Absence of Motor-Evoked Potentials Does Not Predict Poor Recovery in Patients With Severe-Moderate Stroke: An Exploratory Analysis

Journal Pre-proof The Absence of Motor Evoked Potentials Does Not Predict Poor Recovery in Patients with Severe-Moderate Stroke: an Exploratory Analysis Elizabeth S. Powell, MS, Philip M. Westgate, PhD, Larry B. Goldstein, MD, Lumy Sawaki, MD, PhD PII:

S2590-1095(19)30025-4

DOI:

https://doi.org/10.1016/j.arrct.2019.100023

Reference:

ARRCT 100023

To appear in:

Archives of Rehabilitation Research and Clinical Translation

Received Date: 8 March 2019 Revised Date:

24 July 2019

Accepted Date: 16 August 2019

Please cite this article as: Powell ES, Westgate PM, Goldstein LB, Sawaki L, The Absence of Motor Evoked Potentials Does Not Predict Poor Recovery in Patients with Severe-Moderate Stroke: an Exploratory Analysis, Archives of Rehabilitation Research and Clinical Translation (2019), doi: https:// doi.org/10.1016/j.arrct.2019.100023. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the American Congress of Rehabilitation Medicine

MOTOR EVOKED POTENTIALS POST-STROKE

The Absence of Motor Evoked Potentials Does Not Predict Poor Recovery in Patients with Severe-Moderate Stroke: an Exploratory Analysis Elizabeth S Powell, MSa; Philip M Westgate, PhDb; Larry B Goldstein, MDc; Lumy Sawaki, MD, PhDa a

Department of Physical Medicine and Rehabilitation, University of Kentucky,

Lexington, KY, USA b

Department of Biostatistics, College of Public Health, University of Kentucky,

Lexington, KY, USA c

Department of Neurology, University of Kentucky, Lexington, KY, USA

This material has not been published or presented elsewhere. Funding: This research was funded in part by the Cardinal Hill Stroke and Spinal Cord Injury Endowment #0705129700. The funding body had no role in the collection, analysis and interpretation of data, or in writing the manuscript. None of the authors have potential conflicts of interest to be disclosed. Corresponding author: Lumy Sawaki, MD, PhD, University of Kentucky Department of Physical Medicine and Rehabilitation at Cardinal Hill, 2050 Versailles Road, Lexington, KY, 40504 ([email protected]; phone 859/323-6226; fax 859/323-1123)

MOTOR EVOKED POTENTIALS POST-STROKE

1

The Absence of Motor Evoked Potentials Does Not Predict Poor Recovery in

2

Patients with Severe-Moderate Stroke: an Exploratory Analysis

3

Abstract

4

Objective: To better understand the role of the presence or absence of motor evoked

5

potentials (MEPs) in predicting functional outcomes following a severe-moderate stroke.

6

Design: Retrospective exploratory analysis. We compared the effects of the stimulation

7

condition (active or sham), MEP status (+ or -), and a combination of stimulation

8

condition and MEP status on outcome. Within-group and between-group changes were

9

assessed with longitudinal repeated measures ANOVA and longitudinal repeated

10

measures ANCOVA, respectively. The proportions of participants who achieved minimal

11

clinically important differences (MCID) for the main outcome measures were calculated.

12

Setting: University research laboratory within a rehabilitation hospital

13

Participants: 129 subjects with severe-moderate stroke-related motor impairments who

14

participated in previous studies combining neuromodulation and motor training

15

Interventions: Neuromodulation (active or sham) and motor training

16

Main Outcome Measures: Fugl-Meyer Assessment (FMA) and Action Research Arm

17

Test (ARAT)

18

Results: When participants were grouped by stimulation condition or MEP status, all

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groups improved from baseline to immediate post-intervention and follow-up evaluations

20

(all p<0.05). Analysis by stimulation condition and MEP status found that the MEP-

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MOTOR EVOKED POTENTIALS POST-STROKE 21

/active group improved by 4.2 points on FMA (p<0.0001) and 1.8 on ARAT (p=0.003) at

22

post-intervention. The MEP+/active group improved by 5.7 points on FMA (p<0.0001)

23

and 3.9 points on ARAT (p<0.0001) at post-intervention. There were no between group

24

differences (p>0.05). Regarding MCIDs, in the MEP-/active group, 14.5% of individuals

25

reached MCID on FMA and 8.3% on ARAT at post-intervention. In the MEP+/active

26

group, 33.3% of individuals reached MCID on FMA and 27.3% on ARAT at post-

27

intervention.

28

Conclusion: As expected, the MEP+ group had the greatest improvement in motor

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function. However, it was shown that individuals without MEPs can also achieve

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meaningful changes, as reflected by MCID, when neuromodulation is paired with motor

31

training. To our knowledge, this is the first study to differentiate the effects of

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neuromodulation by MEP status.

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Keywords: rehabilitation, motor therapy, transcranial direct current stimulation,

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peripheral nerve stimulation, transcranial magnetic stimulation

35

Abbreviations

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ARAT – Action Research Arm Test

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EDC – extensor digitorum communis

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FMA – Fugl-Meyer Assessment

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MCID – minimal clinically important difference

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MEP – motor evoked potential

41

MSO – maximum stimulator output

42

PNS – peripheral nerve stimulation

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MOTOR EVOKED POTENTIALS POST-STROKE 43

tDCS – transcranial direct current stimulation

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TMS – transcranial magnetic stimulation

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MOTOR EVOKED POTENTIALS POST-STROKE 45

Approximately 795,000 individuals in the United States have a stroke each year 1. More

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than half will be dependent and need help to complete activities of daily living due to

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upper limb impairments 2. Because strokes are occurring at younger ages 3 and

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lifespans are increasing, there is an urgent need to identify interventions that can

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promote functional recovery of the upper limb.

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In the hours and days following a stroke, the presence or absence of motor evoked

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potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) predicts the extent

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of an individual’s motor recovery 4, 5. MEPs are thought to be an indicator of a functional

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corticospinal tract 6. An individual’s prognosis is better if MEPs can be evoked during

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the early period after acute stroke 6, regardless of interventions. There is, however, little

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published data that includes long-term follow-up of patients without MEPs and even less

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in patients with a severe-moderate stroke. Because additive interventions such as

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peripheral nerve stimulation (PNS), transcranial direct current stimulation (tDCS), or

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other neuromodulatory techniques may enhance motor recovery after stroke 7-12, there

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is a need to understand better whether individuals with severe-moderate stroke, who

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are commonly considered to have little potential for functional improvement, may benefit

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from these procedures. Additionally, a better understanding of the mechanisms

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underlying the biological effects of these techniques could help guide a personalized

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approach to treatment. We hypothesized that individuals with severe-moderate stroke-

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related motor impairments without MEPs can still achieve meaningful functional

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improvements, defined as the minimal clinically important difference (MCID), when

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receiving intensive motor training, either with or without additive neuromodulation.

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MOTOR EVOKED POTENTIALS POST-STROKE 67

We conducted an exploratory analysis of data from participants in our previous seven

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studies that combine neuromodulatory stimulation and upper extremity motor training

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who were at least six months post-stroke and had severe-moderate motor impairments

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at the time of enrollment 7, 8, 13-16. The purpose was to better understand the role of

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MEPs in predicting functional outcome with the long-term goal of identifying differences

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between individuals with severe-moderate stroke who do and do not respond to motor

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rehabilitation.

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Methods

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Participants

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This study utilized data collected in seven previous studies conducted by our group in

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our university research lab located within a rehabilitation hospital (six published7, 8, 13-16

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and one unpublished pilot study). All studies were approved by the XX Institutional

79

Review Board. Although the studies differed in methodology and intervention, all

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participants included in this analysis were at least six months post-stroke and had a

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Fugl-Meyer Assessment upper extremity (FMA) score of 34 or lower at baseline. This

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level of impairment is considered to be in the severe-moderate to severe range 17. Any

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participant who had TMS risk factors, and therefore did not undergo MEP assessments,

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was excluded. Participants in these studies received active or sham neuromodulatory

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stimulation (peripheral nerve stimulation and/or transcranial direct current stimulation),

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followed by upper extremity motor therapy.

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Intervention component 1: Neuromodulatory stimulation

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Participants received PNS or tDCS in each of the included studies.

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MOTOR EVOKED POTENTIALS POST-STROKE 89

Peripheral nerve stimulation

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Nerve stimulation was delivered to three nerves. Target nerves varied by participant

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based on their individual impairments. They were chosen from four pre-determined

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targets for stimulation: Erb’s point, posterior interosseous, radial, and median nerves.

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For active PNS, stimulation intensity was adjusted so that small compound muscle

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action potentials between 50-100µV were elicited in the absence of visible muscle

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contraction 18, which was generally below sensory threshold. Sham PNS intensity was

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set to 0V. PNS was delivered for two hours while the participants sat quietly, typically

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reading or watching a movie. Participants, therapists, and evaluators of motor function

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were masked to the treatment condition. Further details can be found in Carrico et al. 7-

99

9

and Salyers et al. 15.

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Transcranial direct current stimulation

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In the studies using tDCS, participants received anodal, cathodal, dual, or sham

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stimulation. In excitatory anodal and inhibitory cathodal stimulation, the active electrode

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was placed over M1 of targeted hemisphere and the reference electrode was placed

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over the contralateral supraorbital area. In dual stimulation, both electrodes were active.

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For active stimulation (anodal, cathodal, dual), intensities from 1.4 to 2mA were used,

106

dependent on the study. Some participants were able to feel tingling under the

107

electrodes at these intensities; however, within 2-5 minutes, sensation of stimulation

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faded. The anodal technique was used for sham stimulation and was designed to mimic

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the sensations of active stimulation, thus maintaining masking 19. Therapists and

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evaluators of motor function were also masked to the condition of tDCS. Further details

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can be found in Chelette et al. 13 and Powell et al. 14. 6

MOTOR EVOKED POTENTIALS POST-STROKE 112

Intervention component 2: intensive motor training

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Intensive motor training occurred immediately after neuromodulation was complete.

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Intensive task-oriented training was either delivered by an occupational therapist (five

115

studies) or robot-assisted training closely supervised by an occupational therapist (two

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studies). In all studies, therapists were masked to the condition of neuromodulatory

117

intervention. The training protocol followed the same principles of the intensive task-

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oriented therapy established with the EXCITE trial 20-22. Because of our participants’ low

119

function, however, we did not constrain the unaffected side. Therapists selected tasks

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from a predetermined battery of tasks. Tasks in this battery were repeatable and had a

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functional goal such as pinching, grasping, reaching, releasing, and/or rotating. Therapy

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was delivered in a 1:1 therapist-to-participant ratio and involved repetitive attempts. The

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difficulty level was adjusted for each participant in a given session. The specific tasks

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chosen and the time practicing each was recorded. Robot-assisted training primarily

125

consisted of reaching and grasp/release movements. Participants were secured in a

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height-adjustable chair with an over the-shoulder harness that buckles at the lap and

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chest. The affected arm rested in an arm trough with the hand grasping a handle inside

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the trough. The arm trough connected to the robotic interface, which included a

129

computer monitor that displayed visual cues in motor training sessions. It also included

130

a robotic frame that provided active assistance to the paretic upper extremity. During

131

training, a monitor displayed an image resembling a pie with eight triangular pieces. A

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target appeared in successive fashion at the center of the pie and at eight locations

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evenly spaced around the edge of the pie. The first 16 repetitions required unassisted

134

participant performance, but the robot assisted with subsequent movements if a

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MOTOR EVOKED POTENTIALS POST-STROKE 135

participant did not demonstrate necessary skill to complete the task. The task sequence

136

included the initial 16 repetitions followed by 12 sets of 80 movements per set, totaling

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960 potentially assisted movements. Training proceeded according to participants’

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reported tolerable levels of comfort and fatigue. For both training with a therapist or with

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a robot, participants were constantly challenged by increasing the difficulty of tasks as

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improvements were made, a concept referred to as shaping.23 The shaping technique is

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a behavioral approach to motor therapy in which trainers (a) elicit performance requiring

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a skill level just beyond that already demonstrated, and (b) provide verbal guidance

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concerning the sequence of movement. Rest breaks were given as needed. For further

144

details, see Carrico et al. 7-9, Powell et al. 14, and Salyers et al. 15.

145

Outcome measures

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Outcome measures were evaluated at baseline (≤7 days before first intervention) and

147

immediately after the intervention period in all studies. Five studies had one follow-up

148

evaluation at 1-month or 3-months post-intervention (follow-up 1).

149

Evaluation of motor function

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The Fugl-Meyer Assessment (FMA) was used as a motor function outcome measure for

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all studies. This assessment evaluates motor function and is based on the theory that

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stroke recovery occurs in a standard progression 24. It has been used extensively in

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stroke populations 24. Five of the studies also used the Action Research Arm Test

154

(ARAT) to measure upper extremity motor capacity. It is particularly responsive to

155

recovery in chronic stroke populations 25.

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MOTOR EVOKED POTENTIALS POST-STROKE 156

Evaluation of cortical excitability

157

Cortical excitability was measured with TMS. Extensor digitorum communis (EDC) was

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the target muscle in all studies, as it is used in finger extension, a movement that is

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often difficult for individuals with severe-moderate motor impairments after stroke. The

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motor strip and surrounding areas of the ipsilesional hemisphere were stimulated to

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determine whether a motor evoked potential (MEP) in the contralateral EDC could be

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elicited. Stimulator intensity was increased in increments of 20% of maximum stimulator

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output (MSO) if a MEP could not be elicited at the previous intensity. When necessary,

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the stimulator intensity was increased up to 100% MSO, if tolerated by the participant.

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Participants for whom a MEP could be elicited at or below 100% MSO at the baseline

166

evaluation were considered MEP positive; those who did not have an MEP at intensities

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up to 100% MSO at baseline were considered MEP negative. Additional information

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regarding complete TMS procedures can be found in Powell et al 14.

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Data analysis

170

The primary outcomes of interest of these analyses were the within-group changes in

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FMA and ARAT from baseline to immediate post-intervention and to follow-up. Changes

172

by group were explored with participants first grouped by stimulation condition (Active or

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Sham) and then by MEP status (MEP positive or MEP negative). An additional question

174

of interest was whether adding neuromodulatory stimulation differentially affects

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recovery in participants who were MEP positive or MEP negative. To address this

176

question, participants were further grouped by both MEP status and stimulation

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condition.

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MOTOR EVOKED POTENTIALS POST-STROKE 178

All analyses were performed using SPSS Statistics 24 (IBM, Armonk, New York) and

179

SAS version 9.4 (SAS Institute, Cary, NC). A p-value of <0.05 was predetermined to be

180

significant. Baseline differences were assessed for FMA, ARAT, age, and months since

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stroke.

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Because interest is in change over time with respect to FMA and ARAT, longitudinal

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repeated measures ANOVA models with unstructured working covariance matrices

184

were fit separately for each outcome, allowing for the assessment of changes to post-

185

intervention and follow-up within the framework of a single model. Importantly, such

186

models allow the estimation and testing of within-group mean changes, which is the

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primary focus of these analyses, with comparison of groups with respect to changes

188

being of secondary importance. However, between-group differences in changes were

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tested. Specifically, we conducted analyses based on longitudinal repeated measures

190

ANCOVA models, adjusting for baseline values, to ensure group comparisons were not

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influenced by baseline differences.

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Additionally, the proportions of participants with available data who obtained a MCID for

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FMA and ARAT at each time point were calculated. A stringent MCID of 9 was used for

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FMA 26 and 5.7 for ARAT 27, 28. No statistical analysis was performed on these

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proportions.

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Results

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Data from 129 participants in the seven studies were included in this analysis.

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Enrollment and follow-ups took place from September 2008 to September 2015. More

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data were available for FMA than ARAT, as all studies included FMA but not all included

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MOTOR EVOKED POTENTIALS POST-STROKE 200

ARAT. Baseline characteristics and demographics are shown in Table 1. There were no

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differences at baseline between the active and sham neurostimulation groups for FMA,

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ARAT, age, or months since stroke. Comparison of MEP negative/Sham, MEP

203

positive/Sham, MEP negative/Active, MEP positive/Active revealed baseline differences

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on FMA, ARAT, and age. The MEP positive/Active group had higher baseline scores on

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FMA and ARAT than the MEP negative/Sham (FMA p=0.015, ARAT p=0.004) and MEP

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negative/Active groups (FMA p=0.032, ARAT p=0.002). The MEP positive/Active group

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was also younger than the MEP negative/Active group (p=0.017). No baseline group

208

differences were found for months since the index stroke.

209

Analysis of within-group changes by sham and active stimulation showed that both

210

groups had improvements on both FMA and ARAT immediately post-intervention and at

211

follow-up (all p<0.05) (Figure 1). The group receiving active stimulation had non-

212

significantly greater improvements than the sham stimulation group on both outcome

213

measures at both time points.

214

Within-group analyses of changes from baseline to immediately post-intervention and

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follow-up with participants grouped by MEP negative or MEP positive status revealed

216

improvements for both groups (all p<0.05) (Figure 2). For both outcome measures and

217

at both time points, the MEP positive group had non-significantly greater improvements

218

than the MEP negative group.

219

The results of the analysis with participants grouped by both stimulation condition and

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MEP status are shown in Figure 3 with improvements on FMA immediately post-

221

intervention for all groups. Improvements were only found for MEP negative/Active and

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MOTOR EVOKED POTENTIALS POST-STROKE 222

MEP positive/Active groups at follow up. For ARAT, improvements were found for MEP

223

positive/Sham, MEP negative/Active, and MEP positive/Active groups both at

224

immediately post-intervention and follow-up. In comparing the different groups, the MEP

225

negative/Sham group always had the least improvement whereas the MEP

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positive/Active group always had the greatest improvement. Both MEP positive and

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negative groups had better outcomes when active stimulation was delivered.

228

Figure 4 shows the proportions of participants in each of the 4 groups who reached or

229

exceeded the MCID on FMA and ARAT. The MEP positive/Active group had the

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numerically greatest proportion of participants who achieved a MCID; for FMA, 33%

231

reached MCID at immediately post intervention and 30% at follow-up and for ARAT,

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27% at immediately post intervention and 41% at follow-up. Small proportions of

233

participants in the MEP negative groups were also able to achieve a MCID. In the MEP

234

negative/Sham group, 24% and 10% reached MCID for FMA at immediately post

235

intervention and follow-up, respectively, and 8% and 0% for ARAT. In the MEP

236

negative/Active group, 14% and 20% reached MCID for FMA at immediately post

237

intervention and follow-up, respectively, and 8% and 10% for ARAT. The distribution of

238

changes from baseline for all participants is shown for FMA (Figure 5) and ARAT

239

(Figure 6). Again, the greatest improvements were in participants in the MEP

240

positive/Active group. The majority of participants in all groups, however, improved.

241

Discussion

242

The results of this exploratory analysis suggest that a subset of individuals with severe-

243

moderate stroke-related motor impairments and without MEPs in response to TMS can

244

nonetheless achieve clinically meaningful improvements, defined as reaching or 12

MOTOR EVOKED POTENTIALS POST-STROKE 245

exceeding the MCID on FMA. Furthermore, neuromodulation such as tDCS and PNS

246

can augment the effects of motor training in these individuals. This preliminary finding is

247

crucial because of the belief that individuals with severe-moderate post-stroke

248

impairments, particularly those without MEPs, have limited or no capacity for

249

neuroplasticity.

250

To better understand the clinical implications of these improvements, MCIDs must be

251

evaluated in those with severe-moderate deficits who are at least six months post-

252

stroke. Various MCIDs for different stroke populations have been estimated for outcome

253

measures, including FMA and ARAT. The FMA MCID estimates of 4.25-7.25 29 and 6.6

254

25

255

a mild to moderate impairment. These MCIDs were not applied in our study because

256

individuals with a severe-moderate impairment were not included in the prior work. A

257

previous study in individuals with chronic, severe impairment utilized a MCID of 3, with

258

the theory that smaller changes may be more impactful in patients with long-term

259

severe impairments than in those with mild impairments 30, 31. The more stringent MCID

260

of 9, which was used in our analysis, was determined in individuals between one and

261

six months post-stroke and with varied levels of impairment, including those with

262

severe-moderate deficits 26. The MCID of 5.7 for ARAT 25, 28, which also was used in our

263

analysis, was calculated from data on individuals with mild to moderate impairments

264

who were at least one year post-stroke. An alternative MCID of 12 on the dominant side

265

and 17 on the non-dominant side, which was calculated in individuals an average of

266

nine days post-stroke with an average ARAT of 22 at baseline 32, has also been

267

proposed. Although this population includes individuals with severe-moderate

have been proposed for individuals who are more than one year post-stroke and have

13

MOTOR EVOKED POTENTIALS POST-STROKE 268

impairments, they are also in the stage in which spontaneous recovery commonly

269

occurs, and hence this MCID is not appropriate to use in individuals beyond the

270

spontaneous recovery phase. As these strikingly varied MCIDs indicate, the definition of

271

“clinically important” depends on both the amount of time that has passed since stroke

272

and the level of impairment. Therefore, it is important that MCIDs be established for

273

individuals at least 6 months post-stroke with severe-moderate impairments to better

274

understand the impact of interventions in this population.

275

Comparison with changes in FMA scores from other studies of individuals with severe

276

impairments at least six months post-stroke can help elucidate the effectiveness of our

277

neuromodulatory interventions paired with motor training, though no other study in this

278

population has accounted for MEP status. A study of 127 individuals at least six months

279

post-stroke with baseline FMA scores ranging from 7 to 38 compared intensive robotic

280

therapy and intensive comparison therapy, with three sessions per week over 12

281

weeks30. FMA scores improved by an average of 3.87 with robotic therapy and 4.01

282

points with intensive comparison therapy. A separate study of 26 individuals with a

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median baseline FMA of 17.5 and maximum of 35, tested a brain machine interface

284

(BMI) for triggering movement of the arm and fingers with an orthosis as well as muscle

285

stimulation to enable individuals to pick up pegs33. Ten days of 40-minute-long BMI

286

sessions and 40 minutes of standard occupational therapy resulted in a median FMA

287

increase of 2 points. A study of 31 more severely impaired individuals, with baseline

288

FMA of 19 or less, compared 45-minute sessions of mirror therapy with passive

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mobilization of the affected upper extremity34. After 24 sessions over eight weeks, the

290

mirror therapy and passive mobilization groups increased only 0.1 and 0.5 points on 14

MOTOR EVOKED POTENTIALS POST-STROKE 291

FMA, respectively. Finally, 18 individuals with a mean baseline FMA of 19.2 participated

292

in a two-phase inpatient study that included 10 days of BMI training and occupational

293

therapy followed by three weeks of hybrid assistive neuromuscular dynamic stimulation

294

for eight hours per day which included 90 minutes of occupational therapy five days per

295

week35. Following the BMI training, FMA scores had increased by 3.3 points, and

296

increased an additional 5.9 points after the hybrid assistive neuromuscular dynamic

297

stimulation, for an increase of 9.2 points from baseline. Our studies yield greater

298

improvements than other studies of similar populations, with the exception of the last

299

mentioned study which required participants to stay in the hospital and wear an

300

assistive device for eight hours every day. The study by Lo et al.30, which had

301

improvements most similar to ours, achieved these results over a period of 12 weeks,

302

whereas ours were achieved in intervention periods of six weeks or less. Therefore,

303

these results suggest that neuromodulatory stimulation may enhance or allow for faster

304

recovery from impairment in this particular population than conventional or other

305

experimental interventions. Again, the aforementioned studies do not report the MEP

306

status of the participants.

307

Our study also shows that there is a spectrum of effects in response to rehabilitative

308

interventions within MEP positive and MEP negative groups. Although the different

309

neuromodulatory interventions and motor training paradigms employed in the studies

310

used in our retrospective analysis may partially explain inter-individual variability, the

311

spectrum of responses is not a novel observation. The majority of studies in stroke

312

rehabilitation, including our work, only report group results and neglect the range of

313

individual responses. There is a need to further our understanding of the interplay of 15

MOTOR EVOKED POTENTIALS POST-STROKE 314

factors that can impact individual responses to neurorehabilitation to help guide

315

personalized neurorehabilitation.

316

Study limitations

317

Our exploratory analysis has several limitations. The protocols of the included studies

318

are heterogeneous. Although each involved neuromodulatory stimulation followed by

319

motor therapy, there was variability in the type of neuromodulatory stimulation and

320

therapy administered. Additionally, the participant sample was heterogeneous and

321

included those with both ischemic and hemorrhagic strokes, various stroke locations,

322

and a wide range of time elapsed since the stroke.

323

Conclusion

324

This analysis suggests that the absence of MEPs in individuals with chronic and severe-

325

moderate post-stroke motor impairments does not necessarily predict poor recovery.

326

When receiving motor training, individuals without MEPs may be capable of

327

improvement, though to a lesser degree than individuals who have MEPs. Recovery is

328

enhanced in those with and without MEPs with neuromodulatory stimulation. Future

329

studies should include participants with severe-moderate deficits.

330 331

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MOTOR EVOKED POTENTIALS POST-STROKE 332

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Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, et al. Heart disease and stroke statistics-2018 update: A report from the american heart association. Circulation. 2018;137:e67-e492 Carandang R, Seshadri S, Beiser A, Kelly-Hayes M, Kase CS, Kannel WB, et al. Trends in incidence, lifetime risk, severity, and 30-day mortality of stroke over the past 50 years. Jama. 2006;296:2939-2946 de los Rios F, Kleindorfer DO, Khoury J, Broderick JP, Moomaw CJ, Adeoye O, et al. Trends in substance abuse preceding stroke among young adults: A population-based study. Stroke. 2012;43:3179-3183 Rapisarda G, Bastings E, de Noordhout AM, Pennisi G, Delwaide PJ. Can motor recovery in stroke patients be predicted by early transcranial magnetic stimulation? Stroke. 1996;27:2191-2196 Pennisi G, Rapisarda G, Bella R, Calabrese V, Maertens De Noordhout A, Delwaide PJ. Absence of response to early transcranial magnetic stimulation in ischemic stroke patients: Prognostic value for hand motor recovery. Stroke. 1999;30:2666-2670 Smith MC, Stinear CM. Transcranial magnetic stimulation (tms) in stroke: Ready for clinical practice? J Clin Neurosci. 2016;31:10-14 Carrico C, Chelette KC, 2nd, Westgate PM, Powell E, Nichols L, Fleischer A, et al. Nerve stimulation enhances task-oriented training in chronic, severe motor deficit after stroke: A randomized trial. Stroke. 2016;47:1879-1884 Carrico C, Chelette KC, 2nd, Westgate PM, Salmon-Powell E, Nichols L, Sawaki L. Randomized trial of peripheral nerve stimulation to enhance modified constraint-induced therapy after stroke. Am. J. Phys. Med. Rehabil. 2016;95:397406 Carrico C, Westgate PM, Powell ES, Chelette K, Nichols L, Pettigrew LC, et al. Nerve stimulation enhances task-oriented training for moderate-to-severe hemiparesis 3-12 months after stroke: A randomized trial. Am J Phys Med Rehabil. 2018;in press Ikuno K, Kawaguchi S, Kitabeppu S, Kitaura M, Tokuhisa K, Morimoto S, et al. Effects of peripheral sensory nerve stimulation plus task-oriented training on upper extremity function in patients with subacute stroke: A pilot randomized crossover trial. Clin Rehabil. 2012;26:999-1009 Boggio PS, Nunes A, Rigonatti SP, Nitsche MA, Pascual-Leone A, Fregni F. Repeated sessions of noninvasive brain dc stimulation is associated with motor function improvement in stroke patients. Restor Neurol Neurosci. 2007;25:123129 Kang N, Summers JJ, Cauraugh JH. Transcranial direct current stimulation facilitates motor learning post-stroke: A systematic review and meta-analysis. J. Neurol. Neurosurg. Psychiatry. 2016;87:345-355 Chelette K, Carrico C, Nichols L, Salyers E, Sawaki L. Effects of electrode configurations in transcranial direct current stimulation after stroke. e-Health Networking, Applications and Services (Healthcom), 2014 IEEE 16th International Conference on. 2014:12-17 17

MOTOR EVOKED POTENTIALS POST-STROKE 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422

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15.

16.

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18.

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22.

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Powell ES, Carrico C, Westgate PM, Chelette KC, Nichols L, Reddy L, et al. Time configuration of combined neuromodulation and motor training after stroke: A proof-of-concept study. NeuroRehabilitation. 2016;39:439-449 Salyers E, Carrico C, Chelette KC, Nichols L, Henzman C, Sawaki L. Doseresponse effects of peripheral nerve stimulation and motor training in stroke: Preliminary data. e-Health Networking, Applications and Services (Healthcom), 2014 IEEE 16th International Conference on. 2014:7-11 Carrico C, Westgate PM, Salmon Powell E, Chelette KC, Nichols L, Pettigrew LC, et al. Nerve stimulation enhances task-oriented training for moderate-tosevere hemiparesis 3-12 months after stroke: A randomized trial. Am J Phys Med Rehabil. 2018;97:808-815 Woytowicz EJ, Rietschel JC, Goodman RN, Conroy SS, Sorkin JD, Whitall J, et al. Determining levels of upper extremity movement impairment by applying a cluster analysis to the fugl-meyer assessment of the upper extremity in chronic stroke. Arch. Phys. Med. Rehabil. 2016 Kaelin-Lang A, Luft AR, Sawaki L, Burstein AH, Sohn YH, Cohen LG. Modulation of human corticomotor excitability by somatosensory input. J Physiol. 2002;540:623-633 Gandiga PC, Hummel FC, Cohen LG. Transcranial dc stimulation (ocs): A tool for double-blind sham-controlled clinical studies in brain stimulation. Clin. Neurophysiol. 2006;117:845-850 Wolf SL, Thompson PA, Morris DM, Rose DK, Winstein CJ, Taub E, et al. The excite trial: Attributes of the wolf motor function test in patients with subacute stroke. Neurorehabil Neural Repair. 2005;19:194-205 Wolf SL, Winstein CJ, Miller JP, Taub E, Uswatte G, Morris D, et al. Effect of constraint-induced movement therapy on upper extremity function 3 to 9 months after stroke: The excite randomized clinical trial. JAMA. 2006;296:2095-2104 Wolf SL, Winstein CJ, Miller JP, Thompson PA, Taub E, Uswatte G, et al. Retention of upper limb function in stroke survivors who have received constraint-induced movement therapy: The excite randomised trial. Lancet Neurol. 2008;7:33-40 Wolf SL, Thompson PA, Winstein CJ, Miller JP, Blanton SR, Nichols-Larsen DS, et al. The excite stroke trial: Comparing early and delayed constraint-induced movement therapy. Stroke. 2010;41:2309-2315 Gladstone DJ, Danells CJ, Black SE. The fugl-meyer assessment of motor recovery after stroke: A critical review of its measurement properties. Neurorehabil. Neural Repair. 2002;16:232-240 van der Lee JH, Beckerman H, Lankhorst GJ, Bouter LM. The responsiveness of the action research arm test and the fugl-meyer assessment scale in chronic stroke patients. J Rehabil Med. 2001;33:110-113 Arya KN, Verma R, Garg RK. Estimating the minimal clinically important difference of an upper extremity recovery measure in subacute stroke patients. Top. Stroke Rehabil. 2011;18 Suppl 1:599-610 Pandian S, Arya KN. Stroke-related motor outcome measures: Do they quantify the neurophysiological aspects of upper extremity recovery? J. Bodyw. Mov. Ther. 2014;18:412-423 18

MOTOR EVOKED POTENTIALS POST-STROKE 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451

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29.

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31.

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33.

34.

35.

Van der Lee JH, De Groot V, Beckerman H, Wagenaar RC, Lankhorst GJ, Bouter LM. The intra- and interrater reliability of the action research arm test: A practical test of upper extremity function in patients with stroke. Arch. Phys. Med. Rehabil. 2001;82:14-19 Page SJ, Fulk GD, Boyne P. Clinically important differences for the upperextremity fugl-meyer scale in people with minimal to moderate impairment due to chronic stroke. Phys. Ther. 2012;92:791-798 Lo AC, Guarino PD, Richards LG, Haselkorn JK, Wittenberg GF, Federman DG, et al. Robot-assisted therapy for long-term upper-limb impairment after stroke. N Engl J Med. 2010;362:1772-1783 Lo AC, Guarino P, Krebs HI, Volpe BT, Bever CT, Duncan PW, et al. Multicenter randomized trial of robot-assisted rehabilitation for chronic stroke: Methods and entry characteristics for va robotics. Neurorehabilitation and neural repair. 2009;23:775-783 Lang CE, Wagner JM, Dromerick AW, Edwards DF. Measurement of upperextremity function early after stroke: Properties of the action research arm test. Arch Phys Med Rehabil. 2006;87:1605-1610 Nishimoto A, Kawakami M, Fujiwara T, Hiramoto M, Honaga K, Abe K, et al. Feasibility of task-specific brain-machine interface training for upper-extremity paralysis in patients with chronic hemiparetic stroke. J. Rehabil. Med. 2018;50:52-58 Colomer C, E NO, Llorens R. Mirror therapy in chronic stroke survivors with severely impaired upper limb function: A randomized controlled trial. Eur. J. Phys. Rehabil. Med. 2016;52:271-278 Kawakami M, Fujiwara T, Ushiba J, Nishimoto A, Abe K, Honaga K, et al. A new therapeutic application of brain-machine interface (bmi) training followed by hybrid assistive neuromuscular dynamic stimulation (hands) therapy for patients with severe hemiparetic stroke: A proof of concept study. Restor. Neurol. Neurosci. 2016;34:789-797

452

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MOTOR EVOKED POTENTIALS POST-STROKE 453

Suppliers

454

a

455

Technologies, Warwich, RI

456

b

457

c

458

d

Peripheral nerve stimulation: S88 stimulator and SIU8T stimulus isolation unit, Grass

Transcranial direct current stimulation: Magstim, Whitland, Dyfed, UK

Transcranial magnetic stimulation: 2002, Magstim, Whitland, Dyfed, UK Neuronavigation: Brainsight, Rogue Research Inc, Montreal, Canada

459

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MOTOR EVOKED POTENTIALS POST-STROKE 460

Titles and captions to figures

461

Figure 1. Change from baseline in behavioral outcome measures by stimulation

462

condition. Statistically significant improvements were observed for both sham and active

463

stimulation groups at both time points on FMA and ARAT. * denotes statistical

464

significance (p≤0.05) and ** denotes statistical significance with the Bonferroni

465

correction for multiple comparisons (p≤0.0125).

466

Figure 2. Change from baseline in behavioral outcome measures by MEP status. MEP

467

negative and MEP positive groups had statistically significant improvements on FMA

468

and ARAT at both time points. The improvements were more pronounced for MEP

469

positives than MEP negatives. ** denotes statistical significance with the Bonferroni

470

correction for multiple comparisons (p≤0.0125).

471

Figure 3. Change from baseline in behavioral outcome measures by stimulation

472

condition and MEP status. All groups had improvements on FMA and ARAT at

473

immediately post intervention and follow-up evaluations. MEP negative/Sham

474

consistently showed the least improvement whereas MEP positive/Active consistently

475

had the most improvement. Statistically significant improvements were consistently

476

found for MEP negative/Active and MEP positive/Active groups. * denotes statistical

477

significance (p≤0.05) and ** denotes statistical significance with the Bonferroni

478

correction for multiple comparisons (p≤0.00625)

479

Figure 4. Proportion of participants who achieved MCID by stimulation condition and

480

MEP status. The MEP positive/Active group had the greatest proportion of participants

481

who achieved MCID on FMA and ARAT at both time points. All groups had at least one

21

MOTOR EVOKED POTENTIALS POST-STROKE 482

participant achieve MCID at the immediately post intervention assessment on FMA and

483

ARAT. Both MEP negative/Active and MEP positive/Active groups had participants

484

reach MCID on FMA and ARAT immediately post intervention and at follow-up.

485

Figure 5. Change in individual scores on FMA at immediately post intervention and

486

follow-up assessments by stimulation condition and MEP status. The majority of

487

participants across all groups showed some amount of improvement (>0) whereas a

488

smaller proportion exceeded the MCID of 9 (dashed line).

489

Figure 6. Change in individual scores on ARAT at immediately post intervention and

490

follow-up assessments by stimulation condition and MEP status. Most participants

491

demonstrated improvements with some participants exceeding the MCID of 5.7 (dashed

492

line).

493

22

Table 1. Baseline characteristics/demographics MEP-/Sham

MEP+/Sham

MEP-/Active

MEP+/Active

FMA*

17.3±7.5 (234)

21.6±8.2 (833)

18.8±7.2 (633)

23.2±7.2 (9-34)

ARAT*

4.7±3.4 (012)

10.6±5.7 (419)

5.7±3.7 (015)

11.6±9.5 (335)

Mean age at enrollment (y)*

66.8±7.0 (46-80)

63.4±12.3 (37-77)

60.0±13.0 (19-80)

66.7±8.9 (41-80)

Time since stroke (months)

46.6±61.5 (6-219)

34.7±37.4 (6-118)

44.9±38.8 (7-182)

51.0±54.4 (6-194)

Sex (M/F)

14/7

6/3

35/34

16/14

Stroke type (ischemic/hemorrhagic)

15/6

7/2

47/22

24/6

Stroke location (cortical/subcortical/cortical and subcortical/other)

12/8/0/1

5/4/0/0

48/19/2/0

20/8/0/2

Handedness before stroke (L/R)

3/18

0/9

5/64

8/22

Paretic UE (L/R)

9/12

5/4

38/31

11/19

sample mean ± standard deviation (range) *Overall significant differences were found between groups.

**

Fugl-Meyer UE motor change

** 5

**

*

4

Action Research Arm Test change

4

6

*

3.5 3

*

**

**

2.5

2 Sh a… 1.5

3 2 1 0 Post - baseline

Follow-up - baseline

Sham Active

1 0.5 0 Post - baseline

Follow-up - baseline

5 **

7

**

6 5

**

4

**

3 2 1 0

**

**

4.5 Action Research Arm Test change

Fugl-Meyer UE motor change

8

4 3.5 3

2.5 MEP neg… 2

**

** MEP negative MEP positive

1.5 1 0.5 0

Post - baseline

Follow-up - baseline

Post - baseline

Follow-up - baseline

** **

7 *

6 5

**

**

**

4 3 2 1 0

6 Action Research Arm Test change

Fugl-Meyer UE motor change

8

5

* *

**

**

4 3 2

MEP neg/Sham MEP ** neg/Sha m

*

MEP neg/Active MEP pos/Active

1 0

Post - baseline

Follow-up baseline

MEP pos/Sham

Post - baseline

Follow-up baseline

Action Research Arm Test MCID reached

Fugl-Meyer UE motor MCID reached

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Post - baseline

Follow-up baseline

100% 90% 80% 70% 60% 50% MEP neg/Sha 40% m 30% 20% 10% 0% Post - baseline

MEP neg/Sham MEP pos/Sham MEP neg/Active MEP pos/Active

Follow-up baseline

35

30

30

25 20 15 10 5 0 -5 -10 -15

Fugl-Meyer UE motor follow-up - baseline

Fugl-Meyer UE motor post - baseline

35

25 20 MEP 15 neg/No Stim MEP pos/No 10 Stim MEP 5 neg/Stim 0 -5 -10 -15

MEP neg/Sham MEP pos/Sham MEP neg/Active MEP pos/Active

20

15

10

5

0

-5

25 Action Research Arm Test follow-up baseline

Action Research Arm Test post - baseline

25

20

15 MEP neg/Sham MEP 10 pos/Sham MEP neg/Active 5

0

-5

MEP neg/Sham MEP pos/Sham MEP neg/Active MEP pos/Active