Clinical trial NCT05369533
Conditions: Stroke
Keywords: stroke rehabilitation telehealth dopamine
Sponsor: University of California, Los Angeles
Start date: 2022-08-01; Completion date: 2024-03-11
Enrollment: 25 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study explores the effects of telerehabilitation and a study medication on rehabilitation outcomes in patients with stroke resulting in arm weakness. Patients with arm weakness due to a stroke that happened in the past 30 days will be randomized into one of three groups: \[1\] TR and placebo (a sugar pill) on top of usual care; \[2\] TR and a medication (Sinemet 25/100) on top of usual care; \[3\] or usual care alone (no TR and no pill, but people in this group will be offered TR once the study is done). TR consists of 70 minutes/day of activities targeting arm function, 6 days a week for 6 weeks.

Detailed description:
This is a randomized, double-blind, placebo-controlled study that involves the use of telerehabilitation to deliver additional therapy for persons with stroke. Participants with arm weakness due to a stroke in the past 30 days will be randomized into one of three groups: (1) TR + Sinemet on top of usual care, (2) TR + placebo (sugar pill) on top of usual care, or (3) usual care only (no TR, no pill). The hypothesis of this study is patients receiving TR will have significantly greater recovery of arm function compared to patients receiving usual care. In addition, Sinemet is hypothesized to significantly enhancing this improvement.

Study participation will last up to 3 months and includes 4 in-person visits. At these visits, patients will undergo a battery of assessments including arm function, a single MRI scan of the brain, and blood draw for genotyping. Patients undergoing TR will receive arm motor training, which consists of 36 sessions of of assigned exercises, games, and stroke education; these are 70 minutes in length and take 6 days a week over 6-8 weeks. Subjects receiving TR will take a pill (Sinemet or placebo) prior to the TR training for the first 18 TR sessions; TR subjects will also continue usual care. Patients in the usual care group will not engage in TR or take a study pill, but will instead continue all of the therapies recommended by their medical team. At the end of the study, participants in the usual care group will be offered TR.

Arms: arm 1: Patients will receive 36 telerehabilitation sessions targeting arm motor function. TR consists of 70 minutes/day of activities targeting arm function, 6 days/week for 6-8 weeks. Half of these sessions are supervised by a licensed therapist, and the other half are done independently. Sinemet is taken one hour before starting TR, for the first 18 sessions. arm 2: Patients will receive 36 telerehabilitation sessions targeting arm motor function. TR consists of 70 minutes/day of activities targeting arm function, 6 days/week for 6-8 weeks. Half of these sessions are supervised by a licensed therapist, and the other half are done independently. Placebo is taken one hour before starting TR, for the first 18 sessions. arm 3: Participants in the usual care group will receive no TR or study pill, but will continue with the recommendations made by their care team. All participants will be offered TR at the end of the study.
Interventions: intervention 1: Telerehabilitation intervention 2: Sinemet Pill intervention 3: Placebo
Intervention descriptions: intervention 1: The telerehabilitation system will deliver rehabilitation treatment sessions via a secured internet-connected computer. TR sessions will be a combination of games, exercises, stroke education, assessments, in addition to videoconferencing with therapists to discuss progress, issues, goals, and changes to the treatment plan. intervention 2: Sinemet 25/100 will be taken 1 hour prior to TR, for the first 18 sessions. intervention 3: Placebo will be taken 1 hour prior to TR, for the first 18 sessions.

Protocol documents:
Prot_SAP_000.pdf: 
Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
Study Overview 
STUDY TITLE: Dopaminergic enhancement of rehabilitation therapy early after stroke 
INSTITUTIONAL REVIEW BOARD (IRB) #: 22-000104 
DESCRIPTION: Telerehabilitation (TR) is defined as delivery of rehabilitation services via 
communication technologies. This study uses an established TR system and protocol to 
supplement usual care, and also asks whether adding a dopaminergic drug enhances TR effects. 
In addition, the predictive value will be examined for two biomarkers that characterize capacity 
for brain plasticity. 
Patients with arm weakness due to a new stroke in the past 30 days will be randomized to 
receive [1] 6 weeks of TR + Sinemet 25/100 once/day, on top of usual care (UC), [2] 6 weeks of 
TR + placebo once/day, on top of UC, or [3] UC alone. TR consists of 70 minutes/day of activity 
targeting upper extremity (UE) function, delivered in the home and (when appropriate) 
initiated in the inpatient rehabilitation facility (IRF) setting. Two previously validated predictive 
biomarkers are hypothesized to prospectively identify treatment responders: first, extent of 
stroke-related injury to the corticospinal tract (CST), obtained via MRI scan; and second, a 
polygene score focused on dopamine neurotransmission. 
The currently planned study uses very similar software and hardware as the TR system as in a 
prior national study that found that this TR system was safe, associated with significant gains in 
arm function3 and in global function14, and had efficacy comparable to that seen when the 
same dose of therapy was delivered in the clinic (i.e., delivered in the same manner as standard 
care). In that prior study, the FDA determined (Q140628) that the investigation was a non-
significant risk device study. 
STUDY AIMS: 
Aim 1. TR+UC is superior to UC alone: A 6-week program of TR targeting arm movement added 
to UC will result in better arm function as compared to UC alone. The primary endpoint is the 
change in Action Research Arm Test (ARAT) from baseline to 1 month after end of therapy. 
Aim 2. TR+Sinemet is superior to TR+placebo: Among patients randomized to TR, gains in arm 
function will be greater in those who take Sinemet (25/100) each day prior to TR, as compared 
to patients who take placebo each day prior to TR. 
Aim 3. Less CST injury and higher dopamine polygene score predict better recovery of arm 
function: Across all subjects, change in arm function will be highest in those with lower % CST 
injury and in those with higher dopamine polygene scores. These relationships will remain 
significant when examining only patients randomized to TR. The drug X gene score interaction 
term will be significant such that the slope of arm gains in relation to the polygene score will be 
smaller (less steep) in those receiving Sinemet.  
 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
Contact Information 
Primary Investigator:  
Steven C. Cramer, MD, MSc, FAAN, FAHA, FASNR 
Professor, Department of Neurology 
David Geffen School of Medicine at UCLA 
710 Westwood Plaza, Reed C239 
Los Angeles, CA 90095-1769 
EMAIL: sccramer@mednet.ucla.edu  
 
 
 
 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
Background 
Patients need higher doses of high-quality rehabilitation therapy: Stroke remains a 
leading cause of human disability. Motor deficits are a substantial contributor to this, 
particularly in the arm: few patients fully recover from arm weakness after a stroke, with the 
remainder demonstrating persistent arm impairments that are directly linked to larger activity 
limitations and participation restrictions, lower quality of life, and decreased well-being15-17. 
Increasing evidence suggests that intensive activity-dependent therapy can improve outcomes 
after stroke18-22. However, most patients do not receive intensive therapy for reasons that 
include difficulty traveling to a provider (particularly in the COVID-19 era), shortage of regional 
rehabilitation care, and poor compliance with assignments. 
The amount of rehabilitation therapy received as part of UC is generally small and inconsistent. 
During the acute stroke admission, the dose of occupational therapy (OT) and physical therapy 
(PT) provided to a patient varies widely across hospitals23. After discharge from the acute 
admission, the type, location, and dose of rehabilitation therapy are also highly variable24-29. 
This is also true in the outpatient setting, where provision of OT and PT after a stroke remains 
sparse and inconsistent. A study of 23,413 U.S. patients found that during the first 30 days after 
discharge from the acute stroke admission, 59% did not see an OT or PT at all30. A later study of 
6,743 adult stroke survivors in the U.S. found that 67% of patients did not receive any 
outpatient rehabilitation therapy31. Medicare generally pays for very few outpatient OT and PT 
sessions32. Outpatient therapy is provided in an inconsistent way31, 33, despite the fact that 
outpatient therapy after stroke has the potential to improve functional status, survival, and 
quality of life; and to reduce the risk for several psychological disorders15, 31, 34-36. Furthermore, 
even when patients can access stroke rehabilitation, the amount of therapy provided in 
standard of care is limited4, 37-40, averaging just 32 arm movements/session4, vastly lower than 
the 600-924 movements/session deemed necessary in animal studies41-43. 
The quality of rehabilitation therapy is also important and can increase the extent to which 
clinical neuroplasticity is harnessed44. Effects are increased when therapy is challenging, 
motivating, and engaging1, 45-48. 
The promise of a telehealth approach for increasing rehabilitation therapy: Telehealth 
approaches have the potential to improve the quantity and quality of rehabilitation therapy 
after stroke. A telehealth approach can increase access to rehabilitation therapy31. A telehealth 
approach also increases the quality of rehab therapy by boosting motivation and thus 
improving patient compliance. 
TR is the delivery of rehabilitation services via communication technologies49. TR therapy is 
delivered by a licensed therapist via a computer and over the internet and can occur either 
synchronously (i.e., live interactions between therapist and patient) or asynchronously (i.e., the 
patient works alone and the therapist reviews performance later). TR follows the same 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
principles of traditional, person-to-person, individualized rehabilitation care. Such telehealth 
therapy provides a powerful supplemental option to brick-and-mortar delivery of rehabilitation 
services50-53, reducing the need for impaired patients to travel and increasing access to care by 
clinicians familiar with stroke rehabilitation, an option useful in regions with a shortage of 
providers. These potential advantages are particularly important in the COVID era. As such, 
even if benefits of TR over usual care (UC) are modest, TR could be of value to many patients as 
an alternative means to access rehabilitation therapy. 
Because TR incorporates a computer, therapy can be provided via games, which promote 
patient participation in health care5-9. Games motivate patients to engage in enjoyable play 
behavior that involves therapeutically relevant movements10, 11, important because patient 
compliance is often low when stroke rehabilitation is delivered through traditional methods54-
56. TR can also reduce the burden on caregivers and increase compliance; costs might also be 
lower57 but this issue will not be examined in the currently proposed clinical trial. 
Mounting evidence that TR helps with motor deficits after stroke: Increasing data 
support the utility of motor TR. A recent meta-analysis reported that all 18 studies of post-
stroke motor TR improved motor disabilities53. Another noted that effects of TR did not differ 
from those seen with in-person rehabilitation or UC, although findings from this review must be 
viewed cautiously given that the authors defined TR quite broadly (e.g., including interventions 
that relied on phone calls, a DVD, email, or an online chat room)58. Other reviews indicate that 
higher TR usage results in greater benefit59, although to date many studies have been small and 
uncontrolled53, 59-62. In one recent review of neurotechnological interventions for upper-limb 
motor rehabilitation, Coscia et al63 stated 
“We also promote the necessary conceptual change from ‘one-suits-all’ treatments within 
inpatient clinical rehabilitation set-ups towards personalized home-based treatment strategies 
by adopting novel technologies….’' 
In this regard, it is important to note that the current proposal employs a telehealth 
intervention that fosters a personalized treatment plan, is structured and therapist-supervised, 
maintains an ongoing relationship between therapist and patient1, is designed for use in the 
home64, and directly emulates the successful approach used in our prior national TR trial3. 
The active ingredients in the current telehealth approach: It is important to characterize 
the therapy that is delivered using telehealth methods. The active TR ingredients underlying the 
substantial behavioral gains seen in our national trial3 can be summarized using the 
Rehabilitation Treatment Specification System (RTSS)65, 66. 
The main treatment targets promoted by the therapist and by TR system usage include five 
skills and habits: [1] improved UE motor function; [2] increased activity throughout the day (i.e., 
when not using the TR system); [3] increased capacity for sustained attention; [4] maintenance 
of a structured daily rehabilitation practice; and [5] healthier lifestyle choices. Treatment 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
targets also include three representations [1] improved mood, confidence, and quality of life; 
[2] increased knowledge about stroke; and [3] increased fun. 
The main direct target65 is improved UE motor function, which arises from CNS motor system 
plasticity and to a lesser extent from improved UE muscle strength; improved UE motor 
function is thus the main skill improved by TR and is captured by serial ARAT scoring. 
The main volitional target65 (i.e., the main accessible/verifiable measure of patient behavior 
that occurs without direct therapist supervision) is maintenance of a structured daily rehab 
practice, measured through daily usage statistics automatically calculated by the TR system and 
provided to patient and therapist.  
The dosing parameter is a daily 70-min therapy session, created by the patient’s treatment 
therapist, which includes 65 min of activity-based arm motor therapy (functional games and 
exercises) plus 5 minutes of stroke education, all of which involve targeted arm movement. The 
target TR dose for treatment therapists to assign is >800 arm movements/day, considerably 
higher than the 32 repetitions/session in routine clinical care4. 
Patient performance of many repetitions of activity-dependent therapy targeting the paretic 
arm is at the core of this TR program. The games in the TR system stress many different 
behaviors as part of motor training (e.g., memory load, sustaining a movement, movement 
precision, accurate timing of movement, and visuomotor tracking of a target).  
The biological model underlying treatment efficacy, therefore, is that UE motor repetitions 
performed during TR activate numerous brain circuits including memory, attention, 
somatosensory, visuomotor, and cognitive circuits to drive motor cortex, with convergence of 
output on the CST. For example, in the “Clay Shooting” game, the patient uses the UE to track a 
flying clay pigeon, activating the dorsal and lateral reaching systems67. In the “Target” game, 
the patient squeezes a force transducer to keep the cursor within increasingly narrow brackets, 
activating sensorimotor and reward circuits68. In the “Slots” game, the patient must time 
button pushes to line up the same image on three successive reels; activating error-detection 
networks69. 
The motor-related circuits activated by TR use have in common reliance on CST as the effector 
pathway, and so the model also suggests that a measure of CST injury will be a useful 
biomarker of treatment-related gains. While there are multiple CSTs arising from primary and 
secondary motor cortices, the focus here will be on CST arising from primary motor cortex; 
secondarily, we will also examine injury to CSTs arising from secondary motor, as we have done 
previously70. 
The rationale for using this 6-week (42-hour) program of therapist-supervised, home-
based TR: This dose and this approach proved to be an effective therapy in the national trial3, 
and so treatment dose and content will not be modified in the currently proposed study. The 
prior national trial found that 6 weeks of TR was safe and associated with substantial gains in 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
UE-FM, Box & Blocks, and mRS scores, among all patients. This was also true among those 
patients who were enrolled >90 days post-stroke, a timepoint where spontaneous motor 
recovery after stroke has generally reached a plateau and thus any gains are very likely 
attributable to the intervention itself3, 14. Given this evidence that the intervention is effective 
at improving arm function, current goals do not aim to change the intervention but instead to 
compare it to a control, UC alone, and to evaluate its efficacy when a dopaminergic drug is 
introduced prior to each day’s TR session. 
Why did the prior national TR trial3 study show significant benefit but 2 recent trials71, 72 of 
activity-based therapy in-clinic did not? These divergent results might be due to the TR trial 
providing a higher therapy dose (42 hours in the TR trial3 vs. 3072-32 hours71), a higher number 
of arm movements per session (1,031/session in the TR trial3 vs ≤300/session71), and studying a 
population that was closer to the time of stroke (4.4 months post-stroke in the TR trial3 vs. 12 
months post-stroke71). Intensity of therapy may also be a factor, which might explain why both 
the prior national TR trial3 and the CPASS trial73 both showed substantial benefits. 
The rationale for investigating increased dopamine neurotransmission with intensive 
rehabilitation therapy: Dopamine is a neurotransmitter that has a key role in learning, and 
plasticity74-77, with increased dopamine associated with greater motor learning and motor 
cortex plasticity78, 79 and decreased dopamine associated with impaired motor learning 80 and 
motor cortex plasticity 79. Dopamine is also important to motivation81, action learning82, action 
selection83, and in the control of voluntary exercise84. Dopamine is also a central component in 
the limbic reward system, and reward significantly influences long-term motor learning85.  
Given these well-established roles, dopaminergic drugs have also been investigated for 
poststroke recovery. One key study that motivates Aim 2 was a randomized, double-blind, 
placebo-controlled study of levodopa performed in patients who experienced a stroke 3 to 26 
weeks prior, were admitted for inpatient rehabilitation, and lacked major depression86. A total 
of 53 patients were randomly assigned to 3 weeks of daily levodopa 100 mg (with carbidopa) or 
placebo coupled with physiotherapy. This study found that levodopa 100 mg/d combined with 
physical therapy was significantly better than placebo combined with physical therapy for 
improving arm and leg motor function at the end of the 3 weeks, measured using the 
Rivermead Motor Assessment. Motor gains were sustained or improved after an additional 3 
weeks. No levodopa-related adverse events were reported. 
A more recent study also found that levodopa was safe but, perhaps due to study design issues, 
did not find a benefit in motor recovery. The Dopamine Augmented Rehabilitation in Stroke 
trial87 was a multicenter, randomized, double-blinded, placebo-controlled trial with pragmatic 
design features that examined 6-weeks of daily carbidopa/levodopa (25/100) given prior to 
rehabilitation therapy in 593 patients recruited 5-42 days post-stroke who could not walk 
independently. Levodopa was safe; the main safety finding was that vomiting after study drug 
administration occurred more often in the levodopa group as compared to the placebo group 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
(6% vs. 3%), a fact that is clearly noted in the informed consent form (ICF). Key concerns exist 
with the design of this study88, concerns that limit interpretation of non-efficacy outcomes. 
First, the target population was not well defined, as this study enrolled patients with any deficit, 
of almost any severity, as long as gait was not independent; furthermore, the diagnosis of 
stroke was based entirely on clinical findings. Second, provision of concomitant physical 
therapy frequently did not follow study protocol. Third, the timing of pill ingestion relative to 
physical therapy was variable (e.g., the study drug was not taken per protocol in 45% of therapy 
sessions). Such details are critically important to trials of stroke recovery, and so perhaps the 
strongest message from this trial was that Sinemet 25/100 is safe early after stroke. 
The rationale for examining whether an intact corticospinal tract is needed to benefit 
from TR: Aim 3 hypothesizes that patients with milder CST injury are more likely to achieve 
gains in arm function. Neural repair after stroke benefits from patient stratification89, as 
patients with stroke are a heterogeneous population, with differing capacities to respond to 
rehabilitation therapy. Although several potential predictors of response to a restorative 
therapy in patients with subacute or chronic stroke have been identified90-93, analysis94 of data 
from patients receiving TR in the prior national trial3 found that clinical measures provided 
limited prediction of TR-related arm motor gains. Following bivariate screening of 43 baseline 
clinical measures from eight categories, a multivariable linear regression model predicted only 
17.6% of the variance in TR-related arm motor gains (p<.004). Other types of measurement 
beyond clinical data are needed to prospectively identify treatment responders. 
Neuroimaging measures are excellent candidates for predicting benefit from rehabilitation after 
stroke. Indeed, such measures can be superior predictors compared to clinical measures. CST 
injury is the focus here because it is a common pathway for TR components: the mechanism of 
action for TR efficacy revolves around cortical plasticity from multiple circuits driving signals 
down the CST--and so greater CST injury would be expected to limit treatment-related 
behavioral gains. Five prior studies from the Cramer lab70, 95-98 support this hypothesis, each 
finding that % CST injury was a significant predictor, explaining 17-33% of variance in arm motor 
recovery during receipt of a restorative therapy in subacute or chronic stroke. Importantly, in 
each of these studies, % CST injury was a better predictor than age, baseline behavioral status, 
and total infarct volume. For example, the largest of these studies97, focused on patients in the 
subacute phase post-stroke, found that ≥75% CST injury had 91.7% positive predictive value 
that a patient would fail to achieve a gain on the Action Research Arm Test that reached or 
exceeded the minimal clinically important difference (MCID) of 5.7 points for this scale99-104. 
These data suggest that treatment non-responders are common and can be accurately 
identified at baseline based on severity of CST injury. 
The method we use for measuring % CST injury involves [1] generating in healthy subjects a 
canonical CST emanating from primary motor cortex using diffusion tensor imaging (DTI) 
tractography, [2] outlining each patient’s infarct on an anatomical MRI, and [3] overlapping 
each infarct on top of the canonical CST tract in MNI standard stereotaxic space. Ideally, we 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
would like to measure the percentage of axons in each CST that is injured by stroke, but MRI 
resolution does not permit this. Towards this approach, the CST is divided into 16 longitudinal 
subsections, aiming to model the trajectory of groups of axons. Each subsection is classified as 
injured or not; as with axons, a subsection need only be destroyed by stroke once along its 
length for it to be classified as injured. 
The rationale for examining whether dopamine genetics predicts benefit from TR and 
benefit from Sinemet: Aim 3 hypothesizes that change in arm function will be highest in 
those with higher dopamine polygene scores. Dopaminergic drugs have long been studied 
towards the goal of improving outcome via enhanced brain plasticity after neural injury such as 
stroke. However, results to date have been inconsistent105-107, with motor learning and 
plasticity improved by dopaminergic drugs in some studies86, 108 but not in others109-111. Genetic 
measures might explain part of this variance and indeed might form a basis to personalize 
medicine by predicting which patients will be responders112, 113. Several prior studies suggest 
the utility of a dopamine polygene score based on 5 common and biologically active genetic 
polymorphisms. One study from my lab found that this polygene score can predict (a) motor 
learning, (b) motor cortex plasticity, and (c) their modulation with Sinemet 25/100114. 
Importantly, the predictive value of this dopamine polygene score was independently validated 
by Diaz Heijtz at the Karolinska Institutet115 in a study of intensive arm motor therapy provided 
to hemiparetic children with cerebral palsy. Separately, my lab also found that this polygene 
score predicted depression scores in healthy subjects and in subjects with major depression116. 
MacDonald et al at University of Auckland found that the same polygene score was able to 
predict extent of impulse control and whether these symptoms responded favorably to a 
dopamine agonist drug117. For these reasons, this polygene score will be tested as a predictor of 
treatment effect in each patient group. 
A pilot study of TR in patients with chronic stroke13 was an extension of the Cramer lab’s 
longstanding experience studying game-based robotic arm motor therapy for patients with 
stroke46, 96, 118-127. A pilot study transferred these and other games to a TR system, then tested it 
in 12 patients with chronic (>6 months post-onset) stroke. Each patient received 4 weeks of 
home-based, therapist-supervised TR targeting arm motor deficits. We found that  
• Patients were highly compliant (97.9% of assigned days) and rated the system 
favorably;  
• Therapists in the clinic were able to remotely review patient performances and 
revise therapy;  
• Videoconferences supported regular communication between the patient and 
treatment team;  
• Arm motor status improved significantly based on the FMA-UE;  


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
• Daily stroke education significantly increased secondary stroke prevention 
knowledge;  
• Screening for depression using telehealth methods was accurate;  
• No computer skills were needed, as computer literacy was not related to usage or 
treatment gains; and  
• With 60 min/day of TR in this pilot study, patients averaged 879 arm 
repetitions/day. 
These results support the feasibility and potential utility of this home-based program for 
improving outcomes after stroke. 
A multisite, randomized, assessor-blinded trial of TR: Subsequently, my lab led an 11-site 
national trial3 in the NIH StrokeNet clinical trials network. The primary aim was to determine 
whether treatment targeting arm movement delivered via a home-based TR system has 
comparable efficacy with dose-matched, intensity-matched therapy delivered in a traditional 
in-clinic setting. A randomized, assessor-blinded, non-inferiority design was employed. Entry 
criteria included stroke with onset 4-36 weeks prior and arm motor deficits (defined as UE-FM 
score of 22-56 of 66). Patients were randomized to TR therapy in the home or therapy at an 
outpatient clinic. All enrollees were assigned 36 sessions (70 minutes each) of arm motor 
therapy plus stroke education. Therapy intensity, duration, and frequency were matched across 
groups. 
Main results of the multisite, randomized, assessor-blinded trial: The 124 enrollees had baseline 
FMA-UE score of 43±8 (mean±SD) points (maximum score, 66 points; higher scores are better), 
and were enrolled 18.7±8.9 weeks post-stroke. Compliance was 98.3% in the TR group and 
93.4% in the in-clinic group. Change in FMA-UE score from baseline to 1-month post-therapy 
(the primary endpoint) was 8.4±7.0 points for the in-clinic group vs. 7.9±6.7 points in the TR 
group. The covariate-adjusted FMA-UE score change was 0.06 (95% CI -2.14, 2.26) points higher 
in the TR group (p=0.959). The non-inferiority margin fell outside this 95% CI, which indicates 
that TR is not inferior to dose-matched therapy provided in-clinic. Motor gains associated with 
TR therapy remained significant whether patients were enrolled early (<90 days) or late (>90 
days) post-stroke. Gains were also significant when examining change in the Box & Blocks Test 
(BBT) score, a measure of arm function (activities limitations). Stroke Knowledge scores also 
increased significantly (p<0.001). A post hoc analysis found that TR was associated with 
improved global function (mRS score) in 39.5% of patients beginning therapy after day 9014, a 
time when functional recovery generally stabilizes128. 
The number of arm movement repetitions over 36 TR treatment sessions was calculated in a 
convenience sample. With 70 min/day of TR, patients averaged 1,031 arm repetitions/day, 33-
times higher than the amount of arm movement provided during standard of care4. 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
In sum, a 6-week course of daily home-based TR supervised by a licensed OT or PT was safe, 
rated favorably by subjects, associated with excellent treatment compliance, and produced 
substantial gains in arm function that were not inferior to a dose-matched.  
A pilot study of TR for patients at an early timepoint after stroke: Most recently, we 
have performed a pilot study of TR in patients who were in the early weeks post-stroke. 
Patients were enrolled during admission to an IRF. Thus far we have enrolled 11 patients at 
California Rehabilitation Institute (Cal Rehab), each of whom had recent stroke and arm paresis. 
Enrollees received the 6-week TR program as described here, using the very same software and 
hardware described here. Each was assessed immediately before and after the 6-week course 
of TR.  
Baseline features include age 62.5±14.4 (mean  SD), median of 21 days post-stroke at time of 
first TR session, median of 6 TR sessions provided while the patient was still admitted to the 
IRF, FMA-UE score 33.2±5.4, and BBT score 7.6±9.6.  
Behavioral gains at the end of 6-weeks of TR included a mean increase in FMA-UE score of 
22.6±10.3 points; in BBT score, 26±8.4. These behavioral gains are strongly driven by 
spontaneous post-stroke recovery and it is difficult to understand which component may be 
attributable to TR effects, but these gains are nonetheless quite favorable.  
In terms of safety, there have been 9 adverse events (AEs), 2 of which were considered possibly 
or probably related to study participation. Both were non-serious. [1] one patient with 
hemianopsia felt nausea while using his own physician-prescribed prism glasses during TR, 
which was relieved by increasing breaks between TR activities and providing the option for anti-
nausea medication; and [2] one patient who was being treated for depression reported feeling 
demotivated and depressed when asked to score anxiety and depression scales online, which 
was addressed by removing these assessments from his future sessions. 
This study establishes the feasibility and safety of providing intensive TR to patients with severe 
motor deficits very early after stroke.  
In sum, we now propose to evaluate this intervention in a larger cohort of patients early after 
stroke, testing whether TR is better than an inactive control, and examining whether 
introducing levodopa enhances the benefits expected from daily intensive arm motor therapy 
delivered via TR. 
 
 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
Schedule of Events 
The table below provides an overview of the schedule of assessments and other tasks that will be completed by subjects in all groups. 
ASSESSMENT/TASK 
ELIGIBILITY 
SCREENING 
VISIT 1 
VISIT 2 
TR 
Week 
1^ 
TR 
Week 
2^ 
TR 
Week 
3^ 
TR 
Week 
4^ 
TR 
Week 
5^ 
TR 
Week 
6^ 
VISIT 3 
VISIT 4 
VISIT 5^^ 
TR Session # 
 
 
 
1-6 
7-12 
13-18 
19-24 
25-30 
31-36 
 
 
 
Study Overview 
X 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent & HIPAA 
X 
 
 
 
 
 
 
 
 
 
 
 
Research Participant’s Bill of Rights 
(handout) 
X 
 
 
 
 
 
 
 
 
 
 
 
Past Medical History 
Demographic/Contact Information 
 
 
 
 
 
 
 
 
 
 
 
 
Interval Medical History 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Adverse Events 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Action Research Arm Test (ARAT)  
X  
Must be <32 
  
 
 
 
 
 
 
 
X  
X 
X  
AROM shoulder and elbow flexion 
OR able to use at least 3 different input 
devices 
X  
At least ≥45° 
 
 
 
 
 
 
 
 
 
 
 
Box and Blocks Test (BBT)α 
OR Wrist extension and finger flexionβ 
Gravity eliminated 
X  
BBT must be ≥1 
 
 
 
 
 
 
 
 
X  
X  
X  
10-s and 3-block BBT 
X  
 
 
 
 
 
 
 
 
X 
X 
X 
3 Rehab Practice Tasks 
X  
Must pass all 
 
 
 
 
 
 
 
 
 
 
 
Center for Epidemiologic Studies 
Depression Scale – 20 item (CES-D)Ω 
X  
Must be ≤24 
 
 
 
 
 
 
 
 
 
 
 
Center for Epidemiologic Studies Short 
Depression Scale – 10 item (CESD-R-10)Ω 
 
 
 
 
 
X 
 
 
X 
 
 
 
Montreal Cognitive Assessment (MoCA) 
X  
Must be >22 
 
 
 
 
 
 
 
 
 
 
 
Visual Acuity Screen 
X 
Must be ≥20/50 
in one eye 
 
 
 
 
 
 
 
 
 
 
 
Trail Making Test: Part A only 
X 
 
 
 
 
 
 
 
 
 
 
 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
Must be >14 
Eligibility Checklist  
 
X  
 
 
 
 
 
 
 
 
 
 
Behavioral Contract  
X  
 
 
 
 
 
 
 
 
 
 
 
Randomization  
X  
 
 
 
 
 
 
 
 
 
 
 
Pharmacy – Fill Prescription 
X  
 
 
 
 
 
 
 
 
 
 
 
MRI Safety Screening Questionnaire  
X  
 
 
 
 
 
 
 
 
 
 
 
Fugl-Meyer Motor Assessment – Upper 
Extremity (FMA-UE) 
 
X 
 
 
 
 
 
 
 
X  
X  
X  
Modified Rankin Scale (mRS)µ 
 
X  
 
 
 
 
 
 
 
X  
X  
X  
Shoulder Abduction Finger Extension 
(SAFE) Score  
 
X  
 
 
 
 
 
 
 
 
 
 
Handedness Inventory  
 
X  
 
 
 
 
 
 
 
 
 
 
Star Cancellation Test (SCT) 
 
X 
 
 
 
 
 
 
 
 
 
 
The Language Screening Test (LAST) 
 
X   
 
 
 
 
 
 
 
 
 
 
Nine Hole Peg Test (NHPT) 
 
X  
 
 
 
 
 
 
 
X  
X  
X  
Stroke Impact Scale (SIS) – ADL subsection  
 
 
 
 
X* 
 
 
 
 
X  
X  
X  
SIS – Hand subsection 
 
 
 
 
X* 
 
 
 
 
X  
X  
X  
Modified Ashworth Scale 
Pecs & Biceps 
 
X  
 
 
 
 
 
 
 
 
 
 
Review of TR System 
 
X  
 
 
 
 
 
 
 
 
 
 
Reaction Time Test 
 
X  
 
 
 
X1 
 
 
X2  
 
 
 
Optimization in Primary and Secondary 
Control (OPS) Scale 
 
X 
 
 
 
X 
 
 
X 
 
 
 
Physical Activity Enjoyment Scale (PACES) 
 
X  
 
 
 
X∑ 
 
 
X∑  
 
 
 
Screening Q re: Restless Legs Syndrome 
 
X  
 
 
X2*  
 
 
 
 
 
 
 
Genetic Testing  
 
X  
 
 
 
 
 
 
 
 
 
 
TR System Delivery 
 
 
 
X  
(TR 
Group) 
 
 
 
 
 
 
X  
(UC 
Group) 
 
Call UC Subjects (reminder re: 
participation and logging therapy hours, 
inquire about adverse events) 
 
 
 
Every 1-2 weeks 
 
 
 
MRI+ 
 
 
X  
 
 
 
 
 
 
 
 
 
Shoulder Pain 
 
 
 
Daily (Start and End of Therapy) 
 
 
 
Fatigue 
 
 
 
Daily (Start and End of Therapy) 
 
 
 
Daily Motor Assessment 
 
 
 
Daily (Start of Therapy) 
 
 
 
Finger Tap Assessment 
 
 
 
Daily (Start of Therapy) 
 
 
 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
Degree of Perceived Effort 
 
 
 
Daily (End of Therapy) 
 
 
 
Stroke Education Quiz 
 
 
 
X 
 
 
 
 
X  
 
 
 
Stroke Education  
 
 
 
 
Daily 
 
 
 
 
Functional Module 
 
 
 
 
 
 
 
X** 
X** 
 
 
 
Euro-QoL Visual Analog Scale (VAS) 
 
 
 
X 
 
 
 
 
X 
 
 
 
General Anxiety Disorder 7-item Scale 
(GAD-7) 
 
 
 
 
X 
 
 
 
 
 
 
 
Medical Outcomes Study (MOS) Social 
Support Survey (SSS) 
 
 
 
 
 
X 
 
 
 
 
 
 
Guess Medication 
 
 
 
 
 
X2  
 
 
 
 
 
 
Brief Resilience Scale  
 
 
 
 
 
 
X 
 
 
 
 
 
Functional Training Module 
 
 
 
 
 
 
 
X  
X  
 
 
 
Patient Satisfaction with TR Survey 
 
 
 
 
 
 
 
 
X 
 
 
 
TR System Pick-up 
 
 
 
 
 
 
 
 
X  
(TR 
group) 
 
 
X  
(UC 
Group) 
^ Only patients in the TR groups will be undergoing TR training for 6 weeks  
α Splint permitted for use during BBT for study eligibility only 
β Patient must show visible flicker (trace movement) in all 4 movements tested, if BBT not ≥1 
Ω Tally score on day assessment is completed, and contact the patient’s care team if the score is high, per SOP guidance 
µ At Visit 1, complete pre-stroke and current mRS; current mRS for all other visits 
∑ additional question to be asked post-assessment (refer to CRF for details) 
*completed within 5 days after DC home (SIS) or during week 2 (SIS or Restless Leg Screening Q); for UC subjects, the SIS ADL and hand and Restless Leg Screening question will be completed during 
Week 2, after randomization 
1completed during start of week 
2completed during last supervised session of week 
+ timing of the MRI may be modified per PI judgment 
**schedule 5-10 minutes on supervised days only, to observe practice of functional task related to goal 
^^ Visit 5 only applies to participants in the UC group who choose to participate in TR training after their initial study participant has ended 
 
 
 
 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
Screening, Recruitment, and Enrollment 
Recruitment: Patients will be recruited from two main sources. First, patients with a recent 
stroke admitted to Cal Rehab, an inpatient rehabilitation facility (IRF) in Los Angeles, CA, will be 
screened and when appropriate offered study enrollment and a Screening Visit. Second, 
patients with a recent stroke who have been discharged home then referred to the study will 
be invited to Cal Rehab for pre-screening and when appropriate study enrollment and a 
Screening Visit. These referrals may come from outside sites.  
Research activities at Cedars-Sinai: One of these referral sites will be Cedars Sinai, who will refer 
patients as above. Cedars personnel will also assist with (1) reviewing and refining study 
procedures, and (2) data analysis and results reporting.  
Pre-screening: Pre-screening will occur before the patient is asked to sign consent. For 
patients admitted to Cal Rehab, pre-screening will consist of review of the medical record plus a 
very brief pre-screening exam that aims to identify severe paralysis, severe cognitive or 
language deficits, or other major abnormalities that clearly indicate that a patient is not eligible 
for the study. For patients referred to the study from the community, pre-screening will occur 
during the initial phone call and during a very brief pre-screening exam performed after the 
patient arrives at Cal Rehab. Patients considered to have a reasonable likelihood of study 
eligibility will be offered study enrollment. The Screening Visit will then proceed, and this takes 
place at Cal Rehab. 
Enrollment 
The initial steps of study enrollment are as follows:  
• Provide the patient with an overview of the study and the study timeline 
• Have the patient sign the ICF and the Health Insurance Portability and Accountability Act 
(HIPAA) Research Authorization for Release of Protected Health Information (PHI) 
• Provide the patient with a copy of the Research Participant’s Bill of Rights  
• Gather demographic data, medical history, and contact information, from the patient, 
from a subsequently obtained copy of medical records, and when possible from the 
electronic health record 
• Complete baseline screening measures to confirm study eligibility, including: 
• Action Research Arm Test (ARAT) 
• Box and Blocks Test (BBT) 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
 
If unable to complete BBT, will examine wrist extension and finger flexion for a 
visible flicker (at least trace contraction must be present for both movements) 
• Examine range of motion against gravity in the paretic shoulder and elbow  
• 3 Rehabilitation Practice Tasks  
• Center for Epidemiologic Studies Depression Scale (CES-D, 10 questions) 
• Montreal Cognitive Assessment (MoCA) 
• Trail Making Test (TMT): Part A 
• Visual Acuity Screen  
• Complete the Eligibility Checklist, which evaluates whether the patient fully meets 
inclusion and exclusion criteria  
• If the patient is an inpatient at Cal Rehab, enter a research progress note into the 
electronic health record (Epic) 
The Screening Visit may be broken into more than one session, as needed. 
If the patient meets all of the eligibility criteria and is amenable to study participation, they will 
given a Visit 1 follow-up appointment, ideally on the next day.  
  
Inclusion and Exclusion Criteria 
Below is a list of the study inclusion and exclusion criteria. The Eligibility Screening packet 
includes an eligibility checklist, which must be completed to confirm whether a patient is 
eligible or ineligible for participation. 
 
INCLUSION CRITERIA 
1. Age 18 years or older 
2. Stroke that has been radiologically verified and has time of onset 30 days or less from 
the time of randomization 
3. ARAT score of <32 (out of 57) at Visit 1 
4. At Visit 1, either  
a. BBT score with affected arm is at least 1 block in 60 seconds OR  
b. There is a visible flicker in each of the following movements with gravity eliminated: 
wrist extension and finger flexion 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
5. At Visit 1, either 
a. The range of motion against gravity must be ≥45 degrees in both the paretic 
shoulder and elbow OR 
b. the patient must be able to use at least 3 different telerehab system input devices 
6. Informed consent and behavioral contract signed by the subject (i.e., no surrogate 
consent) 
 
EXCLUSION CRITERIA 
1. A major, active, coexistent neurological or psychiatric disease (e.g., alcoholism or 
dementia) 
2. Major medical disorder that reduces subject’s ability to comply with study procedures 
3. Severe depression, defined as CES-D score >24 at screening visit 
4. Significant cognitive impairment, defined as presence of either 
a. Montreal Cognitive Assessment (MoCA) score <22 OR 
b. Trail Making Test: Part A score ≤14 
c. Note that lower scores may be permitted if due to aphasia and if the patient is 
specifically allowed by Dr. Cramer 
5. Deficits in communication that interfere with reasonable study participation 
6. Lacking visual acuity, with or without corrective lens, of 20/50 or better in at least one 
eye 
7. Life expectancy <6 months 
8. Pregnant  
9. Botox to arms, legs or trunk in the preceding 4 months, or expectation that Botox will be 
administered to the arm, leg or trunk within 3 months of study enrollment 
10. Unable to successfully perform all 3 rehabilitation exercise test examples 
11. Unable or unwilling to perform study procedures/therapy or attend study visits, or 
expectation of noncompliance with study procedures/therapy 
12. Non-English or non-Spanish speaking, such that subject does not speak either language 
sufficiently to comply with study procedures 
13. Isolation due to active COVID-19 
14. Any contraindication to L-Dopa: 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
a. 
Patient is currently taking a monoamine oxidase inhibitor; if the patient took 
such a drug in the past, it must be discontinued at least two weeks prior to study 
enrollment 
b. 
Known hypersensitivity to any component of Sinemet 
c. 
Narrow-angle glaucoma; if wide-angle glaucoma is present, the patient can only 
be enrolled with explicit written approval from their ophthalmologist 
d. 
History of melanoma or suspected melanoma 
e. 
Patient is currently taking phenytoin, papaverine, isoniazid, or a dopamine D2 
receptor antagonist (such as a phenothiazine, butyrophenone, or risperidone) 
f. 
Currently taking a direct dopaminergic agonist 
15. Expectation that subject will not have single domicile address during 6 weeks of therapy 
that has either Verizon wireless reception or a home WiFi network and that has space 
for TR system, and is within 30 miles of Cal Rehab 
 
Any of the above entry/exclusion criteria can be waived by Dr. Cramer. 
 
In addition, we will enroll up to 3 patients in a beta study, in which Inclusion criteria 2 and 3 
are waived. 
 
 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
Visit 1 
Visit 1 will occur at Cal Rehab. Seven key events occur at Visit 1:  
1. Baseline assessments are completed 
2. Blood is drawn for genetic testing 
3. MRI Screen 
4. The patient is randomized 
5. Dispense study medication (at or shortly after Visit 1) 
6. The patient is asked to sign the behavioral contract 
7. The TR system is introduced. 
 
Baseline Assessments 
Additional assessments will be completed during Visit 1 in order to more fully characterize the 
patient’s functional status at baseline: 
• Fugl-Meyer Arm Motor Assessment for the upper extremity (FMA-UE) 
• Modified Rankin Scale (mRS), scoring both  
• pre-stroke mRS 
• current mRS  
• Shoulder Abduction Finger Extension (SAFE) Score 
• Handedness Inventory (pre-stroke) 
• Star Cancellation Test (SCT) 
• The Language Screening Test (LAST)  
• Nine Hole Peg Test (NHPT) 
• Optimization in Primary and Secondary Control (OPS) Scale 
• Physical Activity Enjoyment Scale (PACES) 
• Screening question for Restless Legs Syndrome 
• Reaction Time Test 
• Modified Ashworth Scale (mAS) 
• paretic pectoralis major  
• paretic biceps brachii 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
All Visit 1 assessments are available in a single “Visit 1” packet, located in the lab’s Box folder. 
Details regarding administration of each assessment is found within individual CRFs. The Visit 1 
folder on Box also includes a handout for TR input devices, which can be given to patients for 
reference. Visit 1 may be broken into more than one session, as needed. 
After all assessments have been completed, provide an overview of how to access and use the 
TR system for daily arm motor training.  
Note that all study visits may be broken into more than one visit to the lab for any patient who 
requests this (e.g., due to time constraints). 
Genetic Testing 
For genetic testing, DNA and genotyping data will be collected from patients under the protocol 
described in IRB#10-001577 using a separate consent process. Two 4 mL tubes of blood will be 
drawn into lavender top (EDTA) collection vials and taken to the genetics lab at UCLA for 
processing, to test the genotype-based biomarker hypothesis (Aim 3). 
MRI Screen 
A standard MRI screen will be conducted at Visit 1. Patients eligible for MRI will proceed to Visit 
2 for the MRI scan, whereas those who are not eligible for an MRI scan may still be eligible for 
study inclusion per Dr. Cramer. The timing of the MRI may be modified per PI judgment. 
 
Randomize the patient 
Using a web-based randomization procedure, the patient will be randomized into one of three 
treatment groups: 
• TR + Sinemet: Patients in this group will receive 36 therapy sessions targeting arm 
motor function starting as soon as possible after randomization (target is next day). This 
therapy is structured as 6 weeks of TR, 6x/week, for 6 weeks. Up to 8 weeks are 
permitted to make up for lost sessions to achieve 36 sessions in which >50% of assigned 
minutes are completed by the patient. For the first 18 sessions (approximately the first 3 
weeks), the patient will take their study pill (Sinemet 25/100) 1-2 hours after breakfast 
or lunch, then 1 hour later begin their 70-min TR session. TR+Sinemet is in addition to 
UC (i.e., the patient is to continue all therapies and medication provided as part of 
standard medical care). 
• TR + placebo: Patients in this group will receive 36 therapy sessions targeting arm motor 
function starting as soon as possible after randomization (target is next day). This 
therapy is structured as 6 weeks of TR, 6x/week, for 6 weeks. Up to 8 weeks are 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
permitted to make up for lost sessions to achieve 36 sessions in which >50% of assigned 
minutes are completed by the patient. For the first 18 sessions (approximately the first 3 
weeks), the patient will take their study pill (placebo) 1-2 hours after breakfast or lunch, 
then 1 hour later begin their 70-min TR session. TR+placebo is in addition to UC (i.e., the 
patient is to continue all therapies and medication provided as part of standard medical 
care). 
• Usual care (UC): Patients in this group will not receive TR or a blister pack of study pills. 
Instead, each will receive UC (i.e., will continue all therapies and medication provided as 
part of standard medical care). In order to maximize participant retention, patients in 
this group will be offered a 6-week course of TR after Visit 4 (i.e., 5-6 months after 
stroke). At the end of their TR therapy, at the time that their TR system is picked up 
from their home, the therapist will perform ARAT, FMA-UE, BBT, NHPT, and mRS in the 
patient’s home. 
Dispense Study Medication 
Study medication will be dispensed at Visit 1, or shortly after. Patients randomized to the 
TR+Sinemet and the TR+placebo groups will be given a blister pack of 18 pills with instructions 
to take one pill an hour after breakfast or lunch 6 days/week for the first 18 sessions 
(approximately the first 3 weeks). TR will begin 1 hour after pill ingestion. Patients will be given 
apple sauce to take with their pill as needed, following dysphagia restriction guidelines, to 
mitigate concerns for potential nausea. As needed, patients may also be provided with an 
antacid drug. Patients in the UC group will not be given a blister pack of study pills or apple 
sauce. 
The UCLA Pharmacy will generate the two types of study pills (i.e., Sinemet 25/100 and 
placebo). These two pills will be indistinguishable internally and externally (i.e., the internal 
powder will be the same color, and the external over-encapsulation will be identical), across 
both pill types. Pills will be organized into an 18-pill blister pack. 
In patients with stroke, oral Sinemet 25/100 once/day is not associated with increased risk or 
with decreased acceptability of risks86, 87 For this reason, the current study does not need to be 
conducted under an investigational new drug application to the FDA. 
Behavioral Contract 
Patients sign a group-specific behavioral contract3, 12. For patients in the two TR groups, this 
contract describes the patient’s commitment to engaging in study-assigned therapy, includes a 
personal goal, outlines a plan to incorporate the paretic UE into daily life, and states the time of 
day when TR will generally begin. 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
TR System Overview  
Patients will be participating in daily (6 days/week) TR training over the course of 6 weeks (up 
to 8 weeks is permitted to complete 36 sessions). If an enrollee is an inpatient at Cal Rehab at 
the time of enrollment, guidance for use of the TR system will be at the end of Visit 1 and at 
subsequent inpatient TR sessions. If the enrollee is an outpatient referred into the study, 
guidance for TR use will occur at Visit 1 and at the time that the TR system is delivered to the 
patient’s home. TR guidance will provide an understanding of the general TR layout, the nature 
of the functional games and exercises used for arm training, other modules such as education 
and assessment, how to respond to instructions (which are presented verbally and non-verbally 
as a TR system feature), and how to use each TR input device. 
 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
Visit 2 
Visit 2 will be conducted on the UCLA campus. At Visit 2, the patient will undergo an MRI scan 
of the brain to acquire structural and functional brain images. Pulse sequences will include T1-
weighted, T2-weighted, resting state BOLD T2*, and diffusion tensor imaging. These data will be 
used to test MRI-based biomarker hypotheses (Aim 3). At this visit, the patient will also be 
asked about any interval medical history and AEs. 
Note: The timing of the MRI may be modified per PI judgment. 
 
TR System Home Delivery 
The TR system should be delivered to the patient’s home (a) as soon as possible after discharge 
from Cal Rehab, for patients enrolled while admitted to Cal Rehab, and (b) as soon as possible 
after Visit 2, for patients referred into the study. Two research staff members should be present 
for all home visits, when possible. 
In addition to setting up the TR equipment and connecting it to WiFi, patients should be given a 
quick overview of the TR system, confirm the patient’s study schedule, and ensure a caregiver 
will be available to assist with transfers and supervision if needed. The patient’s own home WiFi 
should be used to connect the TR system to the internet, if possible, else a study-provided 
wireless modem will be furnished and employed for this purpose, as we have successfully done 
previously129. 
 
 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
TR Therapy 
The telerehabilitation intervention 
Summary: Patients are assigned 70 minutes of telerehabilitation (TR) therapy each day, 6 
days/week, for 6 weeks, targeting the paretic UE. Functional games and exercises comprise 65 
of these daily minutes, and 5 minutes/day is spent on stroke education (which requires 
targeted arm movement).  
Therapy must begin within 7 days of randomization. The first TR session will be a supervised 
session, whether in-person or via videoconference.  
TR is delivered over 36 sessions, each 70-minutes in duration. Of these, 18 sessions are 
supervised by a licensed OT or PT; for patients receiving TR while admitted to Cal Rehab, the 
therapist may be in the same room as the patient or communicate via videoconference, and for 
patients who are at home, the therapist is present via videoconference. The other 18 sessions 
are unsupervised (i.e., no OT or PT is present at any time during the session; for inpatients at 
Cal Rehab, the therapist can sit near the patient, with minimal interaction, at the therapist’s 
judgment). Ideally, a given patient will work with the same therapist1 for the entire 6 weeks. To 
accommodate possible external events (e.g., illness or family reasons), patients are permitted 
up to 8 weeks to complete these 36 treatment sessions. In the prior national trial3, the FDA 
determined (Q140628) that the investigation using an earlier generation of the same device 
was a non-significant risk device study. The FDA made the same determination (Q212693) for 
the current study. When possible, patients begin TR each day at the time indicated in the 
behavioral contract. Patients are free to pause between games and activities, as needed. 
Patients are also instructed to perform all UC that is provided to them–enrollment in this TR 
study does not interfere with any treatment provided as part of standard of care. A session is 
considered completed when the patient has completed >50% of the assigned 70 minutes by 
midnight. After the 36 treatment sessions are completed, or if that does not happen then at the 
end of 8 weeks, the team retrieves the TR system from the patient’s home. 
The TR treatment approach was based in part on an UE task-specific training manual130 and 
Accelerated Skill Acquisition Program72, building on games developed as part of previous 
studies from the Cramer lab that used a game-based approach to therapy after stroke, in the 
context of robotics46, 96, 118-127.  
Feedback to patients is a core feature and comes from two sources. First, therapists give 
feedback on supervised days based on their observations during videoconference plus their 
review of electronic data such as prior days’ device usage and scores on functional games. 
Second, the TR system gives patients feedback (e.g., during a game such as whether a game 
target was hit or not, and after a game when current/past scores game scores are presented). 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
In this way, incorporation of feedback in the current TR system directly builds on OPTIMAL 
theory131. Feedback provided by the TR system during gameplay and at the end of each game 
emphasizes enhanced expectancy and reward during gameplay. Positive feedback is also 
provided by the therapist during supervised sessions. Autonomy is promoted by using a home-
based treatment approach and by having half of treatment days be unsupervised (i.e., there is 
no interaction with a therapist). External focus on attention is facilitated by therapist feedback 
and by the approach to gameplay. 
The active ingredients of TR within the RTSS 65, 66 framework are summarized above, which 
emphasizes that playing the TR functional games is not simply rote movement repetition but 
instead targets specific brain circuits (memory, attention, somatosensory, visuomotor, and 
cognitive circuits) that drive motor output. Specific dosing parameter goals and dose 
progression strategies are outlined for treatment therapists. 
Therapist-facing software 
We developed a therapist-facing web portal that treatment therapists use for treatment 
planning and patient monitoring. All treatment is generated and supervised by a licensed OT or 
PT. Therapists use a graphical interface to drag treatment elements (functional games, 
exercises, and stroke education) into a 70-min planner for each day’s session; they then adjust 
the challenge level (games) and the duration (games and exercises) of each. 
Videoconferences: For the supervised sessions that occur for patients who are living in their 
home, the treatment therapist joins the patient for 60 minutes of their session using HIPAA-
compliant software (VSee; Sunnyvale, CA). Supervised sessions that occur while a patient is still 
admitted to Cal Rehab may have the therapist join the patient via VSee or live in the patient’s 
room, per the therapist’s judgment. During supervised sessions, therapists monitor therapy and 
provide patients with real-time positive feedback, answer questions, perform assessments, 
review treatment plans, and provide encouragement. Therapists also discuss how UE 
movements practiced during TR can be extended to become part of activity in the home. Any 
AEs and serious adverse event (SAEs) are reviewed. Note that 9.7% of patients receiving TR in 
the national trial3 had shoulder pain, and all patients could be helped by their therapist 
remotely, without pausing TR therapy. Therapists write an electronic clinic note after each 
videoconference, as standard good clinical practice. 
The same therapist-facing web portal allows therapists to review, at any time, from any secure 
location: 
Usage statistics: For games and for the stroke education module, we use the TR system’s 
sensors--every game click, tap, squeeze, or shot is sent to the lab server in real time.  
Performance data: We provide therapists with concise graphic readouts of scores on each 
game, over time. In this way, therapists can monitor patient compliance and performance, and 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
then use their professional judgment to modify game/exercise choices and difficulty levels 
accordingly, at any time.  
Patient-facing software 
Each of the 36 TR sessions is 70 min and includes 65 min/day of functional games and exercises, 
plus 5 min/day of stroke education–all of which require arm movements. 
(1) Arm exercises. A total of 114 UE exercises are available, each 1-5 min long and consisting of 
a video showing the assigned movement. Therapists may choose to demonstrate some of the 
exercises during videoconferences on supervised days. In addition, therapists have the option 
to incorporate standard exercise equipment (e.g., Theraband) that is also provided to patients 
at the time the TR system is delivered to the home and that can be incorporated into assigned 
exercises. 
(2) Functional training through games. There are 25 functional games, each 1-5 min long. These 
stress motor control features (e.g., varying movement speed, range of motion, squeeze 
strength, pinch strength, target size and features, extent of visuomotor tracking, memory 
demand, unilateral vs. bilateral movement, or level of cognitive demand). Features are selected 
and adjusted by the therapist, e.g., during the whack-a-mole game, higher difficulty level means 
a broader area where targets can appear and less time to hit the target to score points. 
Therapists also select which of the 11 input devices the patient will use for game play, based on 
UE motor status, e.g., vertical position of the flying bird in the flappy-bird game can be played 
using the grip force cylinder, pinch force cube, or trackpad. Feedback is provided during the 
game (e.g., when targets are hit), at the end of each game (today’s score along with prior 
scores), and at the end of the day (graphs of progress over time). 
(3) Five minutes/day of stroke education. The education content targets 5 categories (Stroke 
Risk Factors, Stroke Prevention, Effects of Stroke, Diet, and Exercise). During unsupervised 
sessions, patients answer multiple-choice questions, delivered via a video Jeopardy game 
format, an approach known to foster learning132, 133, and then receive feedback on their 
answers. Patients must make targeted arm movements to play the Stroke Jeopardy game. 
These 5 min/day significantly increase patient knowledge on stroke-related topics3, 13. A Stroke 
Knowledge Exam is administered through the TR system during the first and the last week, to 
measure knowledge gains in these five categories. 
To begin the day’s TR session, the subject hits a large green tabletop button. After each 
game/exercise is completed, the same green button is hit again to start subsequent 
games/exercises, an approach that provides patients with the freedom to take a break as 
needed. Unsupervised sessions have the same treatment content as supervised sessions but 
without any therapist contact. 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
All patient interactions with the TR system incorporate both verbal and non-verbal instructions. 
Instructions are simple and use a large-font and large symbols. 
TR hardware 
The telerehabilitation system hardware consists of an internet-enabled computer with table, 
chair, and 11 gaming input devices–but no keyboard, as no computer operations are required 
by subjects and no computer literacy is needed for high compliance or for arm improvement. 
The 11 devices are large tabletop buttons, small tabletop buttons, a trackball mouse, rotating 
shuttle wheel, trackpad, grip force cylinder, pinch force cube, a Wiimote equivalent inside 
gaming pistol, a tracking wand, joystick, and an accelerometer attached to an easy grip. 
The console itself is created using a 22cm x 22cm Ikea “Lack” side table, which is made of 
particle board. The legs aren’t used.  The top has its bottom and internal honeycomb structure 
removed, and holes are cut into the top and sides for all the components.  Drawer handles are 
attached for easier handling and transport. 
Gaming input devices are used to move through assignments, drive game play, and enable 
assessments and education. Some of these devices are connected directly to the top of the 
table. These are [1] four 100mm arcade buttons with internal LEDs, [2] a DIY arcade kit that 
includes ten 30mm JAMMA/MAME style arcade push buttons and joystick, [3] a 4.5cm PS/2 
Trackball mouse, [4] a 360-degree Rotary Encoder Digital Potentiometer with Push Button, and 
[5] a USB trackpad.  All of these components are available through Amazon.com except the USB 
trackpad, which we purchased directly from an original equipment manufacturer vendor. The 
Potentiometer is fitted with a ThunderStick GRS Spinner Knob that can be swapped out with 
custom 3D printed tops that require various types of finger grips. 
Other gaming input devices are connected to the side of the table via a plug: [1] a force sensor 
built using a 20kg Load Cell Sensor, [2] a pinch sensor using Interlink model 402 Force-Resistive 
Sensor, [3] a pistol built using an RB-Dfr-553 IR Tracker, [4] a wand that uses another RB-Dfr-
553 IR Tracker, and [5] a BNO055 sensor which is a 9 Degree of Freedom IMU.  All the housings 
for these devices are 3d printed in the lab. For sensors that require 2 wires, we use 3.5mm 
audio jack connectors and lightweight headphone cables. For sensors that require 3 or more 
wires, we use RJ45 Keystone adapters and Monoprice SlimRun ethernet cables to minimize the 
weight.  The pistol is made up of a commercially available Wii Remote gun shell, a 3D printed 
adapter to fit the IR tracker, and splicing of the Wii port connector to an RJ45 connector to 
make it detachable. 
Internally, all components are hooked up to 2 Arduino Mega microcontrollers.  The first 
controller handles all the button inputs and has had its firmware flashed to convert it into a 
standard USB human interface device keyboard; in this way, each button press translates to a 
standard keystroke viewable on any computer. The second microcontroller handles the LED 
outputs as well as other digital and analog sensors, and it communicates directly with a 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
controlling PC using a serial connection. To wire all the components together in a clean manner, 
a circuit board was designed and printed. We used JLCPCB.com for this service. The circuit 
board allows for direct mounting of all components since we can solder on screw terminals, JST 
pin connectors, resisters, and header pins. Using this approach makes things removable and 
reduces the number of wires required to assemble everything. Several of the sensors use an I2C 
connection, so we included an I2C Multiplexer into the circuit, as well as a HX711 AD Weighing 
Module that’s required for the load cell to function correctly. 
The final component is a standard USB hub, which is mounted internally as well, but accessible 
from the outside through a cutout. We used a 7 port USB 2.0 hub. Both Arduinos and the 
trackpad connect to the hub, which has a power connector as well as a USB connector that 
must be connected to a computer. Thin plywood bought from Home Depot and cut to match 
the Ikea Lack Table is screwed onto the bottom of the console to seal it. A barrel jack connector 
on the side of the table that is connected to the Arduino 5V output allows us to power the 
external 940nm IR LEDs necessary for the IR trackers to work. 
The console connects via USB to a computer, such as a Lenovo B50 All-In-One PC, which runs 
our custom TR program, Teamviewer, and VSee. These PCs run Windows 10 Pro and have i5-
4460T Processors, 8GB of RAM, and upgraded with Samsung 500GB SSD drives.  Video chat uses 
the internal webcam. Three 940nm IR LEDs are attached to the front for tracking. 
 
 
 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
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TR-based assessments 
Several behavioral assessments will be completed remotely during Weeks 1 to 6 using the TR 
system. These will be scored during supervised sessions, while the therapist is in the 
videoconference. In addition, once each week, the therapist will ask the patient about interval 
medical history and AEs. 
 
Daily assessments performed using the TR system 
• 
Daily motor assessment (Whack-A-Mole game using the hand, scores # targets hit in 90 seconds) 
• 
Daily finger tap assessment (scores # index finger taps on small button in 10 sec, reported in Hz) 
• 
Daily shoulder pain scoring– uses Visual Analog Scale (VAS) 
• 
Daily fatigue scoring– uses VAS  
• 
Degree of Perceived Effort – uses VAS 
 
Week 1 additional assessments 
• 
EuroQoL Visual Analog Scale (EQ VAS) 
• 
Stroke Education Quiz (5 questions/day x 6 days) 
• 
The patient will be asked about interval medical history and AEs 
 
Week 2 additional assessments 
• 
Stroke impact scale – ADL and Hand subsections (administered during week 2 or within 5 days of 
DC home) 
• 
General Anxiety Disorder 7-item (GAD-7) Scale 
• 
Screening question for possible diagnosis of Restless Legs Syndrome 
• 
The patient will be asked about interval medical history and AEs 
 
Week 3 additional assessments 
• 
Reaction Time Test 
• 
Medical Outcomes Study Social Support Survey (MOS-SSS) 
• 
Center for Epidemiologic Studies Short Depression Scale (CESD-R-10) 
• 
OPS and PACES 
• 
Guess Medication (Patients asked which pill they think they were taking each day.) 
• 
The patient will be asked about interval medical history and AEs 
 
Week 4 additional assessments 
• 
Brief Resilience Scale (BRS) 
• 
The patient will be asked about interval medical history and AEs 
 
Week 5 additional assessments 
• 
The patient will be asked about interval medical history and AEs 
 
Week 6: additional assessments 
• 
Stroke Education Quiz (5 questions/day x 6 days) 
• 
Reaction Time Test 
• 
EQ VAS 
• 
CESD-R-10 
• 
OPS and PACES 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
• 
Patient Satisfaction with Telerehabilitation Survey 
• 
The patient will be asked about interval medical history and AEs 
 
Visit 3 (End of Treatment) 
The end-of-treatment visit will generally be conducted at Cal Rehab, but accommodations for 
home assessment will be made as needed.  
If the testing occurs in the patient’s home, two research staff members should be present, 
when possible: one person to conduct final assessments with the patient and the other to 
deconstruct and clean equipment for transport back to the lab. 
Assessments 
Several standardized assessments will be conducted during this in-person visit: 
• FMA-UE 
• BBT 
• ARAT 
• NHPT 
• mRS 
• SIS-hand and ADL subsections 
• In addition, the patient will be asked about interval medical history and AEs 
 
Deconstructing and cleaning equipment 
A member of the research team will deconstruct, clean, and pack the TR system for transport back to 
the lab while the examiner is conducting assessments with the patient.  
  
 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
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Visit 4 (End of Study) 
The end-of-study visit will generally be conducted at Cal Rehab, but accommodations for home 
assessment will be made as needed; this visit occurs 1 month after Visit 3. Visit 4 may be 
broken into more than one session, as needed. All Visit 4 assessments are available in a single 
“Visit 4” packet, located in the lab’s Box folder. Details regarding administration of each 
assessment is found within individual CRFs. 
Assessments 
The following assessments will be completed during this final in-person visit: 
• ARAT 
• BBT 
• mRS 
• FMA-UE 
• NHPT 
• SIS—ADL and hand subsections 
• The patient will be asked about interval medical history and AEs 
  
Visit 5 (for UC only) 
As previously mentioned, patients in the UC group will be offered a 6-week course of TR after 
Visit 4 (i.e., 5-6 months after stroke). For those subjects who choose to complete this training, 
the same assessments administered at Visit 4 will be re-assessed at Visit 5. These include the 
following: 
• ARAT 
• BBT 
• mRS 
• FMA-UE 
• NHPT 
• SIS—ADL and hand subsections 
• The patient will be asked about interval medical history and AEs 
 
 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
Randomization and Blinding 
Randomization 
A web-based randomization procedure will be used to assign patients to one of three groups in 
a 3:3:2 ratio. The three treatment groups are [1] TR plus Sinemet, [2] TR plus placebo, and [3] 
UC. 
Blinding 
With regard to TR vs. UC, study assessors will be blind to treatment assignment. Several steps 
will be taken to maintain this blind, including having assessments occur in a separate part of the 
building from TR therapy. 
With regard to TR+Sinemet vs. TR+placebo, enrollees and their family members, study 
assessors, study treatment therapists, clinicians involved in UC, the study PI, and all other study 
personnel will remain blinded to type of pill assigned. The sole person unblinded to pill type (for 
patients randomized to either TR+Sinemet or TR+placebo) will be the study statistician. With 
regard to the pill to which a TR patient was assigned, the study PI will be able to break the blind 
at any time in case of a medical emergency requiring this knowledge. To enable this, a 
password-protected file and a hard copy sealed envelope will both be in the PI’s possession and 
will remain unopened unless an emergency unblinding event arises. 
 
 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
Sample Size and Statistical Analysis 
Sample Size 
The primary endpoint is the ARAT, the MCID for which is 5.7 points. This study is powered for 
the Aim 1 analyses, which will compare [1] patients receiving TR (i.e., combining TR+Sinemet 
with TR+placebo) to [2] patients receiving UC. Based on a randomization distribution of 3:3:2 
(TR+Sinemet, TR+placebo, UC), and using a 2-sided alpha of 0.05, this study will have 80% 
power to detect a mean difference between groups of 5.7 points in the change in ARAT-time, 
assuming a SD of 7.4 points97, 139, with a total of 72 patients: 27 in TR+Sinemet, 27 in 
TR+placebo, and 18 in UC.  
The study is funded to enroll 72 patients. Subject dropout may be as high as 20%, and so when 
possible additional patients may be enrolled. 
Statistical Analysis 
We will present descriptive statistics by group for the important covariates including age, site, 
time from stroke to randomization, MEP status, and hours of outside rehabilitation. We will 
also report compliance, defined as the percentage of the 36 sessions during which patients 
complete more than half (≥36 min) of assigned activities. For all analyses, data not normally 
distributed will be appropriately transformed. 
Primary efficacy analysis will use the Intent-To-Treat population, consisting of all randomized 
subjects and multiple imputation for missing data. Secondary analysis will examine the Per-
Protocol population, defined as all subjects with complete data who complete ≥36 minutes of 
assigned activities on ≥30 of the 36 therapy sessions over no more than 8 weeks. Analyses will 
be performed using SAS and R software. 
Logistic regression will be used to create a propensity score135 for treatment group using age, 
time from stroke to randomization, and total hours of outside rehabilitation therapy from Visit 
1 to Visit 4 (or Visit 3 when change is to visit 3). Inverse weights based on this score will be used 
in secondary analyses to compute adjusted change distributions and corresponding p values.   
The primary analyses will be based on the inverse propensity score weighted (adjusted) change 
from base. The corresponding unadjusted changes will also be reported as a secondary analysis.  
Since this is a randomized trial, we expected the primary propensity adjusted and unadjusted 
results to be similar.  
 
 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
Aim 1. TR+UC is superior to UC alone: A 6-week program of TR targeting arm movement added 
to UC will result in better arm function as compared to UC alone. The primary endpoint is the 
change in ARAT score from baseline to 1 month after end of therapy Visit 4). 
The mean differences in ARAT score change from Visit 1 (baseline) to Visit 4 (1 month after end 
of therapy) will be compared on the log scale using an inverse propensity adjusted t test. A 
similar method will be used for the secondary change from Visit 1 to Visit 3 (end of therapy). 
We will first compare the combined TR + UC groups versus the UC group (Aim 1) and then 
compare TR+Sinemet+UC versus TR+placebo+UC under this model. (Aim 2). As a secondary 
analysis, we will report the corresponding unadjusted results. 
The difference in ARAT score change between [1] the combined TR group and [2] the UC group 
will be computed and the distributions compared using ANCOVA, adjusting for Visit 1 ARAT 
score and propensity score. Specifically, this Aim will compare UC vs. the combined two TR 
groups (TR+Sinemet plus TR+placebo). 
Exploratory analyses will examine whether aphasia or neglect affect TR efficacy by determining 
if the extent of aphasia (Visit 1 LAST score) or neglect (Visit 1 SCT score), respectively, is 
correlated with change in ARAT score from Visit 1 to Visit 4. We will use a linear regression 
model with ARAT change as the outcome, and with treatment group, LAST score, and 
propensity score as predictors in order to assess the association. This will be repeated using SCT 
score instead of LAST score. Restricted cubic splines will be used to determine whether the 
relationships of language screening and neglect to ARAT score change are each linear. 
An additional exploratory analysis will examine whether results vary according to the actual TR 
dose (the total number of arm repetitions across the 36 treatment sessions), using similar 
regression methods. Sex will also be explored: while females may have poorer functional 
outcomes after stroke136-138, it is unclear whether the same underlying factors predict that sex 
will also be associated with a poorer response to rehabilitation therapy. 
Analyses will be repeated examining a secondary endpoint, BBT, and then using several tertiary 
endpoints (FMA-UE, CES-D, mRS, NHPT, SIS-ADL, and SIS-hand). The lead secondary endpoint is 
the BBT, and this will be analyzed using alpha=0.05. The tertiary endpoints are considered 
exploratory and will be examined without correction for multiple comparisons. The same 
statistical methods as above will be used except that the dependent measure will be change 
from Visit 1 to Visit 4 in each of the secondary/tertiary endpoints. An additional analysis will 
examine mRS as the dependent variable but instead using a shift analysis (ordinal logistic 
repeated measures regression) of mRS change score from Visit 1 to Visits 3 and 4. 
To aid in the interpretation of the above analyses, additional corollary analyses will repeat 
above but use as the dependent measure change from Visit 1 to Visit 3. This will be done for 
the ARAT as well as for the FMA-UE, BBT, mRS, and SIS-hand subsection. 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
Aim 2. TR+Sinemet is superior to TR+placebo: Among patients randomized to TR, gains in arm 
function will be greater in those who take Sinemet (25/100) prior to daily TR, as compared to 
patients who take placebo prior to TR. 
The above analyses will be repeated but instead comparing patients randomized to 
[1] TR+Sinemet vs. [2] TR+placebo.  
Aim 3. Less CST injury and higher dopamine polygene score predict better recovery of arm 
function: Across all subjects, change in arm function will be highest in those with lower % CST 
injury and in those with higher dopamine polygene scores. These relationships will remain 
significant when examining only patients randomized to TR. The drug X gene score interaction 
term will be significant such that the slope of arm gains in relation to the polygene score will be 
smaller (less steep) in those receiving Sinemet. 
H3A: Using linear regression, we will test whether lower % CST injury predicts higher change in 
ARAT score from Visit 1 to Visit 4, after controlling for baseline ARAT score and clinical 
measures (age, time from stroke to randomization, and total hours of outside rehabilitation 
therapy from Visit 1 to Visit 4). Primary analysis will examine all enrollees. Secondary analysis 
will examine this relationship separately for patients randomized to one of the two TR groups, 
while tertiary analysis will examine this separately across all three treatment groups. 
Restricted cubic splines will be used to determine if the effect of continuous covariates such as 
age are linear. A linear model that includes individual clinical measures will be used rather than 
propensity adjustment so that the effect of % CST injury can be compared to the effects of the 
other covariates. This approach also allows us to test the hypothesis that % CST injury predicts 
ARAT gains beyond what can be learned from clinical variables alone.  
H3B: We will test whether higher dopamine polygene score predicts higher change in ARAT 
score from Visit 1 to Visit 4, after controlling for the same covariates as in H3A. Analyses will 
follow those described in H3A. 
Secondary analysis will repeat H3A and H3B using change in BBT from Visit 1 to Visit 4 as the 
dependent measure. Tertiary analyses will repeat these methods focusing on change in FMA-
UE, CES-D, mRS, NHPT, SIS-ADL, and SIS-hand scores.  
An additional H3B analysis will examine the drug X gene score interaction term in those 
patients randomized to TR (i.e., TR+Sinemet or TR+placebo). Based on our prior findings in 
healthy subjects114, this term is hypothesized to be significant such that the slope of ARAT 
change in relation to the polygene score will be smaller (less steep) in those receiving Sinemet. 
 
 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
References 
1. 
Danzl MM, Etter NM, Andreatta RD, Kitzman PH. Facilitating neurorehabilitation through 
principles of engagement. J Allied Health 2012;41:35-41. 
2. 
Chen Y, Chen Y, Zheng K, et al. A qualitative study on user acceptance of a home-based stroke 
telerehabilitation system. Top Stroke Rehabil 2020;27:81-92. 
3. 
Cramer SC, Dodakian L, Le V, et al. Efficacy of Home-Based Telerehabilitation vs In-Clinic Therapy 
for Adults After Stroke: A Randomized Clinical Trial. JAMA Neurol 2019;76:1079-1087. 
4. 
Lang CE, Macdonald JR, Reisman DS, et al. Observation of amounts of movement practice 
provided during stroke rehabilitation. Archives of physical medicine and rehabilitation 
2009;90:1692-1698. 
5. 
Baranowski T, Buday R, Thompson DI, Baranowski J. Playing for real: video games and stories for 
health-related behavior change. American journal of preventive medicine 2008;34:74-82. 
6. 
Brox, E, Fernandez-Luque L, Tøllefsen T. Healthy Gaming – Video Game Design to promote 
Health. Applied Clinical Informatics 2011;2:128–142. 
7. 
Hansen MM. Versatile, immersive, creative and dynamic virtual 3-D healthcare learning 
environments: a review of the literature. Journal of medical Internet research 2008;10:e26. 
8. 
Lieberman D. Designing serious games for learning and health in informal and formal settings. 
In: Ritterfeld M, Vorderer P, eds. Serious games: Mechanisms and effects. New York: Routledge, 
2009: 117–130. 
9. 
Thompson D, Baranowski T, Buday R, et al. Serious Video Games for Health How Behavioral 
Science Guided the Development of a Serious Video Game. Simulation & gaming 2010;41:587-
606. 
10. 
http://www.rwjf.org/content/rwjf/en/research-publications/find-rwjf-
research/2011/03/advancing-the-field-of-health-games.html. Robert Wood Johnson 
Foundation. Advancing the Field of Health Games: A Progress Report on Health Games 
Research. Robert Wood Johnson Foundation, 2011 [online]. Accessed 9/14/2012. 
11. 
Przybylski A, Rigby C, Ryan R. A Motivational Model of Video Game Engagement. Rev Gen 
Psychol 2010;14:154–166. 
12. 
Wolf SL, Winstein CJ, Miller JP, et al. Effect of constraint-induced movement therapy on upper 
extremity function 3 to 9 months after stroke: the EXCITE randomized clinical trial. JAMA 
2006;296:2095-2104. 
13. 
Dodakian L, McKenzie AL, Le V, et al. A Home-Based Telerehabilitation Program for Patients 
With Stroke. Neurorehabil Neural Repair 2017;31:923-933. 
14. 
Cramer SC, Le V, Saver JL, et al. Intense Arm Rehabilitation Therapy Improves the Modified 
Rankin Scale Score: Association Between Gains in Impairment and Function. Neurology 
2021;96:e1812-e1822. 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
15. 
Winstein CJ, Stein J, Arena R, et al. Guidelines for Adult Stroke Rehabilitation and Recovery: A 
Guideline for Healthcare Professionals From the American Heart Association/American Stroke 
Association. Stroke 2016;47:e98-e169. 
16. 
Stewart JC, Cramer SC. Patient-reported measures provide unique insights into motor function 
after stroke. Stroke 2013;44:1111-1116. 
17. 
Wyller TB, Sveen U, Sodring KM, Pettersen AM, Bautz-Holter E. Subjective well-being one year 
after stroke. Clin Rehabil 1997;11:139-145. 
18. 
Kwakkel G, Wagenaar R, Twisk J, Lankhorst G, Koetsier J. Intensity of leg and arm training after 
primary middle-cerebral-artery stroke: a randomised trial. Lancet 1999;354:191-196. 
19. 
Galvin R, Cusack T, O'Grady E, Murphy TB, Stokes E. Family-mediated exercise intervention 
(FAME): evaluation of a novel form of exercise delivery after stroke. Stroke 2011;42:681-686. 
20. 
Kwakkel G, van Peppen R, Wagenaar RC, et al. Effects of augmented exercise therapy time after 
stroke: a meta-analysis. Stroke 2004;35:2529-2539. 
21. 
Outpatient Service Trialists. Rehabilitation therapy services for stroke patients living at home:  
systematic review of randomised trials. Lancet 2004;363:352-356. 
22. 
Lohse KR, Lang CE, Boyd LA. Is more better? Using metadata to explore dose-response 
relationships in stroke rehabilitation. Stroke 2014;45:2053-2058. 
23. 
Kumar A, Adhikari D, Karmarkar A, et al. Variation in Hospital-Based Rehabilitation Services 
Among Patients With Ischemic Stroke in the United States. Phys Ther 2019;99:494-506. 
24. 
Reistetter TA, Kuo YF, Karmarkar AM, et al. Geographic and facility variation in inpatient stroke 
rehabilitation: multilevel analysis of functional status. Arch Phys Med Rehabil 2015;96:1248-
1254. 
25. 
Hong I, Karmarkar A, Chan W, et al. Discharge Patterns for Ischemic and Hemorrhagic Stroke 
Patients Going From Acute Care Hospitals to Inpatient and Skilled Nursing Rehabilitation. Am J 
Phys Med Rehabil 2018;97:636-645. 
26. 
Buntin MB, Garten AD, Paddock S, Saliba D, Totten M, Escarce JJ. How much is postacute care 
use affected by its availability? Health Serv Res 2005;40:413-434. 
27. 
Kane RL, Lin WC, Blewett LA. Geographic variation in the use of post-acute care. Health Serv Res 
2002;37:667-682. 
28. 
Xian Y, Thomas L, Liang L, et al. Unexplained Variation for Hospitals' Use of Inpatient 
Rehabilitation and Skilled Nursing Facilities After an Acute Ischemic Stroke. Stroke 
2017;48:2836-2842. 
29. 
Newhouse JP, Garber AM. Geographic variation in Medicare services. N Engl J Med 
2013;368:1465-1468. 
30. 
Freburger JK, Li D, Fraher EP. Community Use of Physical and Occupational Therapy After Stroke 
and Risk of Hospital Readmission. Arch Phys Med Rehabil 2018;99:26-34. 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
31. 
Ayala C, Fang J, Luncheon C, et al. Use of Outpatient Rehabilitation Among Adult Stroke 
Survivors — 20 States and the District of Columbia, 2013, and Four States, 2015. Morb Mortal 
Wkly Rep 2018;67:575–578. 
32. 
Pergolotti M, Lavery J, Reeve BB, Dusetzina SB. Therapy Caps and Variation in Cost of Outpatient 
Occupational Therapy by Provider, Insurance Status, and Geographic Region. Am J Occup Ther 
2018;72:7202205050p7202205051-7202205050p7202205059. 
33. 
Chan L, Wang H, Terdiman J, et al. Disparities in outpatient and home health service utilization 
following stroke: results of a 9-year cohort study in Northern California. PM R 2009;1:997-1003. 
34. 
Prvu Bettger JA, Kaltenbach L, Reeves MJ, et al. Assessing stroke patients for rehabilitation 
during the acute hospitalization: findings from the get with the guidelines-stroke program. Arch 
Phys Med Rehabil 2013;94:38-45. 
35. 
Iyer M, Bhavsar GP, Bennett KJ, Probst JC. Disparities in home health service providers among 
Medicare beneficiaries with stroke. Home Health Care Serv Q 2016;35:25-38. 
36. 
Skolarus LE, Feng C, Burke JF. No Racial Difference in Rehabilitation Therapy Across All Post-
Acute Care Settings in the Year Following a Stroke. Stroke 2017;48:3329-3335. 
37. 
Bernhardt J, Chan J, Nicola I, Collier JM. Little therapy, little physical activity: rehabilitation 
within the first 14 days of organized stroke unit care. Journal of rehabilitation medicine : official 
journal of the UEMS European Board of Physical and Rehabilitation Medicine 2007;39:43-48. 
38. 
Sarkamo T, Tervaniemi M, Laitinen S, et al. Music listening enhances cognitive recovery and 
mood after middle cerebral artery stroke. Brain : a journal of neurology 2008;131:866-876. 
39. 
Wade DT, Skilbeck CE, Hewer RL, Wood VA. Therapy after stroke: amounts, determinants and 
effects. International rehabilitation medicine 1984;6:105-110. 
40. 
Kimberley TJ, Samargia S, Moore LG, Shakya JK, Lang CE. Comparison of amounts and types of 
practice during rehabilitation for traumatic brain injury and stroke. Journal of rehabilitation 
research and development 2010;47:851-862. 
41. 
Jeffers MS, Karthikeyan S, Gomez-Smith M, et al. Does Stroke Rehabilitation Really Matter? Part 
B: An Algorithm for Prescribing an Effective Intensity of Rehabilitation. Neurorehab Neural 
Repair 2018;32:73-83. 
42. 
Nudo R, Wise B, SiFuentes F, Milliken G. Neural substrates for the effects of rehabilitative 
training on motor recovery after ischemic infarct. Science 1996;272:1791-1794. 
43. 
Plautz E, Milliken G, Nudo R. Effects of repetitive motor training on movement representations 
in adult squirrel monkeys: role of use versus learning. Neurobiol Learn Mem 2000;74:27-55. 
44. 
Cramer SC, Sur M, Dobkin BH, et al. Harnessing neuroplasticity for clinical applications. Brain 
2011;134:1591-1609. 
45. 
Woldag H, Hummelsheim H. Evidence-based physiotherapeutic concepts for improving arm and 
hand function in stroke patients: a review. J Neurol 2002;249:518-528. 
46. 
Takahashi CD, Der-Yeghiaian L, Le V, Motiwala RR, Cramer SC. Robot-based hand motor therapy 
after stroke. Brain 2008;131:425-437. 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
47. 
Kleim JA, Jones TA. Principles of experience-dependent neural plasticity: implications for 
rehabilitation after brain damage. J Speech Lang Hear Res 2008;51:S225-239. 
48. 
Cramer SC, Riley JD. Neuroplasticity and brain repair after stroke. Curr Opin Neurol 2008;21:76-
82. 
49. 
Richmond T, Peterson C, Cason J, et al. American Telemedicine Association's Principles for 
Delivering Telerehabilitation Services. Int J Telerehabil 2017;9:63-68. 
50. 
Coleman JJ, Frymark T, Franceschini NM, Theodoros DG. Assessment and Treatment of 
Cognition and Communication Skills in Adults With Acquired Brain Injury via Telepractice: A 
Systematic Review. Am J Speech Lang Pathol 2015;24:295-315. 
51. 
Theodoros DG. Telerehabilitation for service delivery in speech-language pathology. J Telemed 
Telecare 2008;14:221-224. 
52. 
Hill AJ, Theodoros D, Russell T, Ward E. Using telerehabilitation to assess apraxia of speech in 
adults. Int J Lang Commun Disord 2009;44:731-747. 
53. 
Sarfo FS, Ulasavets U, Opare-Sem OK, Ovbiagele B. Tele-Rehabilitation after Stroke: An Updated 
Systematic Review of the Literature. J Stroke Cerebrovasc Dis 2018. 
54. 
Duncan PW, Horner RD, Reker DM, et al. Adherence to postacute rehabilitation guidelines is 
associated with functional recovery in stroke. Stroke 2002;33:167-177. 
55. 
Jurkiewicz MT, Marzolini S, Oh P. Adherence to a home-based exercise program for individuals 
after stroke. Topics in stroke rehabilitation 2011;18:277-284. 
56. 
Touillet A, Guesdon H, Bosser G, Beis JM, Paysant J. Assessment of compliance with prescribed 
activity by hemiplegic stroke patients after an exercise programme and physical activity 
education. Ann Phys Rehabil Med 2010;53:250-257, 257-265. 
57. 
Llorens R, Noe E, Colomer C, Alcaniz M. Effectiveness, usability, and cost-benefit of a virtual 
reality-based telerehabilitation program for balance recovery after stroke: a randomized 
controlled trial. Arch Phys Med Rehabil 2015;96:418-425 e412. 
58. 
Laver KE, Adey-Wakeling Z, Crotty M, Lannin NA, George S, Sherrington C. Telerehabilitation 
services for stroke. Cochrane Database Syst Rev 2020;1:CD010255. 
59. 
Jansen-Kosterink S, In 't Veld RH, Hermens H, Vollenbroek-Hutten M. A Telemedicine Service as 
Partial Replacement of Face-to-Face Physical Rehabilitation: The Relevance of Use. Telemedicine 
journal and e-health : the official journal of the American Telemedicine Association 
2015;21:808-813. 
60. 
Chen J, Jin W, Zhang X, Xu W, Liu X-N, Ren C-C. Telerehabilitation approaches for stroke patients: 
systematic review and meta-analysis of randomized controlled trials. J Stroke Cerebrovasc Dis 
2015;24:2660–2668. 
61. 
Laver KE, Schoene D, Crotty M, George S, Lannin NA, Sherrington C. Telerehabilitation services 
for stroke. Cochrane Database Syst Rev 2013;12:CD010255. 
62. 
Agostini M, Moja L, Banzi R, et al. Telerehabilitation and recovery of motor function: a 
systematic review and meta-analysis. Journal of telemedicine and telecare 2015;21:202-213. 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
63. 
Coscia M, Wessel MJ, Chaudary U, et al. Neurotechnology-aided interventions for upper limb 
motor rehabilitation in severe chronic stroke. Brain 2019;142:2182-2197. 
64. 
Chen Y, Abel KT, Janecek JT, Chen Y, Zheng K, Cramer SC. Home-based technologies for stroke 
rehabilitation: A systematic review. Int J Med Inform 2019;123:11-22. 
65. 
Van Stan JH, Dijkers MP, Whyte J, et al. The Rehabilitation Treatment Specification System: 
Implications for Improvements in Research Design, Reporting, Replication, and Synthesis. 
Archives of physical medicine and rehabilitation 2019;100:146-155. 
66. 
Jette AM. Opening the Black Box of Rehabilitation Interventions. Phys Ther 2020;100:883-884. 
67. 
Battaglia-Mayer A, Caminiti R. Corticocortical Systems Underlying High-Order Motor Control. J 
Neurosci 2019;39:4404-4421. 
68. 
Sidarta A, Vahdat S, Bernardi NF, Ostry DJ. Somatic and Reinforcement-Based Plasticity in the 
Initial Stages of Human Motor Learning. J Neurosci 2016;36:11682-11692. 
69. 
Milot MH, Marchal-Crespo L, Beaulieu LD, Reinkensmeyer DJ, Cramer SC. Neural circuits 
activated by error amplification and haptic guidance training techniques during performance of 
a timing-based motor task by healthy individuals. Exp Brain Res 2018;236:3085-3099. 
70. 
Riley JD, Le V, Der-Yeghiaian L, et al. Anatomy of stroke injury predicts gains from therapy. 
Stroke 2011;42:421-426. 
71. 
Lang CE, Strube MJ, Bland MD, et al. Dose response of task-specific upper limb training in people 
at least 6 months poststroke: A phase II, single-blind, randomized, controlled trial. Annals of 
neurology 2016;80:342-354. 
72. 
Winstein CJ, Wolf SL, Dromerick AW, et al. Effect of a Task-Oriented Rehabilitation Program on 
Upper Extremity Recovery Following Motor Stroke: The ICARE Randomized Clinical Trial. JAMA 
2016;315:571-581. 
73. 
Dromerick A, Geeda S, Barth J, et al. Critical Period After Stroke Study (CPASS): A phase II clinical 
trial testing an optimal time for motor recovery after stroke in humans. PNAS 
2021;118:e2026676118. 
74. 
McAllister TW. Polymorphisms in genes modulating the dopamine system: do they inf luence 
outcome and response to medication after traumatic brain injury? J Head Trauma Rehabil 
2009;24:65-68. 
75. 
Diaz Heijtz R, Forssberg H. Translational studies exploring neuroplasticity associated with motor 
skill learning and the regulatory role of the dopamine system. Developmental Medicine and 
Child Neurology 2015;57:10-14. 
76. 
Hosp JA, Luft AR. Dopaminergic Meso-Cortical Projections to M1: Role in Motor Learning and 
Motor Cortex Plasticity. Frontiers in neurology 2013;4:145. 
77. 
Hosp JA, Nolan HE, Luft AR. Topography and collateralization of dopaminergic projections to 
primary motor cortex in rats. Experimental brain research 2015;233:1365-1375. 
78. 
Floel A, Breitenstein C, Hummel F, et al. Dopaminergic influences on formation of a motor 
memory. Ann Neurol 2005;58:121-130. 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
79. 
Meintzschel F, Ziemann U. Modification of practice-dependent plasticity in human motor cortex 
by neuromodulators. Cereb Cortex 2006;16:1106-1115. 
80. 
Matsumoto N, Hanakawa T, Maki S, Graybiel AM, Kimura M. Role of nigrostriatal dopamine 
system in learning to perform sequential motor tasks in a predictive manner. J Neurophysiol 
1999;82:978-998. 
81. 
Salamone JD, Correa M. The mysterious motivational functions of mesolimbic dopamine. 
Neuron 2012;76:470-485. 
82. 
Costa RM. Plastic corticostriatal circuits for action learning: what's dopamine got to do with it? 
Annals of the New York Academy of Sciences 2007;1104:172-191. 
83. 
Surmeier DJ, Plotkin J, Shen W. Dopamine and synaptic plasticity in dorsal striatal circuits 
controlling action selection. Curr Opin Neurobiol 2009;19:621-628. 
84. 
Garland T, Jr., Schutz H, Chappell MA, et al. The biological control of voluntary exercise, 
spontaneous physical activity and daily energy expenditure in relation to obesity: human and 
rodent perspectives. The Journal of experimental biology 2011;214:206-229. 
85. 
Abe M, Schambra H, Wassermann EM, Luckenbaugh D, Schweighofer N, Cohen LG. Reward 
improves long-term retention of a motor memory through induction of offline memory gains. 
Current biology : CB 2011;21:557-562. 
86. 
Scheidtmann K, Fries W, Muller F, Koenig E. Effect of levodopa in combination with 
physiotherapy on functional motor recovery after stroke:  a prospective, randomised, double-
blind study. Lancet 2001;358:787-790. 
87. 
Ford GA, Bhakta BB, Cozens A, et al. Safety and efficacy of co-careldopa as an add-on therapy to 
occupational and physical therapy in patients after stroke (DARS): a randomised, double-blind, 
placebo-controlled trial. Lancet Neurol 2019;18:530-538. 
88. 
Lin DJ, Cramer SC. Principles of Neural Repair and Their Application to Stroke Recovery Trials. 
Semin Neurol 2021;41:157-166. 
89. 
Cramer SC. Stratifying patients with stroke in trials that target brain repair. Stroke 2010;41:S114-
116. 
90. 
Burke E, Cramer SC. Biomarkers and predictors of restorative therapy effects after stroke. Curr 
Neurol Neurosci 2013;13:329. 
91. 
Boyd LA, Hayward KS, Ward NS, et al. Biomarkers of Stroke Recovery: Consensus-Based Core 
Recommendations from the Stroke Recovery and Rehabilitation Roundtable. 
Neurorehabilitation and neural repair 2017;31:864-876. 
92. 
Stinear CM. Prediction of motor recovery after stroke: advances in biomarkers. The Lancet 
Neurology 2017;16:826-836. 
93. 
Ward NS. Restoring brain function after stroke - bridging the gap between animals and humans. 
Nat Rev Neurol 2017;13:244-255. 
94. 
Paik SM, Cramer SC. Predicting motor gains with home-based telerehabilitation after stroke. J 
Telemed Telecare 2021:1357633X211023353. 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
95. 
Nouri S, Cramer SC. Anatomy and physiology predict response to motor cortex stimulation after 
stroke. Neurology 2011;77:1076-1083. 
96. 
Dodakian L, Sharp KG, See J, et al. Targeted engagement of a dorsal premotor circuit in the 
treatment of post-stroke paresis. NeuroRehabilitation 2013;33:13-24. 
97. 
Burke Quinlan E, Dodakian L, See J, et al. Neural function, injury, and stroke subtype predict 
treatment gains after stroke. Ann Neurol 2015;77:132-145. 
98. 
Cassidy JM, Tran G, Quinlan EB, Cramer SC. Neuroimaging Identifies Patients Most Likely to 
Respond to a Restorative Stroke Therapy. Stroke 2018;49:433-438. 
99. 
van der Lee JH, Wagenaar RC, Lankhorst GJ, Vogelaar TW, Deville WL, Bouter LM. Forced use of 
the upper extremity in chronic stroke patients: results from a single-blind randomized clinical 
trial. Stroke 1999;30:2369-2375. 
100. 
Van der Lee JH, De Groot V, Beckerman H, Wagenaar RC, Lankhorst GJ, Bouter LM. The intra- 
and interrater reliability of the action research arm test: a practical test of upper extremity 
function in patients with stroke. Arch Phys Med Rehabil 2001;82:14-19. 
101. 
Donaldson C, Tallis R, Miller S, Sunderland A, Lemon R, Pomeroy V. Effects of conventional 
physical therapy and functional strength training on upper limb motor recovery after stroke: a 
randomized phase II study. Neurorehabilitation and neural repair 2009;23:389-397. 
102. 
Prasad G, Herman P, Coyle D, McDonough S, Crosbie J. Applying a brain-computer interface to 
support motor imagery practice in people with stroke for upper limb recovery: a feasibility 
study. Journal of neuroengineering and rehabilitation 2010;7:60. 
103. 
Bushnell C, Bettger JP, Cockroft KM, et al. Chronic Stroke Outcome Measures for Motor Function 
Intervention Trials: Expert Panel Recommendations. Circ Cardiovasc Qual Outcomes 
2015;8:S163-169. 
104. 
Ward NS, Brander F, Kelly K. Intensive upper limb neurorehabilitation in chronic stroke: 
outcomes from the Queen Square programme. J Neurol Neurosurg Psychiatry 2019;90:498-506. 
105. 
de Boissezon X, Peran P, de Boysson C, Demonet JF. Pharmacotherapy of aphasia: myth or 
reality? Brain Lang 2007;102:114-125. 
106. 
Liepert J. Pharmacotherapy in restorative neurology. Curr Opin Neurol 2008;21:639-643. 
107. 
Floel A, Cohen LG. Recovery of function in humans: cortical stimulation and pharmacological 
treatments after stroke. Neurobiology of disease 2010;37:243-251. 
108. 
Floel A, Hummel F, Breitenstein C, Knecht S, Cohen LG. Dopaminergic effects on encoding of a 
motor memory in chronic stroke. Neurology 2005;65:472-474. 
109. 
Cramer SC, Dobkin BH, Noser EA, Rodriguez RW, Enney LA. Randomized, placebo-controlled, 
double-blind study of ropinirole in chronic stroke. Stroke 2009;40:3034-3038. 
110. 
Restemeyer C, Weiller C, Liepert J. No effect of a levodopa single dose on motor performance 
and motor excitability in chronic stroke. A double-blind placebo-controlled cross-over pilot 
study. Restor Neurol Neurosci 2007;25:143-150. 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
111. 
Sonde L, Lokk J. Effects of amphetamine and/or L-dopa and physiotherapy after stroke - a 
blinded randomized study. Acta Neurol Scand 2007;115:55-59. 
112. 
Pearson-Fuhrhop KM, Cramer SC. Pharmacogenetics of neural injury recovery. 
Pharmacogenomics 2013;14:1635-1643. 
113. 
Stewart JC, Cramer SC. Genetic Variation and Neuroplasticity: Role in Rehabilitation After Stroke. 
J Neurol Phys Ther 2017;41 Suppl 3 Supplement, IV STEP Special Issue:S17-S23. 
114. 
Pearson-Fuhrhop KM, Minton B, Acevedo D, Shahbaba B, Cramer SC. Genetic variation in the 
human brain dopamine system influences motor learning and its modulation by L-dopa. PloS 
one 2013;8:e61197. 
115. 
Diaz Heijtz R, Almeida R, Eliasson AC, Forssberg H. Genetic Variation in the Dopamine System 
Influences Intervention Outcome in Children with Cerebral Palsy. EBioMedicine 2018;28:162-
167. 
116. 
Pearson-Fuhrhop KM, Dunn EC, Mortero S, et al. Dopamine genetic risk score predicts 
depressive symptoms in healthy adults and adults with depression. PLoS One 2014;9:e93772. 
117. 
MacDonald HJ, Stinear CM, Ren A, et al. Dopamine Gene Profiling to Predict Impulse Control and 
Effects of Dopamine Agonist Ropinirole. Journal of cognitive neuroscience 2016;28:909-919. 
118. 
Sanchez RJ, Liu J, Rao S, et al. Automating arm movement training following severe stroke: 
functional exercises with quantitative feedback in a gravity-reduced environment. IEEE Trans 
Neural Syst Rehabil Eng 2006;14:378-389. 
119. 
Liu J, Cramer SC, Reinkensmeyer DJ. Learning to perform a new movement with robotic 
assistance: comparison of haptic guidance and visual demonstration. J Neuroengineering 
Rehabil 2006;3:20. 
120. 
Reinkensmeyer DJ, Maier MA, Guigon E, et al. Do robotic and non-robotic arm movement 
training drive motor recovery after stroke by a common neural mechanism? Experimental 
evidence and a computational model. Conf Proc IEEE Eng Med Biol Soc 2009;2009:2439-2441. 
121. 
Sanchez R, Wolbrecht E, Smith R, et al. A Pneumatic Robot for Re-Training Arm Movement after 
Stroke: Rationale and Mechanical Design. Proceedings of IEEE 9th International Conference on 
Rehabilitation Robotics:  Frontiers of the Human-Machine Interface, Chicago, Illinois 2005:500-
504. 
122. 
Reinkensmeyer DJ, Wolbrecht ET, Chan V, Chou C, Cramer SC, Bobrow JE. Comparison of three-
dimensional, assist-as-needed robotic arm/hand movement training provided with Pneu-WREX 
to conventional tabletop therapy after chronic stroke. American journal of physical medicine & 
rehabilitation / Association of Academic Physiatrists 2012;91:S232-241. 
123. 
Milot MH, Spencer SJ, Chan V, et al. A crossover pilot study evaluating the functional outcomes 
of two different types of robotic movement training in chronic stroke survivors using the arm 
exoskeleton BONES. Journal of neuroengineering and rehabilitation 2013;10:112. 
124. 
Rowe JB, Chan V, Ingemanson ML, Cramer SC, Wolbrecht ET, Reinkensmeyer DJ. Robotic 
Assistance for Training Finger Movement Using a Hebbian Model: A Randomized Controlled 
Trial. Neurorehabil Neural Repair 2017;31:769-780. 


Dopaminergic enhancement of rehabilitation therapy early after stroke (TR-Dopa) 
Protocol_20230721 
125. 
Ingemanson ML, Rowe JR, Chan V, Wolbrecht ET, Reinkensmeyer DJ, Cramer SC. Somatosensory 
system integrity explains differences in treatment response after stroke. Neurology 
2019;92:e1098-e1108. 
126. 
Milot MH, Spencer SJ, Chan V, et al. Corticospinal excitability as a predictor of functional gains at 
the affected upper limb following robotic training in chronic stroke survivors. Neurorehabil 
Neural Repair 2014;28:819-827. 
127. 
McKenzie A, Dodakian L, See J, et al. Validity of Robot-Based Assessments of Upper Extremity 
Function. Arch Phys Med Rehabil 2017;98:1969-1976 e1962. 
128. 
de Havenon A, Tirschwell DL, Heitsch L, et al. Variability of the Modified Rankin Scale Score 
Between Day 90 and 1 Year After Ischemic Stroke. Neurol Clin Pract 2021;11:e239-e244. 
129. 
Cramer SC, Dodakian L, Le V, et al. A Feasibility Study of Expanded Home-Based 
Telerehabilitation After Stroke. Front Neurol 2020;11:611453. 
130. 
Lang C, Birkenmeier R. Upper-Extremity Task-Specific Training After Stroke or Disability. 
Bethesda, MD: AOTA Press, 2013. 
131. 
Lewthwaite R, Wulf G. Optimizing motivation and attention for motor performance and 
learning. Curr Opin Psychol 2017;16:38-42. 
132. 
Wirth LA, Breiner J. Jeopardy: using a familiar game to teach health. J Sch Health 1997;67:71-74. 
133. 
Webb TP, Simpson D, Denson S, Duthie E, Jr. Gaming used as an informal instructional 
technique: effects on learner knowledge and satisfaction. J Surg Educ 2012;69:330-334. 
134. 
Lin KC, Hsieh YW, Wu CY, Chen CL, Jang Y, Liu JS. Minimal detectable change and clinically 
important difference of the Wolf Motor Function Test in stroke patients. Neurorehabil Neural 
Repair 2009;23:429-434. 
135. 
Robins JM, Mark SD, Newey WK. Estimating exposure effects by modelling the expectation of 
exposure conditional on confounders. Biometrics 1992;48:479-495. 
136. 
Paolucci S, Bragoni M, Coiro P, et al. Is sex a prognostic factor in stroke rehabilitation? A 
matched comparison. Stroke 2006;37:2989-2994. 
137. 
Carcel C, Wang X, Sandset EC, et al. Sex differences in treatment and outcome after stroke: 
Pooled analysis including 19,000 participants. Neurology 2019;93:e2170-e2180. 
138. 
Phan HT, Blizzard CL, Reeves MJ, et al. Factors contributing to sex differences in functional 
outcomes and participation after stroke. Neurology 2018;90:e1945-e1953. 
139. 
Harvey RL, Edwards D, Dunning K, et al. Randomized Sham-Controlled Trial of Navigated 
Repetitive Transcranial Magnetic Stimulation for Motor Recovery in Stroke. Stroke 
2018;49(9):2138-2146. (In eng). DOI: 10.1161/STROKEAHA.117.020607.