible 
fainting and rarely infection. 
 
Confidentiality Risk: One additional risk concerns the risk to confidentiality incurred with any 
collection of medical data.  
 
ADEQUACY OF PROTECTION AGAINST RISKS 
 
Recruitment and Informed Consent:  Stroke subjects who meet inclusion criteria and do not 
meet exclusion criteria will be recruited at two sites by consenting professionals:  the Burke 
Rehabilitation Hospital and the Department of Physical Medicine and Rehabilitation of NSUH 
and LIJMC..  Recruitment will be done with direct contact, flyers and letters sent to patients who 
have been enrolled on other research projects.  
 
Recruitment of patients at Burke Rehabilitation Hospital will be primarily based on screening of 
the Burke outpatient list, as well as inpatient medical records for identifying future candidates, 
physician referral, advertising within the Burke network, on the Burke Website and collaborator 
websites.  Participants enrolled at the Burke Medical Research Institute study site will be 
overseen by the Burke IRB, and its associated, approved study protocol and consent form. 
 
Northwell Health physicians 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.  The physician will identify potential study participants.  If the patient 
expresses interest in participation, the physician will either 1) obtain informed consent (if they 
are listed as an investigator on this study) or 2) provide the patient with the study coordinator’s 
contact information or 3) provide the patient’s contact information to study personnel with the 
patient’s permission, which will be documented in the medical record. 
 
After a discussion about the study with a potential subject and a potential subject’s legally 
authorized representative (LAR)/next of kin, interested parties will be given a copy of the 
consent form by one of the study investigators.  The investigator will review and explain the 
consent form.  All information about the study will be provided.  Ample time will be given for 
individuals to ask questions regarding participation and to have questions answered prior to 
signing the consent form.  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.  Only those investigators listed in the study protocol will obtain informed consent.  If an 
individual chooses to enroll, the consent form will be signed before participation begins.  Once 
an individual joins the study and informed consent is obtained, the subject will receive a signed 

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copy of the consent form. The subject may withdraw from the study at any time without 
repercussions to subsequent care.   
If the patient is awake, alert, and oriented to person, place, and time, and demonstrates 
appropriate cognitive and communicative abilities as determined by the treating physician, 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 a witness 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. 
 
A study investigator will obtain informed consent, in person, from interested persons. After a 
discussion about the study with a potential subject, interested persons will be given a copy of 
the consent form by one of the study investigators.  The investigator will review and explain the 
consent form to the person.  All information about the study will be provided.  Ample time will be 
given for persons to ask questions regarding participation and to have questions answered prior 
to signing the consent form.  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.   
 
Investigators may contact (or be contacted by) a potential subject’s LAR/next-of-kin by 
telephone to discuss participation in this research protocol. The investigator will provide 
subject’s 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’s LAR/next-
of-kin ample time to consider participation in the study which may require a follow-up phone 
conversation.  
 
If the subject’s LAR/next-of-kin agrees to allow the decisionally incapacitated patient to 
participate in the research study, the investigator will provide his/her contact information. The 
investigator will explain (and repeat) the next steps necessary for the LAR/next-of-kin to provide 
informed consent, which include the following processes. A written consent form will be sent to 
the LAR/next-of-kin as an email attachment, or left at the nurses’ station on the unit where the 
potential subject is an inpatient.  The LAR/next-of-kin must read the consent form and call or 
email the investigator if he/she to discuss research and resolve issues/questions. If subject’s 
LAR/next-of-kin agrees to participation in the protocol, the investigator will direct him/her to sign 
the consent form and return it to the investigator by mail or fax. Another option would be to scan 
the signed consent form to a PDF file and return it to the investigator as an email attachment. 
An enrollment note must be written by the investigator documenting all phone conversations 
with the LAR/next-of-kin. Printouts of any email correspondence must be placed in the subject’s 

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research chart. After the signed consent form is received, investigator will sign the consent form. 
A copy will be made and sent to the LAR/next-of-kin for his/her records. In cases where consent 
is obtained by e-mail/mail, investigators request a waiver for the need for a witness signature.  
 
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. 
 
Only those investigators listed in the study protocol will obtain informed consent.  If a person 
chooses to enroll, the consent form will be signed before participation begins.  Once an 
individual joins the study and informed consent is obtained, the subject will receive a signed 
copy of the consent form.  The subject may withdraw from the study at any time without 
repercussions to subsequent care.   
 
Protection Against Risk:   
Protection against TMS-related risk: All participants will be screened twice for seizure-related 
risk factors (visit 1 & visit 4). Seizure-susceptible patients will be excluded from the study by 
using this screening questionnaire.  sEMG has no know risks. We will monitor subjects 
continually during the  stimulation  period,  and  will  be  in  constant  contact  with  the  subjects.  
The study can be immediately stopped at the subject’s request.  
 
Protection against tDCS-related risks:  If any redness is apparent where the electrodes were 
placed, a cold compress will be offered to the subject. We will monitor subjects continually 
during the stimulation period, and will be in constant contact with the subjects.  The study can 
be immediately stopped at the subject’s request.  
 
Protection against Robot-related risk: The practical issues regarding the robot control system 
and patient safety include that the software that runs the robot device continuously checks the 
force, speed and position of the robot armed and on the status of the power. This software can 
brake the robot if the force, speed, or position is beyond set ranges. There are two clearly 
visible "shut-down" switches that are always in reach of the technician trainer. In the event of 
software failure, motion beyond the specified range, loss of electrical power, or activation of the 
"shut-down" switch the device stops (brakes) within 2 milliseconds. The robotic arm will only 
move the patient's upper limb, and no other body part will be within the active range of this 
movement (the head for example is well out of the possible range of the movement of the 
robotic arm). The patients hand is attached to the robotic arm with a magnetic clasp, which can 
be released with a sudden pull from the patient or therapist. The entire apparatus is ground-fault 
protected to exceed clinical standards. We will monitor subjects continually during robotic 
training, and will be in constant contact with the subjects.  The study can be immediately 
stopped at the subject’s request.     
 
Protection of Confidentiality: To protect subjects’ confidentiality, each subject will be assigned a 
number, and all data will be stored with the subject number only and not the subject’s name. 
Data will be stored on a password-protected computer and on the cloud data sever, REDcap, 
which is encrypted and password protected Subject charts with medical history and assigned 
subject numbers will be kept in locked file cabinets stored at either the Feinstein robot suite for 
patients enrolled through Northwell Health or the Burke robot suite for patients enrolled through 

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Burke Rehabilitation Hospital. Access to charts will be granted only to study investigators at 
Feinstein and Burke, and CRC staff. Charts will be kept confidential and will not be shared with 
any third parties without permission from the subject.  Any study data containing PHI that is 
transferred between investigators at Feinstein and collaborating institutes will be shared via 
encrypted email or encrypted storage drives. 
 
Of note, Dr. Krebs is a sub-investigator from MIT and will be assisting in the analysis of data 
only. Subject data they receive from this research study will be de-identified. 
 
Data and Safety Monitoring:  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.  
 
 
 
POTENTIAL BENEFIT TO SUBJECTS AND OTHERS 
 
The  risk/benefit  ratio  is  very  low  in  the  proposed  study  due  to  the  established  safety  of  
the  protocol and to the great potential for using the findings to improve rehabilitation methods.   
 
SCIENTIFIC VALUE 
 
The results of this study may help to improve stroke recovery. 
 
 
REFERENCES 
 
1. 
A.H.A. American Heart Association Heart Disease and Stroke Statistics.  Heart Disease 
and Stroke Statistics. American Heart Association Council 2003 Update. 
2. 
Carmichael ST. Translating the frontiers of brain repair to treatments: starting not to 
break the rules. Neurobiology of disease.2010;37:237-242. 
3. 
Nudo RJ, Wise BM, SiFuentes F, Milliken GW. Neural substrates for the effects of 
rehabilitative training on motor recovery after ischemic infarct. Science.1996;272:1791-1794. 
4. 
Volpe BT, et al. Robotic devices as therapeutic and diagnostic tools for stroke recovery. 
Archives of neurology.2009;66:1086-1090. 
5. 
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