The Effect of Treatment With the PathMaker Myoregulator Neuromodulation System Incorporating Trans-spinal Direct Current Stimulation (tsDCS) in Patients With Severe Hand Spasticity After Stroke
Phase: PHASE1
Conditions: Stroke, Cerebrovascular Accident (CVA), Hemiparesis, Spasticity as Sequela of Stroke, Muscle Spasticity, Upper Extremity Paralysis
Sponsor: Northwell Health

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Protocol Title: 
The Effect of Treatment with the PathMaker MyoRegulator™ 
Neuromodulation System Incorporating Trans-spinal Direct Current 
Stimulation in Patients with Severe Hand Spasticity After Stroke  
 
Principal Investigator: 
Bruce T. Volpe, M.D.  
 
 
 
 
Sub-Investigators: 
     
Johanna Chang, M.S., CCC-SLP 
 
 
 
 
Maira Saul, M.D. 
 
 
 
 
Regina Lin, B.S. 
 
 
 
 
 
Scientific Advisor: 
 
Zaghloul Ahmed, PhD  
Department of Physical Therapy, College of Staten Island for 
Developmental Neuroscience, the College of Staten Island, Staten 
Island, New York 10314, and 
 
Graduate Center/The City University of New York, New York, 
New York 10016  
 
 
 
 
 
  
 
 
 
 

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Introduction 
 
Spasticity is a disorder of motor function that results from central nervous system injury 
proximal to the anterior horn cell. It commonly occurs after stroke when it is specifically defined 
as a velocity-dependent increase in stretch reflex that causes decreased motor performance as 
well as pain and discomfort [1]. Put succinctly, spasticity is motor over-activity that interferes 
with functional recovery. Evidence from several sources strongly implicates enhanced 
excitability of spinal motor neurons, and in particular, inter-neurons, in the development and 
maintenance of spasticity [2-7]. Therefore, pharmacological intervention relies on drugs that are 
GABAA modulators (benzodiazepine) and GABAB agonists (baclofen) or α2 adrenergic agonists 
(tizanidine); the presumed mechanism of action of these classes of drugs is to increase inhibitory 
neurotransmission [8]. Other mainstays of pharmacological treatment are neuro-muscular 
blockade agents that block release of Ca2+ (dantrolene) or acetylcholine (botulinum toxin A). In 
addition there are more invasive treatments that are irreversible and depend on injection of 
alcohol or phenol. Successful therapy depends on the route of delivery and the dose. Non-
pharmacological treatments include regular or supervised stretching, use of splints, orthoses or 
electrical stimulation or some combination of these interventions with a pharmacological 
strategy [9]. Most studies have a fixed period of observation, and clinical success is often defined 
by improvement in mobility, transfers, activities of daily living, or reduced co-contraction during 
voluntary movement. Improvements registered in studies are often temporary, and are related to 
the intensity and timing of the treatment. Permanent improvement with absence of spasticity 
happens only when more normal patterns of motor performance emerge. Thus spasticity is a 
common and permanent consequence for most survivors of stroke.  The challenge of current 
spasticity treatments is that they all have unwanted side effects that include altered alertness, 
pain, addiction potential, withdrawal seizures/hallucinations, and weakness, especially for the 
irreversible/surgical procedures.  
We propose a pilot experiment to use an investigational device, the MyoRegulator™ 
Neuromodulation System (MyoRegulator™), which pairs trans-spinal direct current stimulation 
(tsDCS) with peripheral DC stimulation (pDCS), to alter the spasticity in the affected upper 
extremity of patients with stroke.  PathMaker Neurosystems Inc., the manufacturer of the 
MyoRegulator™, refers to this unique paired double stimulation treatment as the DoubleStim™ 
treatment, which will be referred to throughout this study protocol as “DoubleStim”. 
The precedent for tsDCS as a new spinal treatment procedure is based in part on transcranial 
direct current stimulation, tDCS,  which modulates  the  excitability  of  a  targeted  brain  region  
non-invasively  by  altering  neuronal  membrane potentials [15, 16]. tDCS effects are polarity-
specific: anodal stimulation generally increases the excitability, while cathodal stimulation 
decreases it [17-19]. Depending on the current density [20], the depolarization is expected to 
induce acute modifications to the membrane of the neurons, thus inducing alterations in neuronal 
activity [18, 21]. Hence this technique can be used to increase or decrease the excitability of 

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neurons in a brain area, in order to determine if  that  region  plays  an  integral  role  in  a  
specific  motor/cognitive function.  In humans, 13 minutes of tDCS resulted in an increase in 
excitability up to 150% and lasting 90 minutes [22]. 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 [23, 24]. 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 [25]. 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 [26]. Other examples highlighting the efficacy of anodal tDCS include: safety of frontal 
DC brain stimulation [27]; anodal tDCS to dorsolateral prefrontal cortex elicited an improvement 
in working memory [28];stimulation to primary motor cortex improved motor learning [26, 29]; 
tDCS  delivered  to  primary  motor  area  or  to visual  area  V5  induced  improvements  in  
visuo-motor  coordination [30];  anodal stimulation of fronto-polar  regions improved  
probabilistic  classification  learning [31]};  and left prefrontal  cortical  stimulation  lead  to  
increased  verbal fluency [32]. Cathodal stimulation decreases cortical excitability in humans - 
i.e., affected neurons will be less likely to fire [33].  The studies using tDCS attest to efficacy and 
safety of the treatment in stroke patients, as well as its potential for therapeutic applications in 
stroke recovery, and by extension supports the potential application of tsDCS for the treatment of 
spasticity. 
More recently, trans-spinal direct current stimulation of the spinal cord (tsDCS) has been 
proposed as a mechanism to modulate muscle tone and improve motor function.   Trans-spinal 
direct current stimulation (tsDCS) has demonstrated in animal models [10-13], and in computer 
modeling [14] that the electric fields induce differential polarization of the various spinal motor 
neurons so that the dendritic Ca2+ persistent inward current modulates motor neuron excitability. 
More specifically, in an animal model, tsDCS  plus pDCS as part of a DoubleStim regime,  the 
anode placed over the spinal column (cathode over a peripheral nerve) decreased the tone, the 
opposite placement increased the tone [13].  In healthy humans, Winkler et al (2010) 
demonstrated that 2.5 mA of tsDCS can mediate the H-reflex response such that 20 minutes of 
anodal tsDCS significantly reduced H-reflex post-activation depression (e.g. facilitated H-reflex) 
and cathodal tsDCS increased post-activation depression (e.g. decreased H-reflex)[43].  Also in 
healthy controls, Bocci et al (2014) reported that cathodal tsDCS to the cervical or lower thoracic 
spinal cord significantly improved motor recruitment recorded at the ulnar and medial nerves 
with incremental multipoint stimulation of the abductor digiti minimi (ADM) and the abductor 
pollicis brevis (APB)[44]. In individuals with spinal cord injury, 20 minutes of 2.5mA anodal 
tsDCS to the thoracic spinal cord significantly increased spinal reflexes (SRs), while having no 
effect on the SRs of healthy controls [45].  Taken together, these data suggest that tsDCS can 
mediate spinal motor response in healthy controls and individuals with neurological injury.  
Whether this treatment alleviates multi-joint spasticity, post-stroke, needs clinical testing.  

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The PathMaker DoubleStim treatment- trans-spinal direct current stimulation of the spinal cord 
(tsDCS) paired with peripheralDC stimulation (pDCS) as delivered using the MyoRegulator 
system, has been proposed as a mechanism to modulate muscle tone and improve motor 
function.  In this pilot study we will test whether the application of Double-Stim to 30 patients 
with extreme spasticity of the distal muscles of the upper extremity will alter standard clinical 
and objective measurements. We will test the effect after treatment and the cumulative effect 
over several treatments.   
 
Specific Aims 
 
SPECIFIC AIM 1: To evaluate whether a single session of anodal vs. sham DoubleStim will 
transiently alter the clinically and objectively measured spasticity in 12 patients with upper 
extremity spasticity after stroke and 6 healthy controls. 
In patients with chronic post-stroke upper limb spasticity and healthy controls, we will use a 
within-subjects sham-controlled design to determine if a single session of anodal -DoubleStim 
significantly alters upper extremity spasticity as compared to the sham DoubleStim condition.  
We will also examine whether the two  conditions (anodal/sham) differentially affect the two 
subject groups (stroke patients vs. healthy controls).   
 
 
SPECIFIC AIM 2: To determine whether five consecutive sessions of anodal - DoubleStim will 
longitudinally alter clinically and objectively measured spasticity in 30 patients with upper 
extremity spasticity after stroke. 
In patients with chronic post-stroke upper extremity spasticity, we will use a within-subjects 
repeated measures design to determine whether 5 repetitive sessions of DoubleStim  (5 
consecutive sessions of 4mA anodal DoubleStim across 1 week) significantly reduces upper 
extremity spasticity longitudinally. 
 
Preliminary Data 
 
We  recently  demonstrated  that  the  combination  of  transcranial direct current stimulation 
(tDCS—cortical stimulation) 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 
[34]. When tDCS is applied during or after robotic therapy it confers no additional advantage. 

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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.  
Having established that tDCS cortical excitability after-effects could be sustained during robotic 
upper-limb training, we further tested if this combination  of  tDCS  and  robotic  training  
applied over  multiple  practice  sessions  might  translate  to improved   motor   function.  Six 
right-handed patients with chronic stroke (>6 mo since ictus), 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 attest to the safety and potential 
clinical benefit of non-invasive direct current stimulation in individuals with chronic stroke. 
More recently, application of trans-spinal direct current stimulation of the spinal cord (tsDCS) 
has been proposed as a mechanism to modulate muscle tone and improve motor function.  
Ahmed (2014) demonstrated in a mouse model that tsDCS paired with pDCS, i.e., DoubleStim, 
significantly altered muscle tone, with anodal stimulation (spinal-sciatic nerve) inhibiting motor 
neurons and reducing muscle tone, and cathodal stimulation (sciatic nerve-spinal) exciting motor 
neurons and increasing muscle tone [13].  These findings attest to the potential clinical benefit of 
DoubleStim to alleviate the painful and constricting upper-limb muscle spasticity (hypertonia) 
commonly seen post-stroke.  In humans, several recent studies have demonstrated the potential 
benefit of tsDCS to modulate reflex activity, improve motor recruitment at the nerve terminal, 
and increase pain tolerance.  Winkler et al (2010) demonstrated that 2.5 mA of tsDCS can 
mediate the H-reflex response in healthy humans such that 20 minutes of anodal tsDCS 
significantly reduced H-reflex post-activation depression (e.g. facilitated H-reflex) and cathodal 
tsDCS increased post-activation depression (e.g. decreased H-reflex)[43].  Also in healthy 
controls, Bocci et al (2014) reported that cathodal tsDCS to the cervical or lower thoracic spinal 
cord significantly improved motor recruitment recorded at the ulnar and medial nerves with 
incremental multipoint stimulation of the abductor digiti minimi (ADM) and the abductor 
pollicis brevis (APB)[44]. In individuals with spinal cord injury, 20 minutes of 2.5mA anodal 
tsDCS to the thoracic spinal cord significantly increased spinal reflexes (SRs), while having no 
effect on the SRs of healthy controls [45].  Additionally, in a recently published conference 
abstract, Cortes et al. (2015) safely administered 4mA of anodal tsDCS stimulation to the C7 
level of the spinal cord in 10 healthy human control subjects, and noted significant transient 

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changes in MEP amplitude at the FDI muscle as measured with TMS. [50].  Taken together, 
these data suggest that tsDCS can mediate spinal motor response in healthy controls and 
individuals with neurological injury.  Whether this treatment alleviates multi-joint spasticity, 
post-stroke, needs clinical testing.  
These studies support investigations aiming to understand the mechanisms and clinical benefit of 
non-invasive direct current stimulation after stroke, and also demonstrate the safety of tsDCS. 
 
Research Design and Methods 
 
This is a single-blind, sham-controlled pilot study with two consecutive phases.  The first phase 
of the study will examine if a single session of anodal DoubleStim vs. sham DoubleStim will 
transiently, but significantly alter muscle tone in individuals with chronic, post-stroke wrist 
spasticity and in healthy control subjects.  The second phase of the study will measure whether 
repeated treatments with anodal DoubleStim over five consecutive days will significantly reduce 
wrist spasticity in patients with post-stroke hypertonicity of the wrist flexor muscles, as 
compared to a sham stimulation condition.  All patients will be recruited through our referral 
sources in the department of Neurology and Physical Medicine.  Age-matched healthy control 
subjects will be recruited from health system employees and family members of participants with 
stroke via direct contact. All visits will be conducted in the clinical robotics and non-invasive 
brain stimulation suite at the Feinstein.  
Inclusion/Exclusion Criteria for Individuals with Stroke: 
 
Inclusion Criteria:  
1. ≥ 18 years of age 
2. First single focal unilateral hemisphere 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  
(per interview with Speech Pathologist) 
4. A Modified Ashworth score between 1-3 points for wrist flexors and extensor muscles 
5. A minimum of 15 degrees wrist passive ROM for wrist flexion and extension from wrist 
neutral position. 
6. Body fat range of 15-25mm for females/10-20mm for males of adipose tissue at the 
cervical neck level and a body fat range of 10-40mm for females/5-35mm for males of 
adipose tissue at the suprailiac crest, as determined by a body fat caliper. 
 
Exclusion Criteria:  
1. Focal brainstem or thalamic infarcts 
2. Prior surgical treatments for spasticity of the upper limb 

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3. Ongoing use of CNS-active medications  
4. Ongoing use of psychoactive medications, such as stimulants, antidepressants, and  anti-
psychotic medications  
5. Botox or phenal alcohol treatment within 12 weeks of enrollment 
6. Pregnancy in women, as determined by self-report 
7. History of spinal cord injury or weakness 
8. Chronic pain, defined by a report of a “5” or greater on the Wong-Baker Pain Scale 
[51,52]. 
9. Peripheral neuropathy including insulin dependent diabetes as determined by case history 
10. Presence of additional potential tsDCS 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; Loop recorders will be reviewed on a case by case basis by 
PI and the treating Cardiologist to make a determination  
 Highly conductive metal in any part of the body, including metal injury to the eye 
(jewelry must be removed during stimulation); this will be reviewed on a case by case 
basis for PI to make a determination  
 Past history of seizures or unexplained spells of loss of consciousness during the 
previous 36 months 
 
Inclusion/Exclusion Criteria for Healthy Controls 
 
Inclusion Criteria: 
1. ≥ 18 years of age 
2. Body fat range of 15-25mm for females/10-20mm for males of adipose tissue at the 
cervical neck level and a body fat range of 10-40mm for females/5-35mm for males of 
adipose tissue at the suprailiac crest, as determined by a body fat caliper 
 
Exclusion Criteria 
1. Ongoing use of psychoactive medications, such as stimulants, antidepressants, and  anti-
psychotic medications 
2. Presence of additional potential tsDCS risk factors: 
a. 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.)  
b. 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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c. Metal in any part of the body, including metal injury to the eye (jewelry must be 
removed during stimulation)  
d. Past history of seizures or unexplained spells of loss of consciousness during the 
previous 36 months 
3. Pregnancy in women, determined by self-report 
4. History of stroke, brain injury, or neurodegenerative disease  
5. History of spinal cord injury or weakness 
6. Chronic pain, defined by a report of a “5” or greater on the Wong-Baker Pain Scale 
[51,52]. 
7. Peripheral neuropathy including insulin dependent diabetes as determined by case history 
 
 
Visit Schedule: 
Phase I:  Single Session of DoubleStim 
Twelve patients with chronic, post-stroke wrist spasticity and six healthy control subjects will be 
accepted into this study. There will be 3 baseline measurement periods prior to treatment.  
Following the lead-in period, all subjects will participate in a training period to compare muscles 
response during a single session of anodal DoubleStim treatment to a sham-controlled session. 
During the first treatment session, subjects will receive a single 20 minute session of sham 
stimulation, and undergo clinical and/or instrumental measurements before, during, immediately 
following, and 20 minutes after stimulation.  The second treatment session will occur 5-8 days 
after the first.  During the second treatment session, subjects will receive a single 20 minute 
session of anodal DoubleStim, and undergo clinical and/or instrumental measurements before, 
during, immediately following, and 20 minutes after stimulation.  Subjects will undergo 3 
additional follow-up clinical evaluations.  Two of these evaluations will occur 4-7 days after 
each training condition, and the final evaluation will occur one month after study completion. 
  
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 Phase I 

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 Week 2, Visit 4 (approximately 90 minutes) 
 20 min of sham stimulation  
 Instrumental measures with EMG before, during, immediately after, and 20 
minutes following stimulation 
 Sham condition clinical discharge measures 
Follow Up Testing Phase I 
 Week 2, Visit 5 (approximately 60 minutes) 
 Sham condition clinical follow-up measures 
 Instrumental measures with EMG  
Training Period Phase II 
 Week 3, Visit 6 (approximately 90 minutes) 
 20 min of anodal stimulation  
 Instrumental measures with EMG before, during, immediately after, and 20 
minutes following stimulation 
 Anodal condition clinical discharge measures 
Follow Up Testing Phase II 
 Week 3, Visit 7 (approximately 60 minutes) 
 Anodal condition clinical follow-up measures 
 Instrumental measures with EMG  
 Week 7, Visit 8 (approximately 60 minutes) 
 Anodal condition clinical follow-up measures 
 Instrumental measures with EMG 
 
 
Phase I 
Schedule 
 
  
Screen 
1 
Screen 
2 
Screen 
3 
Sham 
Tx 
Sham 
FU 
Anodal 
Tx 
Anodal 
FU 
Anodal 
FU 2 
  
Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 
Visit 6 
Visit 7 
Visit 8 
Informed 
Consent 
X 
  
  
  
  
  
  
 
Medical Hx 
X 
  
  
  
  
  
  
 
Demographic 
Info 
X 
  
  
  
  
  
  
 
Inclusion 
Criteria 
X 
  
  
  
  
  
  
 

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Neurological 
Exam 
X 
  
  
  
  
  
  
 
Medication 
check 
X 
  
  
  
  
  
  
 
Outcome 
Measures 
X 
X 
X 
X 
X 
X 
X 
X 
Instrumental 
Assessment 
X 
X 
X 
X 
X 
X 
X 
 
X 
tsDCS 
(anodal v. 
sham) 
  
  
  
X 
  
X 
  
 
 
Phase II:  Consecutive Sessions of DoubleStim 
Thirty patients with chronic, post-stroke wrist spasticity will be accepted into this study.  There 
will be 2-3 baseline measurement periods prior to treatment.  Following the lead-in period, 
subjects will participate in a sham-controlled training period to compare five, consecutive 
sessions of DoubleStim treatment under the two conditions (anodal vs. sham).  The training 
portion of the study will occur over a total of 3 weeks.  During that time, subjects will attend five 
consecutive, 20-minute sessions of sham stimulation, followed by a week rest interval, and then 
another five consecutive sessions of training under the anodal stimulation condition.  During  
training sessions, subjects  will undergo instrumental measurements before and 10 min post 
stimulation,  and may undergo clinical assessments.  Subjects will also undergo additional follow-
up evaluations throughout the course of the study, the first of which will occur between treatment 
conditions (sham follow-up), and the remaining of which will occur 1x/week after completion of 
both training conditions (anodal follow-up) until the FCR (flexor carpi radialis) EMG response 
during the instrumental muscle tone assessment has returned to baseline, or up to 6 weeks.  
These repeated follow-up measures will be obtained in order to measure the potential 
longitudinal benefits of repetitive DoubleStim treatments.    
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 

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Training Period Phase I 
 Week 2, Visit 4-7 (approximately 60 minutes) 
 20 min of sham stimulation  
 Instrumental measures with EMG  
 Clinical measurements during 1-2 visits 
 Week 2, Visit 8 (approximately 90 minutes) 
 20 min of sham stimulation  
 Instrumental measures with EMG before and 10 min post stimulation  
 Sham condition clinical discharge measures 
Follow Up Testing Phase I 
 Week 3, Visit 9 (approximately 60 minutes) 
 Sham condition clinical follow-up measures 
 Instrumental measures with EMG  
Training Period Phase II 
 Week 4, Visit 10-13 (approximately 60 minutes) 
 20 min of anodal stimulation  
 Instrumental measures with EMG before and 10 min post stimulation  
 Clinical measurements during 1-2 visits 
 Week 4, Visit 14 (approximately 90 minutes) 
 20 min of anodal stimulation  
 Instrumental measures with EMG before and 10 min post stimulation Anodal 
condition clinical discharge measures 
Follow Up Testing Phase II 
 Week 5-10, Visit 15-20  (approximately 60 minutes) 
 Anodal condition clinical follow-up measures 
 Instrumental measures with EMG  
 
PhaseII 
Schedule 
  
Screen 
1 
Screen 
2 
Screen 
3 
Tx Cond 1 
(Sham) 
Cond 1 
FU 
Tx Cond 2 
(anodal) 
Cond 2 
FU 
  
Visit 1 Visit 2 Visit 3 
Visit 
4-7 
Visit 
8 
Visit 9 
Visit 
10-13 
Visit 
14 
Visit 
15-20 
Informed 
Consent 
X 
  
  
  
  
  
  
  
  
Medical Hx 
X 
  
  
  
  
  
  
  
  

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Demographic 
Info 
X 
  
  
  
  
  
  
  
  
Inclusion 
Criteria 
X 
  
  
  
  
  
  
  
  
Neurological 
Exam 
X 
  
  
  
  
  
  
  
  
Medication 
check 
X 
  
  
  
  
  
  
  
  
Outcome 
Measures 
X 
X 
X 
 X 
X 
X 
 X 
X 
X 
Instrumental  
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
tsDCS 
(anodal v. 
sham) 
  
  
  
X 
X 
  
X 
X 
  
 
Clinical Outcome Measures 
Modified Ashworth Scale (Primary):  The MAS is a valid and reliable assessment of spasticity in 
patients with chronic stroke [39-40]. 
 
Tardieu Scale (Primary):   The Tardieu Scale is a valid and reliable measure of spasticity that 
accounts for resistance to passive movement at both slow and fast speeds [41-42]. 
 
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].  Photos and/or video recordings will be taken during this assessment for review 
and scoring by approved clinicians, and also potentially for use in clinical efficacy 
demonstrations of tsDCS.   
 
Robotic Wrist Evaluation: Robotic wrist evaluations will be performed using Interactive Motion 
Technologies™ wrist robot device, which objectively assesses volitional movement (e.g. speed, 

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smoothness, power, and trajectory) across two types of wrist rotation (extension/flexion and 
pronation/supination), as well as one type of forearm rotation. 
 
Instrumental Assessments of Muscle Tone 
Passive muscle resistance will be measured using force transducer that is attached to 
participant’s hand. The force transducer is attached to a stepper motor to move it. The slope of 
muscle resistance will be calculated and used for analysis. The slope of muscle resistance will be 
measured at four speeds.  
DoubleStim Protocol 
 
Procedure:  In this study of cervical trans-spinal DC stimulation (tsDCS) paired with median 
nerve stimulation (pDCS) to treat spasticity of the wrist and hand, participants will be seated in a 
chair with the arm and hand supported comfortably.  The stimulation will be delivered using two 
sets of rubber sponge electrodes(one 3x3 inch anode/cathode pair and one 2x2 inch 
anode/cathode pair). Each disposable electrode sponge will be soaked with saline (0.9% NaCl) 
prior to application.  New electrode sponges will be used for each subject treatment.   
     
The 3x3 inch electrode pair is used to deliver the tsDCS.   The anodal electrode of this pair, 
which will be the active electrode, will be placed to cover the level of C6 to the upper edge of 
T1. These cervical segments contain the motor neuron pools for the wrist flexors muscles (the 
target for testing).  The  cathodal electrode of this pair, which will be the reference electrode, will 
be placed over the skin of the frontal aspect of the iliac crest.   
The 2x2 inch pair of electrodes is used to deliver peripheral DC stimulation (pDCS) to the 
median nerve.  These two electrodes will be placed over the skin on the front of the wrist joint 
such that the anode electrode is placed over the nerve relatively distal to the spine (toward the 
hand) and the cathode electrode will be placed over the nerve relatively proximal to the spine 
(toward the spine) .    
Participants will receive stimulation for 20 minutes. The current passing through the two 
electrode sets will be biased using an adjustable electrical circuit. The current intensity passing 
through the spinal cord and iliac crest electrodes will be 4mA, or the maximally tolerated current 
intensity.  The current intensity passing through the wrist electrodes will be ramped up slowly, to 
ensure that it is subthreshold (causing no electrical activity (EMG) from the innervated muscles), 
at a range from 1-3 mA. Sham DoubleStim will have a comparable set-up to active DoubleStim, 
with 30 seconds of real current ramping to the maximally tolerated current intensity at 
commencement, then after 5 seconds, a slow decrease to no current, sustained for 20 minutes. 
 

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To ensure participant tolerance of stimulation, current will be introduced on sliding scale 
of 2.5mA, 3mA, and 4mA. Beginning with 2.5mA, each patient will receive stimulation 
for 1 minute, and confirm that the stimulation is tolerable.  If tolerated, the current will 
then be increased progressively to 4mA. 20 min of treatment stimulation will then be 
administered at the maximum tolerated threshold for each pt. This tolerability dose will 
be determined prior to every treatment schedule for all patients. 
 
                                      
 
Figure 1. Electrode placement in human subjects to reduce muscle tone. Red: Anode; black: 
cathode. A, electrode placement and connection to the DC device. Note that the DC device 
includes a circuit that can bias the current passing through the wrist electrodes in one custom 
made box. B, the diagrams show the placement of the electrodes in a whole body diagram for 
clarity.  
Electromyography:  Electrical activity of the muscle will be differentially recorded during 
DoubleStim sessions using a bipolar electrode montage placed on the belly of the muscle. 
Recordings will be made from flexor carpi radialis and brevis, and from the extrinsic finger 
flexors (flexor digitorum superficialis, and/or flexor digitorum profundus), which are the muscles 
responsible for post-stroke wrist and finger flexor spasticity.  The stimulator output will be 
adjusted to produce no activity from the muscle (subthreshold), which is approximately 3 to 4 
mA at the spinal-abdominal circuit and about 1 to 3mA at the median nerve circuit (in front of 
the wrist).  
 

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Randomization  
All subjects will undergo the sham stimulation condition first and the active stimulation 
condition  second.  The order of stimulation will not be randomized as this is a small, 
investigational pilot study, and the investigators wish to ensure that the results of the active 
stimulation condition do not carry over into the sham condition. 
Blinding  
This is a single-blind, pilot study.  Subjects will be told that they will participate in both the 
active and sham conditions, but they will not be told the order of stimulation, as non-invasive 
brain stimulation has known placebo effects.  Consequently, the MyoRegulator device will be 
covered such that the participants will remain unaware of condition.  For the sham condition, the 
stimulation automatically ramps down after 30 seconds because the perceived sensation of tDCS 
on the skin has been reported to fade after this period [21].  Though investigators will be aware 
of the order of stimulation, the primary outcome measures are objective (EMG recordings and 
instrumental assessment of muscle resistance), and will serve as valid measurements of changes 
in muscle tone.  
 
Statistical Considerations and Data Analysis 
 
 SPECIFIC AIM 1: To evaluate whether a single session of anodal vs. sham will transiently 
alter the clinically and objectively measured spasticity in 12 patients with upper extremity 
spasticity after stroke and 6 healthy controls. 
Methods to address specific aim 1: We predict the changes in muscle tone will be greater 
following anodal DoubleStim compared with sham DoubleStim. This will be examined with a 
2x2 repeated measures ANOVA for muscle resistance scores with stimulation type (A-
DoubleStim, S-DoubleStim) and group (stroke patient, healthy control) as factors. 
SPECIFIC AIM 2: To determine whether five consecutive sessions of anodal DoubleStim will 
longitudinally alter the clinically and objectively measured spasticity in 30 patients with upper 
extremity spasticity after stroke. 
Methods to address specific aim 2: A 2X2 repeated measures ANOVA for muscle resistance 
scores will be used with stimulation type (A-DoubleStim, S-DoubleStim) and time (admission, 
discharge) as factors.  
 
 

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Protection of Human Subjects 
 
RISKS TO SUBJECTS 
Human Subject Involvement and Characteristics:  We anticipate enrolling 42 patients and 6 
healthy control subjects. Inclusion and exclusion criteria are stated above in the Research Design 
and Methods section.   
Sources of Material:  Sources  of  research  material  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), or copies of medical records from outside hospitals provided by participants.  
Potential Risks:   
tsDCS Risks:  tsDCS is a relatively new nonsignificant risk stimulation approach that uses the 
same direct-current non-invasive stimulation technology as tDCS, though it directs the current 
towards the spinal column instead of the cortex. DoubleStim further incorporates simultaneous 
peripheral stimulation at the nerve of interest again using the same direct-current non-invasive 
stimulation technology.   tDCS (transcranial direct current stimulation) has been used in more 
than 30 research studies involving hundreds of participants.  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) (20). No negative effects were identified.  
Nitsche  and  colleagues (2004)  found  no  measurable  structural  changes  in  brain  tissue  due  
to  tDCS (23).  Similarly, trans-spinal direct current stimulation (tsDCS) has been used in several 
recent research studies without any serious adverse events reported [43-48, 49-50].  Additionally, 
our collaborator on this study, Dr. Zhagloul Ahmed has used tsDCS at the intensity proposed in 
this study in unpublished work with human subjects, without any serious adverse events. 
Documented side-effects of noninvasive direct current stimulation  include the potential for a 
tingling sensation at the time of stimulation and erythema –  redness  of  the  skin  that  is  
uniform  or  mottled  around the  area of stimulation.  The tingling and reddening have been 
found to be transient [20-21].  Our present research indicates that in rare instances, subjects may 
experience more moderate-severe redness and soreness, similar to a sunburn, which may last 1-2 
days after stimulation.  Any subject with this reaction will be examined by PI, and may not be a 
candidate for Doublestim.  Because the DoubleStim device will have two circuits (one at the 
level of the spinal cord and one at the level of the median nerve) there is a small additional risk 

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of overactivation at the nerve.  However, activation at the median nerve will be continuously 
monitored with EMG to ensure that the current intensity passing through the wrist electrodes 
(median nerve) is subthreshold (causing no electrical activity (EMG) from the innervated 
muscles), and at ranges from 1-3 mA, while the stimulation at the level of the spinal cord 
remains at 4mA.  EMG monitoring will ensure that activation of the median nerve remains 
subthreshold, and without risk of overactivation.    
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 by consenting professionals through the Department of 
Physical Medicine and Rehabilitation of NSUH and LIJMC.  Healthy control subjects will be 
recruited healthcare professionals through Northwel Health and healthy family members of study 
participants with stroke.  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.  If the patient expresses interest in participation, the clinician will 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 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.  
 
Partial Request for HIPAA Waiver: In addition to the above efforts to recruit patients, and 
because our experiments have prompted the possibility of a multi-center trial in which many 
more patients will be required than are currently being supplied by the consenting professionals 
in the departments mentioned above, and because we do not have a treating physician of record 
on this protocol, we request partial HIPAA waiver to recruit patients after access to the electronic 
medical records for the in-patient and out-patient population of the Northwell Health system.  
We understand completely that without this waiver we have no general access to medical records 
for the purpose of study subject accrual.  We are requesting this access so that we can 
successfully recruit patients to this study as well as offer alternative treatments in our 
Bioelectronic division, should they not qualify for inclusion in this study or should they seek 
additional services.  

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Version 08.18.17 
 
If granted, we plan to supply the electronic medical record department with a list of identifying 
characteristics, name, address and zip code, telephone number, alternate telephone number, 
physician of record, inclusion / exclusion criteria (appropriate ICD 9 AND ICD 10 codes) to be 
used in generating a list of potential patients. Once we receive the list of potentially eligible 
patients, we will attempt to contact the physician of record for the patient in order to inform the 
physician about the goals and the risks of the study and to obtain permission to contact their 
patient. We will then contact the potential patient-subject (or LAR/next-of kin) by phone and/or 
by recruitment mailer to introduce the possibility of participation in the study described in this 
protocol. By phone, we plan to explain the goals and the risks of participating in this research 
study. We will describe the requirements of participation, review a pre-screening checklist, and 
schedule a meeting with the patient-subject. We will also inform the patient that it is possible if 
they come in for the meeting, s/he they 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 meeting we will review the inclusion and exclusion criteria and explain the details of 
the study, also the goals and risks as is our usual custom in the process of obtaining informed 
consent. We will also inform the patient-subject about the alternative treatments available in our 
Bioelectronic Division.  
 
 
Additionally, participating subjects will be asked to have photos and video recordings taken 
during clinical measures in order to document improvement, and to share potential 
improvements with PathMaker Neurosystems Inc.  These photos videos may be used in 
promotional demonstrations to the public.  Photo and video recording will be optional.  Subjects 
who agree to be recorded will additionally sign the Health System AV authorization form, and 
the signature of this form will be noted on the consent.  During the consenting process, a 
potential subject and/or a potential subject’s legally authorized representative (LAR)/next of kin 
will be given a copy of the consent form and Health System AV Authorization by one of the 
study investigators.  The investigator will review and explain the consent and AV authorization 
forms.  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 and AV authorization forms.  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 

19 
Version 08.18.17 
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.   
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 
two witnesses 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. 
Healthy family members of participants with stroke and employees from the health system will 
be recruited as healthy controls through direct contact.  Health System employees will not be 
consented by anyone with a supervisory role over them, and they will be explicitly told that if 
they decline to participate, it will have no effect on their employment status.  Subject family 
members will not be recruited in the presence of the participant with stroke.  They will be 
informed at the time of recruitment that they can decline to participate in the study, and that their 
decisions will not impact the affected subjects’ participation in the study.  In addition, their 
decision to decline or to participate in the study will not be communicated to the affected subject 
by the research staff, unless permitted by the recruited family member.     
 
Protection Against Risk:   
Protection against DoubleStim-related risks:  If any redness is apparent where the electrodes 
were placed, a cold compress will be offered to the subject. Mild-moderate redness at any 
stimulation site immediately following stimulation is a known side effect of non-invasive 
stimulation.  However, if a subject experiences any greater than mild redness and/or soreness at 
the stimulation site 24 hrs after stimulation, the subject will be deemed intolerant of the 
intervention and Doublestim will be ceased for the duration of the study.  Stimulation at the 
median nerve will be continuously monitored with EMG to ensure that the current intensity 
passing through the wrist electrodes (median nerve) is subthreshold (causing no electrical 

20 
Version 08.18.17 
activity (EMG) from the innervated muscles), and ranges from 1-3 mA, while the stimulation at 
the level of the spinal cord remains at 4mA.  EMG monitoring will ensure that activation of the 
median nerve remains subthreshold, and without risk of overactivation.    
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 of Confidentiality: 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. Data will be stored on a password-protected computer and on the cloud data server, 
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 the Feinstein robot suite. 
Access to charts will be granted only to study investigators and company representatives from 
Pathmaker Neurosystems, Inc.  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/company will be 
shared via encrypted email or encrypted storage drives. 
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.  PathMaker Neurosystems Inc. will also have access to the data upon request. 
 
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 rehabilitation of post-stroke upper extremity 
spasticity. 
 
 
 
 
 
 

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