Effects of Device-assisted Practice of Activities of Daily Living in a Close-to-normal Pattern on Upper Extremity Motor Recovery in Individuals With Moderate to Severe Stroke
Phase: NA
Conditions: Stroke
Sponsor: Northwestern University

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PROTOCOL TITLE:  
Effects of device-assisted practice of activities of daily living in a close-to-normal pattern on upper 
extremity motor recovery in individuals with moderate to severe stroke
PRINCIPAL INVESTIGATOR:
Name: Jun Yao, PhD
Department: Physical Therapy and Human Movement Sciences
Telephone Number: 312-908-9060
Email Address: j-yao4@northwestern.edu
VERSION NUMBER:
Version 12 
VERSION DATE:
May 3, 2023
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f
STUDY SUMMARY:
Investigational Agent(s) 
(Drugs or Devices)
Devices: 1, ReIn-Hand device; 2, ACT3D robot; 3, 
PACT3D robot
IND / IDE / HDE # Since both of them are NSR devices, IDE or IND 
numbers are not available for either of them. 
Indicate
Special Population(s)
 Children 
 Children who are wards of the state 
 Adults Unable to Consent  
 Cognitively Impaired Adults 
 Neonates of Uncertain Viability 
 Pregnant Women 
 Prisoners (or other detained/paroled individuals) 
 Students/Employees 
Sample Size
60
Funding Source
National Institute of Health and PTHMS Departmental 
Fund
Indicate the type of consent 
to be obtained
Written 
Verbal/Waiver of Documentation of Informed Consent
Waiver of HIPAA Authorization 
Waiver/Alteration of Consent Process  
Site
 Lead Site (For A Multiple Site Research Study)
 Data Coordinating Center (DCC)
Research Related 
Radiation Exposure
Yes 
 No 
DSMB / DMC / IDMC
Yes 
No
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OBJECTIVES:
Up to 85% of stroke survivors have hemiparesis that affects the upper extremity (UE) on one side1 and 
usually impacts the hand more than shoulder and elbow2. Currently, for mildly impaired stroke survivors (about 
20-25%)3, constraint-induced movement therapy (CIMT) and modified CIMT have been reported to produce 
significantly greater gains in hand/arm function compared to conventional therapy4,5. However, intervention 
options for a large percent of stroke survivors, who have moderate to severe impairment, are lacking, since 
these individuals do not meet the inclusion criteria for CIMT6,7. 
Device use has been studied to assist arm/hand function for individuals with moderate to severe 
stroke. Positive clinical outcomes have been reported8-10, but the quality of the evidence is low11. One of the 
factors that impact the effects of device-assisted interventions is how the device is used. We suggest that 
devices should assist the practice of Activities of Daily Living (ADLs) in a way that enhances the neural 
activities related to ‘normal’ motor patterns, and minimizes undesired activities related to suboptimal 
compensatory movements. Most of these compensatory movements are obligatory, due to the loss of 
independent joint control, which is clinically called ‘synergy’. 
The importance of practicing ADLs has been demonstrated by previous hand/arm interventions in 
mildly impaired individuals6. However, when success in ADL tasks becomes the primary goal, individuals 
frequently develop compensatory movements12 and evoke neural activities unrelated to the required 
movements. As demonstrated in animal models, compensatory neural activities negatively impact 
neuroplasticity and motor recovery13-18. Conversely, trainings that restrict compensation heightened 
ipsilesional plasticity and enhanced motor recovery20-22, which is defined as the restoration of a back to 
pre-injured state at the levels of function, performance, and neural acvitivites16,19. This has prompted the 
opinion that interventions should focus on maximizing motor recovery versus task accomplishment via 
compensation19.
We aim to investigate the feasibility of maximizing hand motor recovery and minimizing compensation via 
practicing ADLs in an anti-synergy environment in the more severely impaired chronic post-stroke population. 
Specifically, we propose to use devices to address 2 major issues that are commonly presented in this 
population:  1) inability to open the paretic hand23,24, and 2) abnormal UE synergic movement patterns, defined 
as the abnormal coupling between shoulder, elbow, wrist, and fingers23,25,26. Recently, we developed and tested 
an EMG-triggered functional electrical stimulator (named ReIn-Hand) to assist voluntary hand use during the 
practice of ADLs and found promising preliminary results in gaining finger extension ability and UE motor 
function27-30. We also have evidence demonstrating that ACT3D robotic modulation of shoulder abduction 
(SABD) loading during active reaching can reduce the UE synergy both acutely and long-term31-34. By combining 
ReIn-Hand with a robot, we propose a reaching-grasping-retrieving-releasing (GR3) intervention in individuals 
with moderate to severe chronic stroke. This design aims to practice ADLs in an ‘anti-synergy’ pattern, via 
augmenting hand opening by ReIn-Hand and minimizing the effects of the UE synergy by the robot, to maximize 
potential motor recovery. We will measure not only the intervention-induced changes in clinical outcomes, but 
also in UE kinematics and functional and morphologic neuroplasticity to disentangle motor compensation versus 
recovery. 
Aim 1: We will measure the intervention-induced changes in clinical outcomes. We will recruit 60 
individuals with moderate to severe (10≤Fugl-Meyer≤40, and Chedoke≤4) chronic (>1 year) hemiparetic stroke, 
who will be randomly assigned to 2 different groups. The experimental group will receive a ReIn-Hand+robot 
assisted GR3 intervention, and the control group will receive a dose-matched ReIn-Hand assisted GR3 
intervention without robot mediation of SABD load. All stroke participants will be examined using validated 
clinical assessments twice pre-intervention, post-intervention (within one week immediately after the end of the 
intervention, and at 3-months follow-up. We hypothesize that the experimental group will have greater 
improvements than those in the control group, as primarily measured by the Box and Blocks Test.
Aim 2: We will measure the intervention-induced changes in UE kinematics while performing hand 
opening with and without SABD load at pre- and post-intervention tests to attempt to disentangle motor 
compensation from recovery. We hypothesize that at post-intervention, 1) the maximal hand opening area will 
be increased, and less coupled with compensatory forces at the shoulder and elbow; and 2) the above 
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improvements will be significantly larger in the experimental group. These motor performance changes will 
suggest motor recovery at the performance level.
Aim 3: We will measure the intervention-induced changes in neuroplasticity. We will measure 
intervention-induced functional and structural changes in gray matter density (GMD) and white matter integrity 
(WMI) at pre- and post-intervention. We hypothesize that after the intervention both groups will have: 1) hand-
opening related cortical activity shift from the contralesional to the ipsilesional hemisphere, 2) increased GMD 
in ipsilesional and decreased GMD in contralesional sensorimotor cortices; and 3) increased WMI in ipsilesional 
cortico-fugal tracks and decreased WMI in the contralesional cortico-fugal tracks, with larger changes in the 
experimental group compared to that in the control group. These neuroplastic changes will suggest motor 
recovery at the neural level.
This will be the first effort to investigate the effects of device-assisted practice of ADLs in an anti-synergic 
pattern, and thus close-to-normal, on UE motor recovery in individuals with moderate to severe stroke by 
evaluating clinical outcomes, kinematics, and neuroplasticity. If hypotheses are supported, the results may 
impact current clinical practice by pushing towards implementing device-assisted practice of ADLs in an anti-
synergy pattern and potentially benefit a large population.
BACKGROUND:
A. Significance
A large post-stroke population exhibits poor or no voluntary control of the paretic hand1. In our recent 
survey on arm/hand function in 94 post-stroke individuals, participants reported the biggest gap between 
the desired and available function for the paretic hand compared to shoulder/elbow function35. 
Furthermore, from the stroke survivors’ perspective, the most important factor impacting UE recovery is ‘the 
use of the arm in everyday tasks’36. Unfortunately, hand interventions currently largely ignore individuals with 
moderate to severe stroke. Re-engaging this large population in arm/hand interventions via device assistance 
is of great significance. 
We propose to use ReIn-Hand, a smart EMG-driven FES device, and a robot to assist this more 
severely impaired population to practice reaching-grasping-retrieving-releasing (GR3) training in an anti-
synergy pattern. Results will be used to answer the following 3 questions with increased power:
1.
Is a device-assisted intervention that targets performing ADLs in an anti-synergy pattern feasible 
to improve hand and arm function in individuals with moderate to severe chronic stroke? Due to practical 
reasons, this question has not been well studied yet. Currently, one opinion is that patients who cannot 
develop finger extension within the first couple of days after a stroke have limited hope for the return of 
hand dexterity37-40. However, such prediction is largely based on conventional and spontaneous recovery, 
which may not apply to new therapeutic methods. As we know, an initial severe neural injury usually 
results in motor compensation in the early phase41, which in turn causes persistence of ‘learned nonuse.’ 
In a rat model, when this maladaptive compensation was enhanced by training the rat’s non-paretic 
forelimb, such training not only resulted in exacerbated impairments and disuse of the paretic 
forelimb14,15, but also diminished performance improvements in subsequent rehabilitative training of the 
paretic forelimb compared with rats that did not received ‘maladaptive compensation’ training14,42,43. 
These behaviors were found to be the result of increased aberrant formation of synapses by multisynaptic 
boutons17, which reflects ongoing competition for survival between synapses18,44 (i.e., ‘synaptic 
competition’). On the contrary, restricting the non-paretic forelimb and training the paretic one leads to 
increased perforated synapses in peri-lesion areas, reflecting mature and efficacious excitatory 
synapses45. These previous results imply that synapses generated by increased use of paretic limb 
competes with the compensation-induced synapses, probably even in more severely impaired 
individuals. Furthermore, in order to maximize the ability to compete with compensation-induced 
synapsis, we need to assist practices of motor activities in an anti-synergy pattern, rather than 
compensatory strategies. It has been shown that behavioral manipulation impacts the neural and 
vascular repair (e.g., axonal sprouting46-50, synaptogenesis17, dentritic growth51, astrocytic reactions52-54, 
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and vascular remodeling responses55). Therefore, practice ADLs in an anti-synergy pattern can be critical 
for creating desired neural activities while minimizing undesired neural activities. Although the chronic 
phase is not optimum for neural repair, it diminishes the confounding factors caused by participating in 
various therapies as well as the spontaneous recovery. Ability for neural repair may still exist even during 
chronic phase, as previous results and our own preliminary results showed that even long after stroke 
new movement patterns can be developed in response to motor training19, 29 and associated with the 
neuroplasticity similar to that was reported in mildly impaired subacute individuals following CIMT29. As 
an initial feasibility study, we choose the chronic phase that guarantees a ‘worst’ case situation. Answers 
to this question, if positive, are expected to push future related research to sub-acute or acute phase, 
and open a door for this large population back to intervention targeted hand function recovery.
2.
Is progressively modulating shoulder abduction (SABD) load important for implementing device-
assisted ADL-related intervention in more severely impaired individuals? Our lab demonstrated that 
increased SABD load introduced 1) increased involuntary flexion forces at elbow25,32-34, wrist and 
fingers24, 2) decreased voluntary finger extension ability23, and 3) decreased FES-mediated hand 
opening30 on the paretic UE. On the contrary, by providing appropriate SABD-load support while a subject 
actively lifts and reaches, even a severely impaired stroke survivor can reach in a comparable way as a 
healthy control subject does34. Furthermore, when training moderate to severe impaired chronic 
individuals reaching with subject- and need-specific SABD-load, they gained significant range of motion33. 
Practically, although our inclusion criteria require a minimal FES-mediated thumb-index finger distance 
of 4cm on the tabletop, once the subjects lift the paretic arm above tabletop, the FES assistance may not 
result in sufficient hand opening anymore30, and thus may hinder the intervention progress. Furthermore, 
even if the ReIn-Hand can successfully open the paretic hand in the context of SABD-induced synergy, 
such synergy itself can cause abnormal movement patterns at shoulder and elbow, and the associated 
neural activities may result in non-desired synaptic competition. In short, without appropriate SABD-load 
supporting, an intervention can be restricted to a tabletop until a subject gains his/her ability to lifting the 
paretic arm against gravity without maladaptive compensation. However, restricted training on tabletop 
will impact the ability to transfer training to real ADL performances that usually require arm lifting. 
Mechanistically, the primary means to increase hand opening is via using contralateral corticospinal 
tracks (CST)56. With robotic support, we can initially lower the neural demands for driving shoulder and 
elbow, and reserve more residual CST resources (which are limited in stroke) for driving the hand. 
Therefore, implementing SABD control via robot during GR3 is anticipated to be especially important for 
individuals who cannot lift the paretic arm above table without compensation, which is prevalent in 
individuals with moderate to severe stroke25. For these participants, robot will create a haptic environment 
that allows them for the lifting and reaching in an anti-synergy pattern and enhances its associated 
neural/vascular activities. Specifically, we will progressively modulate SABD load in a manner where 
subjects are able to demonstrate 70%-80% FES-mediated opening ability in the experimental group. By 
comparing the intervention-induced changes resulted by practicing GR3 with and without SABD 
modulation, we will be able to shed a light on this question.
3.
Are the intervention-induced changes in individuals with moderate to severe chronic stroke motor 
compensation or recovery? Both previous results from other groups and our preliminary results 
demonstrated intervention-induced changes in this more severely impaired chronic population8,29,33,57. 
However, whether these changes are motor compensation or recovery is still unknown. Although 
compensation is easier to occur, rehabilitation should urge the use of effective ways to maximize motor 
recovery, which refers to the restoration of a function back to a more-normal, pre-injured state16,19 (see 
table 1 for the definition of ‘recovery’ and ‘compensation’ at functional, performance, and neuronal levels, 
respectively). Previous evidence from clinical assessments usually suggests pure compensation during 
the chronic phase58. However, post-intervention increase in the functional use of ipsilesional sensorimotor 
cortices and back-to-normal structural changes were also reported29,59,60. This discrepancy between 
measures at performance and neural levels may be due to the limited resolution of impairment measures, 
like Fugl-Meyer Stroke Assessment61,62 (FMA), the Chedoke-McMaster Stroke Assessment63 (CMSA), 
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etc. Detailed kinematic analysis of motor patterns together with non-invasive neural imaging methods are 
desired to quantify ‘recovery’ versus ‘compensation’64. Up to now, such efforts in more severely impaired 
individuals are very limited. We propose to measure changes in kinematics with high resolutions (a 
position accuracy of 1mm and an angular accuracy at 0.02 degrees for hand opening area, and an 
accuracy of 0.1N for shoulder/elbow force generation), and in functional and structural neuroplasticity to 
shed a light on this question. 
Table 1. Definitions of recovery and compensation at 3 different levels19
Level
Recovery
Compensation
Functional
Successful task accomplishment using limbs or end-
effectors typically used by nondisabled individuals
Successful task accomplishment using 
alternate limbs or end-effectors.
Performance
Restoring the ability to perform a movement in the 
same manner as it was performed before injury.
Performing an old movement in a new 
manner.
Neuronal
Restoring function in neural tissue that was initially 
lost after injury.
Neural tissues acquire a function that it 
did not have prior to injury.
B. Innovation
The combined use of ReIn-Hand and robotic devices will facilitate hand opening and reduce 
abnormal SABD-induced synergy when practicing ADL-related activities. For facilitating hand 
opening, various devices have been used in interventions, including both non-EMG-driven and EMG-
driven ones. Non-EMG-driven devices, like The Ness H200 (Bioness, Inc, Valencia, CA), require pushing 
a button (usually by the unaffected hand) to trigger the assistance8. This type of devices cannot provide 
the synchronized proprioceptive and somatosensory feedback with motor tasks. Such synchronization is 
preferred since it increases Hebbian learning by strengthening the involved synapses65, and acts as a signal 
for axonal sprouting after cortical lesions62. EMG-triggered devices provide this desired synchronization. 
However, current available devices commonly use EMG amplitude to control repeated hand opening 
and/or closing at a fixed sequence, usually with the arm resting on a table. Due to the UE synergies, 
when a stroke user activates proximal muscles during reaching and lifting, EMG-amplitude from both 
finger/wrist flexors and extensors could significantly increase24. Therefore, amplitude based approaches 
cannot reliably control the hand in the context of non-tabletop activities in individuals with abnormal UE 
synergies66. Innovatively, we have designed algorithms to reduce the impact of synergic muscle 
activation67, thus guaranteeing a <1% error rate in the detection of a hand close instead of an open, while 
keeping a >90% accuracy rate of detecting hand opening during a functional arm movement. 
Although ReIn-Hand can detect hand opening in the context of synergic muscle activities, its resulted 
hand opening area is usually reduced with a lifted the arm30. Furthermore, it cannot reduce the expression 
of SABD-induced synergy at shoulder or elbow either. Due to these 2 issues, interventions without 
appropriate SABD-support will either be restricted to a tabletop, thus becoming less ADL-related, or be 
performed with the abnormal movement patterns caused by SABD-induced synergy. We therefore 
innovatively propose to combine ReIn-Hand and robot to allow individuals with moderate to severe stroke 
for the practice of some of ADLs in an anti-synergy movement pattern. By providing the dose-matched 
control group who will only get assistance from ReIn-Hand for hand opening, we will be able to investigate 
the importance of practicing in ‘close-to-normal’ pattern vs. non-controlled way.
The use of robotic-controlled kinematic measures at multiple joints will provide high resolution 
and accurate data to disentangle motor recovery versus compensation. Using an effective ACT3D 
robotic modulation of shoulder load, we have developed and validated a set of methods to reliably 
quantify elbow and hand control abilities under various conditions with high resolution and accuracy31. In 
order to disentangle motor recovery versus compensation for hand control, we propose to use these 
validated methods to quantify intervention-induced changes simultaneously in at multiple joints when 
maximally opening the paretic hand with or without lifting the arm in moderate to severe stroke individuals. 
As suggested, reduced synergy is one of the important signs of motor recovery68. In the proposed study, 
we will measure both hand-opening-induced UE synergies as quantified by coupling torques generated 
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at shoulder and elbow, and the impact of SABD-induced synergy on hand opening ability. When 
performing hand opening without lifting the arm, an intervention-induced increase or decrease in the 
coupling shoulder and elbow torques (i.e., hand-opening-induced UE synergy) will indicate motor 
compensation or recovery, respectively. Furthermore, we will quantify the impact of SABD-induced 
flexion synergy on the hand opening ability. A better maintaining of maximal hand opening area while 
lifting the arm compared to without lifting will indicate motor recovery. Otherwise, a significantly reduced 
hand opening when lifting will indicate motor compensation, since it reflects that when restricting the 
compensation from shoulder by requiring an arm lifting, an individual cannot open the hand anymore. 
The use of multi-modality imaging methods will provide quantitative measures of intervention-
induced neuroplasticity. Motor recovery is not only defined at functional and motor performance levels 
(see table 1), but also at the neural level. Up to now, cortical activities related to hand opening with and 
without lifting the arm following a hand related intervention have not been widely investigated yet. We 
have established validated methods in using high density EEG approach together with subject-specific 
MRI-based brain model in estimating the cortical activities with a time resolution of 1 ms and a spatial 
resolution of 3-5 mm69-73. Using this method, we have previously demonstrated abnormal cortical 
activities that were associated with abnormal synergies71. We expect that a post-intervention shift of 
cortical activity back to ipsilesional sensorimotor cortices will indicate motor recovery since it mimics 
“normal” hand-related cortical activity.
At neuronal level, motor recovery is defined as restoring function in neural tissue that was initially lost 
after injury19. If strictly following this definition, then structural repair has to occur to support it. In animal 
models, evidence for structural changes, such as axonal sprouting, synaptogenesis, dendritic growth, 
and so on, has been reported46-54. In human model, several groups have shown increases in gray matter 
(GM) density in ipsilesional sensorimotor cortices74, along with increases in fractional anisotropy (FA) in 
ipsilesional corticospinal tract (CST)75 in acute and chronic stroke individuals with mild impairments. 
However, since individuals with moderate to severe stroke are largely ignored in current arm/hand 
interventions, it is still unknown whether an arm/hand intervention for these more severely impaired post-
stroke individuals will result in structural changes. Using advanced anatomical and structural magnetic 
resonance imaging (MRI) methods we will measure morphological changes in GM density and 
descending WM integrity. Different from the previous work that focused on the ipsilesional side in mildly 
impaired subjects, we will also innovatively quantify these structural changes in the contralesional side. 
This is based on our recent results that separately evaluated reticulospinal and rubrospinal tract 
microstructure in chronic stroke individuals with UE motor impairment for the first time76. Our results 
demonstrated that individuals with the greatest UE synergy severity and hand impairments post-stroke 
have the highest FA in the contralesional reticulospinal tract, a pattern consistent with increased 
myelination and suggestive of neuroplastic reorganization following stroke-induced compensation76. 
Using a multi-modal MRI approach, the proposed study will provide evidence for morphological 
neuroplasticity in this more severely impaired large population. We anticipate simultaneous structural 
changes in the form of a decrease in the contralesional GM density and FA, and an increase in these 
structural measures in the ipsilesional side. This will agree with ‘synaptic competition’ theory and support 
the motor recovery.
C. Relevant prior experience and gaps, as well as preliminary data
Aim 1: to measure the device-assisted intervention-induced changes in clinical outcomes
Both electronic and robotic devices have been used to assist arm/hand therapy in individuals with 
moderate-severe stroke. As a systemic review summarized, robotic-assisted interventions improved ADL 
scores, arm function and arm muscle strength, but the quality of the evidence was low to very low11. Many 
factors may impact the effects of device-assisted interventions. One of them may be the way to use 
devices. For example, although various devices have been used to facilitate the training of different joints, 
they have never been used in a way to assist both proximal and distal joints during the performance of 
an ADL. A recent large trial used 3 robots to assist 127 participants with moderate-to-severe chronic 
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stroke to practice horizontal reaching (the 1st 3 weeks), grasping without arm lifting (the 2nd 3 weeks), and 
integrating proximal and distal joints (the 3rd 3 weeks)77. At the end of a 12-week intervention, results of 
this device-assisted training was not different from usual care77 or intensive therapy77. Although this 
intervention involved 3 robots and integrated shoulder, elbow and wrist in the last session, the 
intervention did not target any ADL. 
The importance of practicing ADLs has been demonstrated by CIMT in mildly impaired individuals, 
where beneficial effects usually included motor function, arm-hand activities, and self-reported arm-hand 
functioning, immediately after treatment and at long-term follow-up6. When taking the ADL practice out 
of CIMT as used in forced use therapy78-80, there is no evidence for the efficacy of constraint alone78-80. 
In more severely impaired individuals, devices have assisted the practice of ADLs. For example, Bioness 
H-200, a FES device, was used to assist removing items from a dishwasher in moderate chronic 
indiviudals8; and a hand robot was used for reaching and grasping objects in sub-acute mild-severe 
individuals60. These ADL-targeted interventions, all with relatively small size (N is about 10), reported 
better outcomes than the large size study without targeting ADL77, and supported the importance of ADL 
practice in this more severely impaired population. 
It is worth noting that none of previous ADL-targeted interventions support shoulder load to reduce 
the remarkable impact of SABD-induced synergy on function and motor patterns at distal joints23-25,34. 
When success in the ADL task becomes the dominant goal without efforts to reduce synergy, individuals 
frequently develop compensatory movements. One study found that CIMT improved efficiency of paretic 
arm movements by increasing the reliance on trunk movements12, suggesting that CIMT promotes the 
refinement of compensatory movement strategies. While realizing the importance of being able to 
progressively use the paretic UE during ADLs, we also strive for motor recovery with the hope of breaking 
the bottleneck that may be caused by compensation. We propose to combine ReIn-Hand and robot to 
allow participants to repetitively practice reaching, grasping, retrieving, and releasing (GR3) with 
progressively increased challenge. We expect that this intervention will improve motor function (as we 
practice ADLs) and decrease impairment (as we enhance the hand opening29 and reduce the SABD-
induced synergy33 simultaneously). 
Preliminary results: Eight participants with chronic (>1-year post, mean: 11.2 years) severe stroke (UE 
FMA scores 10-24/66) were recruited to participate in a 20-session intervention (3 sessions/week). 
During each session, participants performed 20-25 trials of Reaching, Grasping, Retrieving, and 
Releasing (GR3) a 3cm jar with the assistance of the ReIn-Hand device. Pre, post and 3-month follow-
up clinical assessments, including UE FMA61,62, Chedoke McMaster Stroke Assessment Hand Subscale63 
(CMSA_H), grip dynamometry, the BBT81,82, active and passive goniometrics for wrist and metacarpal 
phalangeal (MCP) flexion and extension (II, V fingers), the Nottingham Stereognosis Assessment83,84 
(NSA), and sensory touch thresholds using monofilaments were performed. Non-parametric Friedman 
tests of differences between pre- and post-intervention measures found significant changes in the BBT 
(λ2=10.38 p< .05), passive and active range of motion (λ2=11.31 p< .05 and λ2=12.45, p< .01, 
respectively), and NSA (λ2=6.42, p< .05). These results suggest that the ReIn-Hand assisted GR3 
intervention may improve voluntary hand control in individuals with severe impairment following stroke. 
Other considerations: 1) Dropout rate: The dropout rate for robot-assisted arm/hand training has been 
reported to be 45 per 1000, which is comparable to that for conventional interventions (42 per 1000)11. 
As adverse events were seldom described, assistive devices are concluded to be safe as a rehabilitation 
tool11. 2) Dosage: A home-based study used the Bioness H-200 to assist 8 moderately impaired 
individuals to repetitively practice a subject-selected ADL (e.g., open jar) every weekday for 8 weeks. It 
reported significant increases on motor function in the group who practiced 120min/session but not in the 
group of 60 or 30min/session85. Furthermore, our own preliminary results using ReIn-Hand to assist 8 
severely impaired individuals to practice GR3 suggested that a dose of 60min/day, 3 weekdays for 6-7 
weeks produced a significant change on the Box and Block Test (BBT), however it was not maintained 
on 3-month follow up27. Our ACT3D-mediated reaching intervention in 13 moderate-severe individuals 
reported significant outcomes at post-intervention test with a dose of 60min/day, 3 weekdays for 8 
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weeks32. In order to balance fatigue and intensity, 
we choose a dose of 90min/day, 3 weekdays for 8 
weeks. This dose is stronger than that used in our 
preliminary 
interventions, 
but 
weaker 
than 
120min/session for 40 sessions. 
Aim 2: to measure the intervention-induced 
changes in biomechanics 
To 
disentangle 
intervention-induced 
improvements due to motor recovery or motor 
compensation, 
quantitative 
measures 
that 
simultaneously quantify multi-joint kinematics with 
high resolution and accuracy have advantages 
compared to clinical assessments19. These 
kinematic measures also closely follow the 
validated clinical assessments such as FMA86. 
Using kinematic measures a few previous studies 
reported that reduced synergy was one of the 
important signs of motor recovery68,87,88. Therefore, 
we propose to quantify maximal hand opening 
area with and without lifting the paretic arm. 
Simultaneously, we will also measure the coupling 
force/distance in X, Y, Z directions generated by 
shoulder and elbow (see figure 1C). This will allow 
us to quantify the impact of SABD-induced synergy 
on hand opening, and impact of hand-opening-
induced synergy on proximal joints. Measuring 
these UE kinematics before and after the two 
interventions have potential to provide information 
about underlying mechanisms that drive any 
potential improvements achieved by the proposed 
interventions.
Preliminary results
Kinematics: 36 individuals (moderate stroke: 
FM=26~40 N=13, severe stroke: FM=10~25 N=13, 
healthy control: N=10) were recruited for this 
study. Each participant was instructed to perform 
following sequent movements: 1) moving the hand 
to the home position; 2) resting for 1s; 3) lifting the 
arm off the table with a shoulder load equal to 25% 
or 50% of the participant’s shoulder abduction 
maximum voluntary torque (MVT) or staying at 
table for 2s; 4) maximal hand opening while 
keeping the arm position. More details of the 
experimental setup and protocol can be found in 
our publication23. Hand pentagon area (HPA), 
defined as the area formed by the tips of thumb 
and fingers (see figure 1A subplot), was used to 
quantify hand opening ability. Forces under thumb 
Figure 1. A) Hand pentagon area (HPA) during hand 
opening task in severe, moderate and control groups 
at table, SABD25 and SABD50 conditions. The 
severe group was not able to generate any 
measurable HPA. The subplots illustrated the HPA 
definition and the HPA that was used for 
normalization that was measured when the non-
paretic hand was maximally stretched on a tabletop.  
B) Grasping force under thumb and fingers during 
opening task. When asked to perform hand opening, 
the severe group was actually generated flexion 
force, which was increased with the increased SABD 
load. The subplot showed an example of force 
measure. C) Intervention-induced relative changes in 
the coupling force in the X, Y, Z directions, 
calculated as (post-pre)/pre, during hand opening 
with (dashed line) and without arm lifting (solid line). 
All the results are negative, reflecting a reduction in 
coupling force after intervention.
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and fingers were recorded to quantify grasping 
force (see figure 1B subplot). We found that 1) 
in individuals with moderate stroke, increasing 
shoulder abduction loading reduced the ability to 
maximally open the hand; and 2), in individuals 
with severe stroke, who were not able to open 
the hand, involuntary grasping forces were 
generated 
and 
increased 
with 
shoulder 
abduction loading23 (see figure 1A and 1B). 
Furthermore, coupling forces generated at 
shoulder and elbow while performing maximal 
hand opening with and without SABD load were 
recorded by the 3D load cell that was attached 
to the forearm orthosis. In 3 severe stroke 
individuals, we compared such coupling forces 
before 
and 
after 
the 
preliminary 
GR3 
intervention as stated in aim 1. As shown in 
figure 1C, when these individuals performing 
maximal hand opening without SABD, the 
overall post-intervention coupling forces at X, Y, 
and Z directions (solid lines) were reduced to 
about 50% of that before intervention. When 
performing the hand opening while lifting up 
again 50% of a subject’s SABD maximal 
voluntary torque, coupling forces at X and Y 
directions (dashed lines) also reduced about 
50%. Please note for the hand opening with 
SABD load, the force in the Z direction was 
controlled by the ACT3D robot, and thus was not 
compared. 
These 
preliminary 
results 
demonstrated the feasibility of quantifying hand 
opening ability and coupling forces at shoulder and elbow with high resolution. Furthermore, results in 
figure 1C supported feasibility of motor recovery after the preliminary GR3 intervention in chronic stroke 
individuals with moderate to severe impairments.
Aim 3: to measure the intervention-induced changes in neuroplasticity 
Aim 3A: neuroplasticity at functional level
Motor recovery is also demonstrated at the neural level. Intervention-induced neural changes have been 
investigated widely using animal models89. For instance, monkeys or rodents trained on a skilled  
‘reaching to grasping’ task express enlarged representation of the digits of the hand or forelimb in 
ipsilesional primary motor cortex (M1) following training as measured by intracortical microstimulation90,91. 
The cortical reorganization underlying effective task-specific arm/hand interventions in acute and chronic 
stroke subjects with mild impairments support those seen in the animal literature described above. 
Several variations of arm/hand interventions, including CIMT, bilateral task-specific training, and hand-
specific robot-assisted practice have shown cortical reorganization such as increased sensorimotor 
activity and enlarged motor maps in the ipsilesional hemisphere related to the paretic arm/hand92-95. 
These results suggest increased recruitment of residual resources from the ipsilesional hemisphere 
following training. In moderate to severe chronic stroke, hand task related cortical activity has been 
reported to involve contralesional or secondary motor areas96-101, reflecting compensatory mechanisms 
at neural level. In these individuals, increased contralesional activity when moving their paretic arm 
Figure 2. A) Lesion locations for the 8 subjects overlaid on 
axial MNI T1 slices. The color bar indicates the number of 
subjects with lesioned tissue in a particular voxel. LH 
indicates the lesioned hemisphere. B) Box plots depicting 
cortical activity ratio prior to and following the intervention 
for Hand Opening without lifting the arm; C) and with lifting 
the arm against 50% of SABD MVT. *p < .05, #p = .06. 
Individual data was plotted when p< 0.1.
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correlates with impairment102,103. Intervention-induced cortical reorganization in individuals with moderate 
to severe stroke was less investigated before, and thus largely remaining unknown. We propose to 
simultaneously measure the changes in cortical activities related to hand opening with and without SABD 
load while measuring the UE kinematics. We expect that hand-opening related cortical activities will shift 
from contralesional sensorimotor cortices back to ipsilesional side. This back to normal change will 
suggest motor recovery at neural level.
Aim 3B: neuroplasticity at structural level
It is widely accepted that neuroplasticity is a key factor for determining outcome104-106. Besides 
functional cortical reorganization that is proposed to study in aim 2, structural changes may also occur. 
In animal models, it has been reported that cortical activity changes significantly influence the targets for 
both local and distant sprouting axons89,107, and thus guide structural changes. For example, in monkeys or 
rodents trained on a skilled reach to grasp task, in addition to functional cortical activity changes 
mentioned above, rapid local structural changes in the form of dendritic growth, axonal sprouting, 
myelination, and synaptogenesis also occur21,108-110. Importantly, these neural changes correspond to 
motor recovery following rehabilitative training in these animals111,112. In human model, rapid acquisitions 
of high-resolution anatomical 3D imaging (MPRAGE) allow for the detection of changes in gray matter 
(GM) density using techniques such as voxel-based morphometery113,114. Furthermore, the inception of 
diffusion tensor imaging (DTI) has allowed for researchers to identify neural tissue connectivity and is 
particularly sensitive to white matter (WM) morphology115. Together, MPRAGE and DTI measures can 
be implemented to detect gray and white matter changes in health, disease, and injury115. Using these 
methods, intervention-induced structural changes in subacute mildly impaired stroke individuals have 
been reported74,75. These results are largely in agreement with findings in animal models, suggesting 
increased synaptogenesis and/or dendritic complexity in GM, along with increased integrity of WM 
tissue74,75. However, since individuals with moderate to severe stroke are largely ignored in current 
arm/hand interventions, it is unknown whether an arm/hand intervention for these more severely impaired 
post-stroke individuals will result in structural changes. If yes, whether structural changes restore the 
function in neural tissue that was initially lost after injury is also a question. 
To answer above questions, we will use anatomic T1 and Diffusion weighted scans to quantify GM 
density, a measure of dendritic complexity, and WM Fractional Anisotropy (FA), a measure of white 
matter integrity, before and after intervention. We hypothesize that following device-assisted GR3 
interventions, moderate to severe chronic stroke individuals will show similar structural changes as 
observed in mildly impaired individuals, demonstrated by 1) an increase in GM density in ipsilesional 
sensorimotor cortices and decreased GM density in contralesional sensorimotor cortices; and 2) increased 
WM integrity in ipsilesional cortico-fugal tracks and decreased WM integrity in the contralesional cortico-fugal 
tracks. Furthermore, above changes will be at a higher level in the experimental group as compared to 
that of the control group.
Preliminary results 
At cortical level: For the 8 individuals that participated the preliminary GR3 intervention as stated in the 
aim 1 preliminary result part, we also quantified the intervention-induced changes in functional cortical 
activity. Surface EEG data related to hand opening with and without lifting the arm were measured before 
and after the intervention; We then reconstructed the cortical activity (see method part for details). 
Reconstructed sources in the regions of interest (ROIs), including bilateral primary sensorimotor cortices 
(primary motor cortex (M1) + primary sensory cortex (S1)) and secondary motor cortices (supplementary 
motor area (SMA) + premotor area (PM)), were used to calculate the 1) cortical activity ratio (CAR), which 
was defined as the total current strength of one ROI normalized by the total combined strength of the 4 
ROIs; and 2) a Laterality Index (LI) that reflects the relative contributions of each cerebral hemisphere to 
the source activity (definitions for both CAR and LI can be found in the method part). Individuals 
demonstrated a shift in cortical activity related to hand opening from the contralesional to the ipsilesional 
hemisphere following the intervention (p<0.05, not depicted). For the table condition, this was driven by 
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decreased contralesional M1+S1 activity and increased ipsilesional secondary motor cortices’ activity 
(p<0.05, see figure 2B); and for the lifting condition, this back-to-normal shift was driven by increased 
ipsilesional M1+S1 activity (p<0.05, see figure 2C). The increased use of ipsilesional resources and 
decreased use of contralesional resources support the motor recovery after the preliminary GR3 
intervention.  
At the structure level: On 19 moderate to severely impaired chronic stroke individuals and 15 healthy 
age-matched controls, we used high-resolution DTI to quantify WM fractional anisotropy (FA) in relation 
to severity of arm synergy (as measured by UE FMA) and hand related motor impairments (FMA hand 
portion). We found that post-stroke the contralesional reticulospinal tract FA correlated significantly with 
both UE synergy severity (r=-0.606, p=0.003) and hand impairment (r=-0.609, p=0.003)76 (see Figure 3). 
This supports the hypothesis that more severely impaired chronic stroke individuals depend more on 
contralesional corticobulbar pathways to compensate for the stroke-induced damage, and that these 
contralesional pathways lack the ability to allow further significant recovery. Furthermore, we examined 
structural GM changes in the 8 individuals who participated in the preliminary study as stated in aim 1 
preliminary results section. Subjects displayed increased GM density in ipsilesional primary sensorimotor 
cortex and decreased GM density in contralesional primary sensorimotor cortex at the level of p<0.00129. 
These findings suggest that despite moderate to severe chronic impairments, post-stroke participants 
maintain ability to show GM structural changes following a ReIn-Hand assisted GR3 intervention. The 
ipsilesional GM density changes are similar as those reported in post-stroke individuals with mild 
impairment. The intervention-induced decrease in contralesional GM density has not reported before. 
This discrepancy may be because compensatory structural changes in contralesional side in mildly 
impaired individuals is not as significant as that in more severely impaired individuals. Overall, our 
preliminary results suggest 
that 
residual 
neuroplasticity 
in 
more 
severely 
impaired 
individuals may have the 
potential 
to 
support 
improved 
hand 
motor 
recovery, 
and 
such 
neuroplasticity 
may 
include structural changes 
corresponding 
to 
both 
inhibiting 
the 
compensatory expression 
and 
facilitating 
motor 
recovery.
STUDY ENDPOINTS:
Aim 1: to measure the device-assisted intervention-induced changes in clinical outcomes
The primary outcome measures will be the Box and Blocks Test (BBT)82-83. The secondary outcomes will 
be the Action Research Arm Test116,117 (ARAT), Quantitative Measure of Hand Opening Area and Closing 
Force (QMHOC), Cutaneous Sensory Touch Threshold (CSTT) Test using Semmes-Weinstein 
Monofilaments, Upper Extremity Fugl-Meyer Assessment61,62 (UE FMA), Chedoke–McMaster Stroke 
Assessment – Hand portion (CMSA-Hand), Sensory Assessment (Stereognosis), Motor Activity Log122-
124 (MAL), the Stroke Impact Scale (hand function domain, SIS_H)125,126 and Revised Nottingham Sensory 
Assessment: Kinaesthesia Subscale (NSA)83,84.
Aim 2: to measure the intervention-induced changes in biomechanics
Figure 3. The correlation of contralesional reticulospinal tract FA with UE synergy 
(A) and hand impairment (B) on 19 moderate to severely impaired chronic stroke 
individuals.
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The primary measure will be overall coupling in X, Y, Z directions generated by shoulder and elbow, 
defined as:
,
|
𝑍𝑜𝑝𝑒𝑛
𝑍𝑚𝑎𝑥| + |
𝑥𝑜𝑝𝑒𝑛
𝑥𝑚𝑎𝑥| + |
𝑦𝑜𝑝𝑒𝑛
𝑦𝑚𝑎𝑥|
where 
 and 
 are the forces measured in Z (vertically down to the floor) direction when a subject 
𝑧𝑜𝑝𝑒𝑛
𝑧𝑚𝑎𝑥
performs the maximal hand opening on the virtual table provided by the robot, and when a subject the 
maximally pushes down to the virtual table, respectively. Similarly, 
 and 
, as well as 
 and 
𝑥𝑜𝑝𝑒𝑛
𝑥𝑚𝑎𝑥
𝑦𝑜𝑝𝑒𝑛
 are the moving distances in X and Y directions, respectively, when a subject performs the maximal 
𝑦𝑚𝑎𝑥
hand opening on the virtual table, and when a subject the maximally moving in X and Y directions, 
respectively.
The secondary outcome measure will be hand opening ability, defined as the ratio between (hand-open-
aperture with 50% subject’s maximal shoulder abduction ability) and (hand-open-aperture with table 
support). When hand opening is not available even with the arm resting on the table, the hand opening 
ability will be defined as  -1x
.
𝐺𝑟𝑖𝑝𝑝𝑖𝑛𝑔 𝑓𝑜𝑟𝑐𝑒𝑆𝐴𝐵𝐷50
𝐺𝑟𝑖𝑝𝑝𝑖𝑛𝑔 𝑓𝑜𝑟𝑐𝑒𝑡𝑎𝑏𝑙𝑒 
Aim 3: to measure the intervention-induced changes in neuroplasticity 
Aim 3a: at functional level
The primary measure will be Laterality Index (LI = (I-C)/(I+C)), where ‘I’ and ‘C’ are the current density 
strengths from the ipsilesional and contralesional sensorimotor cortices (i.e., combined primary 
sensorimotor and secondary motor cortices). 
The secondary measure will be cortical activity ratio 
 for each of the 4 regions of 
𝐶𝐴𝑅= ∑𝑛
1𝑆𝑛/∑𝑚
1 𝑆𝑚
interest (ROIs), where ‘S’ represents the current density strength of one of the nodes, and n and m 
represent the number of nodes in one of the ROIs and whole sensorimotor cortices, respectively. Specific 
regions of interest (ROIs) include bilateral primary sensorimotor cortices (primary motor cortex (M1) + 
primary sensory cortex (S1)) and secondary motor cortices (supplementary motor area (SMA) + premotor 
area (PM)). The cortical activity ratio reflects the relative strength from one ROI as normalized by the 
total combined strength of the 4 ROIs.
Aim 3b: at structural level
The primary measure will be voxel-based changes in gray matter density (GM density) caused by 
intervention.
The secondary measures will be fractional anisotropy of the corticospinal and corticobulbar tracts from 
the both hemispheres.
STUDY INTERVENTION(S) / INVESTIGATIONAL AGENT(S):
This study investigates the feasibility of regaining hand opening ability in individuals with moderate to 
severe stroke using device-assisted intervention. Three devices will be used during intervention:
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1), The ReIn-Hand device: it combines intelligent detection software, “the ReIn-HAND platform”, and an 
FDA approved (510(k)# K021100) electrical stimulator (Empi 300 PV, Vista, CA, or E-Wave Zynex 
Medical, Inc, Englewood, CO). The ReIn-Hand platform wirelessly and simultaneously records surface 
EMG activities from up to 8 upper limb muscles, including: deltoid, biceps brachii, triceps, extensor 
communis digitorum, extensor carpi radialis, flexor digitorum profundus, flexor carpi radialis, and abductor 
pollicis. The device then uses novel signal processing methods to detect hand opening with or without 
arm movements based on EMG features118. Once hand opening is detected, a signal is sent to trigger 
ES to assist with paretic hand opening (see the supplementary material for a video of the use of this 
device). The stimulation electrodes will be placed over finger/wrist extensors; and the stimulation will 
have following parameters: amplitude sufficient for maximal hand opening without discomfort, biphasic 
waveform, frequency 50Hz20% and 300us pulse width, ‘ON’ duration=3s.
2), The arm coordination training 3D robot (ACT3D): ACT3D is a customized research equipment. It 
comprises a modified force-controlled HapticMASTER (HM) robot (MOOG, The Netherlands) integrated 
with a Biodex experimental chair (Biodex Medical Systems, Shirley, NY). The ACT3D allows for low 
inertia movements in three dimensions and can provide a virtual effect of gravity that can be enhanced 
or reduced by imposing forces along its vertical axis (i.e., Z-axis). ACT3D robot will be used to measure 
the forces and moments during the performance of required motor tasks for quantifying the intervention 
-induced changes in biomechanics (i.e., experiments for aim 2), and for providing controlled Z-force 
during determining the intervention parameters when PACT3D is not available. Please note that both 
PACT and ACT3D provide the same control of force in the Z-direction.
3) The passive arm coordination training 3D robot (PACT3D): The PACT-3D generates the required 
endpoint forces using a novel spring system that is passive in nature but can be controlled using an 
actuator to set the desired force. Same as ACT3D, it also allows for low inertia movements in three 
dimensions and can provide a virtual effect of gravity that can be enhanced or reduced by imposing 
forces along its vertical axis (i.e., Z-axis). However, PACT3D is portable, lighter, and with even lower 
inertia as compared to ACT3D robot. PACT3D robot will be used to providing controlled Z-force during 
interventions for the experimental group.
Device Handling: The above three devices will be stored in the laboratories in the Department of 
Physical Therapy and Human Movement Sciences at 645 N Michigan Ave, Chicago, IL 60611. Use of 
one or two of these devices will be only on consented participants by authorized investigators that are 
approved by IRB.
PROCEDURES INVOLVED:
Introduction
The general hypothesis is that the ReIn-hand and robot assisted GR3 intervention will result in improved 
hand/arm motor recovery in individuals with moderate to severe stroke, as measured by clinical 
outcomes, UE kinematics, and neuroplasticity, and such improvement will be larger in the experimental 
group (trained with ‘ReIn-Hand + robot’) as compared to the control group (trained with ‘ReIn-Hand only’). 
The control factors are time (3 levels: pre, post, and 3-month follow up intervention) and group (2 levels). 
Aim 1: to measure the device-assisted intervention-induced changes in clinical outcomes
Experimental Design
A double-blinded, 2-baseline, randomized experimental design will be used (see Figure 4). 
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Power analysis and 
Subjects: Using our 
preliminary 
results, 
we will power the 
study 
to 
detect 
differences 
in 
the 
BBT of a minimum 
effect size of 0.9 at a 
significance level of 
0.01. Based on our power analysis with consideration of dropout rate at 7%, we will recruit 60 (with 56 
valid data in the end) adults (age: 21-81 years) with chronic (>6 months since stroke137) UE hemiparesis 
resulting from unilateral stroke to participate in this study. Main inclusion criteria include: 1) moderate to 
severe UE impairments with UE FMA 10-40119; 2) moderate to severe hand impairment with CMSA_H 
scores between 0 and 4120; 3) ability for the ReIn-Hand device to generate an opening of ≥4 cm between 
thumb and the index finger. Exclusions include: 1) inability to follow 3 step commands121; 2) difficulty in 
sitting for 3 hours by self-report; 3) Chemodenervation: Botox injection within the last 6 months; 4) 
incompatible with MRI scan, and 5) any contraindications to electrical stimulation (e.g. pregnancy, seizure 
in the past 6 months, implanted pacemaker). More detailed inclusion/exclusion criteria can be found in 
the inclusion and exclusion criteria section. 
Randomization: Following consent, the blinded assessor will determine the eligibility using the inclusion 
and exclusion criteria. Participants who satisfy study criteria will undergo baseline assessments 2 times 
prior to randomization/allocation. The training therapist, who will not be blinded, will assign participants 
to the experimental or control group via a computer-generated random, permuted, randomization 
sequence, with consideration of the balance in FMA scores of the 2 groups. 
Interventions: 
Research participants will participate in a 24-session intervention, ~2 hours per session, 3 sessions per 
week, for 8 weeks in total. The individuals involved with the administration of the intervention are two 
training physical therapists (Training PT) and two training technicians. Research participants, training 
PTs, and clinical evaluators will be blind to group assignment.
For all sessions and both groups, research participants will be seated in a seating system with straps 
across the chest and waist to prevent unwanted trunk movement. The training technicians will stretch 
the paretic UE for up to 15 minutes. The ReIn-Hand device will be attached to the paretic upper 
extremity (UE) and then positioned at a home position in 75° shoulder abduction (SABD), 30° shoulder 
flexion, and 60° elbow flexion.
The first session will be a 'parameter adjusting session', during which the training PT will determine 
training parameters, including: 1) SABD load, 2) target(jar) distance, 3) jar width, 4) jar weight, 5) jar 
height, and 6) jar orientation. These training parameters will be established both on the table condition 
and using a robot. The robot modulates the supporting force in Z-direction applied to the arm while 
participants are required to lift the arm, thus changing the shoulder abduction (SABD) load. The SABD 
load will be set as the maximum load that allows the participant to: actively reach the target distance, 
and achieve a ReIn-Hand mediated hand opening no less than 4 cm between the tips of the thumb and 
index fingers. After establishing SABD load, all the additional parameters (#2-6) will be set, first with the 
established SABD load as following: 2) Target distance is 70% of the distance of the max reach of the 
paretic UE when fully supported on a frictionless table created by the robot; 3) Jar width will be 
increased in 0.5 cm increments, by adding padding around the jar, to the max width the participant can 
achieve with the ReIn-Hand; 4) Jar height (i.e., distance from the lowest part of the jar to the surface of 
the table) will be set as 2 cm increments to the max height the participant can successfully (and 
painlessly) reach the jar; 5) Jar orientation (i.e., the relation of the long axis of the jar to the table 
surface) will be set as 2° increments to the maximum amount that allows the participant to successfully 
grasp the jar; and 6) Jar weight will be increased in 100 g increments, stopping if the participant 
Figure 4. Flow chart of the experimental design. The blue area shows the involved experimenters.
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Figure 5. Experimental setup showing a subject using 
the robot while high-density EEG and surface EMG 
signals will be simultaneously recorded. Visual feedback 
will be displayed on a computer screen.
experiences pain or cannot lift the jar. The Training PT will then repeat the steps 2-6 to determine these 
parameters (#2-6) under table condition; i.e., this time without robot support and thus using a height-
adjustable table.
Once the intervention parameters are set, the training technician will guide the participant to perform 
the GR3 activities using these parameters. Participants in the experimental group will be trained using 
the robot. Their forearm of a participant will be attached to an orthosis, which will be firmly attached to 
the robot. Participants in the control group will be trained on a regular height-adjustable table. All 
training sessions will consist of 40 trials (about 1 hour) of 'reaching-grasping-retrieving-and- releasing' 
(GR3) activities, which include: 1) Reaching towards a plastic jar (diameter=3cm, weight=30g when 
empty); 2) Activating finger/wrist extensor muscles to trigger the ReIn-Hand device, which in turn 
assists the opening of the paretic hand while reaching; 3) Grasping the jar; 4) Retrieving the jar to the 
home position and placing it on the table; and 5) Releasing the jar. In order to avoid fatigue, a resting 
time of 20-30 seconds will be provided between trials.
Participants in the control group will be encouraged to perform GR3 activities with the arm above the 
table. The experimental group will get the necessary SABD support via the PACT3D and thus be 
required to reach above the table. Both groups will be provided with the same verbal cues. A successful 
trial requires the completion of all five tasks required during one trial: Reaching towards a plastic jar, 
triggering the ReIn-Hand device, grasping the jar, retrieving the jar to the home position and placing it 
on the table, and releasing the jar. An unsuccessful trial is defined as the failure to complete one of the 
five tasks during one trial. The result of each of the 40 trials will be recorded by the training technician.
The Training PT will review the training performance after each session to determine if adjustment of 
parameters is necessary for the next session. If a participant successfully completes 30/40 trials in 2 
successive sessions, the training PT will re-adjust all the parameters at the following session in order to 
progressively challenge the participant. New parameters then will be implemented by the training 
technician during the following session.
Outcomes: Clinical assessments will be completed by the blinded assessor at baseline (2 times), within 
one week of the end of treatment, and 3 months after completion of treatment. The primary outcome 
measures will be the Box and Blocks Test (BBT)82-83. The secondary outcomes will be the Action 
Research Arm Test116,117 (ARAT), Quantitative Measure of Hand Opening Area and Closing Force 
(QMHOC), Cutaneous Sensory Touch Threshold (CSTT) Test using Semmes-Weinstein Monofilaments, 
Upper Extremity Fugl-Meyer Assessment61,62 (UE FMA), Chedoke–McMaster Stroke Assessment – Hand 
portion (CMSA-Hand), Sensory Assessment (Stereognosis) (SAS), Motor Activity Log122-124 (MAL), the 
Stroke Impact Scale (hand function domain, SIS_H)125,126 and Revised Nottingham Sensory Assessment: 
Kinaesthesia Subscale83,84 (NSA).
In addition, the blinded assessor will also perform the following outcome measures weekly: BBT (about 
5 mins), QMHOC (~10 mins), and CSTT Test (~15 mins). 
Aim 2: to measure the intervention-induced 
changes in biomechanics
Experimental Design
Before and after one week of the intervention, 
we will measure UE kinematics and surface 
EEG data during maximal hand opening with 
and without SABD load. All the participants will 
be seated in a Biodex seating system with straps 
across the chest and waist to prevent unwanted 
trunk movement (Figure 7). The arm will be 
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positioned at a home position in 85° shoulder abduction and 40° shoulder flexion, and 90° elbow flexion 
with the forearm in mid pronation-supination. The hand will rest on a cylinder, attached to forearm orthosis 
that is covered with an array of pressure sensors (Pressure Profile Systems, Inc., Los Angeles, CA 
90045). Furthermore, a six-axis load cell (JR3, model 45E15A) will be used to measure forces generated 
by shoulder and elbow. These forces will also be used by our admittance controlled robot (Moog-FCR 
B.V., the Netherlands) and to measure the weight of the arm. Subsequently, 160 EEG active electrodes 
(Biosemi, Inc, Active II, Amsterdam, The Netherlands) will be mounted on a stretchable fabric cap based 
on a 10/20 system. Skin under each of the electrodes will be prepared to keep the impedance below 5 
k for the duration of the experiment. Additionally, the positions of EEG electrodes on the subject’s scalp 
will be recorded with respect to a coordinate system defined by the nasion and pre-auricular notches 
using a Polaris Krios handheld scanner and reflective markers (NDI, Ontario, Canada). This will allow for 
coregistration of EEG electrodes with each subject’s anatomical MRI data. EMG signals of the 
intermediate head of deltoid (IDL), flexor digitorum profundus (FDP) and extensor digitorum communis 
(EDC) will be recorded using surface electrodes. Furthermore, 5 markers at the size of (9x9 mm) with 
unique optical features will be placed on the tip of the thumb and the 4 fingers, with another marker on 
the back of the hand for reference purposes. Position (with an accuracy of 1mm) and angular (with an 
accuracy at 0.02 degrees) information of fingertips will then be captured by 2 registered portable Moire 
Phase Tracking cameras (Metria Innovation, Inc., Wauwatosa, WI). This will allow for the kinematic 
tracking of the hand pentagon area during the various motor tasks. The total setup time will be about 2 
hours. A break (0.5-1 hour) will follow setup to avoid fatigue.
Before implementation of the main protocol, we will first measure a subject’s maximal voluntary torque 
(MVT) in the direction of SABD, maximum finger grasping forces of the paretic UE, and maximum HPA 
of the non-paretic hand when the hand is maximally stretched on a table top (see figure 4A subplot) for 
normalization purposes. During the main protocol, participants will be instructed to move to the home 
position (the blue ball in figure 7) first, which will trigger the home position to change to a green ball. This 
sign will indicate the experimenter to inform the subject the start of a trial. Participants will then be asked 
to relax in the home position for 5-7s and then to self-initiate the required motor task for 2s, with the eyes 
looking at the paretic hand without blinking or eye moving. Maximal hand opening will be performed in 2 
conditions, including table condition where the arm will rest on the haptic table, and a SABD load condition 
where the arm will be lifted above table against 50% of his/her SABD MVT. Real time visual feedback of 
the participant’s SABD torque will be provided to the experimenter only to control the performance of the 
task. A set of 60-70 trials will be collected for each condition. These trials will be collected in blocks of 
20-30 trials in a random order. Rest periods of at least 15 seconds between trials and ~10 min between 
blocks will be included to avoid fatigue. The total duration of data collection is about 3 hours. 
We will simultaneously collect EEG, EOG and EMG data (all at 1KHz, Active II, Biosemi, Inc., 
Amsterdam, The Netherlands, or ), forces generated by shoulder/elbow (at 256 Hz, ACT3D robot, Moog-
FCS, The Netherlands, or PACT3D robot, Hankamp Rehab BV, Enschede, The Netherlands), 3D-
position of fingertips (at 180Hz, MPT Series 2, Metria Innovation Inc. Milwaukee, WI 53213, Or at 250 
Hz, trakSTAR, Northern Digital Inc. Waterloo, Canada) and the pressures under the thumb and fingers 
(at 512Hz, Pressure Profile Systems, Inc., Los Angeles, CA 90045). We will also measure subject’s 
upper- and forearm lengths.
Aim 3: to measure the intervention-induced changes in neuroplasticity 
Aim 3A: Experimental Design
We will use the EEG data collected during aim 2 to investigate the neuroplasticity at functional level. 
Aim 3B: Experimental Design
Within two weeks prior to and following the intervention, scans will be performed at Northwestern 
University’s Center for Translation Imaging on a 3 T Siemens Prisma scanner with a 64-channel head 
coil. Structural T1-weighted scans will use an MPRAGE sequence (TR=2.3s, TE=2.94ms, FOV 
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256x256mm2) 
producing 
an 
isotropic voxel resolution of 1x1x1 
mm3. DTI will use spin-echo echo-
planar 
imaging 
(TR=5s, 
TW=85ms, matrix size=150x150, 
FOV=225x225mm, 
number 
of 
slices=120) producing an isotropic 
voxel resolution of 1.5x1.5x1.5 
mm3. The sequence will consist of 
diffusion weighting of 1000s/mm2 
in 60 different directions, and 8 
scans with no diffusion weighting 
(b=0 s/mm2).
Statistical Analysis, expected 
outcomes, Potential Problems 
and Alternative Strategies
A voxel-wise General Linear Model will be applied using permutation-based non-parametric testing 
with Threshold-Free Cluster Enhancement127 to detect changes in GM density and FA integrity following 
the intervention and any group differences. Voxel-based threshold of changes in GM density and FA 
integrity will be set at p < .05 Family-wise error corrected.
Alternative methods
We expect that about 50% of our participants will have severe impairment, and thus cannot open 
hand voluntarily. In this case, we will measure the pressure under thumb and fingers before and after 
intervention.
Other methods, such as functional MRI, can also measure the functional cortical reorganization. We 
choose to use high-density EEG approach, since robotic control of SABD loading will be used. This will 
allow us to measure both SABD-induced and hand-opening-induced synergies simultaneously at multiple 
joints and at cortical level. Furthermore, the EEG method is robust to the head movements that are 
commonly associated with the shoulder abduction. We have more than 15-year experience in using high-
density EEG with robot and thus confidant that this approach can give us reliable measures.
Alternative diffusion analysis methods such as probabilistic and deterministic tractography allow the 
recreation of WM tracts through user-specified regions of interest. We choose to instead use TBSS since 
tractography methods may lose validity when passing through lesioned tissue, whereas we can mask out 
lesioned tissue and restrict our analysis to healthy tissue in TBSS while using a whole-brain analytical 
approach. Additionally, it solves the issues of non-ideal registration and the arbitrary nature of choosing 
spatial smoothing extent in analyzing white matter connectivity by using fine-tuned nonlinear registration 
and subsequent projection onto a static white matter tract representation (i.e. mean FA skeleton).  
STUDY TIMELINES
Table 2 lists the duration of an individual’s participation in the various study sessions. 
Visit #
Experimental Sessions
Duration (hours)
Pre-clinical Assessment 1
1.5
1
Pre-intervention MRI + DTI
1
2
2
Pre-clinical Assessment 2 
3D Scanning
1
3
Pre-intervention biomechanical 
+ EEG
3.5-4.5
4-27
Intervention (24 sessions)
Weekly Measures
1.5-2
Post-clinical Assessment 1
1.5
28
Post-intervention MRI + DTI
1
29
Post-intervention biomechanical 
+ EEG
3.5-4.5
30
1-month post-intervention 
1.5
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We will actively recruit subjects 
from the Clinical Neuroscience 
Research Registry (N=700+). We 
will conduct interventions for 7-8 
subjects per year. Considering a 
dropout rate of 7%, we expect that we will recruit and collect data on 60 subjects. This will result in 56 
(with 28 for each of the groups) valid data by the end year of the proposed study. We will keep making 
enrollment effort, until we successfully collected data on 56 participants. 
INCLUSION AND EXCLUSION CRITERIA
The target age range of stroke participants is 21-80 years old. We plan to recruit 60 individuals with 
chronic hemiparetic stroke who have some shoulder and elbow control, but lack basic hand function, to 
participate in the cross-sessional experiments of this study (Upper Extremity (UE) FMA61,62 in the range 
of 10-40/66, Chedoke McMaster Stroke Assessment Hand Subscale63 (CMSA_H) stage of the hand 
section <=4). 
Subjects who have had a stroke will be selected from the Clinical Neuroscience Research Registry, 
maintained by the Physical Therapy and Human Movement Sciences department at Northwestern 
University and the Shirley Ryan AbilityLab (Former Rehabilitation Institute of Chicago - RIC), containing 
more than 700 members. Stroke survivors residing in the Chicago area who wish to participate in the 
study will be considered as well. Tests of the ReIn-Hand system will be performed on the paretic arm of 
individuals with stroke. Clinical assessments will be performed on both the paretic and non-paretic arm. 
The following inclusion criteria will be applied to the stroke participants: 1) Age between 21-80; 2) Paresis 
confined to one side, with substantial motor impairment of the upper limb and some residual voluntary 
movement (UE FMA in the range of 10-40/66, CMSA_H stage of the hand section <=4); 3) Capacity to 
provide informed consent; 4) Ability to elevate their limb against gravity up to at least 75 degrees of 
shoulder flexion and to generate some active elbow extension; 5) Ability to achieve ReIn-Hand device 
assisted hand-open at the level of thumb-to-index finger distance ≥4 cm; 6) MRI compatible; 7) 
Discharged from all forms of physical rehabilitation, 8) Intact skin on the hemiparetic arm, 9) Ability to 
tolerate sitting for no less than one hour, and 10) Montreal Cognitive Assessment (MoCA) score >=23.  
Exclusion criteria are: 1) Motor or sensory impairment in the non-affected limb; 2) Any brainstem 
and/or cerebellar lesion; 3) Severe concurrent medical problems (e.g. cardiorespiratory impairment, 
uncontrolled hypertension, inflammatory joint disease); 4) History of neurologic disorder other than stroke 
(PD, ALS, MS, TBI, peripheral neuropathy); 5) Any acute or chronic painful condition in the upper 
extremities or spine, indicated by a score ≥5 on a 10-point visual analog scale; 6) Using cardiac 
pacemaker, implanted cardioverter defibrillator, neurostimulation system inside brain or spinal cord, bone 
growth box fusion stimulation; 7) Seizure in the past 6 months; 8) Severe upper extremity sensory 
impairment indicated by absent sensation on the tactile sensation subscale (light touch and pressure 
items) of the Revised Nottingham Assessment of Somato-Sensations84,85 (score<4);  
9) 
Chemodenervation: botulinum toxin, Myobloc, phenol block, or dysport injection to any portion of the 
paretic UE within the last 6 months, or phenol/alcohol injections <12 months before participation; 10) 
Unable to passively attain 90 degrees of shoulder flexion and abduction, measured using a goniometer 
based on adapted methods; 11) Flexion contractures larger than 45 degrees in the elbow, wrist,  
metacarpophalangeal joints (MCP) and interphalangeal joints (IP); 12) Pregnant or planning to become 
pregnant; and 13) Participating in any experimental rehabilitation or drug studies; 14) Inability to attend 
intervention sessions 3 times a week during 8 weeks, as well as assessments/evaluations and follow up; 
15) UE musculoskeletal impairment limiting function prior to stroke, 16) currently using oxygen, and 17) 
upper limb amputation.  
While most inclusion criteria will not rule out the potential participation of Registry Members, the 
greatest impacting criteria is the FMA and the ability of opening hand with the aid of the electric stimulation 
clinical session follow-up
31
3-month post-intervention 
clinical session follow-up
1.5
Table 2. The expected duration of participation for study sessions
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device. We anticipate that a minimum of 40% of Registry members (n=700) will be of the moderate to 
severe levels described above and appropriate for participation. 
PARTICIPANT POPULATION(S)
Accrual 
Number:
Category/Group:
(Adults/Children 
Special/Vulnerable 
Populations)
Consented:
Maximum Number to be 
Consented or 
Reviewed/Collected/Screened
Enrolled:
Number to Complete 
the Study or Needed 
to Address the 
Research Question
60/0/0
200/60/80
56
Local
0
0
0
0
Study-wide
0
Total:
60/0/0
200/60/80
56
RECRUITMENT METHODS
Once funded, we will immediately start to work on the proposed study. Subjects who have had a stroke 
will be selected from the Clinical Neuroscience Research Registry, maintained by the Physical Therapy 
and Human Movement Sciences department at Northwestern University and the Shirley Ryan 
AbilityLab (Former Rehabilitation Institute of Chicago - RIC), containing more than 700 members. In the 
registry, basic information, like phone number, address, contact email, onset time of stroke, and so on, 
is listed. Stroke survivors residing in the Chicago area and have other available information satisfying 
our inclusion/exclusion criteria will be contacted by phone or email for recruitment (wording of the 
phone and email has been attached).
In addition to the Clinical Neuroscience Research Registry, the study will be listed on The New Normal 
(TNN) Match and ResearchMatch. Both are web-based recruitment portals offered by the Center for 
Clinical Research, a center in the Northwestern University Clinical and Translational Sciences Institute. 
We will also contract to BuildClinical, LLC to enhance the participant’s recruitment. BuildClinical is a 
data-driven platform that helps academic researchers recruit participants for research studies more 
efficiently using social media, software, and machine learning. BuildClinical has worked with IRBs in the 
US to ensure the adherence to all the appropriate guidelines and procedures. BuildClinical utilizes 
study-specific advertisements to engage participants on digital platforms such as Facebook, Google, 
WebMD, etc., and redirect them to a study-specific landing page should they click it. On the landing 
page, the person can complete an online pre-screen questionnaire that gets routed into BuildClinical's 
platform. BuildClinical's Secure Socket Layer (SSL) software, which encrypts all inputted information, 
keeps participants’ information private and HIPAA compliant. BuildClinical’s backend servers are stored 
in the USA at some of the most secure data centers in the world.
Stroke survivors residing in the Chicago area who wish to participate in the study will be considered as 
well. Flyers will be distributed in rehabilitation centers. In most cases, these subjects are referred by 
participants who are already recruited. 
COMPENSATION FOR PARTICIPATION IN RESEARCH ACTIVITIES
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Participants will be paid $20 per hour for participation in this study, with $10 from NIH support and the 
other $10 from Physical Therapy and Human Movement Sciences departmental funds. If your session 
lasts less than 1 hour, your participation time will be compensated as 1 full hour. If you are here for more 
than one hour, your participation time will be compensated as the nearest half or full hour, whichever is 
closer. 
Participants will be given reimbursement for public transportation expenses or parking fee in 
Northwestern Medical School parking lots (located at 321 E. Erie St. or 222 E. Huron St.) where a parking 
voucher will be provided for your free parking when you drive here. If a cab or rideshare car (Uber or Lyft) 
is needed, we request the participant to contact lab staff to confirm that the fare can be covered before 
scheduling pickup. If using the rideshare program Lyft, the Lyft trip will be booked by a research team 
member through the Lyft application on your behalf. Since it will be booked through a Lyft Concierge 
account that has been set up by the Department of Physical Therapy and Human Movement Sciences, 
there is no cost to the participant. If using a cab or Uber, reimbursement will be paid by check and a 
receipt is required.
Reimbursement and payment will be submitted to the accounting department on a weekly basis. 
Typically, the accounting department will mail you a check 4 weeks after receiving the payment request.
The Accounting Services at Northwestern University will be given your name, address, and Social 
Security Number in order to issue a check for your study participation. Study payments are considered 
taxable income and reportable to the IRS. A Form 1099 will be sent to you if your total payments are 
$600 or more in a calendar year.
WITHDRAWAL OF PARTICIPANTS
Possible reasons for removal include changes in participant health conditions, changes in experimental 
inclusion/exclusion criteria, or other unpredictable conditions. 
Participants are free to choose to stop being in the study at any time.  Already collected data may not be 
removed from the study database. An investigator may review study data related to the participant 
collected prior to the participant’s withdrawal from the study, and may consult public records, such as 
those establishing survival status. If a participant wants to withdraw their data for the further use in our 
research, we will request they write a letter with signature to the PI of this study Dr. Yao. 
RISKS TO PARTICIPANTS
Performing different movements using the arm:  The repeated movements may result in minor muscle 
soreness, fatigue and muscle spasms.  However, our protocols include many rest periods that should 
significantly reduce the risk of these adverse effects.
Surface electrodes: The self-adhesive surface electrodes used to record muscle activity may produce 
minor irritation of the skin. The possibility of irritation will be minimized by cleaning the skin with alcohol 
before and after application of the electrodes. 
Using Electrical stimulator: If the intensity progressively increases during the contraction period, 
then risk of muscle tear or injury is minimal. If a high intensity is applied, participants will experience 
high levels of soreness. We will use the 300 PV Complete Electrotherapy System or E-Wave, both are 
FDA approved, clinically safe device. The stimulation configuration, expect the stimulation intensity, will 
be pre-set up by clinicians. The clinician will also determine a suggested range of intensities, and setup 
the maximal stimulation intensity to protect users. When using at home, the individual with stroke will 
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adjust and determine the required stimulation intensity on daily based on the suggested range of 
intensities from the clinician, with the maximal stimulation intensity pre-set by the clinician.
Taking MRI: This study uses structural and diffusion-weighted magnetic resonance imaging (MRI) to 
look at the brain. These structural and diffusion-weighted MRI are types of scans that use magnetic fields 
and radio waves to make a picture of the brain and will allow us to look at the anatomy and structure of 
the brain, including lesioned tissue and tracts. Some people cannot have an MRI because they have 
some type of metal in their body. For instance, if a participant has a heart pacemaker, artificial heart 
valves, metal implants such as metal ear implants, bullet pieces, chemotherapy or insulin pumps or any 
other metal such as metal clips or rings, they cannot have an MRI. During this test, the subject will lie in 
a small closed area inside a large magnetic tube. Some people are scared or anxious in small places 
(claustrophobic). The MRI scanner makes loud banging noises while taking a measurement, so either 
ear plugs or specially designed headphones will be used to reduce the noise.
POTENTIAL BENEFITS TO PARTICIPANTS
We cannot promise any benefits to participants from taking part in this research. However, the 
literature supports the use of an EMG-driven electrical stimulator (ES) device, which ReIn-hand is in 
this category, in the treatment of the hemiplegic wrist and forearm.  Please note, such benefits are 
based on statistical data, may not apply to all the participants, and may not continue after the research 
has ended.
DATA MANAGEMENT AND CONFIDENTIALITY
Efforts will be made to limit the use and disclosure of personal information, including research study 
and medical records, to people who have a need to review this information. We cannot promise 
complete secrecy. Organizations that may inspect and copy information including the IRB and other 
representatives of this institution. 
Involvement in this research study may result in a loss of privacy, since persons other than the 
investigator and research team might view study records.  Unless required by law, only the following 
people can review study records and they are required to keep personal information confidential:

Authorized members of the Northwestern University workforce, who may need to see 
information, such as administrative staff members from the Office for Research, Office for 
Research Integrity and members of the Institutional Review Board (a committee which is 
responsible for the ethical oversight of the study), 

Representatives of the study sponsor, the National Institute of Health

Representatives of Food and Drug Administration (FDA), and Office for Human Research 
Protections (OHRP)

Registries or other research-related databases: the results of your examinations will be kept in a 
central computer or data registry at the NU Department of Physical Therapy and Human 
Movement Sciences. These results will be stored by research identifier code for privacy of records 
and your records will only be accessed by the investigators listed for this study.
The results of this study may also be used for local and regional scientific and healthcare conference 
presentations, as well as peer-reviewed scientific and medical journal papers. If individual results are 
discussed, participant identities will be protected by using a study code number rather than a name or 
other identifying information
The sponsor, monitors, auditors, the IRB, the Northwestern University Office for Research Integrity, the 
US Office of Research Integrity (ORI), the US Office for the Protection of Human Research Protections 
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(OHRP), the US Food and Drug Administration (FDA) may be granted direct access to medical records 
to conduct and oversee the research. 
PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OF PARTICIPANTS 
Data analysis plan
Aim 1: to measure the device-assisted intervention-induced changes in clinical outcomes
We will first compare the 2 baseline scores in each of the subjects. If no significant differences were 
found on baseline scores, they will be averaged and taken as pre-intervention measures. Otherwise, a 
3rd baseline assessment will be conducted. In the case that no stable baseline scores can be found, the 
subject will be excluded. Then, a two-way (time points: pre, post, 3-month, and groups: experimental and 
control) mixed-effects model will be conducted on ARAT, FMA, BBT, CMSA_H, MAL, SIS_H and NSA 
scores. If any significant effect is found, a post-hoc Bonferroni test will be used to compare the means 
with correction of type II error of multiple comparisons. We expect to see post-intervention improved 
scores on ARAT, FMA, BBT, CMSA_H, MAL, SIS_H and NSA in both groups, with the experimental 
group having greater improvements than that in the control group.
Aim 2: to measure the intervention-induced changes in biomechanics
Hand opening ability: An HPA is defined as the sum of the areas of three triangular areas, formed by 
the thumb and two fingertips, HPA STIM STMR STRL , where 
 denotes the triangular area, T, I, M, 
𝑆∆
R, L are abbreviations for thumb, index, middle, ring and little fingers (Figure 1A). HPA is shown to be an 
effective measure in evaluating hand opening ability30, and will be used as the primary measure in the 
present study to quantify hand opening. All participants will be asked to rest their hand on the cylinder 
prior to the trial and the resting HPA formed by the initial hand posture on the cylinder will serve as 
baseline. The HPA will be baseline corrected to zero while the hand is relaxed on the cylinder and then 
normalized to the maximal HPA. Maximal HPA will be measured when the non-paretic hand is placed on 
a flat surface with maximal finger abduction (see figure 1A subplot). Peak HPA value will first be identified 
during the hand opening period, and then an averaged HPA over a 100ms time window, centered at the 
peak value, will be calculated as the HPA for one trial during a certain abduction condition. In the case of 
generating closing force when opening (as shown in our previous publication23), the grasping forces will 
be calculated as the sum of the forces generated by the thumb and fingers (Figure 1B subplot). To 
quantify the grasping forces, the peak value during the hand grasping period will be first identified, and 
then an averaged grasping force over a 100ms time window centered over the peak value will be 
calculated as the grasping force for one trial. The maximal grasping forces of the paretic hand will 
normalize the grasping force measured during opening. 
Coupling forces generated by shoulder and elbow:  Forces/moments generated by shoulder and 
elbow in the Z directions, as well as the distance in X and Y directions will be measured. Measurements 
in each direction within each of the conditions (i.e., table and SABD50 conditions) will then be averaged 
cross trials, separately. We are interested in the intervention-induced changes in coupling movements, 
defined as 
.
(𝑀𝑝𝑜𝑠𝑡‒ 𝑀𝑝𝑟𝑒)/𝑀𝑝𝑟𝑒
A three-way repeated measure of ANOVA with mixed model will be used to determine whether SABD 
load, time (pre, midtreatment, post, 3m and 6m followup), group, and/or their interaction explains the 
measured changes in HPA, the grasping forces, coupling movements, separately. Data will be first 
examined to determine the presence of outliers (if found, will be removed) and to test for normal 
distribution (if found, will be corrected) using Shapiro-wilk test. Post hoc comparisons with the Bonferroni 
adjustment will be adopted to compare within-subject differences. Statistical significance will be set at 
p<0.05. 
We expect that 1) the GR3 intervention will increase the post-intervention HPA (or reduce the 
grasping force if no HPA can be detected); 2) the post-intervention coupling movements at shoulder and 
elbow during hand opening will be decreased; 3) the impact of SABD-induced synergy on HPA will be 
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reduced in the posttest. Result #1 will reflect the gained hand opening ability and #2-3 will imply the 
improved motor recovery, while results in an opposite trend will imply motor compensation. Furthermore, 
we expect that greater improvement will be found in the experimental group as compared to that in the 
control group, suggesting the importance of practicing ADLs in ‘close-to-normal’ pattern.
Aim 3: to measure the intervention-induced changes in neuroplasticity 
Aim 3A: at the cortical level
For the EEG data, trials beyond 95% confidence intervals for maximum velocities, maximum 
accelerations, and trajectory path position or with eye/muscle movement artifacts in the EEGs will first 
be removed. For the remaining trials, the onset of EMG activity will be detected off-line to align EEG 
signals in individual trials for ensemble averaging across trials for each of the conditions, separately. 
Averaged EEG signals from -2000 ms to +200 ms, with 0 denoting the onset of EMG, will be imported 
into the CURRY software environment (Compumedics Neuroscan Ltd., Charlotte, NC) for low-pass 
filtering with a cutoff frequency of 70 Hz and baseline correction. Cortical activity from -700 to +50 ms will 
then be reconstructed using an inverse method (Low Resolution Electromagnetic Tomography128-133) 
based on a subject-specific boundary element method model. Possible sources will be located on a 
cortical layer with 3 mm distance between each node. Although the inverse calculation will be performed 
over the whole cortex, only the activity in bilateral sensorimotor cortices will be further analyzed. Specific 
regions of interest (ROIs) include bilateral primary sensorimotor cortices (primary motor cortex (M1) + 
primary sensory cortex (S1)) and secondary motor cortices (supplementary motor area (SMA) + premotor 
area (PM)). 
Our primary interest is to investigate the shift of cortical activity. Therefore, we will use the estimated 
current density strengths to calculate a Laterality Index (LI = (I-C)/(I+C)), where ‘I’ and ‘C’ are the current 
density strengths from the ipsilesional and contralesional sensorimotor cortices (i.e., combined primary 
sensorimotor and secondary motor cortices). LI reflects the relative contributions of each cerebral 
hemisphere to the source activity, with a value close to +1 for an ipsilesional source distribution and -1 
for a contralesional source distribution. As the secondary measure, we will quantify a cortical activity ratio 
 for each of the 4 ROIs, where ‘S’ represents the current density strength of one of the 
𝐶𝐴𝑅= ∑𝑛
1𝑆𝑛/∑𝑚
1 𝑆𝑚
nodes, and n and m represent the number of nodes in one of the ROIs and whole sensorimotor cortices, 
respectively. The CAR reflects the relative strength from one ROI as normalized by the total combined 
strength of the 4 ROIs.
Statistical analysis: A three-way mixed model will be used to determine whether SABD load, time 
(pre, post), group, and/or their interaction explains the measured changes in LI, and CAR, respectively. 
We expect that the post-intervention LI will be more positive with increased CAR in the ipsilesional 
activity and decreased CAR in the contralesional activity. Furthermore, we expect that greater 
improvement will be found in the experimental group as compared to that in the control group, suggesting 
the importance of practicing ADLs in ‘close-to-normal’ pattern.
Aim 3B: At the structure level
To calculate GM density, anatomical T1 data will be analyzed with FSL-Voxel Based Morphometry 
(VBM) 
1.1 
(http://www.fmrib.ox.ac.uk/fsl/fslvbm/index.html; 
Oxford 
University, 
Oxford, 
United 
Kingdom)134 using FSL tools135. First, T1 images for participants who have left hemisphere lesions will be 
flipped to ensure the lesions of all subjects are in the right hemisphere. The T1 images will then be brain-
extracted using the Brain Extraction Tool and segmented into GM using FAST4. The resulted GM partial 
volume images will be aligned to Montreal Neurological Institute (MNI) 152 standard space using the 
affine registration tool FLIRT and averaged to create a study-specific gray matter template. Subsequently, 
individual GM partial volume images in native space will be nonlinearly registered to this template using 
FNIRT, modulated to correct for local expansion or contraction due to the non-linear component of the 
spatial transformation, and then smoothed with an isotropic Gaussian kernel with a sigma of 3 mm. 
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To calculate the integrity of the white matter, the FSL software library136 will be used for processing 
of raw diffusion imaging data. The images will be skull-stripped, each diffusion weighted condition will be 
linearly registered to the b=0 s/mm2 to minimize subject motion artifacts, and all data will be subsequently 
corrected for eddy current distortions for preprocessing. The diffusion tensor parameters will be 
calculated from the preprocessed diffusion data to generate fractional anisotropy (FA) maps that will be 
used to perform tract-based spatial statistics (TBSS). All FA maps will be linearly and then non-linearly 
registered to the FMRIB58_FA in Montreal Neurological Institute’s (MNI) standard space using FNIRT. A 
mean FA image will be created from all individual FA images and thinned to generate a common group 
WM skeleton which represents the centers of all tracts common to the group. A FA threshold will be 
applied at 0.2 to minimize potential WM / GM partial volume effects. All FA images will be projected onto 
the common group skeleton for subsequent statistical analysis.
Plan for securing the data 
All of the collected data are for research purposes only, and data will be kept in strict confidence. With 
the exception of the form needed to collect participant contact information required for the success of the 
study, all remaining data collection forms are designed so that only the study identification number 
appears as an identifier. Data collection paper forms will be kept in a locked, secure file cabinet at the 
PI’s office at Northwestern University. Electronic data collection forms will be secured in an encrypted 
study folder stored on the server provided by the Feinberg School of Medicine at Northwestern University. 
Access to the server is regulated and monitored by the PI and only qualified study personnel authorized 
by IRB. The PI, with support from the project manager, will monitor compliance with IRB and HIPAA 
regulations. No identifiable information will be given to any unauthorized person without permission from 
the subject. The consent form will include statements required by the Northwestern IRB regarding 
information disclosure requirements (e.g. NIH, FDA audits, etc).
All data will be merged and stored on the server provided by the Medical School of Northwestern 
University. The database will be secured with password protection. The informatics manager will receive 
only coded information that is entered into the database under those identification numbers. Electronic 
communication with outside collaborators will involve only unidentifiable information. All information 
published on papers or presented at conferences will be identified as a number without identification of 
subject personal information. 
The link between the study identification numbers and identifying information (e.g., name, address, 
age, telephone numbers and email addresses) will be kept separate from the dataset. Only the research 
study staff has need (and necessary access) to cross-reference files such as when it is necessary to 
contact a participant for monthly check-ins, scheduling follow-up appointments and/or clarification of 
survey answers (e.g., interpreting hand-written comments).
All MRI data will be uploaded to the Northwestern University Research Image Processing System 
(NURIPS), an online collaborative research environment for securely storing, managing, analyzing and 
sharing de-identified medical imaging, associated data (e.g. behavioral), and results from advanced 
customizable processing pipelines. NURIPS is supported by both NUIT and FSM-IT and takes 
advantage of the NU high performance computing cluster, Quest. NURIPS is a secure environment that 
supports the latest NU policy and procedures for encryption of data during transit and rest, provides 
granular project level access controls with varying permissions based on user groups, and allows non-
NU collaborators access once they obtain an affiliate NetID. All data are backed up and have restore 
points that go back for 30 days. Users have access to common data analysis pipelines and the 
opportunity to create and share their own pipelines.
Data Quality Control
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All study staff will be trained on all aspects of the study – including data monitoring, quality and 
security. The PI or study staff will review all data collection form on an ongoing basis for data 
completeness and accuracy as well as protocol compliance. 
Data monitoring efforts will include monitoring and review of all self-reports and clinical measures 
data collection forms for completeness. We will contact participants for clarification if returned paper or 
electronic self-reports are incomplete or if handwriting is illegible.
We will also use this contact opportunity to schedule follow-up appointments and remind participants 
about upcoming study appointments. We will closely monitor all data and conversations with participants 
for any reporting of adverse events as noted above. Dr. Yao will regularly create and review reports on 
eligibility, screening, recruitment, retention, reasons for ineligibility, declining participation and 
withdrawals. Information from these reports and monitoring activities will allow for effective and efficient 
identification of protocol deviations and troubleshooting that may or may not require modification to the 
produce, testing protocol or standard operating procedures. 
Data quality will be safeguarded by careful review of all incoming data for completeness. All data in 
paper format will be double-entered in the data set. All online captured data will be reviewed by two 
different research team members. 
Dr. Yao will check data quality reports to describe missing, erroneous, and inconsistent data to ensure 
that the protocol is followed, protocol deviations are tracked, and a high quality of data is maintained. 
Further, double entry of data will be conducted.  
Data quality will also be guaranteed by the creation of and adherence to standard operating 
procedures such as key operating procedures, protocol review and administration, IRB approval and 
continuing review processes, adverse event reporting procedures, data storage and management, and 
emergency procedures in our Lab. The operations manual for our Lab includes policies and standard 
operating procedures for data, lab and clinical security, handling of hazardous materials and 
emergencies, and how to use shared core resources such as NUCATS, the Quantitative Data Sciences 
Core, and all software required for the study. 
Each study undertaken at our Lab has a unique study protocol manual, which will be checked and 
approved by IRB at Northwestern University before recruiting subjects. All the protocols have data 
collection forms for each of the designed experiments/surveys, which list all the steps that will be checked 
while conducting the study. Research staff members undergoing training will have the chance to observe 
an experienced team member in the clinic for a data collection session. The research staff trainee will 
then be observed by the experienced team member to ensure their eligibility for participating. 
Finally, in accordance with Northwestern University IRB requirements, all research team members 
are required to complete training certification in human subjects’ research ethics through the online CITI 
(Collaborative Institutional Training Initiative) certification program - a leading provider of research 
education content. Northwestern University also requires certification from the National Health Institute’s 
online “Protecting Human Research Participants” (which can be accessed at the following url: 
http://phrp.nihtraining.com/users/login.php). Northwestern University’s IRB requires staff orientation on 
all safety and standard operating procedures to conduct research in the clinical environment. All of these 
elements will ensure a high quality of the study data as well as a consistent and comprehensive approach 
practiced by all research team members.
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Data security will be ensured by adherence to all operating procedures, study protocol, and research 
training requirements as noted above. The data will be secured in paper and/or electronic format as 
described above. Data required to review for eligibility screening will be kept in the locked storage cabinet 
in the PI’s office. The link between the study identification numbers and identifying information (e.g., 
name, address, age, telephone numbers and email addresses) will be kept separate from the dataset. 
Only the research study staff has need (and necessary access) to cross-reference files such as when it 
is necessary to contact a participant for scheduling follow-up appointments and/or clarification of survey 
answers (e.g., interpreting hand-written comments). 
PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OF PARTICIPANTS
To ensure the safety of participants, the data monitoring committee (DMC) will periodically evaluated 
the data collected regarding both harms and benefits. The data monitoring committee (DMC) will 
composed of the PI of this study and 2-3 independent monitors. The DMC will review safety data, such 
as adverse events (AE) reported by telephone calls or written case reports via letter or email, either by 
participants or by the experimenters. The DMC will also review efficacy data, such as the clinical 
assessments before and after the intervention. 
The frequency of data review for this study differs according to the type of data and can be 
summarized in the following Data Review Table: 
Table 2. Data Review Table
Data type
Frequency of review
Reviewer
Subject 
accrual 
(including 
compliance 
with 
protocol 
enrollment criteria)
When N=4*n; N is the total number of finished 
subjects, and n=1~15 which is expecting 
resulting in a Quarterly frequency.
DMC
Status of enrolled subjects, as 
of date of reporting
Quarterly, 
DMC
Adherence 
data 
regarding 
study visits and intervention
Quarterly, 
DMC
AEs and rates (including out of 
range values)
Quarterly, 
DMC
Severe AEs
Per occurrence
DMC, 
NICHD
This study will be stopped prior to its completion if: (1) the intervention is associated with adverse 
effects that call into questions the safety of the intervention; (2) difficulty in study recruitment or retention 
will significantly impact the ability to evaluate the study endpoints; (3) any new information becomes 
available during the trial that necessitates stopping the trial; or (4) other situations occur that might 
warrant stopping the trial. The PI will include an assessment of futility in the annual progress report to 
NIH and will consult with the study monitors to assess the impact of significant data loss due to problems 
in recruitment, retention, or data collection.
PROVISIONS TO PROTECT THE PRIVACY INTERESTS OF PARTICIPANTS
Steps that will be taken to protect participants’ privacy interests
During this study, medical history and clinical assessments will be performed at baseline, middle of the 
intervention, post the intervention, and 3 months after the end of the intervention, i.e., follow up test.  However, 
all of the materials collected are for research purposes only, and data will be kept in strict confidence.  Access 
to these files will be limited to authorized research team members. All data generated in this study will be 
identified with an identification code unique to the subject. Confidentiality will be ensured by use of these 
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identification codes. No information will be given to any unauthorized person without permission from the 
subject, except: 1) if necessary to protect participant's rights or welfare (for example, if they are injured and 
need emergency care or when the Institutional Review Board monitors the research or consent process); or 
2) if required by law.
A database will be used to store/manage all the electronic data. This database will be secured with 
password protection. The informatics manager will receive only coded information that is entered into the 
database under those identification numbers.  Electronic communication with outside collaborators will involve 
only unidentifiable information.  All information published on papers or presented at conferences will be 
identified as a number without identification of subject personal information. 
Subject’s feeling at ease
Subjects who choose to be in this study will be informed that they have the right to be treated with 
respect, including respect for the decision whether or not to continue or stop participating in the study. 
All examinations and procedures will be thoroughly explained to each subject to ensure subjects feel at 
ease with the questions, examinations, and procedures involved. Subjects will be informed that if at any 
point they feel uncomfortable about answering any questions on any questionnaires or surveys, they will 
not be required to answer that question. Subjects will be informed that they are free to choose to stop 
being in the study at any time, and that choosing not to be in this study or to stop being in this study will 
not result in any penalty or loss of benefit to which they are entitled. Specifically, the choice not to be in 
this study will not negatively affect the right to any present or future medical treatment.
Subject’s medical record access
The research staff from Northwestern University will obtain a release from the patient, if we need to 
access medical records of the subject.
COMPENSATION FOR RESEARCH-RELATED INJURY
Minimal risk is when the probability and magnitude of harm or discomfort anticipated in the proposed 
research are not greater, in and of themselves, than those ordinarily encountered in daily life or during 
the performance of routine physical or psychological examinations or tests. The proposed research is 
greater than minimal risk. In the event of research-related injury, subjects will not be compensated for 
medical care required because of an untoward outcome resulting from participation in the research study. 
Subjects should seek medical treatment through his or her doctor or treatment center of choice.
As stated in the consent form: “If you become ill or get injured as a result of this study (medications, 
devices or procedures), you should seek medical treatment through your doctor or treatment center of 
choice. You should promptly tell the study doctor about any illness or injury.  The researchers will not 
pay for medical care required because of a bad outcome resulting from your participation in this 
research study. This does not keep you from seeking to be paid back for care required because of a 
bad outcome.”
ECONOMIC BURDEN TO PARTICIPANTS
Taking part in this research study will not lead to any costs to participants. 
CONSENT PROCESS
We will obtain Written Documentation of Consent (HRP-592), a copy of consent has been attached, 
from all subjects.
During phone/email recruiting, basic information of the consent will be already explained to the 
subjects. Upon request, a copy of consent form will be emailed or mailed to the subjects. If not heard 
from the potential subjects, a follow up phone or email may be provided. 
All of the involved studies will be conducted at Department of Physical Therapy and Human 
Movement Science (PTHMS), Northwestern University (address: 645 N Michigan Ave, Suite 1100, 
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Chicago, IL 60611). On arrival to PTHMS for data collection, subjects will undergo a more detailed 
orientation to learn about the study protocol. One of the research team members will answer questions 
related to the study. Once subjects confirm his/her full understanding of the consent form, he or she will 
sign the informed consent. A copy of signed consent will be given to subject. 
If there is a significant change to the research protocol or if there is new information that may alter 
an individual’s willingness to participate in the research, subjects will be provided an updated informed 
consent document and consent will be reobtained.
Non-English Speaking Subjects, minors, and cognitively impaired subjects will not be enrolled.
PROTECTED HEALTH INFORMATION (PHI AND HIPAA)
When choosing to take part in this study, subjects are giving us the permission to use his/her personal 
health information that includes health information in the medical records and information that can identify 
him/her. Health information we may collect and use for this research includes:

Name

Street Address

Telephone number

Date of Birth

Information from a physical examination including only: blood pressure reading, upper 
extremity range of motion, strength, and functional movement assessment.

Medical record related to stroke, and any potential conditions that may impact eligibility 
for MRI scan.

Social Security Number - needed for the Accounts Payable Department at Northwestern 
University in order to issue the study stipend and for the medical records department of 
most hospitals to identify the medical record file.

3D movement analysis of the arm during reaching/grasping tasks.
QUALIFICATIONS TO CONDUCT RESEARCH AND RESOURCES AVAILABLE
The feasibility of recruiting
Subjects who have had a stroke will be selected from the Clinical Neuroscience Research Registry, 
maintained by the Physical Therapy and Human Movement Sciences department at Northwestern 
University and the Shirley Ryan AbilityLab (Former Rehabilitation Institute of Chicago - RIC), containing 
more than 700 members. Stroke survivors residing in the Chicago area who wish to participate in the 
study will be considered as well.
While most inclusion criteria will not rule out the potential participation of Registry Members, the 
greatest impacting criteria is the upper limb motor impairment level (evaluated by Upper Extremity (UE) 
Fugl-Meyer Stroke Assessment 61,62 in the range of 10-40/66, Chedoke McMaster Stroke Assessment 
Hand Subscale63 (CMSA_H) stage of the hand section <=4) and the ability of opening hand with the aid 
of the electrical stimulator device. We anticipate that a minimum of 40% of Registry members (n=700) 
will be of the moderate to severe levels described above and appropriate for participation.
Two experienced research physical therapists (RPTs), each using 5% of their efforts, will supervise 
research staff actively recruit subjects during the first 4 years of this project. This will guarantee an 
enrollment of 15 subjects per year.
The time that you will devote to conducting and completing the research
Dr. Yao, the PI, will spend 20% of her effort on conducting and completing the research. Drs. Dewald, 
Sullivan and Ingo will each spend 5% effort. Drs. Carmona and Drogos will spend 35% of their effort on 
this study.
Facilities and resources
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The facilities and other resources available at Northwestern University include everything needed to 
undertake and complete the proposed research successfully. The appropriate personnel, laboratories, 
and existing equipment are in place. 
Laboratory: The Department of Physical Therapy and Human Movement Sciences (PTHMS) 
includes eight laboratories, each approximately 500 sq. ft. in size.  We will be using three of these 
laboratories to perform our research. One of the laboratories contains height-adjustable tables, 
comfortable chairs and cabinets to conduct the proposed tests. The other 2 labs, which are shielded 
rooms, contain the latest in robotic technology, 3 surface EMG recording systems, 1 active portable 
EEG/EMG system, and 2 wireless EEG/EMG systems. 
Clinical: The NU PTHMS is affiliated with the Shirley Ryan AbilityLab and Northwestern Memorial 
Hospital (NMH). Both hospitals have stroke, spinal cord injury, and head trauma wards as well as a large 
outpatient facility. Subjects chosen for the research component of this proposal belong to our 700+ 
outpatient participant database and the Clinical Research Registry (CRR) maintained through Shirley 
Ryan AbilityLab. The proximity to the Shirley Ryan AbilityLab and NMH, as well as access to the CRR, 
contributes substantially to the recruitment of research participants and, thus, the potential success of 
the proposed study.
Computer: The NU PTHMS maintains a large computer simulation laboratory including the latest 
PCs, a 100 core PSSC labs cluster computer, as well as installed analysis software (Matlab, CURRY, 
Analyzor, Cortech, FMRIB Software Library (FSL)) for EEG/EMG/MRI/DTI data processing, source 
reconstruction and musculoskeletal modeling purposes. Furthermore, Northwestern University, Feinberg 
IT department provides a minimum one Terabyte of desktop mountable storage for research purpose to 
guarantee the safety of the research data. The combination of these information technologies contributes 
to the potential for success by assuring both efficient data handling and optimal communication among 
members of the research team.
Office: The PTHMS investigators working on this project have their own offices at NU. 
Furthermore, the PTHMS department will provide administrative support. These facilities assure that the 
PI and the immediate research team will have the necessary space in which to formulate experiments, 
analyze results, and prepare manuscripts for publication.
Other Resources: 
Machine Shop: The NU PTHMS also maintains a machine and electronics shop (800 sq. ft.) that is 
available to construct and build custom equipment under the direction of the department engineer. The 
machine shop has been expanded to include the latest in computer-controlled milling devices, a large 
electronic bench, aluminum welding equipment, and a brand-new lathe. This equipment allows us to 
manufacture new parts for ReIn-Hand device as needed and repair/upgrade broken parts or electronics.  
The availability of this machine shop provides a valuable resource for on-demand fabrication, alteration, 
and repair of hardware used in our experiments.
HD Video-conferencing facilities: NU-PTHMS has 3 HD videoconference rooms (400 sq. ft.) that 
house brand new HD conference systems with an 80-inch touch screen TVs, which allows for effective 
communication with external collaborators.
Quality of research team members:
The PI, Dr. Yao has more than 15-year experience in exploring the neuromechanisms underlying the 
dysfunction of the upper extremity (UE) following stroke, evaluating the feasibility of restoring UE function 
using various novel rehabilitation techniques. She has led the pilot study using brain computer interface 
for detecting the intention of grasp and release in individuals following stroke (NIH UL1 RR025741 
subproject), as well as the development of an EMG-driven functional electronic stimulation for reliable 
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and intuitive control of the paretic hand (ReIn-Hand) during functional arm activities following stroke (HHS 
grant 90IF0090-01-00, formerly DOE NIDRR H133G120287). Dr. Yao is an expert in EEG-based neural 
imaging. She has also accumulated experience in experimental design for collecting and processing 
biomechanical data.  
The Co-investigators are well-established investigators in their fields. Dr. Dewald has more than 20 years 
of experience in the quantification of abnormal synergies (i.e. loss of independent joint control) and 
developing new quantitative robotic intervention methods in acute and chronic hemiparetic stroke 
subjects. Dr. Sullivan has been involved in the clinical care of stroke survivors for 30+ years. She has 
been engaged in research focusing on testing rehabilitation interventions using appropriate standardized 
measurement tools. She has also been involved in using electrical stimulation to treat stroke since 1988; 
and participated in several clinical trials. Dr. Ingo has a strong background in biophysics and MR imaging.  
He is well versed in structural MR imaging and sequence development in this field.  Dr. Ingo will lead the 
analysis, as well as the design of the MR sequences for Aim 3 of this study.
The two research physical therapists Drs. Carmona and Drogos are both licensed Physical Therapists, 
and have been previously involved in the preliminary interventions using both ReIn-Hand and/or ACT3D 
for 15 years. All the members in the research team have valid CITI training certificates. They have all 
read the IRB. We have weekly meetings to make sure everyone knows their specific duties.
STUDY-WIDE RECRUITMENT METHODS
Once funded, we will immediately start to work on the proposed study. Subjects who have had a stroke 
will be selected from the Clinical Research Registry (CRR), maintained by the Physical Therapy and 
Human Movement Sciences department at Northwestern University and the Shirley Ryan AbilityLab 
(Former Rehabilitation Institute of Chicago - RIC), containing more than 700 members. In the registry, 
basic information, like phone number, address, contact email, onset time of stroke, and so on, is listed. 
Stroke survivors residing in the Chicago area and have other available information satisfying our 
inclusion/exclusion criteria will be contacted by phone or email for recruitment (wording of the phone 
and email has been attached).
In addition to the Clinical Research Registry, the study will be listed on The New Normal (TNN) Match 
and ResearchMatch. Both are web-based recruitment portals offered by the Center for Clinical 
Research, a center in the Northwestern University Clinical and Translational Sciences Institute. 
Stroke survivors residing in the Chicago area who wish to participate in the study will be considered as 
well. Most of cases, these subjects are referred by participants who are already recruited. 
Flyers will also be used in recruitment. These flyers will be disseminated in person or via email or 
through social media to resource organizations and stroke support groups in the Chicagoland area.
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