Effect of Transcutaneous Spinal Cord Stimulation on Spasticity, Mobility, Pain and Sleep in Community Dwelling Individuals Post-Stroke

Effect of Transcutaneous Spinal Cord Stimulation on Spasticity, Mobility, Pain and Sleep in Community Dwelling Individuals Post-Stroke A single case withdrawal design

Belinda Chenery

Thesis for the degree of Master of Science in Movement Science June 2019

Effect of Transcutaneous Spinal Cord Stimulation on Spasticity, Mobility, Pain and Sleep in Community Dwelling Individuals Post-Stroke A single case withdrawal design

Belinda Chenery

Thesis for the degree of Master of Science in Movement Science

Number of credits: 60 ECTS

Supervisor: Anestis Divanoglou

Masters committee: Anestis Divanoglou, Kristín Briem, Þórður Helgason

Department of Physical Therapy

Faculty of Medicine

School of Health Sciences June 2019

Áhrif raförvunar mænu með yfirborðsskautum á síspennu, hreyfigetu, verki og svefn einstaklinga sem hafa fengið heilaslag og búa heima Einliðavendisnið

Belinda Chenery

Ritgerð til meistaragráðu í hreyfivísindum

Fjöldi eininga: 60 ECTS

Umsjónarkennari: Anestis Divanoglou

Meistaranámsnefnd: Anestis Divanoglou, Kristín Briem, Þórður Helgason

Námsbraut í sjúkraþjálfun

Læknadeild

Heilbrigðisvísindasvið Háskóla Íslands

Júní 2019

Thesis for master’s degree in Physiotherapy at the University of Iceland. No part of this publication may be reproduced in any form without the prior permission of the copyright holder.

Prentun: Háskólaprent

Reykjavík, Ísland, 2019

Abstract

Effective treatment modalities for alleviating spasticity and pain and enhancing mobility and sleep are limited post-stroke. Some evidence suggests that techniques of transcutaneous spinal cord stimulation (tSCS) may be beneficial. However, these are typically small pretest-posttest studies with high risk of bias. To date, there are no studies that evaluate the effects of tSCS in stroke. The aim of the current study was to evaluate the effects of daily home-treatment with tSCS on spasticity, mobility, pain and sleep in community dwelling individuals post-stroke. Four cases were included in a single-subject withdrawal research design comprised of two alternating baseline and intervention phases (ABAB). Each phase consisted of three measurement sessions. Clinical, biomechanical and self-report data were collected and analysed with visual and statistical techniques, suitable for single-subject design. The intervention consisted of daily home application of tSCS for three weeks. Treatment efficacy was disparate between participants. For one out of the four cases, the results revealed large effect sizes for spasticity, mobility, pain and sleep when using tSCS the first time. Maintenance of effect size from the first baseline to second intervention phase was statistically significant for mobility, pain and sleep. In the other three cases, apart from an improvement on two occasions for mobility measures, there were no improvements. Repetition of a positive effect size was not demonstrated in any case. The results of the study indicate that tSCS may be a useful tool in post-stroke rehabilitation for alleviating spasticity and pain and enhancing mobility and sleep in some community dwelling individuals post-stroke. This inexpensive, non-invasive and easily accessible home-treatment method may be a suitable tool for some individuals.

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Ágrip

Árangursrík meðferðarform sem miða að því að draga úr síspennu og verkjum og bæta hreyfigetu og svefn eru af skornum skammti fyrir þá sem fengið hafa heilaslag. Vísbendingar eru um að raförvun mænu með yfirborðsrafskautum (tSCS) geti verið gagnleg, en flestar rannsóknir á þessu sviði eru einfaldar tilviksrannsóknir, með tilheyrandi hættu á skekkjum. Ekki eru til neinar kerfisbundnar rannsóknir þar sem áhrif tSCS eru könnuð á einstaklinga sem fengið hafa heilaslag. Markmið þessarar rannsóknar var að kanna áhrif daglegrar tSCS heimameðferðar á síspennu, verki, hreyfigetu og svefn meðal einstaklinga sem fengið höfðu heilaslag og búa heima. Fjórir þátttakendur tóku þátt í rannsókninni. Notast var við einliðavendisnið sem samanstóð af tveimur grunnlínum og tveimur inngripsskeiðum (ABAB snið). Hvert skeið innihélt þrjár mælingalotur. Klínískt mat, lífaflsfræðilegar mælingar og huglægt mat þátttakenda var notað til að meta áhrif íhlutunar. Í samræmi við aðferðafræði einliðasniðsrannsókna var notast við sjónrænar greiningar og viðeigandi tölfræði í greiningu niðurstaðna. Íhlutun gekk út á daglega notkun á tSCS í þrjár vikur. Reiknaðar voru áhrifastærðir til að meta hvort íhlutun hafði áhrif umfram grunnlínu. Niðurstöður voru mismunandi eftir þátttakendum. Í einu tilvikanna sýndu áhrifastærðir töluverð áhrif á síspennu, hreyfigetu, verki og svefn í fyrstu íhlutun. Einnig var tölfræðilega marktækur munur á milli fyrsta grunnlínuskeiðs og seinni íhlutunar á hreyfigetu, verkjum og svefni. Áhrifin sem komu fram í fyrri íhlutun virðast hafa haldið sér inn í seinna grunnlínuskeið, sem bendir til að tíminn á milli hafi ekki verið nægur. Hjá hinum þremur þátttakendunum reyndist ekki munur á milli íhlutunar og grunnlínu, nema í tveimur tilvikum í mælingum á hreyfigetu. Niðurstöður benda til að tSCS geti verið gagnlegt inngrip í endurhæfingu þeirra sem fengið hafa heilaslag í þeim tilgangi að draga úr áhrifum síspennu og verkja, ásamt því að bæta hreyfigetu og svefn. Um er að ræða ódýrt, einfalt og aðgengilegt inngrip sem kann að vera gagnlegt í sumum tilvikum.

Acknowledgements and Funding

Firstly, I would like to express my sincere gratitude to my supervisor, Dr. Anestis Divanoglou, for his encouragement, constructive guidance and insightful suggestions for this research project and dissertation. Your exceptional skills as a supervisor not only kept me afloat and guided me in the right direction but inspired me to reach new potentials and most importantly, enjoy the process.

My deepest gratitude goes to Dr. Þórður Helgason, for his unwavering support and invaluable contribution to the implementation of this project and for his contribution to my Master´s Committee. I gratefully acknowledge the constructive guidance of Dr. Kristín Briem in my Master´s Committee and for her contribution in introducing me to this project.

This research project and thesis would not have evolved without the ambitious research team from Grensás, Rehabilitation Unit of Landspitali - National University Hospital of Iceland: Gígja Magnúsdóttir and Vilborg Guðmundsdóttir, physiotherapists and Guðbjörg Ludvigsdóttir M.D. I am deeply indebted to you and Dr. Þórður Helgason for inaugurating research on tSCS in Iceland, warmly introducing me to your research team and unselfishly participating in formulating and conducting this research project. Your clinical expertise and ongoing search for rehabilitation tools that extend the boundaries of neurological rehabilitation were inspiring and deserve my deepest respect. I will miss our research time together! I cannot thank Halldór Kárason enough for his large and essential contribution in collecting, processing, analysing and presenting data. Thank you Halldór for your exceptional work, prompt responses and patience. Good luck in your future studies in Biomedical Engineering! An immense thank you is due to the Health Technology Centre of Reykjavík University for a successful collaboration and access to your fine facilities and research equipment. I would like to extend my sincere thanks to Milan R. Dimitrijevic, José Luis Vargas Luna, Winfried Mayr and Matthias Krenn, from the University Hospital in Vienna, for their advice and contribution in teaching the research team and myself methods of tSCS application and biomechanical methods of assessing spasticity. An extended gratitude to José and Winfried for welcoming me to your workplace in Vienna and opening my eyes to the clinical possibilities of tSCS.

A very special gratitude goes out to the Icelandic Physiotherapy Association and the National University Hospital of Iceland for their financial support. Also, to the Student Innovation Fund of Rannis for funding preliminary pilot studies on tSCS which helped in preparation of research methods and data processing.

Last, but by no means least, I would like to thank my family: my husband, daughter and son-in-law for their encouragement, practical assistance in data analysis and technical issues and my two teenage sons for their exceptional patience and understanding.

Table of contents

Abstract...... iii Ágrip ...... iv Table of contents ...... vi List of tables ...... viii List of figures ...... viii Abbreviations ...... ix 1 Introduction ...... 1 1.1 Stroke Epidemiology ...... 1 1.2 Stroke ...... 1 1.3 Electrical Stimulation for Post-stroke Treatment ...... 2 1.4 Spinal Cord Stimulation ...... 3 1.5 Transcutaneous Spinal Cord Stimulation (tSCS) ...... 4 1.6 Risks ...... 5 2 Aim ...... 5 2.1 Objective ...... 5 2.2 Research Question ...... 5 2.3 Research Hypothesis ...... 5 3 Method ...... 5 3.1 Research Design ...... 5 3.2 Participants ...... 6 3.2.1 Participant recruitment ...... 6 3.2.2 Inclusion and exclusion criteria ...... 6 3.2.3 Screening ...... 7 3.2.4 Participant Characteristics ...... 7 3.3 Procedure ...... 8 3.3.1 Intervention ...... 9 3.3.2 Measurements ...... 10 3.3.3 Data Collection ...... 18 3.3.4 Data Analysis...... 19 3.4 Ethics ...... 21 3.5 Declaration of Conflicting Interests ...... 21 3.6 Funding ...... 21 4 Results ...... 21 4.1 Spasticity ...... 21 4.1.1 Tardieu Scale ...... 21

4.1.2 Wartenberg Pendulum Test (WPT) - R2n ...... 22 4.1.3 Penn Spasm Frequency Scale (PSFS) ...... 22 4.2 Mobility ...... 29 4.2.1 Ten-metre Walking Test (10mWT) - Comfortable Walking Speed ...... 29 4.2.2 Ten-metre Walking Test (10mWT) – Fast Walking Speed ...... 29 4.2.3 Timed Up and Go (TUG) ...... 29

4.2.4 Five Times Sit-to-Stand Test (FTSTS) ...... 29 4.2.5 Activities-Specific Balance Confidence Scale (ABC scale) ...... 30 4.3 Pain and Sleep ...... 37 4.3.1 11-Point Numerical Rating Scale (NRS) – Pain ...... 37 4.3.2 11-Point Numerical Rating Scale (NRS) – Sleep ...... 37 4.4 Other Results ...... 41 4.4.1 Summary of Effect for each Participant ...... 41 4.4.2 Patient Global Impression of Change (PGIC) ...... 41 4.4.3 Compliance to treatment ...... 45 4.4.4 Other Findings from Participants ...... 45 4.4.5 Lost Data ...... 45 4.4.6 Voluntary Activation of ankle Dorsi- and Plantar Flexion (Co-Contraction) ...... 45 5 Discussion ...... 46 5.1 Spasticity ...... 46 5.2 Mobility ...... 49 5.3 Pain and Sleep ...... 50 5.4 Strengths and Limitations ...... 51 5.5 Research and Clinical Implications ...... 52 6 Conclusion ...... 53 References ...... 54 Appendix 1: Information Sheet to Patients ...... 66 Appendix 2: Informed Consent ...... 69 Appendix 3: Background Information ...... 70 Appendix 4: mRS ...... 71 Appendix 5: Protocol for Measurements ...... 72 Appendix 6: Intervention - Device Settings ...... 75 Appendix 7: The TIDieR Checklist ...... 76 Appendix 8: Logbook ...... 78 Appendix 9: Tolerance for Treatment Questionnaire ...... 79 Appendix 10: Order of EMG Measurements ...... 80 Appendix 11: Self-Report Questionnaire ...... 81 Appendix 12: Hand-held Goniometer Measurements ...... 84 Appendix 13: Ethics Approval ...... 85 Appendix 14: Ethics Renewal ...... 86 Appendix 15: Hospital Approval ...... 88 Appendix 16: Tables for Within-Phase Level, Trend and Variability ...... 89 Appendix 17: Autocorrelation Tables ...... 92

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List of tables

Table 1. Participant characteristics ...... 8 Table 2. Summary of Evaluation Methods ...... 11 Table 3. Between-Phase Effect Sizes (CI95%) for Spasticity ...... 28 Table 4. Between-Phase Effect Sizes (CI95%) for Mobility ...... 36 Table 5. Between-Phase Effect Sizes (CI95%) for Pain and Sleep ...... 40

List of figures

Figure 1. Flow chart showing phases, weeks and data collection points ...... 6 Figure 2. Position of electrodes for tSCS ...... 9 Figure 3. Intervention device ...... 10 Figure 4. Processing of EMG data ...... 14 Figure 5: Placement of goniometers on ankle and knee and EMG sensors on leg muscles ...... 19 Figure 6. Tardieu Scale - Spasticity Angle (°) of muscle reaction to fast movement (R1) of plantar flexors ...... 23 Figure 7. Tardieu Scale – Passive range of motion (°) during slow movement (R2) of ankle into dorsiflexion ...... 24 Figure 8. Wartenberg Pendulum Test - R2n coefficients ...... 25 Figure 9. Penn Spasm Frequency Scale – Spasm Frequency ...... 26 Figure 10. Penn Spasm Frequency Scale – Spasm Severity ...... 27 Figure 11. Ten-metre Walking Test – Comfortable Speed ...... 31 Figure 12. Ten-metre Walking Test – Fast Speed ...... 32 Figure 13. Timed Up and Go ...... 33 Figure 14. Five times Sit-to-Stand Test ...... 34 Figure 15. Results for balance confidence (%), for all participants on the ABC Scale ...... 35 Figure 16. 11-point Numerical Rating Scale – Pain ...... 38 Figure 17.11-point Numerical Rating Scale – Sleep ...... 39 Figure 18. Forest Plot - Phases A1 and B1 ...... 42 Figure 19. Forest Plot - Phases A2 and B2 ...... 43 Figure 20. Patient Global Impression of Change for spasticity, pain and sleep ...... 44

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Abbreviations

10mWT Ten-metre Walking Test 2SDBM two-standard deviation band method A baseline phases ABC Activities-specific Balance Confidence scale B intervention phases CI confidence intervals EMG electromyography ES effect size FTSTS Five Times Sit-to-Stand H hamstrings muscle: biceps femoris (long and short head) mRS modified Rankin Scale MS multiple sclerosis MVIC maximum voluntary isometric contraction NRS 11-point Numerical Rating Scale PGIC Patient Global Impression of Change PROM passive range of motion PSFS Penn Spasm Frequency Scale PSFSF Penn Spasm Frequency Scale – frequency of spasms PSFSS Penn Spasm Frequency Scale – severity of spasms Q quadriceps femoris muscle: rectus femoris R1 spasticity angle - Tardieu Scale R2 passive range of motion - Tardieu Scale

R2n index of spasticity RMS root-mean-square S3 Subject 3 S4 Subject 4 S5 Subject 5 S6 Subject 6 SCATS Spinal Cord Assessment Tool for Spastic Reflexes SCI spinal cord injury SCS spinal cord stimulation SD standard deviation SSRD single subject research design TA tibialis anterior muscle TENS transcutaneous electrical nerve stimulation TS triceps surae muscle: gastrocnemius lateralis tSCS transcutaneous spinal cord stimulation TUG Timed Up and Go test WPT Wartenberg pendulum test

1 Introduction

1.1 Stroke Epidemiology A stroke or cerebrovascular accident is caused by insufficient blood supply (ischaemia) to the brain that deprives the brain of oxygen (anoxia) and nutrients and results in local death of brain tissue (infarction) (Johnson et al., 2016). Strokes are categorized as either ischemic or haemorrhagic. An ischemic stroke is due to closure of a blood vessel from a blood clot (thrombosis or embolus) whereas a haemorrhagic stroke occurs from a ruptured blood vessel, resulting in disruption of the brain´s blood flow (Benjamin Emelia et al., 2018). In an overview of population-based studies on the proportional frequency of stroke types, 67-80% of strokes were classified as ischaemic strokes, 7.3-26.6% as haemorrhage strokes and 2-14.5% as undefined strokes (Feigin et al., 2003).

Incidence of stroke increases rapidly with age, being 670-970/100,000/year for 65-74-year olds in the United States (Roger et al., 2011). Even though ischemic stroke incidence has declined by 13% from 1990-2010, in higher income countries, it is still the 5th leading cause of death in the United States (Benjamin Emelia et al., 2018; Ovbiagele et al., 2011). Around 15% of people who have a stroke, die within the first 30 days and 15-30% are left permanently disabled (World Health Organization, 2019). The World Health Organization puts ischaemic stroke in third place for causing severe levels of disability in the world (Johnson, Onuma, Owolabi, & Sachdev, 2016). In the United States, it is the leading cause of chronic disability and the second leading cause of dementia (Roger et al., 2011). The prevalence of stroke in the United States is around 3% of the adult population, affecting around 7 million people (Roger et al., 2011). In Iceland, the stroke incidence is 144/100000/year for the adult population (aged ≥ 18 years. Of these, 81% are from ischemic stroke, 9% from intracerebral haemorrhage, 7% from subarachnoid hemorrhage and 3% from unknown causes (Hilmarsson et al., 2013).

1.2 Stroke Stroke results in irreversible damage to the brain. Depending on the site and amount of tissue damage, neurological impairments emerge. These impairments include neurological dysfunctions (e.g. sensory, motor and visual) as well as neuropsychological deficits (e.g. memory, language, attention) (Geyh et al., 2004). Motor impairments are the most widely recognized impairments caused by stroke, including symptoms such as muscle weakness (paralysis), loss of dexterity, exaggeration of reflexes (hyperreflexia), spasticity and muscle stiffness (Langhorne et al., 2009). Commonly, a combination of these motor impairments appears after stroke and cause limitations in muscle control and mobility (Geyh et al., 2004). Such limitations can impair the ability to perform and participate in activities of daily living, resulting in disability and participation restrictions (WHO, 2001).

Rehabilitation following stroke is aimed at enhancing recovery of function and ameliorating undesirable secondary symptoms (Stroke Foundation, 2017). Although post-stroke outcomes depend largely on recovery mechanisms that occur in the first six months after stroke (e.g. resolution of diaschisis and recovery of penumbral tissues), functional improvement can extend beyond this timeframe through mechanisms of neural plasticity and behavioural compensation strategies (Kwakkel et al., 2004). For functional improvement to occur, implementation of effective rehabilitation and learning

strategies is crucial and relies on complex training (Warraich et al., 2010). To date, a combination of task-specific training and general aerobic exercise is believed to be the gold-standard treatment for restoring motor function post-stroke (Stroke Foundation, 2017). However, even with intensive training, disability and debilitating symptoms, such as spasticity, pain, and fatigue prevail and frequently impair well-being and quality of life post-stroke (Bethoux, 2015; Gillard et al., 2015; Ingles et al., 1999; Sommerfeld et al., 2012).

Spasticity is defined by the EU spasm consortium as “disordered sensor-motor control, resulting from an upper motor neuron lesion, presenting as intermittent or sustained involuntary activation of muscles” (Pandyan et al., 2005). Research has shown that it arises in over 30% of stroke patients and can lead to muscle contracture, impeded mobility and commonly induces pain (Bhakta, 2000; Harrison et al., 2015). Spasticity has a significant and clinically negative impact on health-related quality of life of stroke survivors (Gillard et al., 2015). Pain commonly develops in the upper and lower limbs within the first 12 weeks after stroke and nearly exclusively emerges in patients with spasticity (Wissel et al., 2010). Pain is more common in post-stroke patients with moderate to severe spasticity (91%), compared to patients with mild spasticity (43%) (Wissel et al., 2010). There is growing evidence that sleep disorders are frequent following stroke (Medeiros et al., 2011; Tang et al., 2015). Commonly, stroke survivors complain of fatigue as their worst symptom and sleep deprivation has been associated with worse recovery outcomes (Duss et al., 2017; Ingles et al., 1999). Studies suggest that promoting sleep enhances neuroplasticity and facilitates recovery after stroke (Hodor et al., 2014). Limited research has been done on the interplay of spasticity, pain and sleep, but anecdotal evidence supports the hypothesis that they may be reciprocally related post-stroke. Sudden painful muscle spasms frequently occur at night, disturbing sleep and causing daytime fatigue that further exasperates spasticity and pain and has adverse effect on mobility. Effective treatment modalities for spasticity and post-stroke pain are limited (Stroke Foundation, 2017). Conventional management of spasticity after stroke include identifying and treating exacerbating factors (e.g., pressure sores, constipation and pain), ideal posture and limb positioning and specific spasticity treatment (e.g., physical treatment, pharmacological treatment; botulinum toxin, baclofen, dantrolene, electrical stimulation and invasive surgical methods) (Bhakta, 2000). However, there is a lack of evidence to demonstrate the effectiveness of physical treatment on spasticity and pain and pharmaceutical interventions have numerous undesirable side effects (e.g., muscle weakness, drowsiness and hepatotoxicity) (Thibaut et al., 2013). As therapeutic options in treating these symptoms are limited, clinicians are often left resourceless and rehabilitation after stroke is hampered (Dietz et al., 2007). For this reason, a multidisciplinary approach of treatment for these conditions is integral in extending the boundaries of post-stroke treatment (Langhorne et al., 2011). To date, such approaches include pharmacological, biological and electrophysiological treatments (Dimyan et al., 2011).

1.3 Electrical Stimulation for Post-stroke Treatment Electrical stimulation methods are recommended as an effective treatment modality in stroke rehabilitation for managing various stroke-related consequences (Stroke Foundation, 2017). Methods of electrical stimulation include peripheral and central stimulation, both aiming to enhance motor

recovery and reduce spasticity and pain (Takeda et al., 2017). Peripheral nerve stimulation (PNS) consists of direct stimulation of muscles, whilst central stimulation involves stimulating the central nervous system, consisting of the brain and spinal cord. Peripheral stimulation administered to paralyzed and spastic regions post-stroke has shown promising positive effects on functional activity, muscle function, spasticity and pain (Alabdulwahab et al., 2010; Mahmood et al., 2019; Sahin et al., 2012). Brain stimulation has received considerable attention in the last 20 years and been demonstrated to enhance recovery after stroke (Rossini et al., 2015). Epidural spinal cord stimulation (SCS) is another central stimulation method that has been used effectively for decades, to treat pain and spasticity (Nagel et al., 2017; Turner et al., 2004). Peripheral and central electrical stimulation of the nervous system may therefore be an effective adjunct to traditional post-stroke treatments to facilitate motor recovery and even enhance neuroplasticity (Dimyan & Cohen, 2011; Fritsch et al., 2010).

1.4 Spinal Cord Stimulation Spinal cord stimulation (SCS) was originally proposed as a potential method of pain relief when it was clinically applied subdural to a cancer patient with striking abolishment of his pain (Shealy et al., 1967). A few years later clinicians applying SCS for pain relief in patients with Multiple Sclerosis (MS), reported a positive effect on motor and sensory function and introduced it as a therapeutic modality for neurological conditions in MS (Cook et al., 1973). A preliminary report on the effects of epidural SCS on patients with MS indicated “a significant improvement in motor, cerebellar, brain stem and sensory function in five patients” (Cook, 1976). Some subsequent trials with SCS confirmed these positive findings on motor and sensory function in MS and found an additional positive effect on urethral sphincter function (Abbate et al., 1977; Cook, 1976; Illis et al., 1980). However, many of these studies can be criticised for methodological reasons as they have small sample sizes, lack a control group, poor description of evaluation methods and lack quantification and statistical analysis of study results. In contrast to positive reports, a 45-month follow-up study on the long term effect of SCS on twenty-three MS patients did not show evidence of an improvement in neurological symptoms after implantation of SCS (Young et al., 1979). In this study, no long-term differences were noted on disability scales and motor and sensory function. However, 50% of the patients in this study did report a subjective improvement. These improvements included increased energy, an improved sense of well-being, a subjective feeling of increased strength and balance as well as more normal sleep patterns. However, six-months later, these subjective improvements were only sustained in 30% of patients. Also, of the 23 patients, 15, or 65% experienced significant complications with the surgically implanted equipment which required 21 operational procedures for corrections (Young & Goodman, 1979).

Despite reservations, the emergence of SCS provided promising results and an alternative method of enhancing motor control and treating debilitating symptoms of upper motor neuron disorders (Nagel et al., 2017). Ongoing studies have included investigation of the effect of SCS on spinal cord injured and found that stimulation to the spinal dorsal columns may be capable of modulating neural circuits, enhancing movement and alleviating spasticity and pain (Dimintrijevic et al., 2012; Mayr et al., 2016; Minassian et al., 2016; Pinter et al., 2000; Sayenko et al., 2014). However, these are typically small pretest-posttest studies with few participants and a high risk of bias. Positive effects of epidural SCS on

spasticity and motor performance have been demonstrated in stroke patients with mild to moderate deficits, although research evidence for the efficacy of epidural SCS in stroke is limited and references outdated (Cioni et al., 1986; Cioni et al., 1989).

Surgical implantation of electrodes was originally in the subdural space but, to simplify surgery and reduce the risk of complications, the electrodes were later exclusively placed epidurally (Gibson-Corley et al., 2014). Current approaches in the location of electrodes look towards theories on central pattern generators (CPG) that suggest that locomotion is modulated and controlled by specific neural circuits, CPG, that are primarily located in the lumbosacral spinal cord (Dimitrijevic et al., 1998; Nagel et al., 2017). These CPG´s are believed to have a high level of automaticity and have been shown to generate a walking pattern in the absence of supraspinal or peripheral inputs (Gerasimenko et al., 2015). Research on stimulation parameters have demonstrated a suppression of severe lower limb spasticity in spinal cord injured participants when the epidural electrodes are placed over the lumbar posterior roots and the stimulation frequency is in a range of 50-100Hz (Murg et al., 2000; Pinter et al., 2000; Rattay et al., 2000). Despite positive findings, epidural spinal cord stimulation, is infrequently used, due to its invasiveness, as the electrodes need to be surgically implanted into the spinal cord (Cameron, 2004; Mayr et al., 2016). For this reason, epidural SCS has solely been an option for severe cases of pain or spasticity (Dones et al., 2018; Nagel et al., 2017; Vakkala et al., 2017).

1.5 Transcutaneous Spinal Cord Stimulation (tSCS) Recent developments of a non-invasive technique of transcutaneous Spinal Cord Stimulation (tSCS) uses electrodes placed on the skin of the lower back and abdomen to target lumbar segmental neural circuits in a similar manner to epidurally placed electrodes (Danner et al., 2011; Dimitrijevic et al., 2004; Minassian et al., 2007). This novel approach uses bilateral short latency rectangular pulses to depolarize lumbosacral posterior roots (Courtine et al., 2007; Krenn et al., 2015; Minassian et al., 2007). The effectiveness of tSCS on motor control and spasticity in individuals with neurological symptoms continues to be explored but preliminary studies suggest that tSCS may reduce spasticity and have a positive effect on motor function (Ladenbauer et al., 2010; Minassian et al., 2007). These effects have been demonstrated to last for a few hours after treatment (Hofstoetter et al., 2014; Mayr et al., 2016). The suggested mechanism for the efficacy of this treatment is akin to that of epidural stimulation (Hofstoetter et al., 2018). In tSCS, electrodes are located on the skin to produce tissue currents that pass through the targeted neural structures, i.e. the large-diameter fibres of the lumbar and upper sacral posterior roots. Computer models have demonstrated how the electric current is distributed in the neural tissue (Danner et al., 2011). Basic principles of spatial electric fields and current distribution apply: the large myelinated afferent posterior root fibres receive the highest stimulation and are depolarized. Among the fibres of the posterior roots are the Ia afferents that make strong synaptic connections on Ia inhibitory interneurons that activate local inhibitory circuits (Jankowska, 1992). Another potential source of the effects may be due to depolarization of the posterior columns and involvement of descending activation of presynaptic inhibition by long loop mechanisms (Holsheimer, 1998; Ladenbauer et al., 2010). Recent pilot studies suggest that tSCS with high frequency (50-100Hz) stimulation may lead to a suppression of spasticity and pain and enhance volitional muscle control (Hofstoetter et al., 2014).

However, studies on tSCS are typically pretest-posttest case reports and pilot studies with limited internal validity and often with a high risk of bias.

1.6 Risks Treatment with tSCS has not demonstrated any adverse side effects or risks, other than occasional skin irritation in some individuals (Cameron, 2004; Minassian et al., 2012).

2 Aim

2.1 Objective The objective of this research is to evaluate the effect of repetitive tSCS on spasticity, mobility, pain and sleep in community dwelling individuals post-stroke.

2.2 Research Question The results from this research aim to answer the research question: What are the effects of daily home application of tSCS for three weeks on spasticity, mobility, pain and sleep in community dwelling individuals post-stroke?

2.3 Research Hypothesis The research hypothesis is that daily application of tSCS for three weeks will reduce spasticity and pain and enhance mobility and sleep, as compared to no treatment.

3 Method

3.1 Research Design

This study used a single-case withdrawal research design with four phases (A1, B1, A2, B2) of alternating baseline (A) and intervention (B). Replication of the baseline and intervention phases provided for two opportunities to demonstrate the causal effects of tSCS on spasticity, mobility, pain and sleep (Barlow and Hersen, 1984). Withdrawal refers to a washout period after the first intervention phase, characterized by removal of the intervention for some time, allowing for the dependent variables to return to previous baseline levels prior to the second baseline phase (Backman et al., 1997). Three measurement sessions were included during each phase (Figure 1). Measurement sessions were at a similar time of the day, on separate days.

The Single-Case Reporting Guideline in Behavioural Interventions (SCRIBE) 2016 Checklist was used to describe the methodology and report the results of this single case study (Tate et al., 2016). Researchers aimed to have one week between measurements. There was some flexibility on the timing of the measurements, based on participant’s availability. More specifically, baseline measurements were performed on separate days, from one day to one week apart and measurement sessions during the intervention phases were at least 4 days apart. Intervention phases lasted for 18 to 21 days. Length of washout periods was to be no less than four weeks and needed to accommodate for the availability

of each individual subject as well as the researchers. The washout period was fifteen weeks for subject 4, seventeen weeks for subject 3 and five weeks for subject 5 and 6.

Figure 1. Flow chart showing phases, weeks and data collection points

This study appertains to a large study on the effects of tSCS on neurological symptoms in different patient groups, termed the „Study of effects of non-invasive spinal cord stimulation on the amelioration of spasticity and enhancing of residual motor control„, which is based at the Landspitali University Hospital of Iceland and the Reykjavík University, and in collaboration with the University of Iceland. Þórður Helgason, associate Professor, PhD, in Biomedical Engineering is the principal investigator of the tSCS project in Iceland.

3.2 Participants

3.2.1 Participant recruitment Potential participants with spastic hemiplegia from stroke were sought through referrals from neurology and rehabilitation physicians and physiotherapists to participate in the study. Participants were screened for eligibility, using the modified Rankin Scale (mRS) to assess disability and interviewed for inclusion/exclusion criteria (Table 1 and 2) (van Swieten et al., 1988). This was conducted via a phone call and interview at the rehabilitation clinic Grensás. Eligible participants willing to participate received a trial session of tSCS to assess treatment tolerance and possible future compliance to treatment.

3.2.2 Inclusion and exclusion criteria The inclusion criteria were: (1) individuals aged 18-75 with chronic (> 1 year) spastic hemiplegia from ischemic or haemorrhagic stroke; (2) mild to moderate disability, quantified as 2-3 on the mRS; and (3) complaints of one or more of the following; pain below waist on hemiplegic side, perceived impaired mobility or sleep.

Exclusion criteria consisted of: (1) presence of other neuromuscular diseases; (2) multiple incidents of stroke; (3) malignant disease; (4) impairment in comprehension or verbal expression; (5) active implant (e.g. cardiac pacemaker, implanted drug pump); (6) passive implant under stimulation site (metal screws and plates for surgical stabilization); (7) alterations in antispastic and pain medication 3 weeks prior to baseline phases or during measurement phases (e.g. botulinum neurotoxin, Baclofen®, Gabapentin®); (8) pregnancy; (9) dermatological issues at stimulation sites; (10) total hypoesthesia or inability to feel electrical stimulation; (11) immobile ankle or knee joint due to severe contracture; (12) presence of complications that affect spasticity at the time of initial assessment, e.g. urinary tract

infection, pressure sores, bone fracture, pneumonia; (13) inadequate assistance for home application; (14) intolerance of tSCS treatment; (15) cognitive impairments that affect compliance to treatment.

Four individuals, with spastic hemiplegia, were chosen to participate in the study. They received an information sheet, in Icelandic, about the researchers, objective of the study, study procedure, potential risks of the intervention, privacy policy and ethics (Appendix 1). They signed an informed consent prior to the study (Appendix 2). Participants filled out a form with baseline questions about their age and gender, hemiplegic side, type of stroke (haemorrhagic or ischemic), year of incident, symptoms, walking aids, spasticity medication and other treatments (Appendix 3). They were advised to make no major changes in medication, physical treatment or physical activity during the research time. Participants received a research number (S3, S4, S5, and S6) to use in data collection. A participant list, connecting the research number to each subject’s personal identification, was stored in a locked electronic folder. Participants were aware of their research number and used it when filling out questionnaires.

3.2.3 Screening MRS is a single item, global outcome rating scale used for rating disability of patient’s post-stroke. It categorizes the level of functional independence compared to pre-stroke abilities on a six point scale from 0 to 5 (van Swieten et al., 1988). The current study included individuals with slight to moderate disability (mRS=2-3). Slight disability is defined by the mRS as being unable to carry out all previous activities, but able to look after own affairs without assistance (mRS=2). Moderate disability is defined as requiring some help, but able to walk without assistance (mRS=3) (Appendix 4).

The mRS has been found to be sensitive to changes in disability after stroke and a change of one point has been found to show a clinically significant change in disability (Dromerick et al., 2003). The UK-TIA (United Kingdom transient ischemic attack) version of the mRS was chosen for this study as interrater reliability data are available for it (Farrell et al., 1991; van Swieten et al., 1988). The mRS does not clearly state whether “assistance” allows for aids such as orthosis or walking aids. Researchers of the current study defined “without assistance” as an ability to walk with or without aids but without assistance from another person.

3.2.4 Participant Characteristics Participant characteristics are summarized in Table 1. Subject 3 (S3): A fifty-eight-year-old female who had suffered a haemorrhagic stroke to her basal ganglia in 2007 resulting in spastic hemiparesis and hypoesthesia to the left side of her body. Her main complaints were pain, stiffness, paresis and hypoesthesia in her left side. She slept well but was commonly fatigued. She had found that medication (Lyrica), physical therapy (soft tissue treatment and exercises) and meditation had helped to treat her mobility, pain and spasticity through the years. She reported the side effects of medication to be low spirits and tiredness. S3 scored 2 on the mRS (Appendix 4). She occasionally used a cane when walking outside. S3 lived with her husband who frequently travelled for work. Other family members assisted with home treatment when he was away.

Subject 4 (S4): A sixty-year-old man who suffered an ischemic stroke in 2017 resulting in hemiparesis to the left side, spasticity, dysesthesia, allodynia, cognitive impairment and neglect. S4 had tried physical

therapy (passive and active stretches), as well as medication (Gabapentin) but had not found they helped to alleviate his spasticity and had no noticeable side effects. S4 was treated with Botox in the leg 3 months prior to his first baseline measurement. He had felt a positive effect of the first Botox injection initially but had not found an effect after that. He complained of pain in his left shoulder and left knee from a torn meniscus. S4 used a crutch for walking. He scored 3 on the mRS. S4 lived at home with his wife that assisted him with treatment.

Subject 5 (S5): A seventy-one-year-old male with left sided hemiparesis after having suffered an ischemic stroke in 2017. His primary complaints were paralysis and spasticity in his left arm and paresis and spasticity in his left leg and much difficulty moving his ankle. Other ailments were muscle cramps and pain in his back and left leg (thigh and calf). For spasticity treatment, S5 received physical therapy three times a week and went twice a week to water aquatics. He took spasticity medication (Gabapentin) four times a day and received Botox injections to his arm and leg every three months. He found physical activity to be important for alleviating his spasticity and was not sure that other treatments helped. He recalled that the Botox injections were helpful for about a month, the first few times he received them, but had found no beneficial effects after that. His last Botox injection was three months prior to his first baseline measurement. He walked without assistance using a crutch and required some help for activities of daily living. S5 scored 3 on the mRS. He lived at home with his wife who accompanied him to the measurement sessions and assisted with the home treatment.

Subject 6 (S6): A seventy-three-year-old male who had suffered an ischemic stroke in 2014, resulting in hemiparesis to his right side, spasticity and hypoesthesia in his right hand and foot. S6 had tried oral medication (Gabapentin), Botox injections and physical therapy (active exercise program) to alleviate his worst symptom of painful muscle cramps, in his right leg, that woke him during the night. None of these treatments had helped his night spasms. S6 received his last Botox injection six months prior to his first measurement and was not interested in continuing with more injections, as they did not help. S6 lived at home with his wife who assisted him with the home treatment. He scored 2 on the mRS and only used a cane when walking longer distances outside.

Table 1. Participant characteristics Participant Gender Age Hemiplegic Year of Ischemic (I) / mRS (yrs) Side stroke Haemorrhagic (H) stroke S3 Female 58 Left 2007 H 2 S4 Male 60 Left 2017 I 3 S5 Male 71 Left 2017 I 3 S6 Male 73 Right 2014 I 2

3.3 Procedure Measurements were performed at the Medical Technology Centre of Landspitali University Hospital and Reykjavik University. A battery of objective and subjective measures was used to measure spasticity, mobility, pain and sleep (Table 2). Participants were measured once a week, unless there needed to be flexibility in measurements based on availability of participants.

To ensure procedural fidelity, researchers followed a measurement protocol for all measurement sessions (Appendix 5). Two physical therapists (BC & GM), experienced in assessing and treating neurological disorders, employed standardized procedural techniques for all outcome measures. Participants received an electrical stimulator after the last baseline measurement in both baseline phases (A1 & A2). A third physiotherapist (VG), with experience in electrical stimulation adjusted the devices according to the procedure described in Appendix 6. She also taught the participants how to apply the treatment and measured and marked the correct position of the electrodes. Laboratory technicians assisted with operating and maintaining field and laboratory research equipment and assisted with the development of procedures and methods using electromyography (EMG). A mechatronics engineer (HK) with experience in programming and processing data was responsible for collecting and processing the digital data from the EMG and goniometers.

3.3.1 Intervention Description of the implementation of the intervention is based on the Template for Intervention Description and Replication (TIDieR) and the checklist presented in Appendix 7 (Hoffmann et al., 2014). The TIDieR is a checklist and guide for describing interventions in studies and aims at improving the quality of description of interventions and their replicability. The intervention consisted of daily home application of tSCS for three weeks. The tSCS was applied using self-adhesive electrodes, one circle electrode (5 cm diameter) positioned centrally to the back, at the level between the T11-T12 spinous processes, which was interconnected with a pair of rectangular reference electrodes (8*13 cm) placed over the lower anterior abdomen, symmetrical to the navel (see Figure 2). Electrodes were connected to the stimulator so that the single vertebral electrode on the back acted as the cathode (black) and the two abdominal electrodes connected to function as a single anode (red) electrode. This setup has been reported to ensure a higher current density and stronger stimulation effect near the spinal cord, with an anteriorly flowing current and good distribution towards the abdomen (Minassian et al., 2007).

Figure 2. Position of electrodes for tSCS

Participants received electrical stimulation with a frequency of 60 Hz, constant current, 360 s width, asymmetrical biphasic charge balanced pulses at an intensity of 90% of the threshold for eliciting muscle reaction as recorded by EMG in the lower limb muscles, every day for 30 mins. The treatment was administered in a supine position. Stimulation parameters were based on former research on epidural SCS for the control of spasticity as well as a previous pilot study on tSCS on spasticity in spinal cord injury (SCI) (Dimitrijevic et al., 2004; Hofstoetter et al., 2013; Pinter et al., 2000).

The device used for electrical stimulation was the Odstock® Dropped Foot Stimulator ODFS pace V1.3 (Odstock Medical Ltd (OML), Salisbury, UK), with the setting on exercise mode (Figure 3). The devices settings were adjusted by a researcher according to procedure (Appendix 5 & 6).

Figure 3. Intervention device

Identical treatment was performed in both B phases of the study. Participants received a single treatment with tSCS immediately after the last baseline measurements in phases A1 and A2. This was done to teach participants how to adjust the device, test for treatment tolerance, stimulation amplitude and participants’ ability to correctly turn the device on and off. Subsequent stimulation sessions were performed at home and participants were required to write down on a log sheet the date and time of each treatment. During the intervention phases (B1 & B2), researchers administered tSCS before electromyographic (EMG) assessments, but after mobility testing (Appendix 5). Participants received new electrodes prior to this treatment. Compliance to treatment was monitored weekly through the appliances´ built in logbook and compared to the participants written logbook (Appendix 8). If the participants experienced any problems with the treatment or the device, they were instructed to contact the researchers as soon as possible. For all stimulation sessions performed at the Research Lab, researchers took note of whether the tSCS was eliciting an increase in lower-limb muscle response. This response was demonstrated on EMG measurements of the Quadriceps Femoris (Rectus Femoris) (Q), Biceps Femoris (Long and Short Head) (H), Tibialis Anterior (TA) and Triceps Surae (Gastrocnemius Lateralis) (TS) muscles. This response was noticed but not recorded. This was done to check whether the intervention device was correctly adjusted and fitted.

3.3.2 Measurements Participants participated in four phases of measurements. Each phase consisted of three data collections sessions on individual days. Therefore, each subject turned up for a total of twelve measurement sessions. Baseline measurements were taken during phase 1 (A1) and phase 3 (A2) (Figure 1). Outcome measures were the same for baseline and intervention phases apart from a questionnaire that participants answered during the intervention phases about their wellbeing and experience with the tSCS (Table 2 & Appendix 9). This questionnaire was used as a screening test for ongoing participant eligibility and tolerance for treatment. It inquired about any uncomfortable experiences as well as

subjective assessment on the positive and negative effects of the intervention and how long the effects lasted.

Measurement sessions took around 60 minutes and were organized in the following order: (1) Questionnaires filled in; (2) Subject stands up and warms up for mobility tests by walking twice around a large table in the research laboratory; (3) Mobility tests taken; (4) Participant takes off shoes and puts on shorts; (5) EMG electrodes and goniometer attached with subject lying on plinth; and (6) EMG measurements taken (after tSCS in intervention phase) (Appendix 5). Objective assessments included clinical and biomechanical measurements of spasticity and voluntary movement, as well as mobility outcome measures (Table 2). Goniometers were used on the ankle and knee of the hemiplegic leg to measure joint movements and EMG recordings taken from the Q, H, TA and TS muscles (see order of EMG measurements in Appendix 10). Subjective assessments included questionnaires with self-reported assessments of spasticity, pain, and sleep (Table 2 & Appendix 11).

Table 2. Summary of Evaluation Methods

Spasticity – Outcome Measures

3.3.2.1.1 Tardieu Scale The Tardieu Scale is a clinical measure of muscle spasticity that involves assessing resistance to passive movement at both slow (V1) and fast speeds (V2 and V3) (Boyd et al., 1999). In doing so, it addresses the velocity-dependent aspect of the phenomenon “spasticity” as defined by Lance and allows for differentiation between neural and soft tissue components of muscle resistance (Patrick et al., 2006). Despite the Tardieu Scale having more acceptance as a clinical scale for spasticity, contradicting evidence exists regarding its reliability, and to date, no concrete evidence demonstrates its superiority to the Ashworth Scale (Haugh et al., 2006). Also, research has failed to find a correlation between changes in measurements on the Tardieu Scale and functional activity (Malhotra et al., 2008). Assessment of spasticity using the Tardieu Scale involves the examiner evaluating the tested muscle reaction to stretch at a specified velocity. The velocity of stretch can be: V1 – as slow as possible; V2 – speed of limb segment falling under gravity; and V3 – as fast as possible. During these movements, the following parameters are noted:

• during fast movement (V2 or V3) o X – the quality of muscle reaction and o Y – the spasticity angle or angle of muscle reaction or catch (R1) and • during slow movement (V1): the passive range of motion (PROM) (R2) (Appendix 12).

For this study, the following parameters were measured clinically whilst muscle reaction was recorded with EMG and joint movement with the goniometers: R1 and R2 for the ankle plantar flexors. These were measured in supine with hip at 45° and knee at 30°. A physical therapist (GM), experienced in using the Tardieu for assessing spasticity, performed all measurements. A larger joint angle indicated an improvement in the spasticity angle (R1) and PROM (R2) of the plantar flexors.

3.3.2.1.2 Wartenberg Pendulum Test (WPT) The Wartenberg pendulum test (WPT) is a biomechanical gravitational method that uses gravity to provoke spasticity (Wood et al., 2005). It is performed with the subject in a sitting position with the knee held in a fully extended position, then released and allowed to swing freely (Wartenberg, 1951). The resulting oscillatory patterns of the swinging leg are then evaluated (Biering-Sorensen et al., 2006). Originally this test was used as a clinical method and scored as the count of swings after release. Other researchers have advanced this test by using goniometers or other methods of joint angle measurements to calculate other components of the stretch reflex, such as time delay, threshold and dynamics (Bajd et al., 1984). The validity of the test is questionable as it does not distinguish between hyper-reflexia and a mechanical resistance to passive stretch (Fowler et al., 1998). Also factors such as state of relaxation, posture, starting angle and muscle length can affect its reliability, but with sophisticated tracking equipment, such as that used in the current study, the test-retest reliability is improved (Bohannon et al., 2009). This test was repeated three times for each measurement session, with a 5 second rest between repetitions (Nordmark et al., 2002). Oscillatory patterns of the swinging leg were evaluated for count of

swings and amplitude of knee displacement. The “index of spasticity” R2n was calculated from the EMG recordings of the Q and H muscles and goniometer data recordings from the knee (Jamshidi et al., 1996). This ratio objectively quantifies spasticity and correlates with other clinical measures of spasticity

(Leslie et al., 1992). The 푅2푛 is a calculated ratio between the initial flexion and resting position of the knee joint. (Peak flexion angle of first swing) − (Starting Knee angle) R = 2n 1.6 ∗ (Final resting knee angle) − (Starting knee angle)

A spasticity index 푅2푛 ≥ 1 indicates non‐spastic conditions, while 푅2푛 → 0 represents severe spasticity (Bajd & Vodovnik, 1984). The mean R2n and standard deviations for three repetitions was calculated for each measurement session.

3.3.2.1.3 Co-Contraction Values The SPASM consortium for measuring spasticity has criticized spasticity measurements involving passive (i.e. not voluntary) movement of the limb (Burridge et al., 2005). It has been argued that such measurements do not necessarily reflect spasticity during active activation of the muscles and that biomechanical approaches of measuring spasticity during voluntary activation of muscles may be more appropriate (Wood et al., 2005). Researchers and clinicians acknowledge that excessive co-contraction can play a significant role in stroke rehabilitation and quality of functional movement (Rosa et al., 2014; Souissi et al., 2018). Co- contraction is defined as a simultaneous contraction of agonist and antagonist muscle groups crossing a joint (Busse et al., 2005). Although little is known about co-contraction profiles during normal movement, muscle co-contraction is increased in neurological disorders and has been shown to impair functional performance (Damiano et al., 2000). To address spasticity during voluntary movement, co-contraction values of the TA and TS muscles were to be computed from the data of voluntary ankle dorsi- and plantar- flexion. Participants were in a sitting position and received standardised instructions to repeat each movement five times (Appendix 5). Each contraction was held for three seconds. To normalize EMG activity (µV) for each session, participants performed a maximum voluntary isometric contraction (MVIC) for each muscle prior to other biomechanical measurements (Appendix 5). The protocol for measuring MVIC was later changed, during the study, from one to three repetitions and an average of the 3 measurements computed. This was done when some calculations of the MVIC were demonstrated to be lower than measurements taken from submaximum muscle contraction during dorsi- and plantar-flexion. The EMG results from voluntary activation were then used to calculate the co-contraction ratio using the following method (Figure 4) (Damiano et al., 2000): (1) The data was squared and smoothed to remove noise and clear out irregular peaks; (2) the maximum root-mean-square (RMS) value of the direct signal was determined between two triggers: the highest value of the smoothed data used as a reference and the first trigger was obtained when the smoothed data exceeds 10% of its highest value and the second trigger was obtained when the smoothed data drops below 10%; (3) the co-contraction values were calculated by normalizing the computed RMS data from TA and TS to the RMS data from the MVIC from each muscle. More specifically, the RMS for TA was divided by the RMS for MVIC and

multiplied by 100 to get the percentage value (TA/TAmax * 100). Values for co-contraction of TS were calculated in the same way (TS/TSmax * 100). A similar method has previously been used for calculating co-contraction in hamstring and quadriceps muscles in patients with knee osteoarthritis (Hortobagyi et al., 2005).

Figure 4. Processing of EMG data Figure shows: A) raw data from EMG; B) squared raw data; C) smooth filtered data from the tibialis anterior muscle (TA) shown in dark green and 10% of its maximal value in pink and the red lines marking the triggers when the data crosses the 10% marking; D) squared data shown with trigger marking for where the data will be extruded; E) Data collection from defined trigger marking.

3.3.2.1.4 Penn Spasm Frequency Scale (PSFS) The Penn Spasm Frequency Scale (PSFS) is a two component self-report measure that assesses the patient´s perception of spasticity. Part 1 assesses the frequency (PSFSF) and part 2 the severity (PSFSS) of muscle spasms (Penn et al., 1989). Part 1 is a 5-point scale that assesses the frequency with which spasms occur ranging from “0=no spasms” to “4=spontaneous spasms occurring more than ten times per hour”. Part 2 is a three-point scale that assesses the severity of spasms ranging from; (1) =mild; (2) =moderate and (3) =severe. If the person indicates they have no spasms in part 1, part 2 is skipped. The PSFS provides a standardized method of rating an individual’s perception of spasms and can assist in complementing clinical measurements of different aspects of spasticity (Biering-Sorensen et al., 2006). This scale can be sensitive to the subject’s perception of treatment efficacy on spasticity, but this depends on the patient group (Snow et al., 1990). For example, correlations of the PSFS with self- report scales of function were found to be weak in SCI (Priebe et al., 1996). The intra-rater reliability of the PSFS was found to be good for 5 to 10 days (ICC = 0.822 & 0.812) and for 4 to 6 weeks (ICC=0.734 & 0.729), for part one and two, respectively (Mills et al., 2018). It´s inter-rater reliability was 0.862 and 0.857 within a 3-day interval for individuals with chronic SCI (Mills et al., 2018). Correlation of the PSFS

with the Ashworth Scale (hip, knee & ankle) and the Spinal Cord Assessment Tool for Spastic reflexes (SCATS) flexor and extensor spams was found to be moderate (Spearman´s r = 0.40-0.51) (Benz et al., 2005). Interestingly, a significant correlation of the PSFS with the SCATS clinic responses was found (Spearman´s r = 0.59), indicating that patients relate spasms more to clonus than other aspects of spasticity (Benz et al., 2005). For this study both parts of PSFS were translated to Icelandic by one the researchers (BC) that has experience in translating outcome measures and was included as questions one and two on questionnaire B (Appendix 5).

3.3.2.4 Mobility - Outcome Measures

3.3.2.4.1 Ten-metre Walking Test (10mWT) The Ten-metre Walking Test (10mWT) measures the time taken for participants to walk a distance of ten metres (Bohannon et al., 1996). To allow for an acceleration and deceleration phase, the tested individual is typically asked to walk a longer distance (anything between 12 to 20m). The time it takes to ambulate 10m located in the middle of the walkway is recorded (Watson, 2002). The results are then converted to calculate the walking speed (m/s) by dividing 10m with the time (s) it takes to walk this distance. Although walking speed over a short distance has been demonstrated to overestimate locomotor capacity after stroke compared to the 6 minutes walking test, the 10 mWT takes a shorter time to administer and has been shown to be a reliable and valid method of measuring walking mobility and disability (Dean et al., 2001). The test-retest reliability of the 10 mWT was found to be excellent in older adults with Parkinson’s disease for comfortable and fast gait speeds (ICC=0.92 and 0.96, respectively) (Lang et al., 2016). Walking velocity has been demonstrated as a strong predictor of walking limitation in the stroke population (Perry et al., 1995). Reference values for stroke individuals are: (1) 0 m/sec = Incapable home ambulation; (2) < 0.4 m/sec = Independent home-bound ambulators; (3) 0. 4 – 0.8 m/sec = Dependent community walkers; (4) > 0.8m/sec: Independent community walkers. Reference values for comfortable and fast walking speed of healthy adults aged 20-79 years are as follows (Bohannon, 1997): for women aged 50-79 years, comfortable speed is 1.40-1.27m/sec and fast speed 2.01-1.75m/sec; and for men within the same age limits, normal speed is between 1.40- 1.33m/sec and fast speed between 2.07- 2.08m/sec. For this study, a 20 m walkway was used consistently in all measurements. To minimalize disruption, researchers stopped all traffic in the corridors whilst this test was taken. A standardised protocol was used for all measurements: one tester (GM) recorded the time and another gave standardised instructions (BC) (Appendix 5). Participants repeated the test twice for a speed they chose as “comfortable” and twice for a speed defined as “fast”. The average was then calculated for both speeds.

3.3.2.4.2 Timed up and go (TUG) The Timed Up and Go (TUG) is a modified and timed version of the “Get up and Go” test (Mathias et al., 1986; Podsiadlo et al., 1991). It assesses physical mobility and the ability to perform sequential

motor tasks and has moderate correlation with other functional measures of mobility and balance (Podsiadlo & Richardson, 1991; Schoppen et al., 1999). The TUG involves measuring the time it takes for the testee to stand up from a chair, walk 3 meters, turn around, walk back to the chair and sit down. Reliability of the TUG in chronic stroke has been demonstrated as excellent (ICC>0.95) (Ng et al., 2005). It has been demonstrated as a responsive test for assessing changes in mobility after stroke (Persson et al., 2014). The mean reference values, categorized by age, for the TUG are as follows: (1) 60-69 year olds = 8.1 seconds; (2) 70-79 year olds = 9.2 seconds; (3) 80 to 99 years olds = 11.3 seconds (Bohannon, 2006). In the current study, standardized instructions were given to participants and the same chair and location used for the TUG (Appendix 5). The height of the chair seat was 45cm. Participants used the same footwear, orthosis and helping aids for all trials throughout the study and did not receive any physical assistance. No encouragement or verbal cues were provided during the test. For each measurement session, the TUG was repeated twice, “as fast as possible” and the mean of the two trials was recorded. One researcher gave the instructions (BC) and another recorded the time from “go” and stopped it as soon as the patient’s buttocks touched the seat (GM).

3.3.2.4.3 Five Times Sit-to-Stand Test (FTSTS) The Five Times Sit-to-Stand test (FTSTS) is a commonly used measure of function in older adults, including those with neurological symptoms. It measures the time (seconds) to stand up and sit down five times, as fast as possible, without using hands to push up from the chair with a seat height of 43- 45cm. Performance on this outcome measure is strongly associated with mobility problems and fall risks (Buatois et al., 2008; Guralnik et al., 1995; Paul et al., 2014). The FTSTS is highly reliable, it has excellent intra-rater (ICC= 0.97-0.976) and interrater reliability (ICC=0.99), as well as test-retest reliability (ICC=0.89-0.99) for individuals with chronic stroke (Mong et al., 2010). In individuals with chronic stroke, it correlates highly with muscle strength of knee flexors (r=0.753). A cut-off score of 12.2 seconds to perform this test discriminates between healthy elderly versus participant with stroke (sensitivity =83%) (Mong et al., 2010; Whitney et al., 2005). An inability to perform the FTSTS in less than 13.5 seconds is associated with increased disability and mobility in nondisabled elderly (Guralnik et al., 1995). There is insufficient evidence about the clinically relevant change and responsiveness of the five-repetition sit-to-stand in the chronic stroke population. The FTSTS was performed once for each measurement session. One tester (GM) recorded the time from “go” and stopped when the participants back touched the seatback, after standardized instructions had been given by another researcher (BC). The same chair, with a seat height of 45cm was used for all measurement sessions (Appendix 5).

3.3.2.4.4 Activities-Specific Balance Confidence Scale – (ABC scale) The Activities-specific Balance Confidence scale (ABC) is a self-reported 16-item questionnaire designed to measure an individual’s confidence in his/her ability to perform daily ambulatory activities without falling (Powell et al., 1995). It consists of 16 items that are scored as a percentage of balance confidence (%), with 0% being no confidence and 100% representing the highest level of confidence.

A total score is calculated as the sum of all answers (%) divided by the total number of answered questions (16). In chronic stroke, the ABC has been demonstrated to have acceptable measurement properties (Botner et al., 2005). It´s test-retest reliability was good (ICC=0.85) (Botner et al., 2005). A moderate and significant positive, linear correlation was found with The Berg Balance Scale (r=0.36, P<0.001) and with gait speed (r= 0.48, p<0.001) (Botner et al., 2005). The internal consistency of the ABC in chronic stroke was excellent (α=0.95) (Talley et al., 2008).

The discriminative and evaluative properties of the ABC scale have been calculated for the elderly population (Myers et al., 1998). They are as follows: (1) < 50% indicates low level of physical functioning characteristic of home care clients; (2) 50 – 80% indicates moderate level of functioning characteristic of elders in retirement homes and persons with chronic health conditions and (3) > 80% indicates high level of function, usually physically active older adults.

The cut-off mark on the ABC scale for an increased risk of falling has been established as a score of 67% (Lajoie et al., 2004). This score has been demonstrated as highly specific (87.5%) and sensitive (84%) for the elderly community (Lajoie & Gallagher, 2004). For patients with pulmonary problems, based estimates of the minimal clinically important difference (MCID) ranged from 14.2 - 18.5% (Beauchamp et al., 2016). Participants answered the ABC scale in each measurement session.

3.3.2.5 Outcome Measures for Spasticity, Pain and Sleep

3.3.2.5.1 11-point numerical rating scale (NRS) – Spasticity, Pain and Sleep The 11-point numerical rating scale (NRS) is a patient-reported outcome in which participants rate their symptoms on an eleven-point numerical scale from 0 (no symptom) to 10 (worst possible symptom). It is most commonly used to assess pain but has also been studied as an outcome measure for other symptoms. Evidence exists for the validity and reliability of the 11-point NRS in measuring symptoms of spasticity, pain and sleep (Alghadir et al., 2018; Cappelleri et al., 2009; Farrar et al., 2008a; Farrar et al., 2001). In these studies, the test-retest reliability for the 11-point NRS was demonstrated as good to excellent for measuring these variables. The test-retest reliability of the NRS for measuring spasticity was good (ICC = 0.83) and excellent for measuring pain and sleep (ICC=0.97-0.90) (Farrar et al., 2008b; Farrar et al., 2001). Validity measures for using the NRS for measuring spasticity found a significant correlation between the NRS and another patient reported outcome of spasticity (PSFS) (r = 0.41 - 0.63), but not with a clinical measure of spasticity (Ashworth Scale) (r=0.24) (Farrar et al., 2008a). An excellent correlation was found between the visual analog scale (VAS) for pain and the NRS (r=0.941) and correlation with sleep disturbance on the Medical Outcomes Study (MOS) Sleep Scores showed a significant relatively strong correlation (r = 0.45-0.42) (Alghadir et al., 2018; Cappelleri et al., 2009). According to studies on the CID for the NRS, a reduction of 30% represented a CID and 18% a MCID on the 11-point NRS when used to assess spasticity and pain (Farrar et al., 2008a; Farrar et al., 2001). During each measurement session, participants were provided with a short NRS questionnaire (Appendix 11) that asked them to rate: (1) the pain they experienced at their back or legs; (2) the extent

pain and spasticity affected their sleep. More specifically, they were asked “On a scale from 0-10, how little or much pain have you had in your back or legs in the last 24 hrs.” and “On a scale from 0-10, how little or much has your spasticity or pain interrupted your sleep in the last 24 hrs.”.

3.3.2.5.2 Patient Global Impression of Change (PGIC) – spasticity, pain and sleep The Patient Global Impression of Change (PGIC) is a self-report measure of the patients’ perception of a change in their condition or symptom (Guy, 2000). It may therefore be more sensitive to changes that are meaningful to the patient (Scott et al., 2015). It is commonly used to assess treatment efficacy in chronic pain syndromes, but has also been used for an array of other conditions (Bogan et al., 2017; Farrar et al., 2008a; Scott & McCracken, 2015). The PGIC is included in the Initiative on Methods, Measurement and Pain Assessment in Clinical Trials (IMMPACT) recommendations as a core outcome measure for chronic pain trials. The PGIC has been used to find the clinically important difference (CID) of the 11-point numerical rating scale (NRS) for pain and spasticity (Farrar et al., 2008a; Farrar et al., 2001). In the PGIC, participants are asked to assess the overall change in his or her specific condition or symptom on a single question scale from 1-7. Four represents “no change”, whereas numbers above and below represent incremental stages of getting worse or better, respectively. This study used the PGIC to assess the participant’s impression of change for the variables of spasticity, pain and sleep. This was done in each measurement session with individual questions on a patient questionnaire (Appendix 11). Questions were based on anecdotal reasoning and knowledge of the clinicians in the research group on spasticity, pain and sleep. Patients were asked “Have you found a change in your spasticity/spasms since the study began?”, “How much or little has your pain changed since the study began?” and “How much or little has your sleep changed since the study began?”.

3.3.3 Data Collection EMG recordings were taken of the Q, H, TA and TS muscles of the hemiplegic leg of each participant. Skin-electro impedance was reduced by preparing the skin with abrasive paste (OneStep EEG-gel) and using conductive gel on electrodes. Placement of electrodes were according to the recommendations for sensor location from the SENIAM Group (Surface ElectroMyoGraphy for the Non-Invasive Assessment of Muscles) for rectus femoris (Q), biceps femoris (H), tibialis anterior (TA), and gastrocnemius lateralis (TS) (Seniam, 2019, February 12). Electro‐goniometers were placed on the lateral side of the knee and ankle, of the hemiplegic side, to measure displacement of these joints during movement. All EMG and goniometer recordings were performed using an eego mylab device (ANT Neuro, Enschede, Netherlands) at a sampling rate of 1024 Hz. Signal processing was performed in Matlab R2014b (The MathWorks, Inc) also using the open-source Matlab toolbox EEGLab (Makeig, S. & Delorme, A. 2004).

Figure 5: Placement of goniometers on ankle and knee and EMG sensors on leg muscles

3.3.4 Data Analysis Statistical analysis was performed in the SSD for R package (Auerback & Zeitlin, Single-System Design Analysis, NY, USA) available for the statistical program R (R Core Team, 2013). Graphical representation of data using the two-standard deviation band method (2SDBM) was done in Matlab R2014b. Data analysis relied on visual and statistical analysis techniques of single subject research design (SSRD) to determine the effects of the independent variable (tSCS) on the dependent variables (spasticity, mobility, pain and sleep) (Wolery et al., 1982). The results for each outcome measure are shown graphically for each participant, during baseline and treatment phases, for within- and between- phase patterns. Graphs show four phases, 2 baseline phases (A1 & A2) and 2 corresponding intervention phases (B1 & B2). Results of participants with a higher level of disability are shown on right (mRS = 3) and a lower level of disability to the left (mRS = 2). Each phase includes 3 data collections. A summary of the descriptive statistics of concomitant changes in the level, trend and variability of data patterns, within phases, is presented in tables as is recommended for research design standards of SSRD (Kratochwill et al., 2012; Lobo et al., 2017). Level refers to the mean score for each data phase. Trend refers to the slope of the progressing data´s best-fitting straight line over time, within each phase. For the trend, the direction and steepness of the slope is noted. A positive trend refers to an accelerating line and a negative trend, a decelerating line. Variability is the fluctuation of the data points which is demonstrated by the standard deviation. The 2SDBM was used to determine statistically significant changes in data points, between the baseline and intervention phases (Nourbakhsh et al., 1994). Two standard deviations (2SD) were calculated from the baseline data and bands were drawn on the graph containing scores within ±2SD from the mean baseline data. These bands extended into each baseline´s consequent treatment phase. A statistically significant change between baseline and treatment phases was inferred if at least two conterminous data points fell outside the 2SD range in the treatment phase (Nourbakhsh & Ottenbacher, 1994). As the PSFS and PGIC are ordinal scales, the results from these outcome measures were not applicable to the 2SDBM. In these cases, results were demonstrated on a graph and a positive or negative change recorded, respectively, if two or more data points in the intervention phase showed an improvement or deterioration.

The effect size (ES) was calculated to determine the strength of between-phase differences in two ways: (1) between each baseline and the consequent intervention phase (A1→B1, A2→B2); and (2) between the first baseline phase (A1) and the last intervention phase (B2) (A1→B2) (Durlak, 2009; Ferguson, 2009). These were conducted for each participant and for each outcome measure. The ES has the advantage of not only evaluating statistical significance but also quantifying the magnitude of change between phases (Ialongo, 2016). ES´s can thus give a better impression of the clinical significance of an intervention (Dunst et al., 2012). The ES uses SD units to estimate the difference between two phases (Auerbach & Zeitlin, 2014). Due to the small sample size and variation in SD between phases, “Hedges G” was the chosen method of calculating ES (Hedges et al., 1985). Hedges G, sometimes called “the corrected ES”, uses a pooled standard deviation from both phases and is the preferred measure of ES for small sample sizes, such as in this study (Rosnow et al., 2003). Parameters for size of effects were: (1) <0.87 = small effect size; (2) 0.87-2.67 = medium effect size and (3) >2.67 = large effect size (Auerbach & Zeitlin, 2014; Bloom et al., 2008). ES´s were presented as positive if the change was to be interpreted as an improvement and negative if the change was a deterioration in performance. This was done to ease interpretation of results between measures as an improvement was a decline in some outcomes and a rise in others. For example, an improvement in performance was a decline in time taken to finish the TUG but in the case of the 10mWT, a rise in speed was interpreted as an improvement. Confidence Intervals (CI) established for a measure of ES indicated the range within which the true

ES was likely to occur. A CI of 95% (CI95) indicated whether statistical significance was reached for the effect size (Coe, 2002). An effect size of zero is interpreted as “no effect”. Therefore, an effect size with a CI95 above zero is interpreted as statistically significant at the 5% level or p<0.05 (Gupta, 2012). Evidence of causal positive effects (medium or large) being repeated twice (A1→B1 & A2→B2) during the study were noted as a “repetition of effect”. Evidence of “maintenance of effect” is noted if a medium or large positive effect was present between A1 and B1 as well as between A1 and B2. A statistically significant “repetition-” or “maintenance- of effect” was noted if the ES for both compared phases showed a CI95 above zero. As the statistical SSD for R package calculated all Hedges G ES´s as positive but indicated whether the % change was positive or negative, the values for interpreted CI95 negative sizes were mirrored around the value of the ES. To assess the effects of confounding variables on the data, autocorrelations were calculated

(Auerbach et al., 2013). First lag autocorrelations were computed using rF2 and “sig of rF2”, to assess the presence of bias in the data (Auerbach et al., 2013). This was done because of the time-series nature of the SSRD used in this study and possible correlation of successive data points that could increase the likelihood of a type I error (i.e. acceptance of a non-existing effect) (Auerbach et al., 2014).

A higher rF2 indicates more influence of the autocorrelation, with positive and negative autocorrelations suggesting liberally and conservatively biased errors, respectively, in the phases (Crosbie, 1987). The p-value for rF2 is provided as “sig of rF2” and indicates the chances of a Type I error in rF2 calculations. A p-value above 0.05 was interpreted as lacking statistical significance and indicated that data in the phase were not autocorrelated. For this study, autocorrelations were calculated prior to ES calculations

for all outcome measures in all phases. If autocorrelation was found in the data, ES was deemed statistically insignificant.

3.4 Ethics The project has been reviewed and approved by The National Bioethics Committee (VSNb2014100022/03.07) (Appendix 13). An extension was approved (no. 14-150-V2) by the National Bioethics Committee on May 10th, 2016 (Appendix 14). The study has also been approved by the executive medical director of the National University Hospital of Iceland in a letter dated 27.10.2014 (Appendix 15).

3.5 Declaration of Conflicting Interests The author and research group declared no potential conflicts of interest with respect to this research or the equipment used in it.

3.6 Funding The author(s) received funding from the Icelandic Physiotherapy Association and the National University Hospital of Iceland. Funding for preliminary pilot studies on tSCS, for preparation of study methods and research on methods of data processing and analysis were received from the Student Innovation Fund of Rannis.

4 Results

4.1 Spasticity Within-phase level, trend and variability of spasticity outcome measures are provided in Table A.1 (Appendix 16). Autocorrelation calculations supported the relevance of all ES calculations for between- phase differences in spasticity outcome measures (p> 0.05) (Table A.4 in Appendix 17).

4.1.1 Tardieu Scale

4.1.1.1 Tardieu (R1) – Spasticity Angle of Plantar Flexors Figure 6 provides the visual representation of data in relation to the spasticity angle for plantar flexors (Tardieu R1) and Table 3 the corresponding data. S4 demonstrated a medium size improvement in the spasticity angle between phases A1 and B1 (ES=2.61, CI95=0.18-4.91). Visual analysis also shows that S4 and S3 demonstrated a decline in the spasticity angle between phases A2→B2 and A1→B1, respectively, but the effect did not reach statistical significance. The intervention did not have any effects on the spasticity angle for S5 and S6. None of the participants experienced repetition or maintenance of effect.

4.1.1.2 Tardieu (R2), Passive Range of Motion (PROM) into dorsiflexion Figure 7 presents the data visually for the results of PROM into dorsiflexion (Tardieu R2) and Table 3 provides the corresponding data. S4 demonstrated a large size improvement in the PROM between phases A1 and B1 (ES=3.57, CI95=0.66-6.38). A repetition and maintenance of effect were also noted

for S4 but did not reach statistical significance. S3´s improvement between phases A2 and B2 are demonstrated visually. The treatment did not have any effects related to PROM for S5 and S6.

4.1.2 Wartenberg Pendulum Test (WPT) - R2n

Figure 8 provides the visual analysis of data related to the R2n (WPT) and Table 3 the corresponding data. Due to lost data, visual and data analysis of R2n are not possible between phases A2 and B2 for participants S3 and S4. For remaining phases, the intervention did not influence R2n. Results for all participants were close to 1, indicating that these participants had a low level of spasticity in the extensor and flexor muscles of the knee.

4.1.3 Penn Spasm Frequency Scale (PSFS) Figures 9 and 10 provide the visual representation of data related to the PSFS- frequency and severity, respectively, and Table 3 the corresponding data. Visual analysis of the first intervention phase for S4 and S5, demonstrated a decline in spasm severity from severe to mild and from moderate to mild, respectively. The intervention did not have any effects related to PSFS for the other participants.

Figure 6. Tardieu Scale - Spasticity Angle (°) of muscle reaction to fast movement (R1) of plantar flexors A statistically significant change between baseline and treatment phases was inferred if at least two conterminous data points fell outside the two standard deviation range (marked by lines) in the treatment phase. An increase in the joint angle indicated an improvement in the Spasticity Angle (R1).

Figure 7. Tardieu Scale – Passive range of motion (°) during slow movement (R2) of ankle into dorsiflexion A statistically significant change between baseline and treatment phases was inferred if at least two conterminous data points fell outside the two standard deviation range (marked by lines) in the treatment phase. An increase in the joint angle indicated an improvement in passive range of motion.

Figure 8. Wartenberg Pendulum Test - R2n coefficients A spasticity index 푹ퟐ풏 ≥ ퟏ indicates non‐spastic conditions, while 푹ퟐ풏 → ퟎ represents severe spasticity.

Figure 9. Penn Spasm Frequency Scale – Spasm Frequency Visual presentation of the results of a self-report measure on the frequency of muscle spasms for each participant.

Figure 10. Penn Spasm Frequency Scale – Spasm Severity Visual presentation of the results of a self-report measure on the severity of muscle spasms for each participant.

Table 3. Between-Phase Effect Sizes (CI95%) for Spasticity

Repetition Maintenance + ± ± Effect Sizes (CI95) of Effect of Effect

Outcome Subjects A1→B1 A2→B2 A1→B2 measures

Tardieu S3 -1.01 (-2.69-0.78) -0.61 (-2.23-1.08) - 2.09 (-4.15-0.10) No No

R1 S4 2.61 (0.18-4.91) * -0.71 (-2.34-1.00) - 1.39 (-0.52-3.18) No No (Spasticity S5 -0.54 (-2.15-1.13) -0.58 (-2.20-1.10) -1.25 (-2.99-0.62) No No Angle) S6 0.11 (-1.50-1.70) 0.53 (-1.13-2.14) 1.30 (-0.58-3.06) No No

Tardieu S3 0.65 (-1.04-2.27) 1.25 (-0.61-3.00) 1.25 (-0.61-3.00) No No

R2 (PROM) S4 3.57 (0.66-6.38) * 1.45 (-0.49-3.25) 1.69 (-0.33-3.59) Yes Yes

S5 1.28 (-0.59-3.04) 0.09 (-1.52-1.68) 0.05 (-1.55-1.65) No No

S6 -1.42 (-3.23-0.49) 1.04 (-0.75-2.74) -1.45 (-0.48-3.26) No No

R2n S3 1.05 (-0.75-2.75) - - - -

S4 -0.62 (-2.24-1.06) - - - -

S5 1.33 (-0.55-3.11) 0.75 (-0.96-2.39) 0.02(-1.58-1.62) No No

S6 0.10 (-1.50-1.70) -1.15 (-2.87-0.68) 0.39 (-1.25-1.99) No No

PSFS - S3 0.65 (-1.04-2.27) 0.65 (-1.04-2.27) 0.87 (-0.88-2.53) No No

Frequency S4 0.92 ( -0.84-2.59) -0.65 (-2.27-1.04) 0.65 (-1.04-2.27) No No

S5 0.65 (-1.04-2.27) 1.38 (-0.53-3.17) 0.92 (-0.84-2.59) No No

S6 - - - - -

PSFS - S3 0.33 (-1.31-1.92) 0.65 (-1.04-2.27) 0.80 (-0.93-2.44) No No

Severity S4 1.84 (-0.24-3.80) - 1.30 (-0.58-3.07) No Yes

S5 1.30 (-0.58-3.07) 0.65 (-1.04-2.27) 1.38 (-0.53-3.17) No Yes

S6 - - - - -

+ Effect size coefficients (ES) and 95% confidence intervals (CI95) for changes of performance from baseline to consequent intervention phase (A1→B1 and A2→B2) as well as from first baseline to last intervention phase (A1→B2). Effect size parameters: (1) <0.87 = small effect size; (2) 0.87-2.67 = medium effect size and (3) >2.67 = large effect size. * CI95 > 0 or CI95 < 0 indicates p<0.05. ±Repetition and maintenance of effect refer to a positive medium to large ES being repeated or maintained, respectively, in the study. ** Maintenance/repetition of effect = statistically significant ES for both phases.

4.2 Mobility Within-phase level, trend and variability of mobility outcome measures are provided in Table A.2 (Appendix 16). Autocorrelation calculations supported the relevance of all ES calculations for between- phase differences of mobility outcome measures (p> 0.05) (Table A.5, Appendix 17).

4.2.1 Ten-metre Walking Test (10mWT) - Comfortable Walking Speed Figure 11 shows the visual representation of the results for comfortable walking-10mWT and Table 4 the corresponding data. An improvement in comfortable walking speed is demonstrated for two participants: S4 with a large effect (ES=4.03, CI95 =0.87-7.11) for the first intervention phase and maintenance of effect (ES=2.27, CI95 =0.01-4.41) and S6 for the second intervention phase, demonstrated visually. Repetition of effect was not demonstrated for any of the participants. The decline in walking speed between A2→B2 for S5 was due to a reported slipping on ice on his way home from his last baseline measurement that resulted in bruising of his left hemiplegic leg. The intervention did not have any effect on comfortable walking speed for S3.

4.2.2 Ten-metre Walking Test (10mWT) – Fast Walking Speed Figure 12 provides the visual representation of the results in relation to fast walking-10mWT and Table 4 the corresponding data. Effects of tSCS on fast walking were demonstrated for two participants. Firstly, for S4, a large effect on walking speed was demonstrated, between A1→B1 (ES=2.98, CI95=0.37-5.47). There was a trend towards maintenance of effect in S4, that did not reach statistical significance

(ES=1.73, CI95=-0.31-3.65). S4´s level for fast walking speed for fast walking was increased from 0.64m/s (A1) to 0.75m/s (B1) after tSCS was initially introduced and did not return to baseline levels after the washout period (0.72m/s = A2) (Table A.2). Secondly, visual analysis demonstrated an improvement in walking speed for S6. The intervention did not have any effects on fast walking for S3 and S5. Repetition of effect was not demonstrated for any of the participants on fast walking-10mWT.

4.2.3 Timed Up and Go (TUG) Figure 13 presents the visual results for the TUG test and Table 4 the corresponding data. Improvements on the TUG were demonstrated visually and statistically for two participants during the first intervention phase: large size for S4 (ES=3.57, CI95=0.66-6.37) and medium size for S5 (ES=2.65, CI95 =0.21-4.98).

There was a trend towards maintenance of effect for S4 (ES=3.91, CI95=0.82-6.93), but not for repetition of effect (ES=1.43, CI95 =-0.50-3.23). S6´s performance on the TUG dropped (ES=-2.31, CI95 = -4.47- - 0.02) during the first intervention phase, when he also reported having a minor flu. The intervention did not have an effect in S3´s performance.

4.2.4 Five Times Sit-to-Stand Test (FTSTS) Figure 14 provides visual representation of data for the FTSTS test and Table 4 the corresponding data. Three participants demonstrated an improvement on the FTSTS after tSCS was introduced: S4 and S6 demonstrated large improvements between phases A1→B1, (ES=2.68, CI95= 0.22-5.00) and A2→B2

(ES=3.24, CI95=0.50-5.87) respectively, and S5´s improvement was demonstrated visually between phases A1 and B1. Maintenance of effect was demonstrated for S4 (ES=2.47, CI95=0.11-4.71).

Repetition of effect was not demonstrated for any of the participants. No effects were demonstrated on S3´s performance on the FTSTS.

4.2.5 Activities-Specific Balance Confidence Scale (ABC scale) Figure 15 presents the results for balance confidence (%) measured with the ABC scale. Visual analysis did not demonstrate any between-phase improvements on this measure for any of the participants. For this reason, no further data analysis was inferred.

Figure 11. Ten-metre Walking Test – Comfortable Speed A statistically significant change between baseline and treatment phases was inferred if at least two conterminous data points fell outside the two standard deviation range (marked by lines) in the treatment phase. An increase in walking speed indicated an improvement in performance. 31

Figure 12. Ten-metre Walking Test – Fast Speed A statistically significant change between baseline and treatment phases was inferred if at least two conterminous data points fell outside the two standard deviation range (marked by lines) in the treatment phase. An increase in walking speed indicated an improvement in performance.

Figure 13. Timed Up and Go A statistically significant change between baseline and treatment phases was inferred if at least two conterminous data points fell outside the two standard deviation range (marked by lines) in the treatment phase. A decrease in time take to complete the test inferred an improvement in performance.

Figure 14. Five times Sit-to-Stand Test A statistically significant change between baseline and treatment phases was inferred if at least two conterminous data points fell outside the two standard deviation range (marked by lines) in the treatment phase. A decrease in test time indicated an improvement in performance.

Figure 15. Results for balance confidence (%), for all participants on the ABC Scale A statistically significant change between baseline and treatment phases was inferred if at least two conterminous data points fell outside the two standard deviation range (marked by lines) in the treatment phase. An increase in balance confidence (%) indicated an improvement in performance.

Table 4. Between-Phase Effect Sizes (CI95%) for Mobility

Repetition of Maint. of ± ± Effect Sizes+ Effect Effect

Outcome Subjects A1→B1 A2→B2 A1→B2 measures

10mWT S3 1.48 (-0.46-3.30) 0.08 (-1.5-1.68) 0.76 (-0.95-2.41) No No

Comfortable S4 4.03 (0.87-7.11) * 0.02 (-1.59-1.62) 2.27 (0.01-4.41) * No Yes ** Speed S5 0.23 (-1.39-1.83) - 2.56 (-4.83- -0.16) * -1.47 (-3.29-0.47) No No

S6 0.02 (-1.50-1.62) 1.24 (-0.61-3.00) 0.38 (-1.26-1.98) No No

10mWT S3 0.58 (-1.10-2.20) 0.24 (-1.37-1.84) 0.7 (-1.01-2.33) No No

Fast Speed S4 2.98 (0.37-5.47) * 0.16 (-1.46-1.75) 1.73 (-0.31-3.65) No Yes

S5 0.55 (-1.12-2.17) -0.93 (-2.59-0.84) 1.17 (-0.66-2.90) No No

S6 -0.54 (-2.15-1.13) 1.27 (-0.60-3.03) -0.13 (1.48- -1.72) No No

TUG S3 0.00 (-1.60-1.60) 0.65 (-1.04-2.28) 1.61 (-0.38-3.48) No No

S4 3.57 (0.66-6.37) * 1.43 (-0.50-3.23) 3.91 (0.82-6.93) * Yes Yes **

S5 2.65 (0.21-4.98) * 0.26 (-1.36-1.86) 0.26 (-1.37-1.85) No No

S6 -2.31 (-4.47- -0.02) * 0.99 (-0.78-2.68) -1.34 (0.55- -3.11) No No

5 TSTS S3 0.79 (-0.94-2.43) -0.99 (-2.67-0.78) 0.74 (-0.98-2.37) No Yes

S4 2.68 (0.22-5.00) * 1.43 (-0.50-3.23) 2.47 (0.11-4.71) * Yes Yes**

S5 2.05 (-0.12-4.09) -1.08 (-2.79-0.73) 1.38 (-0.53-3.17) No No

S6 -0.47 (-1.18-2.07) 3.24 (0.50-5.87) * 1.20 (-0.64-2.94) No No

4.3 Pain and Sleep Within-phase level, trend and variability of outcome measures for pain and sleep are provided in Table A.3 (Appendix 16). Autocorrelation calculations supported the relevance of all ES calculations for between-phase differences in outcome measures for pain and sleep (p> 0.05) (Table A.6, Appendix 17).

4.3.1 11-Point Numerical Rating Scale (NRS) – Pain Figure 16 provides the visual representation of data in relation to pain on the NRS and Table 5 the corresponding data. A large effect and maintenance of effect were demonstrated for S4 in A1→B1

(ES=2.71, CI95= 0.23-5.06) and A1→B2 (ES=4.56, CI95= 1.1-7.95). Repetition of effect was not demonstrated for S4 or any other case. Due to the stability of measurements for S6, ES calculations were not relevant for the first intervention phase. Variability in pain measurements were present throughout the study for S3. The intervention did not have any effect on pain for S3, S5 and S6.

4.3.2 11-Point Numerical Rating Scale (NRS) – Sleep Figure 17 presents the visual data and Table 5 the corresponding data regarding “how much spasticity and pain disrupted sleep”. An improvement in sleep was demonstrated for two participants (S4 and S5). Firstly, S4 demonstrated an infinitely large effect (ES=inf) during the first intervention phase and a large maintenance of effect (ES=5.21, CI95= 1.38-9.00). Stability in the first baseline measurement for S4 showed that this participant rated his sleep disruption as 6/10 on the NRS for all baseline measurements. A week after commencing home treatment with tSCS, S4 reported that sleep disruption had decreased to 0/10. This improvement in sleep continued for all measurements throughout the first intervention phase. Repetition of effect was not demonstrated for S4 (ES=1.62, CI95= -0.37-3.5). Secondly, visual analysis of data for S5 indicated an improvement in sleep during the second intervention phase, but the effect did not reach statistical significance (ES=1.84, CI95= -0.24-3.8). No improvements in sleep were demonstrated for S3 and S6.

Figure 16. 11-point Numerical Rating Scale – Pain Results show answers to the question “On a scale from 0-10, how little or much pain have you had in your back or legs in the last 24 hours?”.

Figure 17.11-point Numerical Rating Scale – Sleep Results show answers to the question “On a scale from 0-10, how little or much has your spasticity or pain interrupted your sleep in the last 24 hours?”.

Table 5. Between-Phase Effect Sizes (CI95%) for Pain and Sleep

Repetition Maintenance Effect Sizes+ of Effect± of Effect±

Outcome Subjects A1→B1 A2→B2 A1→B2 measures

NRS Pain S3 0.70 (-1.01-2.32) 0.13 (-1.48-1.73) 1.37 (-0.53-3.16) No No

S4 2.71 (0.23-5.06) * 1.15 (-0.68-2.87) 4.56 (1.1-7.95) * Yes Yes **

S5 0.60 (-1.09-2.21) -0.65 (-2.27-1.04) 0.18 (-1.43-1.77) No No

S6 - 0.65 (-1.04-2.27) - - -

NRS Sleep S3 1.31 (-0.57-3.07) 0.65 (-1.04-2.27) 1.17 (-0.66-2.90) No Yes

S4 Inf * 1.62 (-0.37-3.50) 5.21 (1.38-9.00) * Yes Yes **

S5 0.25 (-1.38-1.84) 1.84 (-0.24-3.8) 0.65 (-1.04-2.27) No No

S6 0.65 (-1.04-2.27) 0.92 (-0.84-2.59) 0.874 (-0.88-2.53) No No

4.4 Other Results

4.4.1 Summary of Effect for each Participant Figures 18 and 19 provide a summary of the effects for each participant in forest plots for the first and second intervention phase, respectively.

For S4, the overall medium to large improvements demonstrated between A1 and B1 include: 2/5 spasticity measures, 4/4 mobility measures and the single measures for pain and sleep. Although no effects reached statistical significance for S4 between A2 and B2, there are indications of improvements on the TUG, 5TSTS, NRS- Pain and Sleep.

For S5, a medium effect was demonstrated on the mobility scale TUG, during the first intervention, whilst other effects did not reach statistical significance for this participant. The results showed more positive results during the second treatment phase for S6, with a large effect demonstrated on the 5TSTS. No effects were demonstrated for S3.

4.4.2 Patient Global Impression of Change (PGIC) Figure 20 presents participants responses on the PGIC for spasticity, pain and sleep. No further statistical analysis of this data was performed. Participant S4 reported stability (no change) during baseline measurements for all dependent variables and an immediate „minimal“ to „much improved“ impression of change for 17/18 measurements of spasticity, pain and sleep during both intervention phases. For S5, results demonstrated that this participant felt a minimal improvement in spasticity and sleep in all data points for the first intervention phase and for two of three data points in the second intervention phase. S5´s impression of pain did not change after tSCS was introduced. Responses for S3 demonstrated a fluctuation in the perception of change regarding spasticity and sleep throughout the study period. More stability can be seen in the impression of pain for S3, which seemed to decrease in the second baseline phase and to slightly increase in the second intervention phase. S6 reported an immediate minimal improvement of spasticity for all measurements in the first intervention phase and for two of three measurements in the second intervention phase. S6 also reported an immediate improvement in sleep and pain a week after the second intervention phase commenced but did not report ongoing improvement in following measurements

Figure 18. Forest Plot - Phases A1 and B1 This Forest Plot summarizes the overall effect of tSCS on each participant between the first baseline and intervention phase. The dots represent the effect size (ES) and the horizontal line through them provide the 95% confidence intervals (CI95). An effect size with a CI95 above zero (Y-axis) is to be interpreted as a statistically significant improvement at the 5% level or p<0.05. Effect size parameters: (1) <0.87 = small effect size; (2) 0.87-2.67 = medium effect size and (3) >2.67 = large effect size.

Figure 19. Forest Plot - Phases A2 and B2 This Forest Plot summarizes the overall effect of tSCS on each participant between the second baseline and intervention phase. The dots represent the effect size (ES) and the horizontal line through them provide the 95% confidence intervals (CI95). An effect size with a CI95 above zero (Y-axis) is to be interpreted as a statistically significant improvement at the 5% level or p<0.05. Effect size parameters: (1) <0.87 = small effect size; (2) 0.87-2.67 = medium effect size and (3) >2.67 = large effect size.

Figure 20. Patient Global Impression of Change for spasticity, pain and sleep Results show answers to the questions: “Have you found a change in your spasticity/spasms?”, “How much or little has your pain changed?” and “How much or little has your sleep changed?”.

4.4.3 Compliance to treatment Data from the built in and written logbooks showed 100% compliance to daily home treatment of 30 mins of tSCS, during the intervention phases.

4.4.4 Other Findings from Participants

Subject 4 Positive findings for S4 were also confirmed by written reports of improvements given in response to the question “Is there something else you would like to convey?”, which was at the end of the self-report questionnaire (Appendix 11). After commencing initial treatment with tSCS, S4 reported an immediate improvement in his ability to cross a large road whilst the green walking light was still on. This was a road he had been crossing three times a week for a year, to get to physiotherapy, and had never been capable of crossing it completely without the walking light turning red. He also noted more stamina to walk longer distances and a decrease in muscle stiffness. He reported improved sleep during the first intervention phase, because he “didn´t get spasms in his hemiplegic leg during the night”. His improvements in sleep lasted two weeks after he stopped using tSCS after B1. Towards the end of the second treatment phase, S4 reported less pain and spasm in his hemiplegic leg and better sleep but did not experience the same improvements in his walking, as he did during the first intervention phase.

Subject 5 At the end of the first treatment phase, S5 reported finding it easier to push down with his toes when he is walking in the swimming pool.

Subject 6 A week into the first treatment phase, S6 reported feeling better due to less spasms. A week into the second treatment phase, he reported “feeling better” in his whole body and waking up less frequently due to spasms in his hemiplegic leg.

4.4.5 Lost Data Results from six biomechanical measurements were lost. These are 2 measurements (7 & 12) for participants S3, S4 and S5. The reason for this data being unavailable is due to technical issues with goniometers in three measurements and data being ineffectively saved to the hard drive for three measurements.

4.4.6 Voluntary Activation of ankle Dorsi- and Plantar Flexion (Co-Contraction) Biomechanical measurements of co-contraction were rendered inadequate for the SSRD data analysis methods chosen for this study. The reason is twofold: first, only one measurement of the maximal voluntary muscle contraction was taken during phases A1 and B1 for S3 and S4, which created problems with the reliability and validity of this measurement and second, due to lost data from six measurements. The results for co-contraction of voluntary activation of the ankle are therefore not included.

5 Discussion

This is the first study to investigate the effects of tSCS post-stroke. The aim was to evaluate the effect of a three-week daily home application of tSCS on spasticity, mobility, pain and sleep in four community dwelling individuals post-stroke. The results suggest that tSCS can alleviate spasticity and pain and enhance mobility and sleep in some individuals post-stroke. Out of the four participants, one experienced medium to large improvements in spasticity, mobility, pain and sleep when using tSCS for the first time. According to self-report data from the PGIC, this participant found “much improvement” in spasticity, pain and sleep after three weeks of tSCS the first time tSCS was introduced, and “minimal improvement” the second time it was introduced. Hence, the large improvement, measured in most of the clinical and biomechanical outcome measures, correlated to this participant´s impression of change. In addition, this participant´s report of walking faster across a familiar road confirms that these effects were meaningful for him.

There was, however, no repetition of effect for this participant during the second treatment phase. One of the reasons for this may have been due to carryover of effects from the initial treatment phase. Although the washout period was 15 weeks for this participant, his second baseline measurements had not returned to their original values when the second baseline was taken, which indicated that a longer washout period may have been necessary.

For two other participants, the effects of daily application of tSCS for three weeks varied from no effects (i.e. pain and spasticity) to positive effects on some domains (i.e. mobility and sleep). More specifically, S5 improved on the TUG during the first intervention phase and had enhanced sleep during the second intervention phase. Furthermore, S6 demonstrated an improvement in mobility on three outcome measures during the second treatment. For the remaining participant (S3), there were no effects of the treatment on any of the domains. Overall, mobility and sleep were the domains that improved the most with tSCS and participants with moderate disability and higher levels of ankle spasticity were affected more by the treatment. These results imply that tSCS may be capable of reducing some impairments (e.g. pain, sleep disturbances) and improving mobility in some stroke patients. However, reservations remain as to whether the causal effect was due to the intervention or other factors as replication of an effect was not demonstrated in this study. Treatment with tSCS in accordance with the protocol of this study, had no adverse effects and it was easy to administer as home treatment. For this reason, it could be considered as a complementary rehabilitation tool to enhance improvements post-stroke.

5.1 Spasticity

Of the four outcome measures used to evaluate spasticity (i.e. Tardieu R1 and R2; Wartenberg pendulum test R2n, co-contraction of dorsi- and plantar flexors; Penn Spasm Frequency Scale), positive effects were only demonstrated on the two ankle measurements of the Tardieu scale and only for one participant. Baseline measurements of knee spasticity using the WPT demonstrated low level spasticity in all participants at the start of the study, which was not affected by the intervention. Despite positive reports from one participant on the effect of tSCS on spasticity and correlating improvements

demonstrated on the Tardieu Scale, the sensitivity of the PSFS was not enough to detect a change in self-reported spasticity frequency and severity.

Whilst an improvement in the neural component of spasticity, as indicated by the increase in the spasticity angle, can be explained as a result of the intervention, an improvement in the PROM is more difficult to explain. A change in the PROM was unanticipated due to the general conception of it being a measure of the non-neural state of soft tissue stiffness, which should not be affected by tSCS. As tSCS is hypothesized to reduce spasticity by depolarizing the large myelinated afferent posterior root fibres that activate local inhibitory circuits, it´s efficacy should only affect neural components of muscle stiffness. According to the data, this participant´s mean PROM increased by 10° after tSCS was introduced the first time. Based on the standardized methods of measurement and quality assessment of data used in this study (variability, trend and autocorrelation), these improvements in PROM seem credible. It also correlates to other positive results for this participant during this intervention period. Interestingly, the EU Spasm Consortium has rebuked former definitions of spasticity and stated that insufficient evidence exists in the literature to support former definitions of spasticity based exclusively on stretch reflex hyperexcitability (Pandyan et al., 2005). The EU Spasm Consortium suggest that other spasticity pathways, including the supraspinal control pathways and α-motor neurons, may also contribute to the involuntary muscle activation seen in spasticity (Pandyan et al., 2005). Our finding for this one participant, seems to support this hypothesis and indicate that tSCS may be helpful in improving range of motion of joints in some individuals by modulating stiffness of muscles.

Although spasticity is one of the most frequently mentioned symptoms of neurological conditions, it is commonly misinterpreted and has posed a challenge for clinicians and researchers to define, assess and manage (Burridge et al., 2005). The lack of congruence in terminology of spasticity, added to the vast array of techniques used to measure different aspects of this phenomenon, have led to a compromise in its measurement validity. There has been a call for more holistic approaches in spasticity measurement, ones that use valid and reliable measures that are quantitative and sensitive to a change that has clinical relevance to the patient (Pandyan et al., 2005; Platz et al., 2005; Wood et al., 2005). To date, researchers still strive to find one such appropriate outcome measure for spasticity (Pandyan et al., 2006). To bridge this gap, we employed a wide range of objective and subjective outcome measures to quantitatively monitor spasticity over time. A combination of clinical, biomechanical and subjective measures aimed to fulfil the theoretical and methodological considerations of spasticity measurement and provide insight into clinical relevance of any changes. Such an extensive approach did not come without complications. Whilst meticulous care was taken in using standardized protocols for measuring, technical problems and data loss limited the availability and quality of data from biomechanical measurements. Also, unreliable measuring techniques for a maximal voluntary muscle contraction, during the start of the study caused flaws in calculations of co-contraction during voluntary activation of muscles. For this reason, the results for measurements of co-contraction, during voluntary dorsi- and plantar-flexion, did not suffice criteria for single subject research analysis and are thus excluded from this thesis.

The literature is replete with studies on the effect of epidural, endodural and subdural SCS on spasticity in over 25 different neurological conditions (Nagel et al., 2017). However, research evidence

for the efficacy of SCS on spasticity post-stroke is limited. The few studies performed on stroke are older and restricted to epidural SCS to the cervical spine (Cioni et al., 1989; Nakamura et al., 1985). These studies had a number of methodological limitations: (1) their methodology was not described in sufficient level of detail; (2) they lacked internal validity as they did not have a control component and (3) the measurements for spasticity were taken during SCS, which is confounding for a change in electromyographic results (Minassian et al., 2016). One study applied EMG evaluation of spasticity during voluntary, involuntary and reflex motor activity in thirteen stroke patients, before and during implanted SCS (Cioni et al., 1989). This study divided participants into groups based on the effects of SCS and concluded that SCS seemed to be a useful tool in post-stroke patients with mild sensory deficit. However, their evaluation of spasticity lacked a quantitative measure and relied solely on subjective evaluation of spasticity and visual interpretation of pretest-posttest EMG recordings. This study documented that only five of the 13 patients (38.4%) were still successfully using the stimulator in follow-up evaluation but did not specify the time length or reason for patients discontinuing treatment (Cioni et al., 1989). As our study did not employ a clinical measure to assess sensory function, we cannot confirm whether the efficacy of tSCS depended on sensory deficit. Another study, on three patients with acute stroke, used clinical and objective electrophysiological measures for repetitive evaluation of spasticity and mobility before and after implantation of epidural SCS (Nakamura & Tsubokawa, 1985). Quantitative spasticity assessments using the H/M ratio revealed an observed reduction in spasticity for all cases from 3-9 days after SCS began, with improvements still being measured up to 173 days later for some participants (Nakamura & Tsubokawa, 1985). However, the authors stated that SCS yields selective effects and that ongoing treatment with SCS may be unnecessary and proposed that stimulation only be continued whilst effects prevail (Nakamura & Tsubokawa, 1985). A lack of “repetition of effect” in our study supports findings that although SCS could be effective in reducing spasticity, ongoing or repeated treatment may not be beneficial. Further studies need to explore the timeframes for how long effects can last and which stroke patients are more responsive to tSCS. To date, no existing studies have evaluated the effects of tSCS on spasticity post-stroke. One pilot study has been published on the effect of tSCS in individuals with incomplete SCI (Hofstoetter et al., 2014). Pre- and posttest evaluation of spasticity and voluntary motor control was assessed using clinical and biomechanical testing (Hofstoetter et al., 2014). In the post-stimulation testing, visual interpretation of EMG data showed a decline in exaggerated reflexes during clinical testing and less co-contraction and clonus like activity during voluntary movements. In a similar way to our results, the R2n from the Wartenberg pendulum test seemed to be the least sensitive to changes in spasticity after treatment with tSCS. From these preliminary results, authors justified further investigation, with statistically appropriate research methods, into the efficacy of tSCS as temporary relief of spasticity in SCI (Hofstoetter et al., 2014). The results from our study indicate that tSCS may alleviate spasticity in some individuals post-stroke. However, evidence for a treatment effect on spasticity was limited to the Tardieu Scale and not demonstrated biomechanically with the R2n, nor on self-report measures of spasticity and must therefore

be taken with caution. Compared to the results of other studies on the effect of SCS and tSCS on spasticity in SCI, it´s beneficial effects could possibly be less for cerebral spasticity than for spinal spasticity.

5.2 Mobility To our knowledge, this study is the first to explore the effects of tSCS on mobility post-stroke. The results suggest that the effects of tSCS are more apparent for mobility than spasticity. Mobility was the only domain that demonstrated positive effects for more than one participant. These effects were medium to large and were demonstrated on all clinical outcome measures of mobility for one participant during initial treatment. Most of these improvements were maintained throughout the study for this participant and a possible carryover effect was retained after the initial treatment phase as baseline measurements did not return to their original values. Repetition of effects was not demonstrated for any of the participants. Although it is beyond the scope of this study to determine what mechanisms lie behind the potential reason for positive effects of tSCS on mobility, researchers did witness an obvious stimulation- induced increase in EMG activity in all four muscles during tSCS sessions performed at the research lab. It is therefore plausible that the positive effects on mobility could be through excitation of the electrophysiological state of the lumbar locomotor circuitry, thus making the residual descending spinal tracts and motor efferents more responsive to voluntary activation (Hofstoetter et al., 2013). Other researchers in restorative neurology have proposed that the positive effects of SCS on spasticity and mobility are interlinked with enhancement of supraspinal drive and augmentation of excitability in the spinal cord (Minassian et al., 2012). Since the published findings that SCS could elicit stepping pattern in the lower limbs, in the absence of supraspinal control, research on the effect of SCS on mobility has predominately been demonstrated in case studies of individuals with SCI (Dimitrijevic et al., 1998). In one such study, epidural SCS along with task-specific training, was demonstrated to enable a 23 year old man with incomplete SCI to achieve assisted standing and stepping (Harkema et al., 2011). Using specific stimulation parameters for standing and stepping, SCS enabled partial recovery of voluntary muscle activation by modulation of previously silent but spared neural circuits, but this effect only occurred during stimulation sessions. Epidural SCS has also been shown to induce stepping-like activation in complete spinal cord injured individuals (Minassian et al., 2007). The mechanism behind this effect is believed to be due to an increased central state of neural excitability produced by SCS that enables generation of motor output from lumbar locomotor central pattern generators and is turned on by the proprioceptive feedback of passive stepping (Dimitrijevic et al., 1998). Future studies on the effect of tSCS on mobility in stroke patients could possibly investigate the effect of stimulation during functional movements. The few studies that have explored the effect of SCS on mobility in stroke patients are limited to SCS with epidurally implanted electrodes (Cioni et al., 1989; Nakamura & Tsubokawa, 1985). Existing studies demonstrate beneficial effects of SCS on motor performance for some, but not all stroke patients. One study found that SCS enhanced gait and alleviated co-contraction in 7 of 11 patients (Cioni et al., 1989). They found that the best results were obtained in patients with mild sensory loss and that patients with normal sensory function did not benefit from treatment. Another report on the

effects of epidural SCS in motor performance in acute stroke must be viewed with caution as it did not include control elements and large improvements in mobility can be expected during the first months after stroke and thus confound interpretation of a treatment effect of SCS on motor recovery (Nakamura & Tsubokawa, 1985). Research on the effects of tSCS on mobility is limited to very few case studies on individuals with SCI (Hofstoetter et al., 2013; Hofstoetter et al., 2014). These pretest-posttest case studies suggest that the effects of tSCS on mobility are analogous to the effects of epidural SCS. Augmentation of motor function through lumbosacral tSCS was believed to be a result of excitation of voluntary muscle activation during functional activities of treadmill walking and standing and not due to passive stimulation of motor neurons (Hofstoetter et al., 2013; Hofstoetter et al., 2014).

5.3 Pain and Sleep The results from this study imply that tSCS´s largest impact was on pain and sleep for S4, during the first intervention period, and these effects were maintained throughout the study. Despite promising results for pain and sleep, future research is required to determine the efficacy of tSCS on these domains as our results were limited to a single subjective question and a replication of effect was not demonstrated. Although SCS has been used for decades to treat pain syndromes, it is not commonly used for treating post-stroke pain (Kumar et al., 2006). Some studies have suggested that SCS can have therapeutic potential for pain relief in patients with central post-stroke pain and our study findings seem to suggest that this could also be the case for tSCS (Obuchi et al., 2013). To date, no studies have been published on whether SCS can influence sleep in the stroke population, but recent studies have suggested that it can improve sleep when used for pain management in the chronic pain population (De Jaeger et al., 2019; Ramineni et al., 2016). Sleep disturbances are a prevalent symptom in both populations and an improvement in pain has been shown to correspond with improved sleep (Bahouq et al., 2013; Duss et al., 2017). As these symptoms are reciprocally related, treating one may affect the other (Finan et al., 2013). This seemed to be the case for one of our participants who reported that his sleep disruptions, due to spasms and pain, disappeared completely during the first week of tSCS and that they didn´t reappear until fifteen days into the washout period. Although statistical significance was not reached for a change in pain and sleep during the second intervention phase for S4, a trend towards improvement was noted. Alternative methods of electrical stimulation are recommended in stroke clinical guidelines as effective for treating pain (Stroke Foundation, 2017). Transcutaneous electrical nerve stimulation (TENS) has been demonstrated to reduce comorbid spasticity and pain and improve muscle function post-stroke (Levin et al., 1992; Sahin et al., 2012; Yan et al., 2009). The mechanisms behind the effects of TENS on spasticity, mobility and pain after stroke are believed to be regulation of transmission of nociceptive inputs, production of β endorphins that may decrease the excitability of motor neurons and/or facilitation of excitatory motor output due to stimulation of large to medium afferent sensory fibres (Thibaut et al., 2013).

5.4 Strengths and Limitations The SSRD employed in this study was particularly suitable for an in-depth investigation of the effectiveness of the daily application of tSCS for three weeks on spasticity, mobility, pain and sleep. This research design provided a scientifically rigorous alternative to a randomized controlled trial and made it possible to explore multiple effects over time with a battery of clinical and biomechanical measurements, in a manageable number of participants. Although this study does not have a classical control group, such as found in a randomized controlled trial, it does have control elements. Each participant served as their own control by using a repetition of baseline measurements to compare to those taken during the intervention phase. Three data collections were included for each phase, which is the minimum amount needed in order to meet evidence standards criteria of a SSRD (Kratochwill et al., 2012). Having more than three data points for each outcome measure would have increased the internal validity of this study and minimized the impact of other confounding factors and lost data. On two occasions, exogenous factors appeared to have a negative effect on the dependent variable during the intervention phase. On one occasion, this was due to a fall and in another a cold. Confounding elements such as these are undoubtedly inevitable in long term evaluation, but their impact should be accounted for and possibly minimalized by more data collection. Visual and statistical methods of SSRD were used to analyse the magnitude of effects of tSCS on the dependent variables. Statistical significance of a treatment effect was demonstrated using the

2SDBM as well as the ES, including the CI95 for ES. These statistical methods provided comprehensive demonstration and critical interpretation of the results. Not only did they provide a method for evaluating the statistical significance of the results, but also a means for demonstrating the magnitude of the causal effect of the intervention (Lee, 2016). Hedges G was the chosen method for calculating the effect size as it is more appropriate for smaller sample sizes (<20) and shows less bias towards a calculated effect (Ialongo, 2016). The research team involved in this project attempted to maintain integrity in standardized measurement procedures. One of the major limitations of this study is that neither researchers nor participants were blinded. This, together with using a sham treatment as a control, and randomizing the sample could have increased the credibility of the research results by controlling factors such as a placebo effect and assessor´s bias. Methods of sham treatment were considered but not implemented due to practical and ethical reasons. First, researchers found no method of sham treatment with electrical stimulation to be convincing enough, without excluding a possible treatment effect. Second, it would have extended the research time excessively and called for unethical effort, travel cost and time on the participants part, without treatment gain.

To strengthen the internal validity of this study, in determining whether tSCS had a causal effect on the dependent variables, this study employed a withdrawal design with a second intervention phase to evaluate whether the effect could be replicated (Kratochwill et al., 2012). For this reason, a washout period was implemented, between the two treatment phases, that was intended to allow for the dependent variables to return to baseline. The fact that some measures did not return to baseline after the washout period indicates a possible carryover effect on the measures, that may have affected the

capability of demonstrating replication of effect. In retrospect, perhaps a withdrawal SSRD was not relevant and further studies should implement a study design that accounts for possible carryover effects of tSCS and allows for randomization and sham treatment.

5.5 Research and Clinical Implications Indications of some promising results from this study justify further investigation into the effect of tSCS on the stroke population. Whilst randomized controlled clinical trials are generally the most accepted method of measuring effectiveness of a new intervention, they are not always feasible when research time or resources are limited, study populations are small, and when a rigorous assessment of the effectiveness of a new intervention on multiple domains is needed (Lobo et al., 2017). In such cases, properly designed and executed SSRDs can demonstrate strong internal validity to determine the causal effect of an intervention, and provide a rationale for clinical trials in wider settings and populations (Kratochwill et al., 2012; Lobo et al., 2017).

Due to indications of a possible carryover effect in this study, it is possible that a SSRD employing a multiple baseline design would be more appropriate than the withdrawal design used in this study. Multiple baseline design uses methods of staggered introduction of the intervention across time. Participants are randomly assigned to baselines with different lengths, where some participants continue in the baseline phase whilst others enter the intervention phase (Backman et al., 1997). Introduction of the intervention at different times during the study allows for possible blinding of assessors and participants to when the experimental treatment begins. Such implementation could decrease the risk of bias and placebo effect and allow for more measurement sessions during fewer phases.

Based on the results obtained in this study, between-phase changes were demonstrated mostly on clinical and subjective measures, which are less time consuming and easier to administer than biomechanical measurements. Simplifying measurement sessions could allow for a larger sampling group and more measurements. At the same time, biomechanical methods provide objective methods of assessment, which can complement clinical and subjective data. Further research on the effects of tSCS should consider and explore to what extent biomechanical measures of spasticity and muscle activation are related to functional improvements.

Based on the improvements in mobility demonstrated in this study, it would be interesting to explore the effects of concurrent tSCS application during functional activities. Research suggests that it may enhance and even generate movements when lower frequency of stimulation is applied (Gerasimenko et al., 2015). Similarly, use of new technologies from modern sleep research, in addition to the self- reported evaluation, could provide a better insight and higher objectivity on the potential effects of tSCS on quality of sleep.

If future studies do support the use of tSCS post-stroke, evidence of optimal stimulation parameters for tSCS are required, e.g., what settings and devices work best, how long to stimulate for and how many treatment sessions are required. Also, as intervention with tSCS may have a long-term effect, follow-up measurements could give valuable indications to whether and how long improvements can last.

Despite inadequate evidence of the treatment effect of tSCS post-stroke, this treatment method has minimal adverse effects and is easy to administer. It can be applied, with assistance, at home or clinically. The devices used in this study are typically used for peroneal stimulation and functional electrical stimulation in rehabilitation settings. Simpler stimulation devices that are available at most physical therapy units could also be suitable and may be worth pursuing as a form of treatment. Effective treatment methods are limited in chronic stroke, and as symptoms are often reciprocally related, small improvements in some domains can have a widespread and meaningful effect on the patient. For these reasons, tSCS may be considered as an adjunct rehabilitation tool to enhance improvements post- stroke, especially for stroke patients with persisting debilitating problems that have not improved with other intervention strategies.

6 Conclusion To the best of our knowledge, this is the first study that explores the effects of tSCS on spasticity, mobility, pain and sleep post-stroke. From the four cases with stroke who participated in the study, one experienced wide benefit from tSCS treatment, another two experienced moderate benefits, and the last experienced no benefits. Our results suggest that daily home application of 60Hz tSCS for 30mins at the level of T11-T12 may be a useful tool in post-stroke rehabilitation for alleviating spasticity and pain and enhancing mobility and sleep in some community dwelling individuals post-stroke. These findings are clinically important as current physical and pharmaceutical methods are limited and often ineffective in treating these symptoms in chronic stroke. This treatment method has few side effects, it is inexpensive, non-invasive and easily accessible for home treatment.

Despite some positive results, the efficacy of tSCS for the stroke population is still debatable as replication of a causal effect was not clearly demonstrated and a causal effect was not seen for all intervention phases. Further research, applying the multiple baseline SSRD or randomized controlled clinical trials is needed to conclude the effectiveness of this intervention post-stroke.

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Appendix 1: Information Sheet to Patients

Raförvun mænu með yfirborðsrafskautum Upplýsingabréf

Kæri viðtakandi,

Við neðangreindir rannsakendur bjóðum þér að taka þátt í rannsókn.

Rannsakendur Rannsókn þessi er samstarfsverkefni Háskóla Íslands, Háskóla Reykjavíkur og Landspítala Háskólasjúkrahús. Rannsóknin er hluti af meistaraprófi Belinda Chenery, sjúkraþjálfara, undir leiðsögn Anestis Divanoglou, aðstoðarprófessors við Háskóla Íslands.

Ábyrgðarmaður rannsóknarinnar er Þórður Helgason, heilbrigðisverkfræðingur við Vísindadeild Landspítala háskólasjúkrahús og dósent við heilbrigðisverkfræðideild, Háskólans í Reykjavík, Menntavegi 1, 101 Reykjavík sími: 824 5737.

Meðrannsakendur hans eru Belinda Chenery, sjúkraþjálfari, Vilborg Guðmundsdóttir, sjúkraþjálfari, Gígja Magnúsdóttir, sjúkraþjálfari og Guðbjörg Kristín Ludvigsdóttir, endurhæfingarlæknir.

Hægt er að hafa samband við rannsakendur ef upp vakna spurningar vegna rannsóknarinnar.

Anestis Divanoglou: [email protected] Guðbjörg Ludvigsdóttir: [email protected]

Belinda Chenery: [email protected] Vilborg Guðmundsdóttir: [email protected] Gígja Magnúsdóttir: [email protected] Þórður Helgason: [email protected]

Þátttakendur

Þátttakendur eru þeir sem notið hafa þjónustu á endurhæfingardeildinni við Grensás eða eru skjólstæðingar deildarinnar.

Markmið og tilgangur

Í þessari rannsókn er fyrirhugað að skoða hvort að langvarandi meðferð með raförvun í gegnum mænu geti haft færnibætandi áhrif á síspennu í fótleggjum og bætt líðan hjá einstaklingum sem hafa fengið heilablóðfall.

Hvað felst í þátttöku?

Rannsóknin tekur alls 12 vikur en gert er ráð fyrir að hver þátttakandi mæti að meðaltali einu sinni í viku í prófun. Í upphaf 4. og 10. viku færðu raförvunartæki að láni heim auk kennslu í hvernig þú eigi að framkvæma meðferðina sjálfur heima. Meðferðin fer þannig fram að sett er ein lítil rafskaut á hæð við

11. -12. brjósthryggjarlið og tvö stór rafskaut framan á kvið. Rafskautin eru pöruð saman, þau stóru saman og litlu saman, mynda eina rás. Rafstraumur er leiddur frá baki fram í kvið og þannig fæst raförvun á mænu og taugarætur. Þú færð aðstoð við að finna réttu staðsetningu og staðsetningin er merkt með tússpenna.

Meðferðin er framkvæmd daglega, 30 mín í senn, 5 daga vikunnar í alls 3 vikur. Síðan er tekin hvíld frá meðferð í 3 vikur, en þú mætir áfram einu sinni í viku í prófun. Síðustu 3 vikur af rannsókninni endurtekur þú meðferðina daglega heima. Þú verður beðinn um að fylla út dagbók þar sem þú skrásetur notkun tækisins. Til þess að meta áhrif raförvunarinnar eru nokkrar prófanir gerðar til að meta síspennu ásamt því að hreyfigetan er skoðuð. Þú verður einnig beðin(n) um að svara nokkrum spurningarlistum. Prófanir eru gerðar einu sinni í viku. Reikna má með að hver prófun taki um 60-90 mín. Þær vikur sem þú átt að raförva þig, færðu raförvun strax á undan mælingu og getur rannsóknartíminn því verið 30 mín lengur. Þú ert beðinn um að hafa raförvunartækið, stuttbuxur og þægilega gönguskó með þér í allar prófanir. Þátttakendur eru spurðir út í hvaða lyf þeir taka að staðaldri og hvaða lyf þeir hafa tekið rannsóknardaginn. Eingöngu þau lyf sem hafa áhrif á síspennu verða skráð. Ekki verður leitað lyfjaupplýsinga i gagnagrunnum. Þátttakendur eru beðnir um að gera ekki breytingu á notkun spasmalyfja á rannsóknartímabilinu. Þátttaka í þessari rannsókn er valfrjálst. Þú getur valið að taka ekki þátt eða hætta þátttöku hvenær sem er án þess að gefa ástæðu. Þú getur gert þetta með því að hafa samband við rannsakendur eða meðferðaraðilan þinn (sjá upplýsingar um tengiliða hér að ofan). Í því tilfelli munum við afturkalla gögn sem þú hefur veitt. Að yfirgefa rannsóknina mun ekki hafa áhrif á umönnun þína eða þjónustu sem er í boði fyrir þig.

Áhætta vegna þátttöku í rannsókninni

Megin áhætta við raförvun eru óþægindi undan rafskautum. Óþægindin geta falist í ertingu í húð og verkir eða skrítin tilfinning við raförvunina. Hugsanlega getur raförvunin ýft upp undirliggjandi bakverki en hún getur einnig dregið úr verkjum í baki. Þetta eru skammvinn áhrif og valda ekki varanlegum skaða.

Tryggingar í rannsókninni

Þátttakendur í rannsókninni eru tryggðir samkvæmt landslögum á sama hátt og aðrir sjúklingar Landspítala háskólasjúkrahúss. Engar sérstakar bótatryggingar gilda fyrir þessa rannsókn en sjúklingar hafa sama lagalegan rétt og aðrir sjúklingar LSH.

Greiðslur eða umbun

Ekki verður um neinar greiðslur né umbun að ræða fyrir þátttöku í rannsókninni.

Persónuvernd

Rannsóknin tekur mið af alþjóðlegum samþykktum, svo sem Helsinki-sáttmálanum og tilmælum Alþjóða heilbrigðisstofnunarinnar um siðfræði og mannhelgi í vísindarannsóknum. Öll rannsóknargögn verða varðveitt leyndarmerkt á öruggum stað hjá ábyrgðarmanni á meðan á úrvinnslu þeirra stendur og unnin án persónuauðkenna. Öllum rannsóknargögnum verður eytt að lokinni úrvinnslu þeirra og eigi síðar en fimm árum eftir rannsóknarlok.

Skriflegt upplýst samþykki

Leitað verður eftir skriflegu samþykki þeirra þátttakenda sem leggja upplýsingar og efnivið í þágu rannsóknarinnar. Þátttakendum er frjálst að hafna þátttöku eða hætta í rannsókninni á hvaða stigi sem er, án útskýringa og án áhrifa á þá þjónustu sem þeir eiga rétt á.

Hverjir hafa samþykkt rannsóknina

Rannsóknin er unnin með samþykki Vísindasiðanefndar, tilkynning hafur verið send til Persónuverndar, aðrir leyfishafar eru yfirlæknir endurhæfingardeildar og lækningaforstjóri Landspítala háskólasjúkrahúss. Ef þú hefur spurningar um rétt þinn sem þátttakandi í vísindarannsókn getur þú snúið þér til Vísindasiðanefndar, Hafnarhúsinu v/Tryggvagötu, 101 Reykjavík, tölvupóstfang: [email protected].

Með von um góðar undirtektir, fyrir hönd rannsóknarhópsins

______Þórður Helgason, ábyrgðarmaður rannsóknarinnar

Appendix 2: Informed Consent

Upplýst samþykki

Raförvun mænu með yfirborðsrafskautum Í þessari rannsókn verður skoðað hvort langvarandi meðferð með raförvun í gegnum mænu geti minnkað síspennu og bætt hreyfigetu í fótleggjum hjá einstaklingum sem hafa fengið heilablóðfall. Rannsóknin tekur alls 12 vikur en gert er ráð fyrir að hver þátttakandi mæti að meðaltali einu sinni í viku í prófun á því tímabili. Í upphaf 4. og 10. viku færðu raförvunartæki að láni heim auk kennslu í hvernig þú eigi að framkvæma meðferðina sjálfur heima. Þú færð aðstoð við að finna réttu staðsetningu og staðsetningin er merkt með tússpenna. Meðferðin er framkvæmd daglega, 30 mín í senn, 5 daga vikunnar í alls 3 vikur. Síðan er tekin hvíld frá meðferð í 3 vikur, en þú mætir áfram einu sinni í viku í prófun. Síðustu 3 vikur af rannsókninni endurtekur þú meðferðina daglega heima. Þú verður beðinn um að fylla út dagbók þar sem þú skrásetur notkun tækisins. Á meðan á rannsókn stendur hefur þú greiðan aðgang að rannsóknaraðilum, ef spurningar vakna eða þú þarft aðstoð við framkvæmd.

Til þess að meta áhrif raförvunarinnar eru nokkrar prófanir gerðar til að meta síspennu ásamt því að hreyfigeta er skoðuð. Þú verður einnig beðinn um að svara nokkrum spurningarlistum. Prófanir eru gerðar einu sinni í viku. Reikna má með að hver prófun taki um 60-90 mín. Þær vikur sem þú átt að raförva þig, færðu raförvun strax á undan mælingu og getur rannsóknartíminn því verður 30 mín lengur. Þú ert beðinn um að hafa raförvunartækið, stuttbuxur og þægilega gönguskó með þér í allar prófanir. Megin áhætta við raförvun eru óþægindi undan rafskautum. Óþægindin geta falist í ertingu í húð og verkir eða skrítin tilfinning undan raförvuninni. Þetta eru skammvinn áhrif og valda ekki varanlegum skaða. Ég staðfesti hér með undirskrift minni að ég hef lesið upplýsingarnar um rannsóknina sem mér voru afhentar og hef fengið tækifæri til að spyrja rannsakendur spurninga og fengið fullnægjandi svör og útskýringar á atriðum sem mér voru óljós. Ég hef af fúsum og frjálsum vilja ákveðið að taka þátt í rannsókninni. Mér er ljóst, að þó ég hafi skrifað undir þessa samstarfsyfirlýsingu, get ég stöðvað þátttöku mína hvenær sem er án útskýringa og án áhrifa á þá þjónustu sem ég á rétt á í framtíðinni.

______Dagsetning Nafn þátttakanda

Appendix 3: Background Information

Nr. Þátttakanda: ______Dagsetning: ______

Aldur: ______Kyn: ______

Mán/Ár heilablóðfalls: ______Tegund heilablóðfalls: Blæðing/ Blóðtappi

Staðsetning heilablóðfallseinkenna (hæ/vi):______

Aðaleinkenni og vandamál eftir heilablóðfallið: ______

Notar þú hjálpartæki við göngu? Hvaða?______

Hvað gerir þú til að minnka síspennuna?______

Tekur þú lyf við síspennu ef svo er hver?______

Finnst þér þau draga úr síspennu? Já / Nei

Hafa þau önnur áhrif og þá hver? ______

Ef þú hefur fengið botox: hvar (handlegg eða fótlegg), hversu oft og hvenær fékkstu síðast? ______

Ef þú tekur lyf eða hefur fengið aðra meðferð, hvað hefur hjálpað þér mest? ______

Dagsetningar á rannsóknartímabilinu sem þú getur ekki mætt í mælingu (t.d. vegna hugsanlegrar utanlandsferðar? ______

Appendix 4: mRS

MODIFIED RANKIN SCALE (MRS)

Patient Name: ______

Rater Name: ______

Date: ______

Score Description

0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent and requiring constant nursing care and attention 6 Dead

TOTAL (0–6): ______

Appendix 5: Protocol for Measurements

Transcutaneous Spinal Cord Stimulation - stroke

Questionnaires and information sheets 1. Phase and Measurement: A1 / M1: i. Information sheet ii. Informed consent iii. Allocated participant number iv. Background information v. mRS A1 / M3: i. End of measurement session – teach tSCS ii. Logbook sent home B1 and B2 / M4-6, 10-12: i. Check logbook ii. Tolerance for treatment questionnaire (A) All measurement sessions: 2. Self-report questionnaire (B) 3. ABC Scale 4. Book next measuring session

Mobility Outcome Measures

5. Ten-metre Walking Test – 20m walkway a. Comfortable Speed – twice Instructions given in Icelandic: „Þegar ég segi NÚ, þá áttu að leggja af stað og ganga beint af augum á þínum venjulega gönguhraða sem þér finnst þægilegur. Haltu göngunni áfram þar til ég segi stopp.” „ Viðbúin/-nn, nú”. English translation:” I will say ready, set, go. When I say go, walk at your normal comfortable speed until I say stop “. „ Ready, set, go”. b. Fast Speed – twice Instructions given in Icelandic: „Þegar ég segi NÚ þá áttu að leggja af stað og ganga beint af augum eins hratt og þú getur. Haltu göngunni áfram þar til ég segi stopp.” „ Viðbúin/-nn, nú”. English translation: “I will say ready, set, go. When I say go, walk as fast as you safely can until I say stop”. „ Ready, set, go”. 6. Timed up and go – seat height 46cm. Use same chair for all measurements.

Instructions given in Icelandic: „Þegar ég segi nú þá áttu að standa upp, ganga að þessari línu á gólfinu, snúa við, ganga til baka að stólnum og fá þér sæti. Ég vil að þú gerir þetta eins hratt og þú getur”. English translation: On the word GO you will stand up, walk to the line on the floor, turn around and walk back to the chair and sit down. Do this as fast as you can. 7. 5 times sit to stand - 90° flexion in hips, knees and arms crossed. Instructions given in Icelandic: „Stattu upp eins hratt og þú getur 5 sinnum, án þess að stoppa á milli. Krosslegðu hendur fyrir framan brjóstkassa og réttu alveg úr þér á milli endurtekninga. Þú þarft að byrja og enda með bakið á stólbakinu en þarft ekki að snerta stólbakið á milli endurtekninga. Við tímasetjum þig með skeiðklukku. Tilbúin(n), byrja." English translation: “Stand up and sit down as quickly as possible 5 times, keeping your arms folded across your chest. We will record your time. Ready, go” 8. Ask whether the participant needs to go to the toilet. Participant puts on shorts.

Biomechanical measurements = EMG + goniometers

9. Find locations for EMG electrodes. Skin prepared with skin abrasion using cotton buds and abrasive gel. Black electrode placed proximally and red 2 finger widths more distally. Earth electrode place on crista iliaca. Location of electrodes (seniam.org) a. Quadriceps Femoris (Rectus Femoris): The electrodes need to be placed at 50% on the line from the anterior spina iliaca superior to the superior part of the patella. b. Tibialis anterior: The electrodes need to be placed at 1/3 on the line between the tip of the fibula and the tip of the medial malleolus. c. Gastrocnemius (Lateralis): Electrodes need to be placed at 1/3 of the line between the head of the fibula and the heel. d. Biceps femoris (Long and Short Head): The electrodes need to be placed at 50% on the line between the ischial tuberosity and the lateral epicondyle of the tibia. 10. Check whether EMG and goniometers are working. tSCS treatment in phases B: a. Locate position for tSCS electrode: one self-adhesive circle electrode (5 * 5 cm diameter) placed horizontally and central to the spinal cord at the level of T11-T12 spinous processes and interconnected with a pair of rectangular reference electrodes (8*13 cm) placed over the lower anterior abdomen, symmetrical to the navel. Electrodes connected to the stimulator so that the single vertebral electrode on the back acts as the cathode (black) and the two abdominal electrodes connected to function as a single anode (red) electrode. b. Device: Odstock® Dropped Foot Stimulator ODFS pace V1.3, exercise mode. Constant current, 360µs width asymmetrical biphasic charge balanced pulses at an intensity of 90% of the threshold for eliciting reflexes in the lower limb muscles (PRM reflexes) for 30 mins, lying in a supine position. 60 Hz. Time: 30mín.

c. Monitor muscle reaction during tSCS with EMG

11. Place goniometers laterally on knee and ankle of hemiplegic leg: 12. Maximum muscle contraction taken (measurements 1-4). 13. Recordings taken for calibration of goniometers (measurements 5-6)

Spasticity Measurements

14. Tardieu – supine: 45° hip flexion, 30° knee flexion. a. Plt.flexors of ankle i.PROM (R2°) at slow speed (V1) – measured manually (measurement 7) ii. angle of catch (R1°) for fast speed (V3) – measured manually (measurement 8) iii.quality of muscle reaction (X) b. Knee flexors (hamstrings) i.PROM (R2°) at slow speed (V1) – measured manually (measurement 9) ii. angle of catch (R1°) for fast speed (V3) – measured manually (measurement 10) iii.quality of muscle reaction (X)

15. Wartenberg Pendulum Test – (measurement 11) Instructions given in Icelandic: „Ég ætla að lyfta fætinum upp í beina stöðu og þú átt að slaka 100% á á meðan, helst með lokuð augu. Síðan kem ég til með að sleppa fætinum. Á meðan þetta próf er gert skaltu ekki hjálpa til og reyna að vera eins máttlaus í fætinum og þú getur. Við endurtökum þetta próf þrisvar sinnum “. English translation:” I’m going to lift your leg up straight and you should relax 100% meanwhile, preferably with closed eyes. Then I will let go of your leg. While doing this test, do not assist and try to be as relaxed as you can in your leg. We repeat this test three times.” Examiner: Wait for EMG activity to die down before letting go of leg. Repeat three times, 5 seconds between repetitions.

16. 5* Voluntary activation og dorsiflexion and 5* voluntary activation of plt. flexion Instructions given in Icelandic: “Þegar ég segi krepptu upp, krepptu ökklan eins langt upp og þú getur, og þegar ég segi slaka skaltu slaka fætinum niður. Prófaðu að framkvæma hreyfinguna einu sinni áður en við byrjum að mæla“. English translation:” When I say dorsiflex, move your foot up as far as you can and when I say relax, relax it down. Try and perform the movement once before we start measuring”. Check whether the participants understands the instructions correctly. Examiner gives the instructions and cues to hold the contraction by say „contract, contract, contract and relax “. Examiner gives 3 seconds after relaxation before asking the participant to repeat the movement. Repeat 5 times (measurement 12). Method repeated for plantar flexion by asking participant to plantar flex instead of dorsiflexing (measurement 13). 17. Biomechanical equipment removed

Appendix 6: Intervention - Device Settings

Instructions for tSCS device settings

Device used: Odstock® Dropped Foot Stimulator ODFS pace V1.3 (Odstock Medical Ltd (OML), Salisbury, UK).

Pick exercise settings

Exercise Waveform - asymmetric

Exercise Frequency - 60hz (max)

Exercise duration - 30 min

On period - 20 sec

Off period - 0 sec

Ramp duration – 0.0 sec

Exercise Current - individually chosen with pulse width of 50%

During treatment, start with 50% pulse width and increase to 100%

Appendix 7: The TIDieR Checklist

Appendix 8: Logbook

Appendix 9: Tolerance for Treatment Questionnaire

Appendix 10: Order of EMG Measurements

1. Max. contraction Quadriceps

2. Max. contraction Hamstrings

3. Max. contraction Tibialis Ant.

4. Max. contraction Tibialis Surae

5. Knee calibration

6. Ankle Calibration

7. Tardieu PF R2/V1

8. Tardieu PF R1/V3

9. Tardieu H R2/V1

10. Tardieu H R1/V3

11. Wartenberg

12. Voluntary activation dorsiflexion

13. Voluntary activation plantar flexion

Appendix 11: Self-Report Questionnaire

Appendix 12: Hand-held Goniometer Measurements

Subject number: Phase: ______Date: ______Measurement: ______

Calibration of goniometers – EMG recording Knee: Start: ______F End: ______F / E Ankle: Start: ______PF /DF End: ______DF / PF

Muscle Side V R2 (°) R1 (°) X (H/V) PROM Catch (0-5)

Triceps surae V1

Triceps surae V3

Hamstrings V1

Hamstrings V3

Quality of muscle reaction (X)

0 No resistance throughout passive movement

1 Slight resistance throughout, with no clear catch at a precise angle

2 Clear catch at a precise angle, followed by release

3 Fatigable clonus (<10secs) occurring at a precise angle

4 Unfatigable clonus (>10secs) occurring at a precise angle

5 Joint Immobile

Spasticity Angle

R2 Full range of motion achieved when muscle is at rest and tested at V1

R1 Angle of catch seen at velocity V3

Velocity to stretch (V)

V1 As slow as possible

V3 As fast as possible (>natural drop)

Appendix 13: Ethics Approval

Appendix 14: Ethics Renewal

Appendix 15: Hospital Approval

Appendix 16: Tables for Within-Phase Level, Trend and Variability

Appendix 17: Autocorrelation Tables