The feasibility of action observation combined with repetitive task practice on upper limb

outcomes in moderately impaired chronic stroke survivors

Dissertation

Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy

in the Graduate School of The Ohio State University

By

Christine Griffin

Graduate Program in Health and Rehabilitation Science

The Ohio State University

2020

Dissertation Committee

John Buford, PhD, PT, Advisor

Marcia Bockbrader, MD, PhD

Erinn Hade, PhD

Anne D. Kloos, PT, PhD, NCS

Salvador Bondoc, OTD, OTR/L, BCPR, CHT, FAOTA

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Copyrighted by

Christine Griffin

2020

2
 Abstract

Stroke is one of the leading causes of severe long term-disability in the United

States, primarily due to the secondary complication of weakness or paralysis in one half

of the body called hemiplegia. Action observation (AO) is an intervention technique for

hemiplegia that involves watching a video of another person performing a task, and then

physically performing the same task. Repetitive task practice (RTP) is another

intervention that utilizes repetitive physical performance of a task. Both have been found

to be effective individually to decrease UL motor impairment and increase UL functional

performance for patients with hemiplegia, but a novel combination of these two

interventions has not been explored before.

In the progression of the scientific process for developing novel research

questions and guiding study procedures, feasibility and pilot (Phase II) studies answer

essential questions about the conduct of a trial, study procedures, and scientific

assessment. Within Thabane’s categorization system, the four main reasons for

completing feasibility and pilot studies are 1) process, 2) resources, 3) management, and

4) scientific. The novel combination of AO and RTP to decrease the effects of post stroke

UL hemiplegia has not been studied before, and needs to be investigated in a Phase II

feasibility and pilot study prior to completing a Phase III Randomized Control Trial

(RCT).

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 The objective of this dissertation was to complete a pilot randomized controlled

single-blinded, parallel-group study comparing AO plus RTP to Placebo plus RTP. This

trial aims to determine 1) the process feasibility (retention rate, recruitment rate,

enrollment, and understanding of study questionnaires, follow rate, and subject

compliance with treatment protocol), and scientific feasibility (safety/ occurrence of

adverse events), 2) the scientific reason for feasibility of response to intervention in UL

motor impairment outcomes, 3) the scientific reason for feasibility of response to

intervention in UL functional performance outcomes.

Results from Chapter 2: Four out of seven feasibility criteria for success were

met, and enough subjects were retained in the study sample to detect change in upper

limb motor impairment outcomes. The research protocol is feasible to deliver with

adjustments made that were discovered in this study.

Results from Chapter 3: There was a significant response of change on the Upper

Extremity Fugl Meyer motor impairment assessment for the combination of AO plus

RTP on the hemiplegic UL. There is possible benefit of reduced spasticity at the elbow

occurring after the intervention.

Results from Chapter 4: There was a significant difference between randomized

groups in the Arm Motor Activity Test (AMAT) Total Functional Ability score for the

combination of AO plus RTP on the hemiplegic UL.

Conclusion: The research protocol is feasible to deliver with adjustments made

that were discovered in this study. When assessing response to intervention, there was a

significant difference between randomized group in UL motor impairment and UL

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functional performance outcome measures. These responses to the process and scientific

reasons for feasibility would indicate that a larger Phase III RCT should be completed to

determine efficacy for the intervention of AO plus RTP in the moderately impaired

chronic stroke survivor population.

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 Acknowledgments

This research was funded by the Ohio State University Alumni Grant for

Graduate Research and Scholarship, the LSVT Global Small Student Grant for graduate

students in Occupational Therapy, and the National Center for Advancing Translational

Sciences, Grant UL1TR002733.

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 Vita

1998 Bachelor’s of Science: Biology/ Pre-Occupational Therapy,

Capital University, Minors: Music Performance and Psychology

2000 M.S. – Occupational Therapy, University of Indianapolis

2001 – 2014 Clinical Occupational Therapist in Skilled Nursing Facilities,

Acute Care, Inpatient Rehabilitation Hospital, and Outpatient
Therapy Clinics

2006 Board Certified in Physical Rehabilitation, AOTA

2012 – 2018 Research Assistant, School of Health and Rehabilitation Sciences,

The Ohio State University

2014 – 2020 Clinical Instructor, Division of Occupational Therapy, School of

Health and Rehabilitation Sciences, The Ohio State University

Publications

Juckett, L.A., Wengerd, L.R., Faieta, J., & Griffin, C.E. (2020). Evidence-Based Practice

Implementation in Stroke Rehabilitation: A Scoping Review of Barriers and

Facilitators. American Journal of Occupational Therapy, 74(1), 1–14.

doi: 10.5014/ajot.2020.03548

vii
Griffin C., Rennie M., Seifert A., Buford J. (2019). Action Observation in Upper

Extremity Rehabilitation for Moderately Impaired Stroke: A Literature Review. Archives

of Physical Medicine and Rehabilitation 100 (12), e166-e167

Juckett, L., Wengerd, L., Faieta, J., & Griffin, C. (2018). Analyzing Strategies for

Implementing Evidence-Based Practice in Stroke Rehabilitation. Archives of Physical

Medicine and Rehabilitation, 99(10), e116.

Griffin, C. (2017). Fidelity of Neuro-Developmental Technique in Acute Stroke

Literature with Current NDTA Recommendations. Archives of Physical Medicine and

Rehabilitation, 98(12), e162-e163.

Griffin, C., Schilaty, N. D., Willigenburg, N. W., Hewett, T. E., & Page, S. J. (2016).

Upper Extremity Reaching Kinematics Correlates With Scores on Upper Extremity

Behavioral Measures in Moderately Impaired Stroke. Archives of Physical Medicine and

Rehabilitation, 97(12), e14-e15.

Griffin, C., Faieta, J., Persch, A., Peters, H., & Page, S. (2016). Portable, EMG-

Triggered, Myoelectric Bracing: Restoring Arm Use and Participation in Stroke. Archives

of Physical Medicine and Rehabilitation, 97(10), e137-e138.

viii
Griffin, C. (2014) Management of the Hemiplegic Shoulder, Topics in Stroke

Rehabilitation, Jul-Aug;21(4):316-8. doi: 10.1310/tsr2104-316.

Fields of Study

Major Field: Health and Rehabilitation Science

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 Table of Contents

Abstract .............................................................................................................................. iii

Acknowledgments.............................................................................................................. vi
Vita.................................................................................................................................... vii
List of Tables .................................................................................................................... xii
List of Figures .................................................................................................................. xiii
Chapter 1. Introduction ....................................................................................................... 1
Chapter 2 The Feasibility of a Randomized Controlled Trial for Action Observation
Combined with Repetitive Task Practice on Upper Extremity Outcomes in Moderately
Impaired Stroke Survivors ................................................................................................ 23
Abstract ......................................................................................................................... 23
Introduction ................................................................................................................... 25
Methods......................................................................................................................... 27
Results ........................................................................................................................... 35
Discussion ..................................................................................................................... 39
Chapter 3 The Feasibility of Action Observation Combined with Repetitive Task Practice
on Upper Extremity Motor Impairment Outcomes in Moderately Impaired Stroke
Survivors: A Pilot Study ................................................................................................... 44
Abstract ......................................................................................................................... 44
Introduction ................................................................................................................... 46
Methods......................................................................................................................... 52
Results ........................................................................................................................... 61
Discussion ..................................................................................................................... 67
Chapter 4: The Feasibility of Action Observation Combined with Repetitive Task
Practice on Upper Extremity Functional Outcomes in Moderately Impaired Stroke
Survivors: A Pilot Study ................................................................................................... 73
Abstract ......................................................................................................................... 73

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 Introduction ................................................................................................................... 76
Methods......................................................................................................................... 80
Results ........................................................................................................................... 85
Discussion ..................................................................................................................... 99
Chapter 5 Conclusion...................................................................................................... 105
Bibliography ................................................................................................................... 110

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 List of Tables

Table 1 Characteristics of participants enrolled in study. ................................................. 37

Table 2 Criterion for success definitions and results ........................................................ 37
Table 3 Sequence of AO recording and matched physical RTP ....................................... 55
Table 4 List of exercises possible for home exercise programs ....................................... 55
Table 5 Expected sampling characteristics of UEFM score distributions. ....................... 57
Table 6 Characteristics of participants enrolled in study .................................................. 62
Table 7 Comparison of baseline characteristics of subjects who completed the study to
those who withdrew .......................................................................................................... 63
Table 8 UEFM Total Linear Regression Analysis ............................................................ 63
Table 9 Modified Ashworth Scale Improvement Percent form Pre to Post 2 .................. 65
Table 10. Questions asked in quantitative survey. ............................................................ 84
Table 11. Characteristics of participants enrolled in study. .............................................. 87
Table 12. Comparison of characteristics of subjects who completed the study to those
who withdrew.................................................................................................................... 88
Table 13. Linear regression of outcome measures for the comparison of AO plus RTP to
Placebo plus RTP. ............................................................................................................. 90
Table 14. Linear regression of outcomes for AMAT Trained Tasks in AO plus RTP v. PV
plus RTP. .......................................................................................................................... 92
Table 15. Results of the survey of participants. ................................................................ 98

xii
 List of Figures

Figure 1 Action Observation............................................................................................... 8

Figure 2 CONSORT Flow Diagram. ................................................................................ 38
Figure 3 Practice Schedules for Action Observation (AO) and Repetitive Task Practice
(RTP) approaches.............................................................................................................. 51

xiii
 Chapter 1. Introduction

Currently in the United States, 7.0 million Americans have experienced a stroke,

with approximately 795,000 people experiencing a new or recurrent stroke each year

(Virani et al., 2020). This averages to someone in the United States experiencing a stroke

every 40 seconds (Virani et al., 2020). Additionally, it is estimated that the prevalence of

stroke survivors in the United States will increase by an additional 3.4 million adults by

2030 (Ovbiagele et al., 2013). After the neurological event of a stroke, a common

secondary impairment is upper limb (UL) hemiparesis, which affects 88% of stroke

survivors (Dobkin, 1997). This motor impairment impedes activities of daily living

(ADL) performance, and makes stroke one of the leading causes of severe long term-

disability (Virani et al., 2020).Traditional stroke therapy interventions intended to

decrease the effects of UL hemiplegia, while commonly used (Wengerd, 2019), offer

limited benefit (Hafsteinsdóttir et al., 2007; Hafsteinsdóttir et al., 2005; Kollen et al.,

2009). In the chronic phase of stroke recovery (after six months), 39% of stroke survivors

reported difficulty with necessary activity of daily living (ADL) self-care tasks, and 54%

reported difficulty with instrumental activities of daily living (IADL) such as housework

and shopping (Mayo et al., 2002). Due to the growing stroke population, there is a

significant need for effective rehabilitative interventions targeting UL hemiparesis.

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Stroke Rehabilitation

Stroke survivors at all levels of severity require rehabilitation to help facilitate

stroke recovery. Stroke rehabilitation is a process designed to decrease disability and

increase the performance of ADL tasks (Belagaje, 2017). The primary purpose of stroke

rehabilitation is to improve function, prevent decline, and “achieve the highest possible

level of independence (physically, psychologically, socially, and financially) within the

limits of the persistent stroke impairments” (Belagaje, 2017). The continuum of patient

care for stroke rehabilitation is provided in various inpatient settings such as acute care,

skilled nursing facilities, inpatient rehabilitation hospitals, and in a variety of outpatient

settings such as home health and outpatient rehabilitation clinics. The majority of stroke

survivors will require stroke rehabilitation (Jørgensen et al., 1995) at more than one level

of the continuum of patient care to facilitate individual stroke recovery.

One of the primary rehabilitation disciplines that most often addresses post-stroke

UL recovery is Occupational Therapy (OT). In the rehabilitation process, OT

practitioners focus on maximizing performance in ADL and IADL tasks (Wolf & Nilsen,

2015). OT practitioners that were surveyed about which interventions are commonly

utilized as the standard of care in stroke rehabilitation identified a variety of exercise and

task-oriented activities. The most common reported interventions implemented in therapy

sessions were strength training, manual therapy, bilateral upper extremity training,

stretching, task-oriented training, and weight-bearing (Wengerd, 2019). Specifically, with

mild and moderate stroke survivors, the surveyed OT practitioners reported using

education 20% of the time, musculoskeletal interventions 39% of the time, and activities

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targeting function 41% of the time (Wengerd, 2019). During an analysis of individual

therapy sessions in the outpatient setting to determine which treatment activities comprise

a therapy session, functional and task-oriented activities comprised 59% of an overall

treatment session, and occurred in 87% of sessions. Occupational tasks such as meal

preparation and grooming occurred in 18% of an overall treatment session (Wengerd,

2019). While all activities completed in the reported standard of care are valuable, there

is limited focus on specifically decreasing motor impairment of the hemiplegic side. With

88% of stroke survivors experiencing UL hemiparesis (Dobkin, 1997), interventions that

directly address this impairment are urgently needed.

The Moderately Impaired Chronic Stroke Population

Stroke results in multiple physical, cognitive, perceptual, and emotional

impairments, and can affect stroke survivors with varying levels of impairment. Stroke

severity, and the extent to which hemiparesis impacts overall function has been classified

into three different levels: mild, moderate, and severe (Teasell et al., 2018). Jorgensen

and colleagues found at the initial onset of stroke, 41% of patients classified as mild

stroke, 26% classified as moderate, and 19% classified as severe stroke (Jørgensen et al.,

1995). When assessing the stroke severity distribution and recovery ability, two-thirds of

stroke survivors that had mild to moderate stroke classifications were able to achieve

independence in ADL tasks and able to recover well (Jørgensen et al., 1995). Since stroke

survivors with a mild stroke tend to have fewer impairments and a high recovery ability,

their rehabilitation needs are generally less than that of those who experience moderate

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and severe stroke. Rehabilitation from a mild stroke is managed primarily at the

outpatient level, and therefore the benefit from rehabilitation in these patients is limited

(Teasell et al., 2018). Stroke survivors with moderate stroke have greater rehabilitation

needs, show significant improvements in all areas through recovery, and improve the

most with rehabilitation (Stineman et al., 1998). This moderate stroke group is the main

focus of the rehabilitation process continuum of care through inpatient and outpatient

rehabilitation services (Teasell et al., 2018). Due to the higher use and benefit of

rehabilitation services, the moderate stroke population is in greater need of rehabilitation

intervention approaches to address recovery.

The post-stroke recovery process is a progression that it thought to involve

different combinations of neurological mechanisms immediately post stroke and

throughout chronic recovery. Immediately following stroke in the acute phase of

recovery, a significant amount of spontaneous recovery is thought to result from

neurological local process changes (Teasell & Hussein, 2018). These local process

changes include reduction of edema around the neurological lesion (Lo, 1986), and rapid

resolution of suppressed cortical activity that occurs during the initial lesion (Nudo et al.,

2001). While spontaneous improvement in stroke outcome occurs quickly post-stroke

(Teasell & Hussein, 2018), significant improvement can occur multiple years post-stroke,

in the chronic phase of recovery (Thickbroom et al., 2004). Throughout the process of

stroke recovery, improvement occurs through a combination of spontaneous

improvements along with motor learning and neurological reorganization called

neuroplasticity (Nudo, 2003). Typically, the rate of recovery is high within the first 6

4
months following stroke, and tends to show slower improvements after 6 months

recovery, with increasing dependence on the longer term processes involved with motor

learning and neuroplasticity. Through the chronic phase of stroke recovery,

neuroplasticity is considered to be crucial for the rehabilitation process to improve

outcomes. With a significant amount of stroke survivors’ mortality occurring five years

or greater post-stroke (Koton et al., 2014), there is a large population of chronic,

moderately impaired stroke survivors in need of UL stroke rehabilitation approaches that

induce motor learning and neural plasticity to improve stroke outcomes.

Neuroplasticity

Neuroplasticity is the ability of neurons to change their structure or function (Kim

& Linden, 2007), and is considered essential for recovery from damage to the central

nervous system. In contrast with the previous scientific consensus that the brain develops

during early childhood and then remains relatively static (Pascual-Leone et al., 2005), we

now know cortical maps can be modified by experience, learning, and sensory input.

Elbert and colleagues (Elbert et al., 1995) found that cortical representation of a mapped

area representing the hand and fingers can be enlarged if a person regularly performs a

skilled motor task such as proficiently playing a string instrument. In animal studies,

Nudo and colleagues (Nudo et al., 1996) found that after damage to the motor cortex

associated with the hand, training with skilled tasks resulted in increased hand cortical

representation in regions previously occupied by shoulder and elbow representations. The

principles of experience-dependent neural plasticity (Kleim & Jones, 2008) establish the

5
components that need to be implemented in UL rehabilitation interventions and improve

outcomes. Intense UL rehabilitation involving these principles facilitates neuroplasticity,

which increases the size of the cortical areas representing the affected limb (Jenkins et al.,

1990) and may facilitate subcortical changes, as well (Herbert et al., 2015). Rossini and

colleagues (Rossini et al., 2007) have concluded cortical plasticity and reorganization are

likely mechanisms driving functional recovery following stroke. Thus, there is a need to

implement and expand the use of skilled experience-dependent motor tasks in those with

UL hemiplegia to improve overall stroke rehabilitation.

Learned Non-Use

A significant factor resulting in decreased participation in functional ADL tasks

with the hemiplegic UL is thought to be learned non-use. This maladaptive phenomenon

occurs when the stroke survivor attempts to perform a functional task with the hemiplegic

arm but receives negative feedback from limited success (Wolf et al., 1989). This cycle

results in discouraging the use of the UL and encourages the use of the non-hemiplegic

UL to complete ADL tasks (Taub et al., 1994; Wolf et al., 1989). Due to the increased

use of the non-hemiplegic limb, this stimulates the expansion of motor maps in the

contralesional hemisphere instead of promoting neuroplastic changes in the lesioned

hemisphere (Nudo, 2013), which contributes to the cycle of nonuse. Interventions that

counteract the effects of learned non-use by encouraging the use of the hemiplegic UL

during functional tasks are needed to break this cycle.

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 Early approaches to break the cycle of learned non-use included constraint-

induced movement therapy (CIMT), where the non-paretic limb was restrained with a

cast or a mitt, forcing the individual to use the impaired limb for functional tasks (Wolf et

al., 2006). The key component in CIMT is most likely the massed practice effect on the

impaired limb, not the restraint of the non-impaired side. Current practice has focused on

interventions that address hemiplegia without the use of a restraint. Repetitive task

practice includes massed practice of the impaired side, and as described later, its efficacy

is well established (Skidmore et al., 2012; Thomas et al., 2017). More recently, other

principles of motor learning for the impaired limb involving pre-practice instructions

have been developed for clinical use. One intervention that has shown early promise is

Action Observation, described in the next section.

Action Observation

Action observation (AO) is an intervention technique that involves performing a

functional task after watching a video depicting the physical performance of the same

task (Buccino et al., 2004), an approach that has been found to increase movement and

function in adults with and without stroke (Cowles et al., 2013; Franceschini et al., 2012;

Sale et al., 2014). (Figure 1.1) Rizzolatti and colleagues (1996) determined that AO in

humans significantly increased the ability to learn motor sequences that are useful in

achieving goal-directed behaviors such as grasping items with the hand. Gonzalez-Rosa

and colleagues (Gonzalez-Rosa et al., 2015) found that individuals demonstrated higher

motor performance, and more efficient activation of cortical resources as measured with

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electroencephalographic (EEG), when combining AO with learning a new complex

coordination task than without AO. Mattar and Gribble (2005) found that AO facilitates

motor learning, with participants showing a better performance after observing a motor

pattern than they did with no observation.

Action Observation therapy regimen being completed of first and third

person perspectives. On the left, the individual views the action from the
third person perspective. On the right, the performance is presented from
the first person perspective.

Figure 1 Action Observation.

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 AO enhances the effects of motor training, and the ability to recall movement

patterns when combined with motor training (Celnik et al., 2006). Cantarero and

colleagues (Cantarero et al., 2011) found that AO contributes to use-dependent

neuroplasticity, and is functionally relevant to task performance for motor training.

In stroke survivors, AO has been shown to improve outcomes in the UL. Multiple

reviews have determined that AO is an efficacious intervention to decrease UL motor

impairment and increase UL function (Borges et al., 2018; Kim, Kyeongmi, 2015; Peng

et al., 2019; Sarasso et al., 2015; Zhang et al., 2019). Ertelt and colleagues (2007) found

through functional magnetic resonance imaging (fMRI) that neural activations rose

significantly after participating in AO regimens. These results indicated that AO had a

positive impact on motor recovery when compared to the control group with no AO

regimen (Ertelt et al., 2007). After participating in AO therapy, stroke survivors had

remarkable cortical activation pattern changes as demonstrated by the EEG-based brain

mapping system (Kuk et al., 2016). Numerous studies using behavioral measures found

that, when stroke survivors implement AO to assist with learning how to utilize their

hemiplegic UL during tasks, there are significant improvements in several areas. These

areas include decreased motor impairment, reduced spasticity, improvements in dexterity,

ADL performance, UL function, and participation in everyday ADL tasks (Cowles et al.,

2013; Ertelt et al., 2007; Franceschini et al., 2012; Fu. Jianming et al., 2017; Kim et al.,

2016b; Kuk et al., 2016; Sale et al., 2014; Sugg et al., 2015; Zhu et al., 2015).

AO training is thought to activate visuomotor neurons of the mirror neuron

system (MNS). The MNS was originally discovered during animal studies involving

9
direct measurement of neuronal activity in the cerebral cortex. Rizzolatti and colleagues

(Rizzolatti et al., 1996) monitored neuronal activity in monkeys. They found the F5 area

of a monkey’s ventral premotor cortex became active when it observed another monkey

or a human perform a specific task, and also when the monkey itself performed the same

task (Rizzolatti et al., 1996). When the monkey observed an object static on a table, or

observed an UL movement, or made an UL movement without interaction with a target

object, the mirror neurons did not respond (Rizzolatti et al., 1996). The MNS was only

active during tasks involving prehension, the interaction of the hand with the object. The

MNS discharged most strongly when the activity had a specific, meaningful goal for the

monkey (Fogassi et al., 2005). The MNS demonstrated a higher amount of activity when

food was being grasped for the purpose of consuming it, and less activity when required

to perform the non-meaningful activity of moving food from one location to another on

the table without food consumption (Fogassi et al., 2005). Additionally, there was no

response of the MNS during observation of food being grasped using a tool such as tongs

or a utensil (Rizzolatti et al., 1996). The neurons were only active during observed

movements that were purposeful, likely to produce a reward, and required a grasp with

the hand.

A neural correlate of the MNS has been confirmed to be present in humans

through brain and neurophysiological imaging studies, and is thought to underlie the

strong human ability to learn by imitation (Rizzolatti & Craighero, 2004). In humans, the

MNS mechanism is located in various areas analogous to those in the monkey, including

the ventral premotor cortex, the rostral inferior parietal lobe, the posterior section of the

10
inferior frontal gyrus, and the intraparietal sulcus (Kandel et al., 2013). During a fMRI

study, the same cortical areas became active during both hand movements observed in

AO, and during physical motor execution of the hand (Iacoboni et al., 2001). Cross and

colleagues found similar results in the MNS: premotor and inferior parietal regions

showed a degree of similar fMRI activity for AO and physically performing the same

tasks (Cross et al., 2009). Following stimulation with transcranial magnetic stimulation

(TMS) to the motor cortex, motor evoked potentials (MEPs) of the hand increased during

observation of movements by another human (Fadiga et al., 1995). When the physical

performance of the observed activity was completed, the MEP pattern was the same

during both the physical performance and during observation of the activity (Fadiga et

al., 1995). Gangitano and colleagues utilized the same technique utilizing TMS and

measuring MEPs of the hand, and found that MEPs became larger or smaller to match

hand movements in the observed video (Gangitano et al., 2001). These studies confirmed

the presence of an MNS in humans by similar MEPs when activities were observed and

performed.

Repetitive Task Practice

Repetitive Task Practice (RTP) is the performance of goal-directed, functional,

task-specific activities that are completed with intensive repetitions and high effort with

the hemiplegic UL (Wolf et al., 2002), an approach that has been shown to be effective in

UL stroke rehabilitation (Skidmore et al., 2012; Thomas et al., 2017). Many studies

investigating RTP and UL hemiplegia post-stroke have found a significant decrease in

11
UL motor impairment and found it is highly effective for increasing UL recovery in

chronic stroke survivors (Arya et al., 2012; Bosch et al., 2014; Ross LF et al., 2009;

Timmermans et al., 2010; Winstein CJ et al., 2004). Additionally, RTP is an effective

intervention for facilitating neuroplasticity to increase cortical representation for the UL

(Classen et al., 1998; Jang et al., 2003; Kami et al., 1995). Therefore, this effective

intervention method is well supported with many benefits and is critical to a stroke

survivor's UL rehabilitation recovery process.

Activities included in the RTP approach are intensive repetitions of functional

tasks that are completed with the hemiplegic UL, with practice sessions designed to last

the duration of a 30 to 60 minute therapy session (Blennerhassett & Dite, 2004; Kwakkel

et al., 1999). Throughout the session, stroke survivors perform the repetitive practice of

functional tasks within the available voluntary motion of the UL (Winstein et al., 2004).

Therapists provide physical assistance when the stroke survivor is unable to perform

specific components of the functional task, and verbal and tactile cues to keep the

participants challenged, motivated, and engaged (Blennerhassett & Dite, 2004). To

encourage problem-solving, if the stroke survivor makes an error, the therapists will

provide verbal and tactile cues to help correct the error, but will not provide physical

assistance unless the stroke survivor is unable to perform a specific component of the

task. Allowing for error to occur, and for the stroke survivor to correct it, increases the

individual's ability to carryover task completion to future repetitions, as well as other

functional tasks (Timmermans et al., 2010). Throughout the session, the therapist also

will grade the difficulty of the activities to increase or decrease the level of challenge to

12
the participant, so the functional activity is completed with success and challenge

(Timmermans et al., 2010). Grading the difficulty of the activity could include many

options, such as requiring the participant to reach a further distance for objects, changing

the weight or material type of the object they are reaching for, or changing the position of

the participant, such as adjusting their sitting or standing position.

Combination of Two Interventions: AO plus RTP

Innovative interventions that decrease the impact of UL hemiplegia in stroke

survivors are needed. Both AO and RTP are effective for improving UL outcomes, but

have not been combined before. AO is thought to facilitate learning of movement and

motor planning of the hemiplegic UL during functional ADL tasks and has been found to

result in significant improvement in UL function (Ertelt et al., 2007; Fu. Jianming et al.,

2017; Kim & Kim, 2015a; Kim et al., 2016b; Lee et al., 2013; Sugg et al., 2015; Zhu et

al., 2015). RTP targets the use of the hemiplegic UL during functional ADL tasks

explicitly, and significantly increases UL recovery in chronic stroke survivors (Skidmore

et al., 2012; Thomas et al., 2017). Both AO and RTP individually have support for

significant decrease of UL motor impairment in stroke survivors, yet have not been

combined in clinical trials. The increased learning of movement patterns that are

completed in AO, combined with the intensive repetitions that are completed in RTP, has

the potential to have a high impact on UL functional performance in ADL tasks.

Determining the efficacy of AO combined with RTP could meet the need of utilizing

13
innovative interventions in millions of individuals in the rapidly increasing stroke

population.

The main defining feature of the combination of AO and RTP would be the

practice schedule during the therapy session. The AO practice schedule is an alternating

balance in time spent between video observation and physical practice (e.g., 6 min AO, 6

min practice) that lasts for a 30 – 90 minute intervention session (Ertelt et al., 2007; Zhu

et al., 2015). The RTP practice schedule is completing physical practice for as much of a

30 – 60 minute session as the patient can tolerate (Blennerhassett & Dite, 2004; Kwakkel

et al., 1999), allowing for rest breaks, inactive time, and transition between activities.

Combining these practice schedules based on previously established research could occur

in any variety of ways. The schedule chosen for this dissertation is more fully described

in Chapters 2, 3, and 4, and was designed to provide an increased amount of physical

practice compared to the traditional AO schedule, while capitalizing on periods of

physical rest during the RTP schedule to provide the AO intervention.

One reason why AO was considered a promising adjunct to RTP is the high

incidence of perceptual impairments and apraxia in stroke survivors (Donkervoort et al.,

2000). Therefore, it was reasonable to postulate that additional training through pre-

practice instructions in the form of AO would be needed prior to physical performance to

assist with motor learning. With AO providing visual motor learning during functional

tasks, this could potentially improve motor performance of the hemiplegic UL during

physical practice. In sum, there is theoretical support and demonstrated efficacy for each

of these therapies, AO and RTP, individually. However, there has not been a scientific

14
study completed of AO and RTP combined. Given that these therapies use somewhat

distinct neural systems, and also share common elements for motor execution, there is the

potential for a synergistic, beneficial effect between these approaches that might exceed

the benefit from either alone. The first step in a study to combine these approaches

should be feasibility and pilot testing to establish the scientific groundwork to complete a

randomized control trial.

Feasibility and Pilot Studies

Understanding the critical functioning components of research studies is

imperative for planning intervention trials. Without proper planning for the

implementation and completion of a study, the trial may result in interventions being less

effective, limitations being created by the conduct of the study, and the whole of the

study being inefficient (Eldridge et al., 2013). In pharmaceutical studies, there are 4

phases of clinical trials before approval of a drug. In Phase I, the trial is non-randomized

and designed to find a dose that is tolerated with the lowest toxicity within a small sample

size. Phase II may or may not be randomized with a small sample size, and focuses on

preliminary evidence on clinical efficacy. Phase III trials assess efficacy and safety with

randomized groups and large sample sizes. Phase IV trials continue after the drug is

approved, and are designed to monitor for side effects and interactions with other drugs

(National Comprehensive Cancer Network, 2020; Thabane et al., 2016). Feasibility and

pilot studies are Phase II studies, which are a crucial part of the development and

progression of the scientific process for developing research questions, refining

15
assessments and interventions, and guiding study procedures (Leon et al., 2011).

Feasibility and pilot studies answer essential questions about the conduct of trials,

preventing severe problems from occurring in large scale Phase III trials, are an essential

piece of the research process (Eldridge et al., 2013), and are routinely performed in

clinical trials for UL stroke rehabilitation research (Alon et al., 2007; Brkic et al., 2016;

Caliandro et al., 2012; Hayward et al., 2013; Liu & Chan, 2014; Woodbury et al., 2009).

Within the phases of research, the Phase II feasibility and pilot trials examine

research questions from a different perspective than the remaining phases. Feasibility and

pilot trials examine the overall functionality of how a study should be completed as

opposed to focusing on one single active ingredient to be tested, as in a large hypothesis

testing Phase III study (Tickle-Degnen, 2013). These items of functionality include the

feasibility of the study design for factors including recruitment, assessment procedures,

randomization, retention, and eligibility criteria (Leon et al., 2011). Essentially, these are

the components that make a study operate and function. While many factors influence

internal and external validity to a study, feasibility and pilot studies examine many active

ingredients of the functionality of a study to decrease the occurrence of threats to validity

in a larger trial (Tickle-Degnen, 2013).

The terminology of feasibility studies and pilot studies are often used

interchangeably, which has created confusion in the scientific community about the

purpose and methods of how these studies should be completed (Arain et al., 2010). The

most explicit definitions and distinctions between feasibility and pilot studies come from

the National Institute for Health Research (NIHR) Glossary from the United Kingdom.

16
Feasibility studies are defined as "pieces of research done before a main study in order to

answer the question "Can this study be done?". They are used to estimate important

parameters that are needed to design the main study" (National Institute for Health

Research, 2020). Examples of the pieces to be examined in feasibility studies would be

retention rate, refusal rate, eligibility criteria, or success of data collection. A pilot study

is defined as "a smaller version of the main study used to test whether the components of

the main study can all work together. It is focused on the processes of the main study, for

example to ensure that recruitment, randomization, treatment, and follow-up assessments

all run smoothly" (National Institute for Health Research, 2020). Additionally, a pilot

study would examine a subject's response to treatment (Thabane et al., 2010). Elbridge

and colleagues (Eldridge, Lancaster, et al., 2016) view pilot studies as a subset of

feasibility studies, with feasibility studies determining if a trial can be completed, helping

determined whether the researcher should proceed with a larger trial. A pilot study would

then be a study that is completed on a smaller scale (Eldridge, Lancaster, et al., 2016).

While the four phases of research are routinely applied throughout the scientific

community, the scientific purpose of Phase II feasibility and pilot studies is often

misunderstood and confused with Phase III trials. The purpose is neither null hypothesis

testing nor to determine the effectiveness of an intervention, but is instead an early phase

development function to enhance the success of larger subsequent randomized control

trials (Lancaster, 2015; Leon et al., 2011; Moore et al., 2011). The objective of feasibility

and pilot testing is to focus on the items of uncertainty that will need to be addressed

when planning the next phase III larger scale study (Lancaster, 2015). Leon and

17
colleagues (Leon et al., 2011) explain that hypothesis testing should not be used in

feasibility and pilot studies for two fundamental reasons: limited information is known

about the methods of the study, and the sample size is too small. Large sample sizes are

required for appropriately powered statistical null hypothesis testing, which is not an

expectation of feasibility and pilot studies (Tickle-Degnen, 2013). If hypothesis testing

were completed with feasibility and pilot testing, it should be interpreted with caution due

to scientific limitations (Lancaster, 2015). A misinterpreted nonsignificant null

hypothesis test could lead to an area of research being stopped when valuable research

could be continued (Tickle-Degnen, 2013).

Another area of scientific purpose often misunderstood with feasibility and pilot

studies is the use of establishing effect size. While there has been previously widespread

use of pilot study results to estimate between-group effect sizes, both Kraemer and

colleagues (Kraemer et al., 2006) and Leon and colleagues (Leon et al., 2011) argue

against this practice. Due to the small sample size of pilot studies, the estimation could

easily result in a false positive (Type I error) or false negative (Type II error), which

could mislead the Phase III study results. Estimates of effect size are more accurate with

larger sample sizes, and it is highly recommended that it should not be a specific aim of

the pilot study proposal (Leon et al., 2011). With the small sample sizes in pilot studies,

there is not enough accuracy with estimating effect size to serve as a foundation for

decision making and design in a larger study (Kraemer et al., 2006).

A distinctive feature of feasibility and pilot studies, when compared to Phase III

studies, is the measurement of outcomes and statistical analysis. Due to the exploratory

18
and descriptive nature of feasibility and pilot testing, research objectives and outcome

measures are not stated in a hypothesis but are stated in "criterion for success" (Lancaster,

2015; Thabane et al., 2010). These are directly stated levels or standards of completion

for feasibility outcomes that the research team deems successful. When the criterion for

success components do not meet the established standard, then those components should

be modified or removed entirely from the subsequent larger trial (Leon et al., 2011).

Outcomes from feasibility and pilot studies should be measured in descriptive statistics,

necessary data about operations of a study, and qualitative analysis (Tickle-Degnen,

2013). It is recommended that confidence interval estimation be utilized instead of

hypothesis testing, due to the imprecision of estimates that will result from a small

sample size (Lancaster et al., 2004).

To clearly measure and analyze outcomes for feasibility and pilot studies, a well-

organized conceptual framework is needed to guide clear reporting. Eldridge and

colleagues (2016) established the Consolidated Standards of Reporting Trials

(CONSORT) statement extension for randomized pilot and feasibility trials, which

provides a checklist for documents, abstracts, and flowchart for studies (Eldridge, et al.,

2016). As an extension of the CONSORT statement, Thabane and colleagues (2010)

established a clear and systematic categorization of purposes and associated outcome

measures for feasibility and pilot studies. This categorization system serves as the main

framework for how the studies in this dissertation will assess and report outcomes. The

four main reasons for competing feasibility and pilot studies are 1) process, 2) resources,

3) management, and 4) scientific (Thabane et al., 2010). The process category

19
encompasses items that determine what processes are essential to the function of the

phase III study, such as retention, recruitment, and eligibility. Outcomes for this category

are reported in rates of how each element was met. Items that are in the resources

category assess time and budget concerns in the operation of the phase III study, such as

how much time is required to complete the study, how long it takes to complete forms,

what equipment is available during the study, and facility capacities. The outcome

measures for resources are reported in terms of the amount of time to complete

components, and the rates of equipment or software success. The management category

involves components that determine if there are any human or data management

problems, such as physical building location were the study is being completed,

functionality of data collection forms, and thoroughness of data entry. Examples of data

collected for this category would be qualitative reports from subjects and study

personnel, and occurrence of missing data. The final category of scientific includes if

there are any safety concerns and what the responses were to the control or experimental

conditions. Measurements for this category would be number of occurrence of adverse

events and responses to the intervention (Thabane et al., 2010).

Objectives

The overall objective of this dissertation is to determine the feasibility of the

novel combined intervention of AO and RTP in moderately impaired chronic stroke

survivors. Each chapter in this dissertation will focus on different reasons for competing

feasibility and pilot studies. Chapter 2 examined two reason for feasibility and pilot

20
studies of process and scientific (Thabane et al., 2010), and the primary purpose was to

determine the feasibility of a Randomized Control Trial (RCT) protocol that combines

AO and RTP for upper extremity rehabilitation in moderately impaired stroke survivors.

Chapter 3 examined the scientific reason for feasibility and pilot studies, and the purpose

was to determine the response to intervention through detecting changes in UL motor

impairment outcomes in the AO plus RTP practice schedule compared to a placebo plus

RTP practice schedule in the chronic, moderately impaired stroke survivor. Chapter 4

examined the scientific reason for feasibility and pilot studies, and the purpose was to

determine the response to intervention through detecting changes in UL functional

performance outcomes in the AO plus RTP practice schedule compared to a placebo plus

RTP practice schedule in the chronic, moderately impaired stroke survivor.

Conclusion

Feasibility and pilot studies are critical to the development of research and are

necessary for sound research planning. With each development of novel science and

research, establishing the process, resources, management, and scientific components of

feasibility creates a foundation for large randomized control trials. The novel

combination of AO and RTP has not been implemented with stroke survivors previously,

and is need of feasibility and pilot testing. The combination of AO providing visual

motor learning for functional tasks prior to the physical performance during RTP could

potentially increase motor performance of the hemiplegic UL, creating a synergism of

interventions for a large stroke population in need of UL rehabilitation. Due to the higher

21
rehabilitation needs of moderately impaired stroke survivors and the large chronic stroke

population, this feasibility and pilot study will focus on the novel combination of AO and

RTP in the moderately impaired chronic stroke population.

22
Chapter 2 The Feasibility of a Randomized Controlled Trial for Action Observation
Combined with Repetitive Task Practice on Upper Extremity Outcomes in
Moderately Impaired Stroke Survivors

ABSTRACT

Purpose

The primary purpose of this study was to determine the feasibility of a trial that combines

Action Observation (AO) and Repetitive Task Practice (RTP) for upper extremity

rehabilitation in moderately impaired stroke survivors. Specifically, we examined the

feasibility under the general classifications of Process (e.g., recruit, enroll, and retain

subjects in the study, and subjects understanding study questions, completing follow up,

and compliance with treatment protocol), and Scientific (e.g., the safety of completing the

intervention).

Methods

Chronic stroke survivors with upper limb (UL) hemiplegia were recruited for six months

(June 2019 – December 2019) and followed for 12 weeks. Subjects were assessed at three

distinct time points of pre-test (Pre), post-intervention (Post 1), and 1-month post-

intervention (Post 2). The intervention was completed in one hour sessions, three times

per week, for eight weeks (total of 24 sessions). Numbers of subjects recruited, enrolled,

remaining in the study, and occurrence of adverse events was recorded. Research team

23
members recorded the subject’s ability to understand questionnaires, and compliance

with treatment session attendance protovol.

Results

A total of sixteen subjects were recruited, (100% recruitment rate), and fifteen subjects

met inclusion/exclusion requirements and enrolled (94% enrollment rate). Of the fifteen

subjects enrolled, eleven subjects remained in the study through the primary endpoint

(73% retention rate). Six out of the eleven subjects that completed the intervention were

fully compliant with intervention session attendance of all 24 sessions (55%), with the

mean attendance of 19.9 (standard deviation 5.0). All subjects reported an understanding

of study questionnaires and outcome measures (100%), and none of the subjects reported

an adverse event (0%).

Conclusion

The research protocol is feasible to deliver with adjustments made that were discovered

in this study. Further research to explore the efficacy of AO combined with RTP is

indicated with a larger Phase III trial with a fully powered sample size.

24
 INTRODUCTION

With 7.0 million people in the United States having experienced a stroke, stroke is

one of the leading causes of serious long term-disability amongst Americans (Virani et

al., 2020). A common secondary impairment following stroke is hemiparesis, which is a

motor impairment causing limited active movement, decreased coordination, and

impaired sensation on one side of the body (Fisher & Curry, 1965). Hemiplegia of the

upper limb (UL) impedes movement necessary to complete performance and ultimately

independence in activities of daily living (ADL). Due to the difficulties associated with

UL hemiplegia and negative feedback from limited success when completing functional

ADL tasks, stroke survivors limit the initiation and use of the hemiplegic UL, which

leads to learned non-use (Wolf et al., 1989). This results in discouraged and limited use

of the UL during functional ADL talks, and encourages the use of the non-hemiplegic UL

(Taub et al., 1994; Wolf et al., 1989). As a result, therapeutic intervention is needed to

encourage the use of hemiplegic UL and to increase performance and independence

during ADL tasks.

An intervention that has been supported to increase the performance of the

hemiplegic UL is action observation (AO). This intervention technique involves

performing a functional task after watching a video depicting the physical performance of

the same task (Buccino et al., 2004). Multiple reviews have determined that when stroke

survivors are utilizing AO to assist with learning of movement and motor planning of

their hemiplegic UL during tasks, there are significant improvements in measures of

motor impairment, dexterity, spasticity, ADL performance, UL function, and

25
participation in everyday ADL tasks (Borges et al., 2018; Kim, Kyeongmi, 2015; Peng et

al., 2019; Sarasso et al., 2015; Zhang et al., 2019). AO is a promising intervention to be

utilized with stroke survivors to counteract the effects of learned non-use.

Another intervention implemented with stroke survivors to address UL

hemiplegia is Repetitive Task Practice (RTP). When utilized with stroke survivors, this

intervention is the performance of goal-directed, functional, task-specific activities that

are completed with intensive repetitions and high effort with the hemiplegic UL (Wolf et

al., 2002). RTP and has shown to be effective in UL stroke rehabilitation by significantly

decreasing UL motor impairment and increasing functional ADL performance. RTP is

highly effective for increasing UL recovery in chronic stroke survivors (Arya et al., 2012;

Bosch et al., 2014; Ross et al., 2009; Timmermans et al., 2010; Winstein et al., 2004).

While both AO and RTP are efficacious interventions for post-stroke UL

hemiplegia individually, these interventions have not been combined before. The

combination of AO providing visual motor learning for functional tasks prior to the

intense physical performance during RTP could potentially increase motor performance

of the hemiplegic UL. This synergistic combination of AO and RTP seems promising,

and requires scientific investigation into the feasibility of completing a study with chronic

moderately impaired stroke survivors. This would determine if subjects would participate

and remain in the study, and if the research team would have the resources and

managerial abilities to complete a RCT. Results from this study would guide the research

team to determine if an AO and RTP combined protocol would be feasible for a larger

RCT that is adequately powered to determine the efficacy of the intervention groups.

26
Study Objectives

The objectives of this study were to determine the feasibility within the general

classifications for conducting pilot studies as established by Thabane (Thabane et al.,

2010) for a trial that combines AO and RTP for upper extremity rehabilitation in

moderately impaired stroke survivors. Within Thebane's (2010) general categories of

process, resources, management, and scientific, we explored the following feasibility

outcomes:

1. Process: we examined our ability to recruit, enroll, and retain subjects in the

study. We also examined the subjects’ understanding of study questionnaires,

completing follow up, and compliance with treatment session protocol attendance.

2. Scientific: we examined the safety of completing the intervention.

METHODS

This pilot feasibility study utilized a randomized controlled single-blinded,

parallel-group study design. Adult (> 18 years old) chronic (> 6 months) community-

dwelling stroke survivors with UL hemiplegia were recruited to participate at a clinical

site (The Ohio State University Medical Center, Columbus, OH) over a six month period

(June 2019 – December 2019). Potential subjects that responded to recruitment materials

were considered for eligibility and recorded in a subject screening log. All study

procedures, consents, brochures, and study personal were approved by the Biomedical

Sciences Institutional Review Board (IRB) at The Ohio State University (#2019H0197)

prior to recruitment. This study was registered with ClinicalTrials.gov (identifier #

NCT04015271). All intervention method delivery was compliant with the Intervention
27
Description and Replication (TIDieR) (Hoffmann et al., 2014) checklist for reporting of

acceptability and repeatability. The reporting of this feasibility pilot trial was in

compliance with the CONSORT extension for randomized pilot and feasibility trials

(Eldridge, Chan, et al., 2016).

Subjects were randomized through a simple computer-generated random numbers

table to a group assignment of experimental conditions of AO plus RTP practice schedule

or the control condition of Placebo Video (PV) plus RTP. A blinded assessor completed

assessments on each subject at three distinct time points, pre-test (Pre), post-intervention

(Post 1), and 1-month post-intervention (Post 2). A blinded intervention therapist

provided intervention for one hour, three times per week, for eight weeks (total of 24

sessions), and subjects also completed a daily 30-minute Home Exercise Program (HEP).

A non-treating and non-assessing research personnel developed the simple computer-

generated random numbers table for group assignment, and trained members of the

research team that were blinded to group assignment completed intervention and

assessment. The treating therapist was blinded to intervention through being given a code

indicating which recording to play from randomization. At the start of each recording, the

AO or PV images were delayed in the video by 30 seconds for the therapist to ensure that

the video was playing accurately but is blinded to which video it is. Once the therapist

was sure that the patient was comfortable and the video is working properly, within the

30 second delay the therapist placed a privacy border between the therapist and the

participant observing the recording to maintain blinding of group assignment. Written

instructions for observing AO and PV appeared at the beginning of the video. At end of

28
the video, written instructions appeared that ask the participant to not discuss content of

the video with the therapist.

Within seven days after consent and screening, pre-testing (Pre) was completed.

Within seven days of pre-testing, subjects began receiving the intervention three times

per week for eight weeks (total of 24 sessions). Within seven days after the intervention

was completed post testing 1 (Post 1) was completed, and four weeks after Post 1

completed, post testing 2 (Post 2) was completed. Full study completion for subjects

required 14 weeks. This pilot study ended once the total number of subjects required for

the sample size was enrolled and had completed all follow-up sessions.

Inclusion criteria were as follows: (1) Confirmed medical diagnosis of stroke; (2)

UEFM score ranging from 17 to 49 (Woodbury et al., 2013); (3) post-stroke > 6 months;

(4) > 24 on the Folstein Mini Mental Status Examination (MMSE); (5) age in the range

from 18 to 85; (6) experienced only one stroke; (7) discharged from all forms of physical

rehabilitation intervention; (8) visually acuity of 20/50 or greater with or without

corrective lenses; (9) > 19 on the Hooper Visual Organization Test; (10) unilateral stroke

only; (11) Cerebral stroke; (12) age of onset of stroke greater than 18 years old.

Exclusion criteria included the following: (1) < 18 years old; (2) > 5 on a 10-point visual

analog pain scale in the affected UL; (3) > 2 on the Modified Ashworth Scale in the

affected UL to exclude individuals with hypertonia, spasticity, joint rigidity, and joint

contracture; (4) participating in any experimental rehabilitation or drug studies; (5)

uncontrolled cardiovascular, or pulmonary disease, or other disease that would preclude

involvement in a therapeutic treatment; (6) neurological disorder other than stroke; (7) >

29
31 on Beck Depression Inventory ("Severe Depression"); (8) unable to regularly attend

treatment sessions and follow-up due to distance from the center or inadequate social

support; (9) Cerebellar stroke with ataxia.

Study recruitment materials were distributed in central Ohio to stroke support

groups, individuals known to the research team, local Occupational and Physical Therapy

clinicians, and medical departments in central Ohio, including Physical Medicine &

Rehabilitation, and Occupational and Physical Therapy. Clinicians at local stroke clinical

locations and in Ohio State academic departments were made aware of the studies via

clinician to clinician communication.

All successfully recruited subjects who appeared to meet general eligibility

criteria, on the basis of an in-person screen, received information about study procedures

and were asked if they were interested in participating in the study. If subjects were

eligible to participate but declined to consent, the reason for declining was recorded. All

subjects completing informed consent were then screened for eligibility of enrollment,

and reasons for non-enrollment were recorded. All enrolled participants were randomized

to group assignment, completed pre-testing, and initiated the treatment protocol of an

intervention for one hour, three times per week, for eight weeks (total of 24 sessions), and

a daily 30 minute Home Exercise Program (HEP). Follow up testing was completed

within seven days after completion of the intervention (Post 1), and one month after

completion of the intervention (Post 2). In-person face to face visits occurred at each of

the study interaction points.

30
 Safety monitoring was completed throughout the study, and procedures were

established so that if any study-related adverse events occurred, they could be recorded

and reported appropriately to the IRB and the subject's physician. Subject study activity

was recorded, such as withdrawal from the study, attending follow up sessions,

understanding of study questionnaires, and response to intervention. Resource and

management feasibility for study personnel was recorded, such as length of time to

complete outcome measures and study questionnaires, and the success of data entry into

electronic data capture

The target pilot trial sample size was a total of up to 15 subjects with a 2:1

allocation ratio, with up to 10 randomized to AO plus RTP and up to 5 randomized to PV

plus RTP. Continued study participation was expected to be high (>75%) in the novel

combination therapy AO plus RTP group and to not fall far below 50%. With 10

participants in the AO plus RTP group, the two-sided 90% confidence interval for an

80% retention rate would span from 49%-96%.

The outcomes measures for this study were chosen to measure feasibility and fell

under the broad classifications of process, resources, management, and scientific as

established by Thabane (Thabane et al., 2010). The definitions of outcomes for this study

included these:

• Recruitment rate – The research team's ability to recruit subjects to participate in

the trial throughout the study.

• Retention rate – The subject remaining in the study through follow up.

31
 • Enrollment rate – The research team's ability to enroll subjects in the study

following consent and screening.

• Compliance with intervention – The subject being compliant with attending and

completing all 24 intervention sessions in the treatment protocol.

• Completing follow up – The subject remaining in the study after initiation of

intervention through follow up.

• Understanding of study questionnaires – The individual subjects reporting that

they understood the questions in the study questionnaire.

• Safety/ occurrence of adverse events – Adverse events were defined as “any

unfavorable and unintended sign (including an abnormal laboratory finding),

symptom, or disease temporally associated with the use of a medicinal

(investigational) product, whether or not related to the medicinal (investigational)

product” (U.S. Department of Health and Human Services Food and Drug

Administration, 2018). Serious Adverse Events were defined as “Any untoward

medical occurrence that at any dose: Results in death, is life-threatening, requires

inpatient hospitalization or prolongation of existing hospitalization, results in

persistent or significant disability/incapacity” (U.S. Department of Health and

Human Services Food and Drug Administration, 2018).

Demographic information was collected at baseline and extracted from the

medical records where possible, which included: age, sex, hemiplegic side of the body, if

the hemiplegic side of the body was the same as the dominant side, race, ethnicity,

32
amount of time from stroke onset to the enrollment in the study, type of stroke, and stroke

lesion location. Information for recruitment, consent, and screening was recorded in a

subject screening log at the baseline time point. Eligibility, retention, follow up,

understanding of study questionnaires, compliance with intervention session attendance,

and the occurrence of adverse events were recorded on study case report forms (CRF)

throughout the study process.

Criterion for success: We considered this feasibility study a success if the

following criteria were met by the completion of all follow-up visits:

• Primary feasibility objective: Intervention retention rates - Criteria for success

was defined as greater than 75% of subjects would remain in study through follow

up.

• Recruitment rate - Criteria for success was defined as at least 80% of eligible

subjects could be recruited.

• Enrollment - Criteria for success was defined as at least 80% of screened subjects

would be eligible for enrollment in the study

• Understanding of study questionnaires - Criteria for success was defined as

greater than 80% of subjects would understand the questions in the surveys.

• Complete follow up - Greater than 90% of subjects will remain in study after

initiation of treatment

• Treatment Protocol Compliance - Greater than 90% of subjects will maintain

compliance with the study protocol for intervention sessions

33
 • Safety occurrence of adverse events - Criteria for success was defined as less than

5% of subjects would experience an adverse event.

Data were recorded on paper documentation and were maintained in a fashion that

is consistent with accepted Good Clinical Practices (U.S. Department of Health and

Human Services Food and Drug Administration, 2018). Data were entered and stored in

an Electronic Data Capture (EDC) system using Research Electronic Data Capture

(REDCap) electronic data capture tool hosted at Ohio State University (Harris et al.,

2009, 2019). “REDCap is a secure, web-based software platform designed to support data

capture for research studies, providing 1) an intuitive interface for validated data capture;

2) audit trails for tracking data manipulation and export procedures; 3) automated export

procedures for seamless data downloads to common statistical packages; and 4)

procedures for data integration and interoperability with external sources” (Ohio State

University Center for Clinical and Translational Science).

Statistical Methods

To describe the patient cohort, descriptive statistics, including the mean and

standard deviation or count and percentage, were calculated for patient demographics,

clinical characteristics and functional measures at baseline (Pre).

Feasibility analysis consisted of means, standard deviation, percentages, and

frequencies for retention rates, recruitment rate, enrollment rate, understanding of study

questionnaires, follow up rate after initiation of treatment, compliance with treatment

34
protocol session attendance, and the occurrence of adverse events. The Statistical

Package for Social Sciences version 26.0 (IBM Corp. Released 2019. IBM SPSS

Statistics for Macintosh, Version 26.0. Armonk, NY: IBM Corp.) was used for all data

analysis.

RESULTS

The demographic and stroke history characteristics of all enrolled subjects in the

study are summarized in (Table 2). Overall, 4 (26.7%) participants were women, 13

(86.7%) were White Non-Hispanic, and the average age was 57.8 (Standard Deviation

(SD) 12.4). The most prevalent type of stroke was ischemic 13 (86.7%), with the most

frequent identified location as the middle cerebral artery 6 (40.0%). The majority of

strokes occurred on the left side and resulted in right hemiparesis 10 (67%). The average

time since stroke was 8.8 (8.3) years. Results for the criterion for results are shown in

Table 3.

Process feasibility

A total of sixteen subjects were recruited (100% recruitment rate), consented, and

screened over a 5-month period from July 2019 to December 2019 (See Consort

Diagram, Fig 2). Of the sixteen subjects that were recruited, all subjects agreed to all

parts of the study. Fifteen subjects meeting inclusion/ exclusion requirements were

identified, fifteen subjects were enrolled (100% enrollment rate), and zero subjects

declined consent/ participation. After randomization, two subjects withdrew from the

study after pre-testing and two subjects withdrew within the first week after initiation of

intervention sessions. All four subjects that withdrew reported logistical difficulties of
35
parking at the academic medical setting and transportation to the facility, and one subject

reported increased family obligations due to family illness. Of the fifteen subjects

enrolled, eleven subjects remained in the study (73% retention rate) through Post 2 after

enrollment and pre-test. Of the thirteen subjects that initiated intervention, eleven

subjects remained in the study after initiation of intervention (84.6%). Of the eleven

subjects that remained in the study, all subjects completed post-testing sessions at Post 1

and Post 2, and all subjects reported understanding of study questionnaires and outcome

measures (100%). Six out of the eleven subjects that completed the intervention were

fully compliant with intervention session attendance of all 24 sessions (55%), with the

mean attendance of 19.9 (standard deviation 5.0).

36
Table 1 Characteristics of participants enrolled in study.

Group AO plus RTP Placebo plus RTP

Number of Subjects: N 10 5
Age in years: Mean (SD) 56.8 (13.9) 59.8 (9.7)
Sex: N (%) F M F M
3 (30%) 7 (70%) 1 (20%) 4 (80%)
Race/Ethnicity: N (%)
White Non-Hispanic 9 (90%) 4 (80%)
Black Non-Hispanic 1 (10%) 1 (20%)
Hispanic 0 0
Side L R L R
Dominant Hand: N (%) 2 (20%) 8 (80%) 0 (0%) 5 (100%)
Affected by Hemiparesis 4 (40%) 6 (60%) 1 (20%) 4 (80%)
Affected Same Side as Dominant: N 5 (50%) 4 (80%)
(%)
Years after stroke to enrollment: Mean 8.9 (8.3) 8.2 (9.2)
(SD)
Ischemic stroke: N (%) 8 (80%) 5 (100%)
Stroke location
MCA: N (%) 4 (40%) 2 (40%)
Unknown: N (%) 6 (60%) 3 (60%)

Table 2 Criterion for success definitions and results

Feasibility Measure Definition of Criteria for success Results

Process feasibility
Retention rate * Greater than 75% of subjects would remain in 11/15 (73%)
study after initiation of treatment
Recruitment rate At least 80% of eligible subjects could be recruited 16/16 (100%)
Enrollment At least 80% of screened subjects would be eligible 15/16 (94%)
for enrollment in the study
Understanding of study Greater than 80% of subjects completing post 11/11 (100%)
questionnaires testing would understand the questions in the
survey
Complete follow up Greater than 90% of subjects will remain in study 11/13 (85%)
after initiation of treatment
Treatment Protocol Greater than 90% of subjects will maintain 6/11 (55%)
Compliance compliance with the study protocol for
intervention sessions
Attendance Mean (SD) 19.9 (5.0)
Scientific Feasibility
Safety/ occurrence of Less than 5% of subjects would experience an 0 (0%)
adverse events adverse event
* Primary feasibility objective, SD = Standard Deviation

37
 Screened prior to eligibility
Screened assessment (n= 16)

Excluded (n= 0)
¨ Reasons (n= 0)

Enrollment Assessed for eligibility (n= 16)

Excluded (n= 1)
¨ Not meeting inclusion criteria (n= 1)
¨ Declined to participate (n= 0)
¨ Other reasons (n= 0 )

Randomized (n= 15)

Allocation
AO plus RTP intervention (n= 10) Placebo plus RTP intervention (n= 5)
¨ Received allocated intervention (n= 9) ¨ Received allocated intervention (n= 4)

¨ Did not receive allocated intervention ¨ Did not receive allocated intervention
(withdrew from follow up) (n= 1) (withdrew from follow up) (n= 1)

Follow-Up
Lost to follow-up (withdrew from study) (n= 1) Lost to follow-up (withdrew from study) (n= 1)
Discontinued intervention (n= 0) Discontinued intervention (n= 0)

Assessment
Assessed for Criteria 1 (n= 10)
Assessed for Criteria 2 (n= 10)
Assessed for Criteria 3 (n= 10)
Assessed for Criteria 4 (n= 8)
Assessed for Criteria 5 (n= 9)
Assessed for Criteria 6 (n= 8)
Assessed for Criteria 7 (n= 10)
Assessed for Criteria 1 (n= 5)
Assessed for Criteria 2 (n= 5)
Assessed for Criteria 3 (n= 5)
Assessed for Criteria 4 (n= 3)
Assessed for Criteria 5 (n= 4)
Assessed for Criteria 6 (n= 3)
Assessed for Criteria 7 (n= 5)

Figure 2 CONSORT Flow Diagram.

38
Scientific Feasibility

None of the eleven subjects that completed the study reported an adverse event

related to the study protocol (0% experienced an adverse safety event). The response to

intervention is described in further detail in Chapter 3 & 4.

DISCUSSION

The feasibility outcomes in this study were met in four out of seven criteria for

success. The primary feasibility objective was not met with a retention rate of 73%. The

retention rate was expected to be 75%, which would indicate that 8 - 9 subjects in the AO

plus RTP experimental group would remain in the study through the end of the protocol.

While the retention rate was not met, there were 8 subjects remaining in the AO plus RTP

group, which was still enough subjects in the study sample to detect change in the

primary upper limb motor impairment outcome.

Meeting majority of the criteria would indicate that this research protocol is

feasible for a larger RCT that is adequately powered to determine the efficacy of the

intervention groups (Arain et al., 2010). Results found from this feasibility study will

provide a sound basis for further research on AO plus RTP for the moderately impaired

stroke survivor. While successful, several points of improvement were identified by

subjects and research personnel to increase the success rate of the feasibility of the study.

The process feasibility objectives were focused on the ability of the research team

and subjects to complete the core functionality of a study, such as recruitment, retention,

enrollment, compliance, and understanding study questionnaires (Thabane et al., 2010).

39
As previously discussed, there was a 73% retention rate and 85% follow up rate due to

four subjects withdrawing from follow up after Pre testing and within the first week of

intervention. The main reason for subjects withdrawing from the study were logistical

difficulties of parking at the academic medical setting and transportation around the

academic medical center campus. While the parking garage was located immediately

beside the study location, it was a large eight-floor structure available to all visitors for

the entire medical center campus, with a total of 826 parking spaces and only 24

accessible spaces (CampusParc at The Ohio State University, 2019). Participants

frequently reported being unable to find an available accessible parking space, being

required to park on the top floors, and noted that the elevators were frequently not

operating correctly, which required long waits or utilizing the steps to the first floor.

Additionally, there were physical building limitations in the study location of accessibly,

and construction was completed during the time frame of completing the study.

Recommendations for future studies would be to complete any human subject research in

designated outpatient medical facilities, where established infrastructure to manage

parking logistics such as valet and proximity parking for patient is addressed, and

accessibility issues have been addressed and resolved. With all subjects who dropped out

reported the same problem suggests that with this resolved, retention would be likely to

improve.

A positive process feasibility indication of this trial was the 100% rate of

recruitment, consent, and 94% enrollment rate (Arain et al., 2010; Tickle-Degnen, 2013).

These results would indicate that recruitment materials and methods that were utilized

40
were effective, there is a large enough population of moderately impaired stroke

survivors in the central Ohio area to complete the study, and this population of stroke

survivors are willing to participate in research studies. Subjects provided consent and

were screened prior to enrollment into the study. With a 94% enrollment rate, this would

indicate that the subject inclusion and exclusion criteria were at an appropriate level for

including subjects into the study.

A process feasibility objective that did not meet the criterion for success was

treatment session attendance compliance of 55% with a mean attendance of 19.9 (5.0) out

of 24 sessions. The criterion for success was defined as subjects attending all 24 sessions

in the treatment protocol. Due to the nature of human subject research and human life

events, subjects missed intervention sessions. Frequently reported reasons for missing

sessions were illness, family events and obligations, medical appointments, time

management difficulties, and parking and transportation complications. While the

research team’s ability to prevent majority of the reported reasons for missing

intervention sessions is limited, changing the location of where the study is completed to

improve accessibility, transportation, and parking might alleviate some barriers and

increase compliance.

The scientific feasibility objective was focused on the safety of the intervention

with research subjects (Thabane et al., 2010). While there have been several studies

conducted previously with stroke survivors in the chronic phase of recovery with no

serious adverse events (Ertelt et al., 2007; T. Kim et al., 2016b; Kuk et al., 2016; Lee,

Daehee et al., 2013; Sugg et al., 2015), and it was not anticipated that there would be

41
safety concerns in this study, careful safety monitoring throughout the study was

completed. No adverse events related to the study occurred (adverse event or serious

adverse event), which indicates there is a low safety risk to subjects completing the AO

plus RTP and Placebo plus RTP protocols.

Strengths, Limitations, and Future Directions

Through the completion of this feasibility study, several strengths, limitations,

and future directions were identified. The main strength identified is that there is a low

safety risk to participants indicated for completing the research protocol, without a higher

than expected risk of an adverse event. Another main strength identified is that subjects

were willing to participate in the study, which was shown through strong recruitment,

consent, and enrollment rates.

Limitations that could be related to bias and external validity would be the

interaction of setting and treatment. The majority of the limitations identified by research

personnel and subjects were related to the physical location of where the study was

completed in an academic medical center. The building is located in the center of the

medical campus that is primarily dedicated to inpatient hospital services and is not

conducive to the high transportation and logistical needs of outpatient services.

Recommendations for future studies would be to complete the study in an outpatient

rehabilitation facility where physical access to the building, parking, and physical

accessibility within the building have already been addressed and mitigated.

Conclusion

42
 Through the process of completing this feasibility study, the research team found

that the research protocol was feasible to deliver. With adjustments made to the

implementation of the research operations that were discovered in this study, further

research to explore the efficacy of AO combined with RTP is indicated with a larger

sample size. This study shows that completing an adequately powered comparative trial

is likely to be successful due to the ability to recruit and retain subjects. Careful attention

should be given to the physical location and infrastructure and efficiencies for post

testing should be explored.

43
 Chapter 3 Preliminary Efficacy of Action Observation Combined with Repetitive
Task Practice on Upper Extremity Motor Impairment Outcomes in Moderately
Impaired Stroke Survivors: A Pilot Study

ABSTRACT

Background and Purpose

Action observation (AO) is an intervention technique that involves watching a video of

another person performing a task with the upper limb (UL), and then physically

performing the same task. This intervention has been found to decrease UL motor

impairment in chronic stroke, as well as repetitive task practice (RTP) which is repetitive

physical performance of a task with the hemiplegia UL. Both have been found to be

effective individually to decrease UL motor impairment, but have not been combined

before. The purpose of this feasibility pilot study was to determine preliminary efficacy

to the intervention through detecting changes in UL motor impairment outcomes in the

AO plus RTP practice schedule compared to placebo plus RTP in the chronic, moderately

impaired stroke survivor. Determining the response to intervention in this Phase II study

is part of the scientific process that could lead to a larger Phase III study.

Methods

A pilot randomized controlled single-blinded, parallel-group pilot study was completed

with 15 chronic moderately impaired stroke survivors. Subjects were randomized to AO

plus RTP practice schedule, or in the control condition of Placebo Video plus RTP, and

completed an intervention for one hour, three times per week, for eight weeks (total of 24
44
sessions), along with a daily 30 minute Home Exercise Program. The outcome measures

of the Upper Extremity Fugl Meyer (UEFM) and Modified Ashworth Scale (MAS) were

completed at pretest (Pre), post intervention (Post 1), and 1 month post intervention (Post

2).

Results

10 subjects were allocated to AO plus RTP and 5 subjects to Placebo Video plus RTP.

The linear regression model that estimated the difference in the change revealed

significant evidence of a larger improvement in the AO plus RTP group at Post 2, with

the difference in the average change in UEFM was 8.2 (90% CI 4.0 - 12.4, one-sided p-

value=0.006). The Fisher’s exact test was used to detect the difference between

randomized groups in the proportion of patients who improved between Pre and Post 2

for the MAS revealed no significant difference for Elbow Flexion (two-sided p-

value=.060) and Elbow Extension (two-sided p-value=.055).

Conclusion

In this small feasibility pilot study of moderately impaired stroke survivors, there

was a significant response of change on the UEFM motor impairment assessment for the

combination of AO + RTP on the hemiplegic UL, and a possible benefit of reduced

spasticity at the elbow occurring after the intervention. Decreased motor impairment and

spasticity of the UL would increase movement and coordination to facilitate post stroke

recovery. This response to intervention would indicate that a larger Phase III RCT should

be completed to determine efficacy for the intervention in the moderately impaired

chronic stroke survivor population.

45
 INTRODUCTION

Feasibility and pilot studies are a crucial part of the progression of the scientific

process for developing research questions, refining interventions, and guiding study

procedures (Leon et al., 2011). Essential questions about the conduct of a trial, study

procedures, and scientific assessment can be answered prior to proceeding to a larger

scale subsequent Phase III trial (Eldridge et al., 2013). One of the scientific reasons to

complete feasibility and pilot studies is to determine if there is a response to intervention

in the experimental or control conditions (Thabane et al., 2010). This is especially true

for research designed for large populations with impactful conditions such as stroke

survivors. It is estimated that 7.0 million people in the United States have experienced a

stroke, with approximately 795,000 people experiencing a new or recurrent stroke each

year (Virani et al., 2020). Additionally, it is estimated that the prevalence of stroke

survivors in the United States will increase by an additional 3.4 million adults by 2030

(Ovbiagele et al., 2013), exceeding 10 million in total. Stroke is included in the top 18

diseases contributing to living with disability, and is one of the leading causes of severe

long term-disability (Virani et al., 2020). Within the categorization of severity of stroke,

the large population of moderately impaired stroke survivors have higher rehabilitation

needs, improve the most with rehabilitation in all areas through recovery, and these

individuals are the main focus of the rehabilitation process continuum of care through

inpatient and outpatient rehabilitation services (Jørgensen et al., 1995; Stineman et al.,

1998; Teasell et al., 2018).

46
 Secondary complications are often reported by stroke survivors, with a common

secondary impairment of upper limb (UL) hemiparesis affecting 88% of stroke survivors

(Dobkin, 1997). Hemiparesis is a motor impairment which can involve incomplete or

complete paralysis of one side of the body, and the presentation includes decreased active

range of motion, spasticity, and weakness (Fisher & Curry, 1965). Hemiparesis in the UL

is one factor that impedes performance of activity of daily living (ADL) tasks, making

stroke one of the leading causes of severe long term-disability (Virani et al., 2020).

Traditional stroke therapy interventions intended to decrease the effects of UL

hemiplegia, while commonly used (Wengerd, 2019), offer limited benefit (T.

Hafsteinsdóttir et al., 2007; T. B. Hafsteinsdóttir et al., 2005; Kollen et al., 2009).

Rehabilitation interventions are needed to counteract post stroke hemiplegia and increase

motor performance of the UL.

Action observation (AO) is one such intervention technique that has been found to

increase movement in the UL (Cowles et al., 2013; Franceschini et al., 2012; Sale et al.,

2014). This technique involves watching a video of another person performing a task

with the UL, and then having the patient perform the same task (Buccino et al., 2004).

AO training is intended to activate visuomotor neurons of the mirror neuron system

(MNS). The MNS has been confirmed to be present in humans through brain and

neurophysiological imaging studies, and is thought to be a part of the system that

provides human’s with such high ability to learn by imitation (Rizzolatti & Craighero,

2004). While many neural systems are involved in observation, the MNS is identified by

its dual role in observation and motor performance. During functional magnetic

47
resonance imaging (fMRI) studies, cortical areas defined as a part of the MNS are active

during both arm movements observed in AO and during physical motor execution of the

same arm movements (Cross et al., 2009; Iacoboni et al., 2001).

When AO is implemented with stroke survivors, it has been found to effectively

decrease the detrimental effects of hemiplegia in the UL (Cowles et al., 2013;

Franceschini et al., 2012; Sale et al., 2014). Numerous studies have found that when AO

is used to help stroke survivors learn how to utilize their hemiplegic UL during tasks,

there are significant improvements in motor dexterity, with reductions in spasticity and

impairment (Cowles et al., 2013; Ertelt et al., 2007; Franceschini et al., 2012; Fu.

Jianming et al., 2017; Kim et al., 2016b; Kuk et al., 2016; Patrizio Sale et al., 2014; Sugg

et al., 2015; Zhu et al., 2015). When implementing AO, there is a distinctive practice

schedule of alternating between observation and physical practice, with a matched

amount of time spent in each (Figure 3). Previous studies have utilized a range of time

from 30 seconds to 10 minutes for the matched observation, and physical practice, over

sessions ranging in duration from 15 to 90 minutes. These studies presented the

observation videos from the first and third person perspective, with the models for the

videos representing diversity through gender, race, ethnicity, and age (Cowles et al.,

2013; Ertelt et al., 2012; Franceschini et al., 2012; Fu. Jianming et al., 2017; Kim & Kim,

2015b; Kim et al., 2016b; Lee et al., 2013; Sale et al., 2014; Sugg et al., 2015; Zhu et al.,

2015).

Another highly effective intervention for UL rehabilitation is Repetitive Task

Practice (RTP), the performance of goal-directed, functional, task-specific activities that

48
are completed with intensive repetitions and high effort with the hemiplegic UL (Wolf et

al., 2002). This intervention has been shown to be effective for decreasing UL motor

impairment in chronic stroke survivors (Arya et al., 2012; Bosch et al., 2014; Ross et al.,

2009; Skidmore et al., 2012; Thomas et al., 2017; Timmermans et al., 2010; Winstein CJ

et al., 2004). During this intervention, stroke survivors perform the repetitive practice of

functional tasks within the available voluntary motion of the UL (Winstein et al., 2004).

Therapists provide physical assistance when the stroke survivor is unable to perform

specific components of the functional task, and verbal and tactile cues are given to keep

the participants challenged, motivated, and engaged (Blennerhassett & Dite, 2004). The

RTP practice schedule is to complete physical practice for a 30 – 60 minute session

(Blennerhassett & Dite, 2004; Kwakkel et al., 1999). Although rest breaks, inactive time,

and transition between activities is included within the session, RTP practice schedules

are intended to include as many repetitions into the session as the patient can reasonably

tolerate.

While AO and RTP have both been found to decrease the effects of UL

hemiplegia motor impairment individually (Arya et al., 2012; Franceschini et al., 2012;

Fu et al., 2017; Kim & Kim, 2015a; Sale & Franceschini, 2012; Shimodozono et al.,

2013; Sugg et al., 2015; Timmermans et al., 2010; Zhu et al., 2015), they have not been

combined. Due to the high occurrence of perceptual impairments and apraxia in stroke

survivors (Donkervoort et al., 2000), additional training may be needed prior to physical

performance to assist with motor learning. The visual motor learning component of AO

during functional tasks could potentially increase awareness of movement, and increase

49
the success with motor performance of the hemiplegic UL during physical practice. In the

most optimistic scenario, combining these two interventions might improve motor

performance in a synergistic way that exceeds the benefit of either alone. Because of the

large incidence and substantial disability associated with stroke, even modest increases in

the effectiveness of therapy could have a substantial impact to benefit the millions of

individuals in the rapidly increasing stroke population (Virani et al., 2020).

To combine these interventions, a novel practice schedule needs to be created.

The typical AO schedule is time matched practice of observation and physical practice

across a 30 – 90 minute intervention session (Ertelt et al., 2007; Zhu et al., 2015). In

RTP, the practice schedule is to complete intense physical practice for a 30 – 60 minute

session (Blennerhassett & Dite, 2004; Kwakkel et al., 1999), which includes rest breaks,

inactive time, and transition between activities. For this pilot study, a practice schedule

of 6 minutes of observation (Ertelt et al., 2007), 24 minutes of RTP, 6 more minutes of

observation, and another 24 minutes RTP was chosen (Figure 3). This schedule provided

an increased amount of physical practice compared to the traditional AO schedule, and

allowed physical rest during the RTP schedule, while still meeting the total amount of

physical practice previously established (Blennerhassett & Dite, 2004; Kwakkel et al.,

1999).

50
 A. Typical AO Schedule
Action Observation Time 6 min 6 min 6 min 6 min 6 min

Physical Practice Time 6 min 6 min 6 min 6 min 6 min

B. Typical RTP Schedule

Physical Practice Time 60 min

C. Combined AO and RTP Schedule

Action Observation Time 6 min 6 min

Physical Practice Time 24 min 24 min

A. A typical AO schedule balances equal time spent between action observation and physical
practice of the task. In this example, ten 6-minute periods are used to create a one hour session.
B. A typical RTP schedule masses physical practice into an hour in one session. The breaks
required for rest (not shown) are kept to a minimum.
C. To combine the approaches, the present study used a sequence with 6 minutes of AO followed
by 24 minutes of practice in two successive blocks

Figure 3 Practice Schedules for Action Observation (AO) and Repetitive Task Practice (RTP)
approaches.

The overall objective of this feasibility pilot study was to determine the response

to intervention through detecting changes in UL motor impairment outcomes in response

to the AO plus RTP practice schedule compared to a Placebo plus RTP in the chronic,

moderately impaired stroke survivor. This will address the scientific reason for feasibility

by determining a response to intervention, and if this study design can proceed to a larger

scale subsequent Phase III trial (Eldridge et al., 2013; Thabane et al., 2010). The

combined effect of the AO plus RTP approaches in moderately impaired chronic stroke

survivors could provide expanded opportunities for rehabilitation in millions of

individuals in the rapidly increasing stroke population.

51
 METHODS

This pilot study utilized a randomized controlled single-blinded, parallel-group

study design. Subjects in this study participated in experimental conditions of AO plus

RTP practice schedule, or in the control condition of Placebo Video (PV) plus RTP. A

blinded assessor completed assessments on each subject at three distinct time points,

pretest (Pre), post intervention (Post 1), and 1 month post intervention (Post 2). After

consent and screening, subjects were randomized to a group assignment and completed

an intervention for one hour, three times per week, for eight weeks (total of 24 sessions),

along with a daily 30 minute Home Exercise Program (HEP). A simple computer-

generated random numbers table was used to randomly assign eligible subjects to a

group. All study visits, including consent, screening, intervention, and outcome

measurement sessions, were completed face to face. The full study required 14 weeks

per subject for completion. This study took place an outpatient basis in an academic

research setting within an academic medical center. The research setting included a

designated treatment area for intervention and a testing area to administer outcome

measures. All study procedures, consents, brochures, and study personnel were approved

by the Biomedical Sciences Institutional Review Board (IRB) at The Ohio State

University prior to recruitment.

The AO therapy regimen included watching a 6 minute video of another person

completing a specified functional task that matched the subjects' hemiplegic side (Figure

3). Models for the videos consented to video recording for educational and research

purposes. Videos were from a first and third person perspective, and models represented

52
diversity through gender, race, ethnicity, and age. Subjects were instructed to carefully

watch the AO video and prepare to physically perform the task with their hemiplegic side

immediately after observing the video (Figure 1). The control placebo videos were 6

minutes and included a series of changing static images without animals, human beings,

or sound (i.e., pictures of buildings, trees, cruise ships, mountains, beach umbrellas, beds,

and tables).

The RTP therapy regimen emphasized repeated physical performance with the

hemiplegic UL for 24 minutes of a specified functional task that was matched to the AO

recording (Figure 3). Activities for RTP were chosen from the Arm Motor Ability Test

(AMAT) to show the learning of specific functional tasks at Post 1 and Post 2 (Table 4).

The therapist provided continuous feedback via verbal and tactile cues to encourage

performance and keep the subject engaged. The therapist provided physical assistance

when the stroke survivor was unable to perform specific components of the functional

task such as fully extending digits to grasp an object, and emphasized the use of the

hemiplegic UL during tasks requiring bilateral coordination of the upper limbs. If the

subject made an error, the therapist provided verbal and tactile cues to help correct the

error but did not provide physical assistance unless the stroke survivor was unable to

perform a specific component of the task. To manage fatigue and challenge while the

subject was performing the task, the therapist provided consistent feedback, and adjusted/

graded the task in each therapy session so that the subject was incrementally challenged

to increase motor skill.

53
 The practice schedule for each therapy session was established as completing AO

or Placebo Video observation for 6 minutes, completing RTP for 24 minutes, AO or

Placebo Video observation for 6 minutes, and completing RTP for 24 minutes. (Figure 3).

Each subject was also required to complete a Home Exercise Program (HEP). This

program included practicing components and movement patterns of the functional task(s)

that were difficult for the patient to perform during RTP intervention for 30 minutes each

day outside of scheduled intervention sessions (Table 5), and were customized for

repetitions and resistance to each subject’s performance and tolerance.

Study personnel who completed the intervention and who administered the

outcome measures were blinded to group assignment. The treating therapist was blinded

to intervention; a code was used to indicate which recording to play for the subject. At

the start of each recording, the AO or PV images were delayed in the video by 30 seconds

with a simple title screen stating that, “The Video will Start in 30 Seconds.” This

allowed the therapist to ensure that the video was playing accurately and that the patient

was comfortable. Within the 30 second delay, the therapist placed a privacy border

between the therapist and the participant observing the recording to maintain blinding of

group assignment. Once the 30 second delay elapsed (and the therapist could no longer

see the video), written instructions for observing AO and PV appeared in the video

directing the subject to watch the video carefully; instructions for the AO video also

stated that the video would show people completing an everyday task, and the subject

would be asked to do the same task with their affected arm. At the end of each video,

54
written instructions appeared instructing the subject to not discuss any part of the content

of the video with the therapist.

Table 3 Sequence of AO recording and matched physical RTP

Video # Content on Action Observation Video When Administered

1 Put on a t-Shirt Weeks 1-2
2 Pick up and Bring Sandwich to Mouth Weeks 3-4
3 Eat Food with Spoon Weeks 5-6
4 Cut Meat with Knife and Fork Weeks 7-8

Table 4 List of exercises possible for home exercise programs

Scapular Elevation Shoulder Flexion Elbow Flexion Wrist Flexion

Scapular Protraction Shoulder Abduction Elbow Extension Wrist Extension
Scapular Retraction Shoulder Internal Rotation Forearm Supination Digit Flexion
Scapular Depression Shoulder External Rotation Forearm Pronation Digit Extension
Digit Opposition
Exercises could include passive range of motion, active range of motion, or strengthening for
these movements

Study personnel received training prior to the first subject enrollment for the

standardization of outcome testing and for the treatment intervention to ensure

consistency and fidelity throughout the study. Each outcome measure session was video

recorded so that quality checks could ensure the accuracy of scoring from study

personnel. Each of the study personnel were required to demonstrate proficiency in

outcome assessment by completing a competency, and were determined to be accurate by

the primary investigator to ensure fidelity among study personnel. Each intervention

session was video recorded to ensure the accuracy of protocol administration by the

therapists.

55
Participants

The target population was moderately impaired chronic stroke survivors in an

outpatient setting. All consenting of subjects was completed by authorized study

personnel. The Informed Consent Form for this study was reviewed with the potential

subject to ensure that the risks and benefits of study participation were fully understood.

Prior to any data collection, subjects who agreed to participate in the study signed the

Informed Consent Form. Once the Informed Consent Form was signed, screening

measures were completed to determine eligibility. The Mini Mental State Exam (MMSE)

was administered to determine the subject’s cognitive ability to participate in the study.

The MMSE has been validated as a cognitive function survey instrument and has been

widely used with stroke survivors. Subjects had to score ≥24 on the MMSE to qualify for

the study.

Overall, the inclusion criteria were as follows: (1) confirmed medical diagnosis of

stroke (2) UEFM score in the range from 17 to 49 (Woodbury et al., 2013) (3) post

stroke > 6 months; (4) > 24 on the Folstein Mini Mental Status Examination (MMSE);

(5) age in the range from 18 to 85; (6) experienced only one stroke; (7) discharged from

all forms of physical rehabilitation intervention; (8) visual acuity of 20/50 or greater with

or without corrective lenses; (9) > 19 on the Hooper Visual Organization Test; (10)

unilateral stroke only; (11) Cerebral stroke; and, (12) age of onset of stroke greater than

18 years old. The exclusion criteria were as follows: (1) < 18 years old; (2) > 5 on a 10-

point visual analog pain scale in the affected UL; (3) > 2 on the Modified Ashworth Scale

in the affected UL to exclude individuals with hypertonia, spasticity, joint rigidity, and

56
joint contracture; (4) participating in any experimental rehabilitation or drug studies; (5)

uncontrolled cardiovascular, or pulmonary disease, or other disease that would preclude

involvement in a therapeutic treatment; (6) neurological disorder other than stroke; (7) >

31 on Beck Depression Inventory (“Severe Depression”); (8) unable to regularly attend

treatment and follow-up sessions due to distance from the center or inadequate social

support; and, (9) cerebellar stroke with ataxia.

The target pilot trial sample size was a total of up to 15 subjects, with up to 10

randomized to AO plus RTP and up to 5 randomized to PV plus RTP. Continued study

participation was expected to be high (>75%) in the novel combination therapy AO plus

RTP group and to not fall far below 50%. With 10 participants in the AO plus RTP

group, the two-sided 90% confidence interval for an 80% retention rate would span from

49%-96%. Based on previously reported effect size and variation measures for UEFM

(Graef et al., 2016), the study sample size (10 in the novel intervention combination and 5

in the usual therapy group) had at least 80% power and 5% one-sided type I error to

detect changes in UEFM between 8-9 points at Post 2 which assumed the characteristics

in Table 5. A liberal dropout rate of 15% was assumed indicating that 8 - 9 subjects in the

active experimental group would remain in the study through the end of the protocol.

Table 5 Expected sampling characteristics of UEFM score distributions.

Subjects in active tx grp Change from baseline in UEFM SD of change

9 8.8 9.0
10 8.0 9.0
SD = Standard Deviation; Assumes 80% power and 5% one-sided type one error.

Study recruitment materials were distributed in central Ohio to stroke support

groups, individuals known to the research team, local Occupational and Physical Therapy
57
clinicians, and medical departments in central Ohio including Physical Medicine &

Rehabilitation, Occupational Therapy, and Physical Therapy. Clinicians at local stroke

clinics and in Ohio State academic departments were made aware of the studies via

clinician to clinician communication.

Outcome Measures

The Upper extremity section of the Fugl-Meyer Scale (UEFM) was used to

measure motor impairment (Fugl-Meyer et al., 1975). Items for the UEFM are scored on

a 3 point ordinal scale (0 = cannot perform, 2 = can perform fully), and are totaled for a

maximum of 66 possible points. Items in this measure assess reflex activity, volitional

movement with and without synergy patterns in the shoulder, wrist, and hand, and

coordination/ speed of movement. The UEFM has been shown to have excellent inter-

rater reliability (r = 0.98 – 0.995) (Gladstone et al., 2002), and intra-rater reliability (r =

0.995 – 0.996) (Duncan et al., 1983), and very good face validity and content validity

(Gladstone et al., 2002). Due to strong psychometric properties, the UEFM is highly

recommended for use as a research outcome measure for evaluating changes in motor

impairment (Gladstone et al., 2002). The measurement of change between Pre and Post 2

was the primary measure of interest and was used for analysis.

The Modified Ashworth Scale (MAS) (Bohannon & Smith, 1987) was used as a

measure of spasticity in the UL. Spasticity of the elbow, wrist, and metacarpophalangeal

(MCP) joints were measured on a 6-point ordinal scale with scores ranging from 0 – 4: (0

[0]= no increase in muscle tone; 1 [1]= slight increase in tone manifested by catch and

58
release or by minimal resistance at the end of the range of motion; 1+ [2]= slight increase

in tone, manifested by at catch, followed by minimal resistance throughout the remainder

(less than a half) of the range of motion; 2 [3]= more marked increase in tone through

most of the range of motion, but affected part(s) easily moved; 3 [4]= considerable

increase in muscle tone, passive movement difficult; 4 [5] = affected part(s) rigid). A

decrease in MAS score and impact of spasticity on movement would indicate

improvement. The MAS has adequate content validity (latency r = 0.937, p < 0.01,

amplitude r = 0.635, p < 0.01) (Min et al., 2012), excellent construct validity (Lee et al.,

2015), and adequate test re-test reliability (Kw = 0.84-0.96, Kw = 0.70-0.96) (Gregson et

al., 2000).

In this study, the MAS was coded by rank of the ordinal scale for analysis with

the maximum of a 5 and the 1+ converted to a 2 (Chen et al., 2020). The measurement of

improvement from Pre to Post 2 was the outcome measure of interest. For analysis of

change, scores for the MAS from Pre to Post 2 were dichotomized to 0 = no improvement

or worsening (no increase in score or decrease in score), and 1 = improvement (increase

in score).

During each intervention session, the subject wore a Fitbit™ Charge 2 three-axis

accelerometer on the affected UL. Accelerometers have been used with moderately

impaired stroke survivors in previous studies (Noorkõiv et al., 2014). The goal for the

Fitbit was to quantify the amount of UL motor activity during an intervention session and

also to measure heart rate. Data collected from the accelerometer was synced with a

computer via Bluetooth or USB and exported for data analysis. Accelerometers have

59
shown to be valid and reliable methods of measurement for the physical activity of stroke

survivors (Gebruers et al., 2010).

Statistical Methods

To describe the patient cohort, descriptive statistics, including the mean and

standard deviation or count and percentage, are calculated for patient demographics,

clinical characteristics and functional measures at baseline (Pre). Data was extracted from

the medical record (age, gender, type of stroke, handedness, hemiplegic side, date of

stroke) where possible. Linear regression was used to test if there was evidence of a

difference in the change score between baseline and Post 2 for the AO plus RTP and

Placebo plus RTP treatment groups. The linear regression model estimated the difference

in the change along with a 90% confidence interval (CI) and p-value. Fisher’s exact test

was used to test if there was evidence for a difference between randomized groups in the

proportion of patients who improved between baseline and Post 2 for the MAS. If any

data are missing, then the mechanism causing the missing data and the need for

imputation must be considered (Jakobsen et al., 2017). Data that are missing completely

at random (MCAR) do not cause bias and imputation of data is not required. The

Statistical Package for Social Sciences (SPSS) version 26.0 (IBM Corp. Released 2019.

IBM SPSS Statistics for Macintosh, Version 26.0. Armonk, NY: IBM Corp.) was used

for all data analysis.

60
 RESULTS

Participant Characteristics at Baseline

The primary objective of this pilot study was to determine if there was evidence

of preliminary efficacy of AO plus RTP as compared to Placebo plus RTP in the UEFM

and other UL motor impairment outcomes. A total of 15 subjects were enrolled,

consented, and randomized (see the CONSORT flow diagram, Figure 2). Four subjects

withdrew from the study follow up within the first week of intervention, with all 4 stating

the reason for withdrawal was parking and transportation. The demographic and stroke

history characteristics of all enrolled subjects in the study are summarized in (Table 6 &

7). Overall, 4 (26.7%) participants were women, 13 (86.7%) were White Non-Hispanic,

and the average age was 57.8 (Standard Deviation (SD) 12.4). The most prevalent type of

stroke was ischemic 13 (86.7%), with the most frequent identified location as the middle

cerebral artery 6 (40.0%). The majority of strokes occurred on the left side and resulted in

right hemiparesis 10 (67%). The average time since stroke was 8.8 (8.3) years.

Outcome Measures

UEFM

The average UEFM score at Pre was 26.5 (10.1) and 37.4 (12.1) at Post 2 for the

AO plus RTP group, for an average change between Pre and Post 2 of 10.9 (3.7) (90% CI

8.4 – 13.3); the average UEFM score at Pre was 30.0 (7.9) and 32.7 (9.7) at Post 2 in the

Placebo plus RTP group for an average change of 2.7 (2.1) (90% CI -0.8 – 6.2). There

was significant evidence of a larger improvement in the AO plus RTP group at Post 2.

61
The difference in the average change in UEFM was 8.2 (90% CI 4.0 - 12.4, one-sided p-

value=0.006) (Table 8).

Table 6 Characteristics of participants enrolled in study

Group AO + RTP Placebo + RTP

Number of Subjects: N 10 5
Age in years: Mean (SD) 56.8 (13.9) 59.8 (9.7)
Sex: N (%) F M F M
3 (30%) 7 (70%) 1 (20%) 4 (80%)
Race/Ethnicity: N (%)
White Non-Hispanic 9 (90%) 4 (80%)
Black Non-Hispanic 1 (10%) 1 (20%)
Hispanic 0 0
Side L R L R
Dominant Hand: N (%) 2 (20%) 8 (80%) 0 (0%) 5 (100%)
Affected by Hemiparesis 4 (40%) 6 (60%) 1 (20%) 4 (80%)
Affected Same Side as Dominant: N (%) 5 (50%) 4 (80%)
Years after stroke to enrollment: Mean (SD) 8.9 (8.3) 8.2 (9.2)
Ischemic stroke: N (%) 8 (80%) 5 (100%)
Baseline Functional Performance Scores: Mean (SD)
UEFM: Mean (SD) 25.7 (9.5) 26.4 (7.6)
MAS Elbow Flexion: Median (Min, Max) 2 (1, 3) 2 (1, 3)
MAS Elbow Extension: Median (Min, Max) 2 (1, 3) 2 (1, 3)
MAS Wrist Flexion: Median (Min, Max) 2 (1, 3) 2 (1, 3)
MAS Wrist Extension: Median (Min, Max) 2.5 (1, 3) 2 (0, 3)
MAS MCP Flexion: Median (Min, Max) 3 (0, 3) 2 (0, 3)
MAS MCP Extension: Median (Min, Max) 1.5 (0, 3) 1 (0, 3)
AO = Action Observation, RTP = Repetitive Task Practice, F = Female, M= Male, L = Left, R = Right, MCA = Middle
Cerebral Artery, UEFM = Upper Extremity Fugl-Meyer, MAS = Modified Ashworth Scale

62
Table 7 Comparison of baseline characteristics of subjects who completed the study to those
who withdrew

Group AO + RTP Enrolled Placebo + RTP Enrolled

Completion Status Analyzed Withdrew Analyzed Withdrew
N 8 2 3 2
Age in years: Mean (SD) 56.5 (15.5) 58.0 (8.5) 64.7 (9.9) 52.5 (0.7)
Sex: N (%) F M F M F M F M
2 (25%) 6 (60%) 1 (50%) 1 (50%) 0 3 (100%) 1 (50%) 1 (50%)
Race/Ethnicity: N (%)
White Non-Hispanic 7 (88%) 2 (100%) 2 (67%) 2 (100%)
Black Non-Hispanic 1 (13%) 0 1 (33%) 0
Hispanic 0 0 0 0
Side L R L R L R L R
Dominant Hand: N (%) 2 (25%) 6 (75%) 0 (0%) 2 (100%) 0 (0%) 3 (100%) 0 (0%) 2 (100%)
Affected by Hemiparesis: N (%) 4 (50%) 4 (50%) 0 (0%) 2 (100%) 1 (33%) 2 (67%) 0 (0%) 2 (100%)
Dominant side is affected side 3 (38%) 2 (100%) 2 (67%) 2 (100%)
Time post stroke (yrs): Mean (SD) 9.8 (9.1) 5.3 (0.4) 4.6 (3.4) 13.5 (14.8)
What do I think about this?
Ischemic stroke: N (%) 7 (88%) 2 (100%) 3 (100%) 1 (50%)
Stroke location
MCA: N (%) 4 (50%) 0 1 (33%) 1 (50%)
Unknown: N (%) 4 (50%) 2 (100%) 2 (67%) 1 (50%)
Baseline Motor Impairment Scores
UEFM: Mean (SD) 26.5 (10.1) 22.5 (7.8) 30.0 (7.9) 21.0 (2.8)
MAS Elbow Flx: Median (Min, Max) 2 (1, 3) 2 (2, 2) 2 (1, 2) 2.5 (2, 3)
MAS Elbow Flx: Median (Min, Max) 2 (1, 3) 2 (1, 3) 2 (1, 2) 2.5 (2, 3)
MAS Wrist Flx: Median (Min, Max) 2 (1, 3) 2.5 (2, 3) 1 (1, 2) 2.5 (2, 3)
MAS Wrist Ext: Median (Min, Max) 2.5 (1, 3) 2 (1, 3) 1 (0, 2) 2.5 (2, 3)
MAS MCP Flx: Median (Min, Max) 3 (0, 3) 2.5 (2, 3) 2 (0, 3) 2.5 (2, 3)
MAS MCP Ext: Median (Min, Max) 1 (0, 1) 2 (1, 3) 1 (0, 1) 2 (1, 3)
AO = Action Observation, RTP = Repetitive Task Practice, F = Female, M= Male, L = Left, R = Right, MCA = Middle
Cerebral Artery, UEFM = Upper Extremity Fugl-Meyer, MAS = Modified Ashworth Scale, Flx = Flexion, Ext =
Extension

Table 8 UEFM Total Linear Regression Analysis

2
Group Pre Post 2 Change Difference in the df F R p
Mean Mean Mean (SD) Change (90% CI) value*
(SD) (SD)
AO plus RTP 26.5 37.4 10.9 (3.7) 8.2 (4.0 - 12.4) 1, 9 12.8 .59 .006
(10.1) (12.1)
Placebo plus 30.0 (7.9) 32.7 (9.7) 2.7 (2.1)
RTP
Abbreviations: AO = Action Observation, RTP = Repetitive Task Practice, UEFM = Upper Extremity Fugl-
Meyer. *One sided P value

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MAS: Elbow Flexion

The median (min, max) for the Elbow Flexion MAS score at Pre was 2 (1, 3) and

1 (0, 2) at Post 2 for the AO plus RTP group, with the number of subjects improving

(increase in score) between Pre and Post 2 of 6/8; the median Elbow Flexion MAS score

at Pre was 2 (1, 2) and 2 (1, 2) at Post 2 in the Placebo plus RTP group, with the number

of subjects improving between Pre and Post 2 of 0/3. There was not significant evidence

of more frequent improvement in the AO plus RTP group at Post 2. The difference in the

in the number improved in MAS was 6 (95% CI 1.2 – 13.3, two-sided p-value=0.060)

(Table 9).

MAS: Elbow Extension

The median for the Elbow Extension MAS score at Pre was 2 (1, 3) and 0.5 (0, 2)

at Post 2 for the AO plus RTP group, with the number of subjects improving between Pre

and Post 2 of 8/8; the median Elbow Extension MAS score at Pre was 2 (1, 2) and 1 (1, 2)

at Post 2 in the Placebo plus RTP group, with the number of subjects improving between

Pre and Post 2 of 1/3. There was not significant evidence of more frequent improvement

in the AO plus RTP group at Post 2. The difference in the in the number improved in

MAS was 7 (95% CI 0.1 – 1.7, two-sided p-value=0.055) (Table 9).

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Table 9 Modified Ashworth Scale Improvement Percent form Pre to Post 2

Joint Tested AO plus RTP Placebo plus RTP Difference in Fisher’s

(n=8) (n=3) number improved Exact Test
Number improved Number improved (95% CI) p value*
(%) (%)
Elbow Flexion 6 (75%) 0 (0%) 6 (1.2 – 13.3) 0.060
Elbow Extension 8 (100%) 1 (33%) 7 (0.1 – 1.7) 0.055
Wrist Flexion 7 (88%) 1 (33%) 6 (0.6 – 338.8) 0.152
Wrist Extension 7 (88%) 1 (33%) 6 (0.6 – 338.8) 0.152
MCP Flexion 5 (63%) 2 (67%) 3 (0.1 – 13.6) 1.000
MCP Extension 5 (63%) 0 (0%) 5 (1.1 – 6.5) .182
Abbreviations: AO = Action Observation, RTP = Repetitive Task Practice. Improvement = Increase in
MAS score of one 1 point or greater from Pre to Post 2. *Two sided P value

MAS: Wrist Flexion

The median for the Wrist Flexion MAS score at Pre was 2 (1, 3) and 1 (0, 2) at

Post 2 for the AO plus RTP group, with the number of subjects improving between Pre

and Post 2 of 7/8; the median Wrist Flexion MAS score at Pre was 1 (1, 2) and 1 (1, 1) at

Post 2 in the Placebo plus RTP group, with the number of subjects improving between

Pre and Post 2 of 1/3. There was not significant evidence of more frequent improvement

in the AO plus RTP group at Post 2. The difference in the in the number improved in

MAS was 6 (95% CI 0.6 – 338.8, two-sided p-value=0.152) (Table 9).

MAS: Wrist Extension

The median for the Wrist Extension MAS score at Pre was 2.5 (1, 3) and 0.5 (0,

1) at Post 2 for the AO plus RTP group, with the number of subjects improving between

Pre and Post 2 of 7/8; the median Wrist Extension MAS score at Pre was 1 (0, 2) and 1

(0, 1) at Post 2 in the Placebo plus RTP group, with the number of subjects improving

between Pre and Post 2 of 1/3. There was not significant evidence of more frequent

65
improvement in the AO plus RTP group at Post 2. The difference in the in the number

improved in MAS was 6 (95% CI 0.6 – 338.8, two-sided p-value=0.152) (Table 9).

MAS: MCP Flexion

The median for the MCP Flexion MAS score at Pre was 3 (0, 3) and 1 (0, 3) at

Post 2 for the AO plus RTP group, with the number of subjects improving between Pre

and Post 2 of 5/8; the median MCP Flexion MAS score at Pre was 2 (0, 3) and 0 (0, 1) at

Post 2 in the Placebo plus RTP group for an with the number of subjects improving

between Pre and Post 2 of 2/3. There was not significant evidence of more frequent

improvement in the AO plus RTP group at Post 2. The difference in the in the number

improved in MAS was 3 (95% CI 0.1 – 13.6, two-sided p-value=1.000) (Table 9).

MAS: MCP Extension

The median for the MCP Extension MAS score at Pre was 1 (0, 1) and 0 (0, 1) at

Post 2 for the AO plus RTP group, with the number of subjects improving between Pre

and Post 2 of 5/8; the median MCP Extension MAS score at Pre was 1 (0, 1) and 1 (0, 1)

at Post 2 in the Placebo plus RTP group, with the number of subjects improving between

Pre and Post 2 of 0/3. There was not significant evidence of more frequent improvement

in the AO plus RTP group at Post 2. The difference in the in the number improved in

MAS was 5 (95% CI 1.1 – 6.5, two-sided p-value=0.182) (Table 9).

Fitbit Accelerometry

The data that were collected from the Fitbit Charge 2 three-axis accelerometer

was inconsistent between subjects. All tasks were completed while subjects were seated,

yet the Fitbit is designed to measure steps taken while walking. It was hoped that the arm

66
movements would be registered as steps. For subjects who scored closer to the lower

range of the UEFM inclusion criteria in the study, no movement or “steps” were detected

on the Fitbit, presumably because the arm movements were less vigorous. Subjects who

were closer to the higher UEFM inclusion criteria range demonstrated some detected

“steps” on the Fitbit, but the visibly observed number of arm movements noted by the

therapist did not match the data collected from the Fitbit. Additionally, the data output

from the Fitbit was challenging to download in a format that could be analyzed. As a

result of these complications, data from the Fitbit Charge 2 three-axis accelerometer was

not analyzed, and this device is not recommended for further use in stroke rehabilitation

research for the upper limb.

DISCUSSION

In this pilot study, we explored the scientific reason for feasibility of response to

the intervention (Thabane et al., 2010) of a novel combination of AO plus RTP compared

to placebo plus RTP to determine if this study can proceed to a larger Phase III study in

the scientific process. With a small sample size, this study demonstrated a significant

change in the primary outcome of change in score from Pre to Post 2 in the UEFM with

the AO plus RTP intervention when compared to the Pre to Post 2 change in score for the

Placebo plus RTP group. These results indicate evidence of improved UEFM overall

score for those randomized to the AO plus RTP intervention, and that this novel

intervention combination should be explored further in a larger Phase III trial with a fully

powered sample size (Arain et al., 2010; Tickle-Degnen, 2013). The visual learning

67
approach of the AO intervention seemed to increase the ability for subjects to understand

motor patterns required for specific tasks, and the combination with RTP reinforced the

visual learning with physical performance. The overall response of this promising

intervention for motor impairment could lead to the decreased impairment due to

hemiplegia in many stroke survivors.

Imputation was not completed for the data of the four withdrawn subjects in the

analysis as recommended by Jakobsen and colleagues (2017). As seen in Table 7, the

demographic and baseline data of the four withdrawn subjects do not appear substantially

different to the subjects that remained in the study, and could likely be a random sample

of the entire group. There was no indication that reasons for the subjects to withdraw or

for missing data were related to subjects’ medical conditions or study intervention, and

the assumption of these data missing completely at random (MCAR) (Jakobsen et al.,

2017) appear reasonable. Under this assumption of MCAR, this missing data does not

cause bias, but due to the small sample size, does cause an enlarged standard error.

Additionally, the data missing were confined to the dependent variable only (Jakobsen et

al., 2017).

Overall the amount of spasticity in the elbow, wrist, and MCP’s decreased in both

groups in this exploratory measure of spasticity. However, for each joint that was tested,

the number of subjects that improved in the AO plus RTP group was not significant when

compared to the number of subjects that improved in the Placebo plus RTP group. The

number of subjects that improved in the AO plus RTP group for elbow flexion and elbow

extension were very close to significance when compared to the Placebo plus RTP group.

68
This outcome could be as a result of the small sample size, with an insufficient number of

subjects to fully determine the effects of the intervention. While the p-value was not

significant, the objective of this study was for feasibility and determining if the study

should proceed to a larger Phase III trial, and not efficacy (Arain et al., 2010; Lancaster,

2015; Tickle-Degnen, 2013). A decrease in UL spasticity would increase the ability for a

stroke survivor to isolate joint movement and overall coordination. This ability to

decrease the overall impact of motor impairment in the UL would increase coordination

and reach during movement patterns. There is an indication of some effect on spasticity

with the AO plus RTP intervention, and this exploratory measure should be examined

further with a fully powered Phase III trial to more fully examine the effects.

Another limitation could potentially be the use of the MAS to measure spasticity.

The MAS has acceptable validity, but the inter-rater reliability of the MAS is limited and

varies across studies (Ansari et al., 2006; Fleuren et al., 2010; Gregson et al., 2000;

Meseguer-Henarejos et al., 2018). In the original design of this pilot trial, the MAS was

utilized as a screening tool only to exclude subjects that demonstrated spasticity so severe

that it would limit active range of motion of the UE. The rationale was, if subjects

demonstrated greater than a two on the MAS, the movements of the UL would be greatly

limited due to hypertonia, spasticity, joint rigidity, and joint contracture. High spasticity

was expected to significantly limit the subject’s ability to participate in the RTP portion

of the protocol. After initiation of the intervention, several subjects were reporting

decreased spasticity in their affected UL throughout the day and demonstrating decreased

spasticity in intervention sessions. The effect was not anticipated in the original study

69
design. To measure changes in spasticity from baseline to the end time point, the

protocol was updated and approved by Biomedical Sciences Institutional Review Board

to utilize the MAS at follow up time points of Post 1 and Post 2. For the subsequent fully

powered RCT, we recommend the Modified Modified Ashworth Scale (MMAS) (Ansari

et al., 2012), which has addressed and resolved the inter-rater reliability issues that have

been encountered with the MAS.

Limitations and Future Directions

This study was the first to examine the scientific reason of feasibility of response

to intervention for the combination of AO plus RTP on UL motor impairment outcome in

chronic moderately impaired stroke survivors. Generalizability of the results to the entire

stroke population is difficult due to the nature of the small sample size in this pilot study,

and only moderately impaired stroke survivors were included in the study. Due to the

objective of this study of feasibility in the response of the intervention in moderately

impaired stroke survivors, the results of this study would indicate that a larger RCT

should be completed to determine the efficacy of the intervention.

When assessing possible internal validity risk, there is a possibility of

performance bias due to not being possible to blind the intervention to the participants.

Subjects were aware they were observing an AO video or a placebo video of static

images. This is a typical limitation in rehabilitation studies. Subjects might not know

which intervention they are receiving or how the study condition groups are different, but

the subjects are aware they are receiving an intervention. In the future RCT with a fully

70
powered sample size, blinding will be maintained with research personnel during

intervention and outcome measure collection to minimize the risk of bias.

A potential future direction of research for this intervention would be to examine

the neural pathways and systems that are engaged by the combination of AO and RTP in

stroke survivors. Functional magnetic resonance imaging (fMRI) is a method to measure

neural activity by detecting changes in blood flow in the brain (Logothetis et al., 2001).

The use of fMRI can assist with identifying specific areas of the brain that are active

during mental processes and the patterns of brain activation that are associated (Huettel et

al., 2014). Using fMRI would be beneficial to understand the potential synergistic effect

between AO and RTP, and the neurologic impact on the stroke recovery. Additional

research questions that could be explored with the use of fMRI could be: (1) changes in

the MNS performance with an increased amount of physical performance of RTP; (2)

changes in cortical mapping following the AO plus RTP intervention; and (3) differences

in neural systems engaged by the combination of AO and RTP versus Placebo and RTP

at various time points during the treatment.

Conclusion

The purpose of this pilot study was to explore the scientific feasibility of response

of the intervention through detecting changes in UL motor impairment outcomes and

determine if a larger RCT should be completed to determine the efficacy of AO plus

RTP. In this small feasibility pilot study of moderately impaired stroke survivors, there

was a significant response of change on the UEFM motor impairment assessment for the

combination of AO plus RTP on the hemiplegic UL. There was also a trend suggesting a

71
possible benefit of reduced spasticity at the elbow occurring after the intervention. This

response to intervention would indicate that a larger Phase III RCT should be completed

to determine efficacy for the intervention in the moderately impaired chronic stroke

survivor population

72
 Chapter 4: Preliminary Efficacy of Action Observation Combined with Repetitive
Task Practice on Upper Extremity Functional Outcomes in Moderately Impaired
Stroke Survivors: A Pilot Study

ABSTRACT

Background and Purpose

Decreased functional use of the hemiplegic upper limb (UL) post stroke is a result of

multiple secondary impairments that occur following stroke that include physical,

cognitive, perceptual, and emotional limitations. Action observation (AO) is an

intervention technique that improves functional performance with observing another

person perform a functional task and then physically perform the same task. Repetitive

task practice (RTP) also improves functional performance through repetitively

performing a functional task with the hemiplegic UL. While effective individually, these

interventions have not been combined before. The purpose of this feasibility pilot study

was to determine the response to intervention through detecting changes in UL functional

performance outcomes in the AO plus RTP practice schedule compared to Placebo plus

RTP in the chronic, moderately impaired stroke survivor. Determining the response to

intervention in this Phase II study is part of the scientific process that could lead to a

larger Phase III study

73
Methods

A feasibility randomized controlled single-blinded, parallel-group pilot study was

completed with 15 chronic moderately impaired stroke survivors. Subjects were

randomized to AO plus RTP practice schedule, or in the control condition of Placebo

Video plus RTP, and completed an intervention for one hour, three times per week, for

eight weeks (total of 24 sessions), along with a daily 30 minute Home Exercise Program.

The outcome measures of the Arm Motor Ability Test (AMAT), Motor Activity Log

(MAL), and Stroke Impact Scale 2.0 (SIS) were completed at pretest (Pre), post

intervention (Post 1), and 1 month post intervention (Post 2), and a quantitative survey of

the subject’s perception of the intervention (i.e., helpful, meaningful, or beneficial) was

completed at Post 2.

Results

10 subjects were allocated to AO plus RTP and 5 subjects to Placebo Video plus RTP.

The linear regression model that estimated the difference in the change revealed

significant evidence of a larger improvement in the AO plus RTP group at Post 2, with

the difference in the average change in the AMAT Total Functional Ability of 8.3 (90%

CI 2.2 - 14.5, p-value=0.034). The amount of change from Pre to Post 2 for both the

MAL (Amount of Use 90% CI -36.9 – 27.8, p-value=0.801, How Well 90% CI -27.2 -

34.2, p-value=0.840) and SIS (90% CI -1.1 - 3.3, p-value=0.378) were not significant.

Majority of response to the quantitative survey of the subject’s perception of the

intervention was agree and strongly agree to all questions for both the AO plus RTP and

Placebo plus RTP groups. Overall, both the AO plus RTP and Placebo plus RTP groups

74
reported they were satisfied with and enjoyed the intervention, the intervention was

beneficial and meaningful, the task learned we helpful, the videos helped them perform

the tasks, the tasks completed in the intervention helped them complete the tasks at home,

and they improved over the course of the study.

Conclusion

In this small feasibility pilot study of moderately impaired stroke survivors, there

was a significant response of change on the AMAT Total Functional Ability score for the

combination of AO plus RTP on the hemiplegic UL. This response to intervention would

indicate that a larger Phase III RCT should be completed to determine efficacy for the

intervention in the moderately impaired chronic stroke survivor population.

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 INTRODUCTION

Functional limitations following stroke greatly impact performance of activities of

daily living (ADL) and instrumental activities of daily living (IADL). In the chronic

phase of stroke recovery, 39% of stroke survivors reported difficulty with the necessary

ADL self-care tasks, and 54% reported difficulty with IADL tasks such as housework and

shopping (Mayo et al., 2002). These functional limitations are a result of multiple

secondary impairments that occur following stroke that include physical, cognitive,

perceptual, and emotional limitations. While the physical motor impairment of

hemiplegia in the upper limb (UL) would seem to be the primary limiting factor, the

improvement of motor impairment does not necessarily result in the improvement in

functional ADL performance. This is due to the multiple systems that are needed to

interact with the environment and complete tasks, such as sensory, proprioception, vision,

perceptual, cognitive, emotional, and physical (Schmidt et al., 2018). Completing

functional tasks post stroke is limited by all of the secondary impairments combined,

such as perceptual impairments, sensory deficits, coordination deficits, and cognitive

impairments (Teasell & Hussein, 2018). With the growing stroke population estimated to

exceed 10 million people in the United States by 2030 (Ovbiagele et al., 2013), and

significant reduction in functional performance of ADL and IADL tasks after stroke,

there is a significant need for effective rehabilitative interventions targeting functional

performance of the hemiplegic UL.

One of the primary reasons for the decrease in participation in functional ADL

tasks after stroke is thought to be learned non-use of the hemiplegic UL. This

76
maladaptive phenomenon is said to occur when the stroke survivor attempts to perform a

functional task with the hemiplegic UL, but receives negative feedback from limited

success. This negative feedback would then result in encouraging the use of the non-

hemiplegic UL and discouraging the use of the hemiplegic UL (Taub et al., 1994; Wolf et

al., 1989). At the cortical level, increased use of the non-hemiplegic limb stimulates the

expansion of motor maps in the contralesional hemisphere instead of promoting changes

in the lesioned hemisphere (Nudo, 2013). Encouraging the use of the hemiplegic UL

during functional tasks improves functional performance (Wolf et al., 2006), and is

greatly needed to counteract the effects of learned non-use.

An intervention technique that encourages the use of the hemiplegic UL through

visual training and physical use is Action Observation (AO). This technique involves a

stroke survivor watching a video of another person performing a functional task, and then

physically performing the same task with their hemiplegic UL (Buccino et al., 2004). The

visual motor learning component of AO enhances the effects of motor training and the

ability to recall movement patterns when combined with motor training (Celnik et al.,

2006). AO has also been found to encourage the use of the hemiplegic UL, and is

functionally relevant to task performance for motor training (Cantarero et al., 2011).

Consequently, AO can result in significant improvement in UL function during ADL

tasks (Ertelt et al., 2007; Fu et al., 2017; Kim & Kim, 2015a; Kim et al., 2016a; Lee et al.,

2013; Sugg et al., 2015; Zhu et al., 2015).

Another intervention that directly addresses the use of the hemiplegia UL is

Repetitive Task Practice (RTP). RTP specifically targets the use of the hemiplegic UL

77
during functional ADL tasks, and significantly increases UL recovery in chronic stroke

survivors (Aichner et al., 2002; Byl et al., 2003; Dombovy, 2004; Jang et al., 2003;

Shepherd, 2001). This intervention includes the performance of goal-directed, functional,

task-specific activities that are completed with intensive repetitions and high effort with

the hemiplegic UL (Wolf et al., 2002), and has shown to be effective in UL stroke

rehabilitation (Skidmore et al., 2012; Thomas et al., 2017). Additionally, RTP is an

effective intervention to increase cortical representation for the UL (Classen et al., 1998;

Jang et al., 2003; Kami et al., 1995). Therefore, this very effective intervention method is

well supported with many benefits for a stroke survivor's UL rehabilitation recovery

process.

While both AO and RTP have been found to improve the functional performance

of the hemiplegic UL individually, they have not been previously combined. The visual

learning component of AO could potentially increase learning for understanding

movement patterns that would be utilized during RTP. There is a high occurrence of

perceptual impairments and apraxia in stroke survivors (Donkervoort et al., 2000),

indicating poor understanding of motor planning and interaction of the UL with

functional objects. AO could provide the additional training that is needed prior to

physical performance in RTP to assist with motor learning to create a synergistic effect

during functional tasks. Exploring the effects of AO combined with RTP could establish

a novel intervention to meet the needs of functional performance of the UL in millions of

individuals in the rapidly increasing stroke population.

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 When examining novel interventions, feasibility and pilot studies answer essential

questions about the conduct of trials, preventing severe problems from occurring in

subsequent large scale Phase III trials, and are an essential piece of the research process

(Eldridge et al., 2013). Examining the feasibility of the combined intervention of AO and

RTP on functional outcome performance is no exception, and the functionality of the

study needs to be examined. One of the scientific reasons to complete feasibility and pilot

studies is to determine if there is a response to intervention in the experimental or control

conditions (Thabane et al., 2010). Investigating the response to intervention for this novel

combination on UL functional performance can provide information for the future design

of a larger scale Phase III trial (Eldridge et al., 2013; Thabane et al., 2010)

As described in Chapter 3, a novel practice schedule for the combined

intervention of AO and RTP was required. For this study, the practice schedule selected

for a 60 minute intervention session was 6 min AO, 24 min RTP, 6 min AO, and 24 min

RTP (Figure 3). This practice schedule was designed to provide an increased amount of

physical practice compared to the traditional AO schedule, and to allow sufficient

physical rest during the RTP schedule while still meeting the total time of practice

required for RTP as indicated by previous research (Blennerhassett & Dite, 2004; Ertelt

et al., 2007; Kwakkel et al., 1999; Zhu et al., 2015). The combination of AO providing

visual motor learning for functional tasks prior to the physical performance during RTP

could potentially increase motor performance of the hemiplegic UL, creating a synergism

of interventions for a large stroke population in need of UL rehabilitation.

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 The overall objective of this feasibility pilot study was to determine the response

to intervention through detecting changes in UL functional performance outcomes in

response to the AO plus RTP practice schedule compared to a placebo plus RTP in the

chronic, moderately impaired stroke survivor. Determining the response to intervention in

this Phase II study is part of the scientific process potentially leading to a larger Phase III

study (Eldridge et al., 2013; Thabane et al., 2010). The functional impact of improving

performance in ADL and IADL tasks would benefit millions of stroke survivors, and

decreased the impact of disability.

METHODS

As described in Chapter 3, a randomized control, single blinded, parallel-group

pilot study design was completed. Subjects participated in experimental conditions of AO

combined with RTP or control condition of Placebo Video (PV) combined with RTP. A

blinded assessor completed assessments on each subject at three distinct time points of

pretest (Pre), post intervention (Post 1), and 1 month post intervention (Post 2). Subjects

completed an intervention for one hour, three times per week, for eight weeks (total of 24

sessions), along with a daily 30 minute Home Exercise Program (HEP) (Table 5). The

full details of information regarding the methods that were completed in this study are

available in chapter 3.

The four tasks that were chosen to be completed during the intervention were

from the Arm Motor Ability Test (AMAT) assessment to measure the change in

performance of trained tasks from pretest to Post 2 (Table 4). The AMAT assessment

80
includes a total of nine functional tasks that are completed with the UL, and four of the

nine tasks were selected based on the commonality of the tasks to be completed by

subjects in everyday life.

As described in Chapter 3, the target population was moderately impaired chronic

stroke survivors in an outpatient setting. The full details of inclusion/ exclusion criteria,

sampling, and recruiting are available in Chapter 3.

Outcome Measures

The Arm Motor Ability Test (AMAT) (McCulloch et al., 1988) was used to

measure UL function during ADL tasks. Nine ADL tasks with subcomponents were

scored on a functional ability (FA) 6-point ordinal scale (0 = does not perform with

affected arm; 1 = Involved arm does not participate functionally; however, attempt is

made to use the arm; 2 = Does; but requires assistance of uninvolved extremity for minor

readjustments or change of position, or requires more than two attempts to complete; 3 =

Does; but movement is influenced to some degree by synergy or is performed slowly

and/or with effort; 4 = Does; movement is close to normal, but slightly slower; may lack

precision, fine coordination or fluidity; 5 = uses arm at a comparable level to unaffected

side) with a maximum score of 100, and a quality of movement (QOM) 6 point ordinal

scale (0 = no movement initiated; 1 = Partial range movement accomplished; 2 =

Movement accomplished, but is influenced by synergy, or is accompanied by excessive

compensatory movements; 3 = Some isolated movement, but influenced to some degree

by synergy, or movement with little influence of synergy but performed slowly, or

81
moderate incoordination and lack of accuracy; 4 = Movement close to normal, but

slightly slower, or lacks precision, fluidity or precise coordination of movement; 5 =

Fluid and coordinated activity, speed of movement appears within normal limits), with a

maximum score of 100. Each ADL task had subcomponents that were timed separately,

with a total maximum of 1,560 seconds for all items. The AMAT has high inter-rater

reliability (r = 0.97 – 0.99), internal consistency (r = 0.94 – 0.99), sensitivity to change (r

= 0.96 – 0.99) as well as having satisfactory concurrent validity (Kopp et al., 1997). The

outcome measure of interest for the AMAT was the measurement of change between Pre

and Post 2.

The Motor Activity Log (MAL) was used to measure affected upper limb

functional activity limitations in everyday ADL tasks outside of the clinical setting. The

MAL is a semi-structured interview that allows subjects to self-report how much and how

well they are utilizing their affected upper limb during 30 ADL tasks. Activities are

ranked on a 6-point ordinal Amount of Use (AOU) scale (0 = Did not use my weaker

arm, 5 = Used my weaker arm as much as before the stroke) with a maximum score of

150, and a 6-point ordinal How Well Scale (HW) scale (0 = The weaker arm was not

used at all for that activity, 5 = The ability to use the weaker arm for that activity was as

well as before the stroke) with a maximum score of 150. The MAL has excellent test

retest reliability (AOU r = 0.70 to 0.85 and HW r = 0.61 to 0.71) and high internal

consistency (AOU: a= 0.88; HW: a= 0.91) (van der Lee et al., 2004). The measurement

of change between Pre and Post 2 on the MAL was the outcome measure of interest.

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 The Stroke Impact Scale 2.0 (SIS) was used to measure weather any motor and

functional changes indicate changes in disability and quality of life. The SIS is a self-

report questionnaire that includes 64 questions over 8 domains. These domains are: (1)

Strength; (2) Memory; (3) Emotion; (4) Communication; (5) Activities of Daily Living;

(6) Mobility; (7) Hand function; (8) Social Participation; and (9) Stroke Recovery. Items

are scored on a 5 point ordinal scale and a 0 to 100 recovery scale, with a maximum score

of 377. Each domain met or approached the standard of 0.9 alpha-coefficient, the intra-

class correlation coefficients for test-retest reliability ranged from 0.70 to 0.92, and the

correlations with established outcome measures were moderate to strong (0.44 to 0.84)

(Duncan et al., 1999). The measurement of change between Pre and Post 2 on the SIS

was the outcome measure of interest.

A quantitative survey that utilized Likert scales was chosen to examine the

subject’s perceived experience of the intervention, and assist with the assessment of the

study’s feasibility. Responses to the survey provided an expanded understanding of the

intervention (Dillman et al., 2014; Driscoll et al., 2007), and were completed on a 5 point

ordinal Likert scale (1 = Strongly disagree, 5 = Strongly Agree). The survey was

developed based on tasks being completed in the intervention perceived as beneficial,

purposeful, and meaningful (Bigelius et al., 2010; Calvo-Merino et al., 2005; Edwards et

al., 2006; Lee et al., 2015), discussions with academic and clinical professionals, and

personal experience in the research and clinical fields. All questions were reviewed by an

inter-professional academic and clinical panel of experts to determine face and content

validity. Feedback was provided on content and clarity, and four iterations of the survey

83
were reviewed with subsequent revisions made. The final version of the survey included

eight items (Table 10); the subjects understanding of questions in the survey was

reviewed in chapter of 1 of this document. The survey was found to have acceptable

internal consistency reliability (8 items; Cronbach's alpha= .711).

Table 10. Questions asked in quantitative survey.

Q1. I am highly satisfied with the arm rehabilitation program I completed.

1= Strongly 2 = Disagree 3 = Neutral 4 = Agree 5 = Strongly Agree
disagree
Q2. I enjoyed the arm rehabilitation program I completed.
1= Strongly 2 = Disagree 3 = Neutral 4 = Agree 5 = Strongly Agree
disagree
Q3. Completing the arm rehabilitation program was beneficial/ helpful to me.
1= Strongly 2 = Disagree 3 = Neutral 4 = Agree 5 = Strongly Agree
disagree
Q4. Completing this arm rehabilitation program was meaningful/ important to me.
1= Strongly 2 = Disagree 3 = Neutral 4 = Agree 5 = Strongly Agree
disagree
Q5. The tasks I completed in the therapy program were helpful for me to learn.
1= Strongly 2 = Disagree 3 = Neutral 4 = Agree 5 = Strongly Agree
disagree
Q6. Watching the videos helped me complete tasks in the therapy sessions.
1= Strongly 2 = Disagree 3 = Neutral 4 = Agree 5 = Strongly Agree
disagree
Q7. The therapy tasks I completed in therapy sessions helped me perform those tasks at
home and during the day
1= Strongly 2 = Disagree 3 = Neutral 4 = Agree 5 = Strongly Agree
disagree
Q8. I have made improvements since the beginning of the therapy in this study.
1= Strongly 2 = Disagree 3 = Neutral 4 = Agree 5 = Strongly Agree
disagree

84
Statistical Methods

To describe the patient cohort, descriptive statistics, including the mean and

standard deviation or count and percentage, were calculated for patient demographics,

clinical characteristics and functional measures at baseline (Pre). Data were extracted

from the medical record (age, gender, type of stroke, handedness, hemiplegic side, date of

stroke) where possible. Linear regression was used to test if there was evidence of a

difference in the change score between baseline and Post 2 for the AO plus RTP and

Placebo plus RTP treatment groups. The linear regression model estimated the difference

in the change along with a 90% confidence interval (CI) and p-value. Frequencies and

denominators for the quantitative survey were calculated for each question and group

assignment across the five Likert scale choices. If any data were missing, then the

mechanism causing the missing data and the need for imputation must be considered

(Jakobsen et al., 2017). Data that were missing completely at random (MCAR) do not

cause bias and imputation of data is not required. The Statistical Package for Social

Sciences (SPSS) version 26.0 (IBM Corp. Released 2019. IBM SPSS Statistics for

Macintosh, Version 26.0. Armonk, NY: IBM Corp.) was used for all data analysis.

RESULTS

One of the objectives of this pilot study was to determine if there was evidence of

preliminary efficacy of AO plus RTP as compared to Placebo plus RTP in the AMAT,

AMAT trained tasks, MAL, and SIS UL functional outcomes. A total of 15 subjects were

85
enrolled, consented, and randomized (see the CONSORT flow diagram, Figure 2). Four

subjects withdrew from the study follow up within the first week of intervention, with all

4 stating the reason for withdrawal was parking and transportation. The demographic and

stroke history characteristics of all enrolled subjects in the study are summarized in

(Table 11 & 12). Overall, 4 (26.7%) participants were women, 13 (86.7%) were White

Non-Hispanic, and the average age was 57.8 (Standard Deviation (SD) 12.4). The most

prevalent type of stroke was ischemic 13 (86.7%), with the most frequent identified

location as the middle cerebral artery 6 (40.0%). The majority of strokes occurred on the

left side and resulted in right hemiparesis 10 (67%). The average time since stroke was

8.8 (8.3) years.

Functional Outcome Measures

AMAT

The average AMAT Total Time at Pre was 1078.7 (418.5) and 757.0 (368.4) at

Post 2 for the AO plus RTP group, for an average change between Pre and Post 2 of

321.7 (160.7); the average AMAT Total Time at Pre was 848.3 (679.9) and 723.8 (679.2)

at Post 2 in the Placebo plus RTP group for an average change of 124.5 (212.6). There

was not significant evidence of a larger improvement in the AO plus RTP group at Post

2. The difference in the average change in AMAT Total Time was 197.2 (90% CI -18.2 -

412.7, one-sided p-value=0.128) (Table 13).

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Table 11. Characteristics of participants enrolled in study.

Group AO plus RTP Placebo plus RTP

Number of Subjects: N 10 5
Age in years: Mean (SD) 56.8 (13.9) 59.8 (9.7)
Sex: N (%) F M F M
3 (30%) 7 (70%) 1 (20%) 4 (80%)
Race/Ethnicity: N (%)
White Non-Hispanic 9 (90%) 4 (80%)
Black Non-Hispanic 1 (10%) 1 (20%)
Hispanic 0 0
Side L R L R
Dominant Hand: N (%) 2 (20%) 8 (80%) 0 (0%) 5 (100%)
Affected by Hemiparesis 4 (40%) 6 (60%) 1 (20%) 4 (80%)
Affected Same Side as Dominant: N (%) 5 (50%) 4 (80%)
Years after stroke to enrollment: Mean (SD) 8.9 (8.3) 8.2 (9.2)
Ischemic stroke: N (%) 8 (80%) 5 (100%)
Baseline Functional Performance Scores: Mean (SD)
AMAT Total Time (s) 1084.3 (426.6) 1085.3 (586.2)
AMAT Total FA 32.3 (14.1) 35.0 (21.0)
AMAT Total QOM 31.8 (13.5) 34.8 (21.2)
MAL Amount of Use 14.4 (13.1) 17.2 (14.7)
MAL How Well 16.5 (17.3) 18.4 (16.9)
SIS Total Score 286.8 (35.2) 273.6 (29.3)
AO = Action Observation, RTP = Repetitive Task Practice, F = Female, M= Male, L = Left, R = Right, MCA = Middle
Cerebral Artery, AMAT = Arm Motor Activity Test, FA = Functional Ability, QOM = Quality of Movement, MAL =
Motor Activity Log, SIS = Stroke Impact Scale

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 Table 12. Comparison of characteristics of subjects who completed the study to those who
withdrew.

Group AO plus RTP Enrolled Placebo plus RTP Enrolled

Completion Status Analyzed Withdrew Analyzed Withdrew
N 8 2 3 2
Age in years: Mean (SD) 56.5 (15.5) 58.0 (8.5) 64.7 (9.9) 52.5 (0.7)
Sex: N (%) F M F M F M F M
2 (25%) 6 (60%) 1 (50%) 1 (50%) 0 3 (100%) 1 (50%) 1 (50%)
Race/Ethnicity: N (%)
White Non-Hispanic 7 (88%) 2 (100%) 2 (67%) 2 (100%)
Black Non-Hispanic 1 (13%) 0 1 (33%) 0
Hispanic 0 0 0 0
Side L R L R L R L R
Dominant Hand: N (%) 2 (25%) 6 (75%) 0 (0%) 2 (100%) 0 (0%) 3 (100%) 0 (0%) 2 (100%)
Affected by Hemiparesis: N 4 (50%) 4 (50%) 0 (0%) 2 (100%) 1 (33%) 2 (67%) 0 (0%) 2 (100%)
(%)
Dominant side is affected 3 (38%) 2 (100%) 2 (67%) 2 (100%)
side
Time post stroke (yrs): Mean 9.8 (9.1) 5.3 (0.4) 4.6 (3.4) 13.5 (14.8)
(SD)
Ischemic stroke: N (%) 7 (88%) 2 (100%) 3 (100%) 1 (50%)
Stroke location
MCA: N (%) 4 (50%) 0 1 (33%) 1 (50%)
Unknown: N (%) 4 (50%) 2 (100%) 2 (67%) 1 (50%)
Baseline Motor Impairment Scores: Mean (SD)
AMAT Total Time 1078.7 (418.5) 1106.9 (640.8) 848.3 (679.9) 1440.9 (168.4)
AMAT Total FA 33.8 (15.0) 26.5 (10.6) 44.3 (23.5) 21 (0.0)
AMAT Total QOM 32.9 (14.7) 27.5 (9.2) 44.3 (23.5) 20.5 (0.7)
MAL Amount of Use 16.4 (14.1) 6.5 (2.1) 15.7 (19.9) 19.5 (7.8)
MAL How Well 19.1 (18.6) 6 (2.8) 18.3 (23.6) 18.5 (4.9)
SIS Total Score 288.6 (38.4) 279.5 (26.2) 269.0 (40.4) 280.5 (4.9)
AO = Action Observation, RTP = Repetitive Task Practice, F = Female, M= Male, L = Left, R = Right, MCA = Middle Cerebral
Artery, AMAT = Arm Motor Activity Test, FA = Functional Ability, QOM = Quality of Movement, MAL = Motor Activity Log,
SIS = Stroke Impact Scale

88
AMAT Total Function

The average AMAT Total Functional Ability score at Pre was 33.8 (15.0) and

43.8 (15.9) at Post 2 for the AO plus RTP group, for an average change between Pre and

Post 2 of 10 (5.4); the average AMAT Total Functional Ability score at Pre was 44.3

(23.5) and 46.0 (22.3) at Post 2 in the Placebo plus RTP group for an average change of

1.7 (2.5). There was significant evidence of a larger improvement in the AO plus RTP

group at Post 2. The difference in the average change in AMAT Total Functional Ability

was 8.3 (90% CI 2.2 - 14.5, one-sided p-value=0.034) (Table 13).

AMAT Total Quality of Movement

The average AMAT Total Quality of Movement score at Pre was 32.9 (14.7) and

42.0 (16.9) at Post 2 for the AO plus RTP group, for an average change between Pre and

Post 2 of 9.1 (6.6); the average AMAT Total Quality of Movement score at Pre was 44.3

(23.5) and 45.7 (22.8) at Post 2 in the Placebo plus RTP group for an average change of

1.3 (2.5). There was not significant evidence of a larger improvement in the AO plus RTP

group at Post 2. The difference in the average change in AMAT Total Quality of

Movement was 7.8 (90% CI 0.4 - 15.1, one-sided p-value=0.084) (Table 13).

AMAT Total Mount of Use

The average MAL Amount of Use score at Pre was 16.4 (14.1) and 37.1 (26.9) at

Post 2 for the AO plus RTP group, for an average change between Pre and Post 2 of 20.7

(25.9); the average MAL Amount of Use score at Pre was 15.7 (19.9) and 41.0 (46.2) at

Post 2 in the Placebo plus RTP group for an average change of 25.3 (26.6). There was not

89
significant evidence of a larger improvement in the AO plus RTP group at Post 2. The

difference in the average change in MAL Amount of Use was 3.5 (90% CI -36.9 – 27.8,

one-sided p-value=0.801) (Table 13).

Table 13. Linear regression of outcome measures for the comparison of AO plus RTP to
Placebo plus RTP.
2
Group Pre Post 2 Change Difference in the df F R p-
Mean (SD) Mean (SD) (Pre - Post 2) Change value*
Mean (SD) (90% CI)
AMAT Total Time
AO + RTP 1078.7 (418.5) 757.0 (368.4) 321.7 (160.7) 197.2 (-18.2 -412.7) 1, 9 2.8 0.24 0.128
Placebo + RTP 848.3 (679.9) 723.8 (679.2) 124.5 (212.6)
AMAT Total Functional Ability
AO + RTP 33.8 (15.0) 43.8 (15.9) 10.0 (5.4) 8.3 (2.2 - 14.5) 1, 9 6.2 0.41 0.034
Placebo + RTP 44.3 (23.5) 46.0 (22.3) 1.7 (2.5)
AMAT Total Quality of Movement
AO + RTP 32.9 (14.7) 42.0 (16.9) 9.1 (6.6) 7.8 (0.4 - 15.1) 1, 9 3.8 0.30 0.084
Placebo + RTP 44.3 (23.5) 45.7 (22.8) 1.3 (2.5)
MAL Amount of Use
AO + RTP 16.4 (14.1) 37.1 (26.9) 20.7 (25.9) 3.5 (-36.9 – 27.8) 1, 9 0.07 0.01 0.801
Placebo + RTP 15.7 (19.9) 41.0 (46.2) 25.3 (26.6)
MAL How Well
AO + RTP 19.1 (18.6) 39.4 (26.4) 20.3 (26.9) 3.5 (-27.2 - 34.2) 1, 9 0.04 0.00 0.840
Placebo + RTP 18.3 (23.6) 35.2 (37.4) 16.9 (15.2)
SIS Total Score
AO + RTP 288.6 (38.4) 301.8 (37.3) 13.1 (15.2) 1.1 (-1.1 - 3.3) 1, 9 0.86 0.087 0.378
Placebo + RTP 269.0 (40.4) 283.3 (40.5) 14.3 (21.4)
Abbreviations: AO = Action Observation, RTP = Repetitive Task Practice, AMAT = Arm Motor Activity Test, MAL =
Motor Activity Log, SIS = Stroke Impact Scale
*one sided p value

MAL How Well Score

The average MAL How Well score at Pre was 19.1 (18.6) and 39.4 (26.4) at Post

2 for the AO plus RTP group, for an average change between Pre and Post 2 of 20.3

(26.9); the average MAL How Well score at Pre was 18.3 (23.6) and 35.2 (37.4) at Post 2

in the Placebo plus RTP group for an average change of 16.9 (15.2). There was not

significant evidence of a larger improvement in the AO plus RTP group at Post 2. The

90
difference in the average change in MAL How Well was 3.5 (90% CI -27.2 - 34.2, one-

sided p-value=0.840) (Table 13).

SIS Total Score

The average SIS Total Score at Pre was 288.6 (38.4) and 301.8 (37.3) at Post 2 for

the AO plus RTP group, for an average change between Pre and Post 2 of 13.1 (15.2); the

average SIS Total Score at Pre was 269.0 (40.4) and 283.3 (40.5) at Post 2 in the Placebo

plus RTP group for an average change of 14.3 (21.4). There was not significant evidence

of a larger improvement in the AO plus RTP group at Post 2. The difference in the

average change in SIS Total Score was 1.1 (90% CI -1.1 - 3.3, one-sided p-value=0.378)

(Table 13).

AMAT Trained Tasks

Cutting Meat Time

The average Cutting Meat Total Time at Pre was 169.8 (98.5) and 106.3 (66.2) at

Post 2 for the AO plus RTP group, for an average change between Pre and Post 2 of 63.5

(45.6); the average Cutting Meat Total Time at Pre was 150.8 (108.8) and 148.4 (90.2) at

Post 2 in the Placebo plus RTP group for an average change of 2.4 (33.7). There was not

significant evidence of a larger improvement in the AO plus RTP group at Post 2. The

difference in the average change in Cutting Meat Total Time was 61.1 (90% CI 7.4 -

114.8, one-sided p-value=0.066) (Table 14).

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Table 14. Linear regression of outcomes for AMAT Trained Tasks in AO plus RTP v. PV plus
RTP.
2
Group Pre Post 2 Change Difference in the df F R p-
Mean (SD) Mean (SD) Mean (SD) Change (90% CI) value*
Cutting Meat Total Time
AO + RTP 169.8 (98.5) 106.3 (66.2) 63.5 (45.6) 61.1 (7.4 - 114.8) 1, 9 4.4 0.326 0.066
Placebo + RTP 150.8 (108.8) 148.4 (90.2) 2.4 (33.7)
Cutting Meat Total Functional Ability
AO + RTP 4.8 (2.6) 6.9 (2.5) 2.1 (1.5) 1.8 (0.2 - 3.4) 1, 9 4.1 0.311 0.075
Placebo + RTP 6.0 (3.6) 6.3 (3.5) 0.3 (0.6)
Cutting Meat Total Quality of Movement
AO + RTP 4.5 (2.5) 6.6 (3.0) 2.1 (1.9) 1.8 (-0.3 - 3.9) 1, 9 2.5 0.215 0.151
Placebo + RTP 6.0 (3.6) 6.3 (3.5) 0.3 (0.6)
Picking up Sandwich Total Time
AO + RTP 55.7 (48.3) 44.6 (40.9) 11.1 (25.8) -26.7 (-61.1 - 7.8) 1, 9 2.0 0.183 0.189
Placebo + RTP 61.8 (58.2) 24.1 (33.1) 37.7 (33.7)
Picking up Sandwich Total Functional Ability
AO + RTP 4.5 (2.5) 5.3 (2.3) 0.8 (1.4) -0.6 (-2.2 - 1.1) 1, 9 0.4 0.044 0.536
Placebo + RTP 4.7 (3.1) 6.0 (2.0) 1.3 (1.2)
Picking up Sandwich Total Quality of Movement
AO + RTP 4.4 (2.3) 5.4 (2.6) 1.0 (1.7) 0.0 (-1.9 - 1.9) 1, 9 0.0 0.000 1.000
Placebo + RTP 4.7 (3.1) 5.7 (2.5) 1.0 (1.0)
Using a Spoon Total Time
AO + RTP 124.1 (55.1) 85.6 (46.6) 38.5 (23.6) 4.4 (-37.8 - 46.6) 1, 9 0.0 0.063 0.853
Placebo + RTP 106.4 (87.1) 72.3 (93.9) 34.1 (57.1)
Using a Spoon Total Functional Ability
AO + RTP 5.4 (2.5) 7.0 (2.6) 1.6 (1.1) 0.3 (-1.2 - 1.8) 1, 9 0.1 0.015 0.724
Placebo + RTP 6.3 (4.2) 7.7 (4.5) 1.4 (1.5)
Using a Spoon Total Quality of Movement
AO + RTP 5.0 (2.3) 6.8 (2.9) 1.8 (1.2) 0.4 (-1.1 - 2.0) 1, 9 0.2 0.026 0.635
Placebo + RTP 6.3 (4.2) 7.7 (4.5) 1.4 (1.5)
Putting on a Shirt Total Time
AO + RTP 192.2 (85.6) 117.7 (73.7) 74.5 (89.7) 60.7 (-38.7 - 160.0) 1, 9 1.3 0.122 0.292
Placebo + RTP 150.3 (133.0) 136.4 (141.8) 13.9 (26.1)
Putting on a Shirt Total Functional Ability
AO + RTP 4.9 (2.9) 6.0 (2.1) 1.1 (2.7) 1.8 (-1.2 - 4.8) 1, 9 1.2 0.116 0.306
Placebo + RTP 7.0 (3.5) 6.3 (3.1) -0.7 (1.2)
Putting on a Shirt Total Quality of Movement
AO + RTP 4.8 (2.7) 5.9 (2.6) 1.1 (3.0) 1.5 (-2.0 - 4.9) 1, 9 0.6 0.063 0.458
Placebo + RTP 7.0 (3.5) 6.7 (3.5) -0.3 (1.5)
Abbreviations: AO = Action Observation, RTP = Repetitive Task Practice, AMAT = Arm Motor Activity Test
*one sided p value

92
Cutting Meat Function

The average Cutting Meat Total Functional Ability score at Pre was 4.8 (2.6) and

6.9 (2.5) at Post 2 for the AO plus RTP group, for an average change between Pre and

Post 2 of 2.1 (1.5); the average Cutting Meat Total Functional Ability score at Pre was

6.0 (3.6) and 6.3 (3.5) at Post 2 in the Placebo plus RTP group for an average change of

0.3 (0.6). There was not significant evidence of a larger improvement in the AO plus RTP

group at Post 2. The difference in the average change in Cutting Meat Total Functional

Ability was 1.8 (90% CI 0.2 - 3.4, one-sided p-value=0.075) (Table 14).

Cutting Meat Quality

The average Cutting Meat Total Quality of Movement score at Pre was 4.5 (2.5)

and 6.6 (3.0) at Post 2 for the AO plus RTP group, for an average change between Pre

and Post 2 of 2.1 (1.9); the average Cutting Meat Total Quality of Movement score at Pre

was 6.0 (3.6) and 6.3 (3.5) at Post 2 in the Placebo plus RTP group for an average change

of 0.3 (0.6). There was not significant evidence of a larger improvement in the AO plus

RTP group at Post 2. The difference in the average change in Cutting Meat Total Quality

of Movement was 1.8 (90% CI -0.3 - 3.9, one-sided p-value=0.151) (Table 14).

Picking up Sandwich Time

The average Picking up Sandwich Total Time at Pre was 55.7 (48.3) and 44.6

(40.9) at Post 2 for the AO plus RTP group, for an average change between Pre and Post

2 of 11.1 (25.8); the average Picking up Sandwich Total Time at Pre was 61.8 (58.2) and

24.1 (33.1) at Post 2 in the Placebo plus RTP group for an average change of 37.7 (33.7).

There was not significant evidence of a larger improvement in the AO plus RTP group at

93
Post 2. The difference in the average change in Picking up Sandwich Total Time was -

26.7 (90% CI -61.1 - 7.8, one-sided p-value=0.189) (Table 14).

Picking up Sandwich Function

The average Picking up Sandwich Total Functional Ability score at Pre was 4.5

(2.5) and 5.3 (2.3) at Post 2 for the AO plus RTP group, for an average change between

Pre and Post 2 of 0.8 (1.4); the average Picking up Sandwich Total Functional Ability

score at Pre was 4.7 (3.1) and 6.0 (2.0) at Post 2 in the Placebo plus RTP group for an

average change of 1.3 (1.2). There was not significant evidence of a larger improvement

in the AO plus RTP group at Post 2. The difference in the average change in Picking up

Sandwich Total Functional Ability was -0.6 (90% CI -2.2 - 1.1, one-sided p-value=0.536)

(Table 14).

Picking up Sandwich Quality

The average Picking up Sandwich Total Quality of Movement score at Pre was

4.4 (2.3) and 5.4 (2.6) at Post 2 for the AO plus RTP group, for an average change

between Pre and Post 2 of 1 (1.7); the average Picking up Sandwich Total Quality of

Movement score at Pre was 4.7 (3.1) and 5.7 (2.5) at Post 2 in the Placebo plus RTP

group for an average change of 1 (1.0). There was not significant evidence of a larger

improvement in the AO plus RTP group at Post 2. The difference in the average change

in Picking up Sandwich Total Quality of Movement was 0.0 (90% CI -1.9 - 1.9, one-

sided p-value=1.000) (Table 14).

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Using a Spoon Time

The average Using a Spoon Total Time at Pre was 124.1 (55.1) and 85.6 (46.6) at

Post 2 for the AO plus RTP group, for an average change between Pre and Post 2 of 38.5

(23.6); the average Using a Spoon Total Time at Pre was 106.4 (87.1) and 72.3 (93.9) at

Post 2 in the Placebo plus RTP group for an average change of 34.1 (57.1). There was not

significant evidence of a larger improvement in the AO plus RTP group at Post 2. The

difference in the average change in Using a Spoon Total Time was 4.4 (90% CI -37.8 -

46.6, one-sided p-value=0.853) (Table 14).

Using a Spoon Function

The average Using a Spoon Total Functional Ability score at Pre was 5.4 (2.5)

and 7.0 (2.6) at Post 2 for the AO plus RTP group, for an average change between Pre

and Post 2 of 1.6 (1.1); the average Using a Spoon Total Functional Ability score at Pre

was 6.3 (4.2) and 7.7 (4.5) at Post 2 in the Placebo plus RTP group for an average change

of 1.4 (1.5). There was not significant evidence of a larger improvement in the AO plus

RTP group at Post 2. The difference in the average change in Using a Spoon Total

Functional Ability was 0.3 (90% CI -1.2 - 1.8, one-sided p-value=0.724) (Table 14).

Using a Spoon Quality

The average Using a Spoon Total Quality of Movement score at Pre was 5.0 (2.3)

and 6.8 (2.9) at Post 2 for the AO plus RTP group, for an average change between Pre

and Post 2 of 1.8 (1.2); the average Using a Spoon Total Quality of Movement score at

Pre was 6.3 (4.2) and 7.7 (4.5) at Post 2 in the Placebo plus RTP group for an average

change of 1.4 (1.5). There was not significant evidence of a larger improvement in the

95
AO plus RTP group at Post 2. The difference in the average change in Using a Spoon

Total Quality of Movement was 0.4 (90% CI -1.1 - 2.0, one-sided p-value=0.635) (Table

14).

Putting on a Shirt Time

The average Putting on a Shirt Total Time at Pre was 192.2 (85.6) and 117.7

(73.7) at Post 2 for the AO plus RTP group, for an average change between Pre and Post

2 of 74.5 (89.7); the average Putting on a T-Shirt Total Time at Pre was 150.3 (133.0)

and 136.4 (141.8) at Post 2 in the Placebo plus RTP group for an average change of 13.9

(26.1). There was not significant evidence of a larger improvement in the AO plus RTP

group at Post 2. The difference in the average change in Putting on a T-Shirt Total Time

was 60.7 (90% CI -38.7 - 160.0, one-sided p-value=0.292) (Table 14).

Putting on a Shirt Function

The average Putting on a Shirt Total Functional Ability score at Pre was 4.9 (2.9)

and 6.0 (2.1) at Post 2 for the AO plus RTP group, for an average change between Pre

and Post 2 of 1.1 (2.7); the average Putting on a Shirt Total Functional Ability score at

Pre was 7.0 (3.5) and 6.3 (3.1) at Post 2 in the Placebo plus RTP group for an average

change of -0.7 (1.2). There was not significant evidence of a larger improvement in the

AO plus RTP group at Post 2. The difference in the average change in Putting on a Shirt

Total Functional Ability was 1.8 (90% CI -1.2 - 4.8, one-sided p-value=0.306) (Table

14).

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Putting on a Shirt Quality

The average Putting on a Shirt Total Quality of Movement score at Pre was 4.8

(2.7) and 5.9 (2.6) at Post 2 for the AO plus RTP group, for an average change between

Pre and Post 2 of 1.1 (3.0); the average Putting on a Shirt Total Quality of Movement

score at Pre was 7.0 (3.5) and 6.7 (3.5) at Post 2 in the Placebo plus RTP group for an

average change of -0.3 (1.5). There was not significant evidence of a larger improvement

in the AO plus RTP group at Post 2. The difference in the average change in Putting on a

Shirt Total Quality of Movement was 1.5 (90% CI -2.0 - 4.9, one-sided p-value=0.458)

(Table 14).

Survey Results

All subjects in the AO plus RTP group and the placebo plus RTP group completed the

survey for assessing the subject’s perception of the intervention. (Table 10, Table 14,

Figure 4) Both groups strongly agreed that they were highly satisfied with the

intervention (62.5% AO plus RTP group, 100% Placebo plus RTP group), and 87% of

the AO plus RTP group strongly agreed they enjoyed the intervention with 66.7% of the

Placebo plus RTP group agreeing. Both groups strongly agreed the intervention was

beneficial/ helpful (75% AO plus RTP group, 66.7% Placebo plus RTP group),

meaningful/ important (75% AO plus RTP group, 100% Placebo plus RTP group), the

tasks completed were helpful to learn (50% AO plus RTP group, 66.7% Placebo plus

RTP group), and they made improvements with the intervention (87.5% AO plus RTP

group, 66.7% Placebo plus RTP group). Subjects in the AO plus RTP group agreed

97
(62.5%) that watching the videos helped them complete tasks in the therapy sessions,

while subjects in the Placebo plus RTP group evenly reported (33.3%) for neutral,

agreed, and strongly agreed. When asked if the tasks completed in the therapy sessions

helped them perform those tasks at home during the day, 75% of subjects in the AO plus

RTP group agreed, while subjects in the Placebo plus RTP group evenly reported

(33.3%) for neutral, agreed, and strongly agreed.

Table 15. Results of the survey of participants.

Group Strongly Disagree Disagree Neutral Agree Strongly Agree

Q1. I am highly satisfied with the arm rehabilitation program I completed.
AO + RTP 0 (0%) 0 (0%) 1 (12.5%) 2 (25%) 5 (62.5%)
Placebo +RTP 0 (0%) 0 (0%) 0 (0%) 0 (0%) 3 (100%)
Q2. I enjoyed the arm rehabilitation program I completed.
AO + RTP 0 (0%) 0 (0%) 0 (0%) 1 (12.5%) 7 (87.5%)
Placebo +RTP 0 (0%) 0 (0%) 0 (0%) 2 (66.7%) 1 (33.3%)
Q3. Completing the arm rehabilitation program was beneficial/ helpful to me.
AO + RTP 0 (0%) 0 (0%) 0 (0%) 2 (25%) 6 (75%)
Placebo +RTP 0 (0%) 0 (0%) 0 (0%) 1 (33.3%) 2 (66.7%)
Q4. Completing this arm rehabilitation program was meaningful/ important to me.
AO + RTP 0 (0%) 0 (0%) 0 (0%) 2 (25%) 6 (75%)
Placebo +RTP 0 (0%) 0 (0%) 0 (0%) 0 (0%) 3 (100%)
Q5. The tasks I completed in the therapy program were helpful for me to learn.
AO + RTP 0 (0%) 0 (0%) 0 (0%) 4 (50%) 4 (50%)
Placebo +RTP 0 (0%) 0 (0%) 0 (0%) 1 (33.3%) 2 (66.7%)
Q6. Watching the videos helped me complete tasks in the therapy sessions.
AO + RTP 0 (0%) 0 (0%) 0 (0%) 5 (62.5%) 3 (37.5%)
Placebo +RTP 0 (0%) 0 (0%) 1 (33.3%) 1 (33.3%) 1 (33.3%)
Q7. The therapy tasks I completed in therapy sessions helped me perform those tasks at home during the day.
AO + RTP 0 (0%) 0 (0%) 0 (0%) 6 (75%) 2 (25%)
Placebo +RTP 0 (0%) 0 (0%) 1 (33.3%) 1 (33.3%) 1 (33.3%)
Q8. I have made improvements since the beginning of the therapy in this study.
AO + RTP 0 (0%) 0 (0%) 0 (0%) 1 (12.5%) 7 (87.5%)
Placebo +RTP 0 (0%) 0 (0%) 0 (0%) 1 (33.3%) 2 (66.7%)
AO = Action Observation, RTP = Repetitive Task Practice

98
 DISCUSSION

In this pilot study with a small sample size, we explored the scientific reason for

feasibility of response to the intervention (Thabane et al., 2010) for a novel combined

intervention of AO plus RTP compared to placebo plus RTP on UL functional outcomes

in moderately impaired stroke survivors. This was done to determine if this design can

proceed to a larger fully powered Phase III study in the scientific process (Arain et al.,

2010; S. M. Eldridge, Lancaster, et al., 2016; Tickle-Degnen, 2013). There was a

significant change in AMAT functional ability total score from Pre to Post 2 with the AO

plus RTP intervention when compared to the Pre to Post 2 change in score for the

Placebo plus RTP group, with the difference in the average change was 8.3 (90% CI 2.2 -

14.5). An increase in this score would indicate increased independence in functional tasks

completed, and movement patterns have increased coordination. With this positive

response to treatment for the AO plus RTP combined intervention, further investigation

should be completed in a subsequent Phase III trial.

Imputation was not considered due to the very small samples size for the data of

the four withdrawn subjects in the analysis as recommended by Jakobsen and colleagues

(2017). As seen in table 12, the demographic and baseline data of the four withdrawn

subjects are similar to the subjects that remained in the study, and could likely be a

random sample of the entire group. The reasons for the subject’s withdraw and for

missing data did not appear to be related to subject’s medical condition or study

intervention, and was considered to be missing completely at random (MCAR) (Jakobsen

et al, 2017).

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 The overall functional AMAT functional ability score was significant for change

from Pre to Post 2, yet the scores for the individual trained tasks were not. This could be

explained for multiple reasons. Clearly there was an overall response to intervention as

shown in the total score change in score from Pre to Post 2, indicating that some subjects

improved in different tasks than others. Although one might expect the most

improvement on the tasks that were specifically trained, a small sample size was unlikely

to provide the statistical power required for this level of posthoc analysis. Additionally,

the AMAT has been standardized as an entire assessment and not standardized for the

individual sub scores (Kopp et al., 1997; McCulloch et al., 1988). Assessing the response

to treatment in the individual trained tasks was exploratory, and was not used as an

outcome to determine if the intervention should proceed to a larger Phase III trial.

While not significant, it is important to note that the AO plus RTP group gained 1

– 2 points on the FA and QOM scales on the trained tasks. An increase on the FA scale

from a score of 1 (Involved arm does not participate functionally) to a score 2 (Does task

but requires assistance for minor readjustments or change of position) would indicate an

increase from non-functional performance to functional performance with minor

assistance. A score of 3 (Does task but is performed slowly and/or with effort) would

indicate full independence but a slower rate (Kopp et al., 1997; McCulloch et al., 1988).

In the moderately impaired stroke survivor that tends to have lower functional

performance, an increase of 1 – 2 points would indicate that a subject improved from

some level of assistance to independence with performance of functional tasks.

100
 The exploratory outcome measures for UL functional activity limitations and

quality of life of the MAL and SIS also had no significant for change in score from Pre to

Post 2 for the AO plus RTP group compared to the placebo plus RTP group. These self-

report questionnaires have been standardized for internal consistency and test retest

reliability (Duncan Pamela W. et al., 1999; van der Lee J.H. et al., 2004), yet by the

nature of a self-report questionnaires, the responses are dependent on subject perception

of performance. While subjects are able to understand the questions that are in the self-

report questionnaires, the subject might have a different perception of their performance

compared to actual performance. Additionally, it is unknown if the subjects were

performing the tasks completed in the intervention session at home throughout the day.

While it is supported that RTP significantly increases UL functional performance during

ADL tasks in the clinical setting (Aichner et al., 2002; Byl et al., 2003; Dombovy, 2004;

Jang et al., 2003; Shepherd, 2001), Waddell and colleagues have found that stroke

chronic survivors do not translate UL functional ADL performance learned in the

clinical setting to the everyday performance outside of the clinic (Waddell et al., 2017).

There is a possibility that subjects were not carrying over tasks, which would result in

MAL and SIS scores that would not have a change in score from Pre to Post 2. Due to the

dependence on subject perception of performance and carryover of tasks from clinical

setting to everyday performance, these measures should remain secondary and

exploratory outcome measures in any subsequent larger trial.

Overall, subjects in both the AO plus RTP group and the Placebo plus RTP group

had a positive perception of the study as reported on the quantitative survey. The majority

101
of responses to all of the questions were Agree or Strongly Agree. This would indicate

that overall, subjects thought the study was beneficial and meaningful. While responses

were generally the same for both the AO plus RTP and the Placebo plus RTP, it is

important to note that the Placebo plus RTP group thought the program was beneficial

and helpful. This would mean that there was no resentment of the subjects in the Placebo

plus RTP group receiving a placebo assignment. Additionally, subjects in the Placebo

plus RTP group reported positively that watching the videos helped them complete tasks

in the therapy sessions. After observing the placebo video, subjects in the control group

would often report to the research team that they enjoyed the video because it was

relaxing, it helped them to be calm before performing RTP, and there was no report of

dissatisfaction with observing static images. This suggests that the placebo condition had

the intended effect the subjects perceiving they were receiving a useful intervention, so

that the effect of AO above and beyond the placebo effect was real.

Limitations and Future Directions

The nature of feasibility and pilot testing is to examine the overall functionality of

how a study should be completed as oppose to focusing on one single active ingredient to

be tested as in a large hypothesis testing Phase III study (Tickle-Degnen, 2013). The

purpose of this feasibility study was to determine the response to intervention through

detecting changes in UL functional performance outcomes in response to the AO plus

RTP practice schedule compared to a placebo plus RTP in the chronic, moderately

impaired stroke survivor. With a significant change in score in the AO plus RTP group

102
total AMAT Functional Ability compared to the Placebo plus RTP group, would indicate

that a larger RCT should be completed to determine the efficacy of the intervention.

Interpreting the results from this study for efficacy should be interpreted with caution due

to the scientific limitations of a small sample size (Lancaster, 2015). This is an early

phase development Phase II study to enhance the success of a subsequent randomized

control trial (Lancaster, 2015; Leon et al., 2011; Moore et al., 2011).

One limitation of the survey is that only quantitative questions were included. A

mixed method survey that combines quantitative and open ended qualitative questions

could provide a more comprehensive understanding of the subject’s experience. A future

Phase III study should include a mixed methods survey so that a more comprehensive

understanding of the subject experience can be understood.

A potential future direction for this combined intervention would be examining

the effects of functional performance with different severities and chronicity of stroke,

types complexity of tasks completed in AO and RTP, and examining functional

performance of trained tasks in everyday performance outside of the clinic. Stroke

survivors in the acute phase of recovery are in need of interventions to increase functional

performance, as well as severely impaired stroke survivors. The combination of AO and

RTP could be a beneficial intervention for both populations. A variety of complexity of

tasks would be required to meet the needs of severely impaired stroke survivors with

lower motor and functional ability. Functional tasks utilized for the severely impaired

stroke population would require more gross motor movement and less hand movement

and coordination. Examining if carryover of performance of functional tasks into

103
everyday life outside of the clinical setting would influence overall functional

performance for stroke survivors. Potentially customizing the specific task completed in

AO and RTP to the subject’s typical everyday performance could improve overall

performance outside of the clinical setting.

Conclusion

The purpose of this feasibility pilot study was to determine the response to

intervention through detecting changes in UL functional performance outcomes in

response to the AO plus RTP practice schedule compared to a placebo plus RTP in the

chronic, moderately impaired stroke survivor. When assessing response to intervention in

this small pilot study, there was a significant positive response for change of the AMAT

functional use total score for the combined intervention of AO plus RTP. These results

indicate that a larger Phase III RCT with a fully powered sample size should be

completed to determine efficacy for the AO plus RTP in the moderately impaired chronic

stroke survivor population.

104
 Chapter 5 Conclusion

Within the four phases of clinical trials, Phase II feasibility and pilot studies are

important to the development and progression of the scientific process (Arain et al., 2010;

Eldridge, Lancaster, et al., 2016; Tickle-Degnen, 2013). Feasibility and pilot studies

answer essential questions about the conduct and functionality of trials, and establish

vital operational information needed for the next subsequent large scale Phase III trial

(Eldridge et al., 2013). The purpose is not to determine the efficacy of an intervention,

but is instead an early phase development function to enhance the success of larger

randomized control trials (Lancaster, 2015; Leon et al., 2011; Moore et al., 2011).

Thabane and colleagues (2010) established a clear and systematic categorization the four

main reasons for competing feasibility and pilot studies, which are: 1) process, 2)

resources, 3) management, and 4) scientific. The novel combination intervention of

Action Observation (AO) plus Repetitive Task Practice (RTP) had not been investigated

before, and completing Phase II feasibility and pilot studies with this intervention with

chronic moderately impaired stroke survivors was appropriate.

Summary of Findings

The previous three chapters have presented the results of multiple research

questions for the feasibility of the AO plus RTP intervention compared to a placebo plus

RTP control group for Upper Limb (UL) outcomes in the chronic, moderately impaired

105
stroke survivor. In chapter 2 the process and scientific reasons for feasibility and pilot

studies were examined. The data revealed that 1) the retention rate was appropriate to

maintain the sample size needed for analysis, 2) the recruitment rate was appropriate for

the study completion, 3) enrollment rate was appropriate for the study completion, 4)

subjects understood survey questions, 5) there was a lower follow up rate due to parking

at the facility the study was completed at, 6) majority of subjects were compliant with

attendance to intervention session, and 7) there is a low safety with risk as shown with

no occurrence of adverse events.

Chapter 3 and 4 presented the results of one of the scientific reasons to complete

feasibility and pilot studies of response to intervention. Both chapters presented results

detecting changes in outcomes in response to the AO plus RTP practice schedule

compared to placebo plus RTP in the chronic, moderately impaired stroke survivor, with

chapter 3 utilizing UL motor impairment outcomes and chapter 4 utilizing UL functional

performance outcomes. In chapter 3 the data revealed that there was a significant

response of change on the Upper Extremity Fugl Meyer motor impairment assessment for

the combination of AO plus RTP on the hemiplegic UL, and there was also a trend

suggesting a possible benefit of reduced spasticity after the intervention. In Chapter 4 the

data revealed that there was a significant positive response for change of the Arm Motor

Ability Test for functional performance of the UL for the combined intervention of AO

plus RTP, and that all subjects had a positive perception of the study in a quantitative

survey.

106
Implications for Future Research

With the results that were revealed chapters 2, 3, and 4, all chapters had

appropriate or positive outcomes for the feasibility examining AO plus RTP compared to

Placebo plus RTP in moderately impaired stroke survivors. This would indicate the study

design should progress in the phases of clinical trials to a Phase III trial (Arain et al.,

2010; S. M. Eldridge, Lancaster, et al., 2016; Tickle-Degnen, 2013), which will assess

efficacy and safety with randomized groups and large sample sizes (National

Comprehensive Cancer Network, 2020; Thabane et al., 2016).

Potential future directions for the combined intervention of AO plus RTP would

be examining the effects of functional performance with different severities and

chronicity of stroke, types of complexity of tasks completed in AO and RTP, and

examining functional performance of trained tasks in everyday performance outside of

the clinic. Additional potential future direction for research for this intervention would be

to examine the neural pathways and systems that are engaged by the combination of AO

and RTP in stroke survivors through functional magnetic resonance imaging (fMRI). This

would be beneficial to understand the potential synergistic effect between AO and RTP,

and the neurologic impact on the stroke recovery.

Potential Mechanisms for a Combined Effect between AO and RTP

There are many possible reasons for the apparent beneficial, combined effect of

AO plus RTP revealed in this study. As a pilot and feasibility study, the present results

cannot lead to the conclusion that there is definitely a synergistic effect; a phase III trial

107
would be required to establish that (Eldridge, Lancaster, et al., 2016). The present results

do, however, provide pilot data suggesting that it is reasonable to hypothesize that a

phase III study could be expected to demonstrate such an effect. In order to justify such a

study, there not only needs to be the kind of feasibility and pilot data presented here,

there also needs to be a solid theoretical justification as the scientific rationale.

Potential theoretical reasons for why AO plus RTP could have a combined effect

would be the occurrence of cortical activity during observation of skilled task

performance. The observation completed could serve as “repetition of task” of cortical

activity. Repetition of a skilled task is a key component of neuroplasticity, resulting in

cortical mapping changes. AO could provide additional repetition without the effects of

fatigue that occur during physical performance, creating a more robust intervention

session. Additionally, the observation of a task is skilled training of effective movement

patterns that the stroke survivor is not able to physically perform. The observation of

effective functional movement patterns could provide cortical activity that is unique from

physical performance that has impairment and compensatory movements. This would

provide training that could not occur in a traditional therapy session of the survivor

completing physical repetitions and the therapist provide verbal cues and physical

assistance.

Summary

Completing a Phase III trial for the efficacy of AO plus RTP in moderately impaired

stroke survivors, expanding to acute and severely impaired stroke survivors, and

108
examining neural pathways and systems all has the potential to impact millions of stroke

survivors in the United States. With stroke being one of the leading causes of severe long

term-disability (Virani et al., 2020), positively influencing motor impairment and

functional performance will have a great impact on independence in millions of

individuals.

109
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