Education, Faculty of
Kinesiology, School of
DSpace
UBCV
Squair, Jordan W.
Master of Science - MSc
University of British Columbia
Previous work has demonstrated that mobility is consistently one of the most, if not the most important function persons with a spinal cord injury (SCI) desire following their injury. By increasing functional mobility, even slightly, there may be improved independence, leading to improved quality of life. While the current clinical examination for determining the level and severity of an SCI has proven to be very reliable and useful for standardizing SCI classification, it still has significant limitations that may limit a patient’s future mobility. For example, the measures used to assess motor function in the limb following a SCI may not be sensitive enough to detect minimal levels of preserved motor function, as they are limited to manual palpation and/or visual inspection. Furthermore, the extent of preservation of trunk musculature and the vestibulospinal pathway following an SCI remains unclear. Therefore, there is a need for more sensitive measures of remaining motor activity and a need to examine the integrity of individual motor pathways. Using transcranial magnetic stimulation (TMS) and vestibular evoked myogenic potentials (VEMPs), this thesis examined the integrity of the cortico- and vestibulospinal pathways in 16 persons with a motor-complete SCI and 16 able-bodied (AB) matched controls. Despite being clinically classified as motor-complete, persons with an SCI showed some observable muscle activity to cortico- and vestibulospinal stimulation, as well as in response to voluntary contractions. In general, the corticospinal responses in the SCI group were delayed compared to their AB matched controls. The muscle activity detected using TMS related to voluntary activation; however, TMS appears to detect preserved muscle activity below that which can be voluntarily activated. Overall, the results from this thesis provide evidence for the use of TMS and VEMPs to assist in determining the neurophysiological integrity of various motor pathways in persons with a motor-complete SCI. Using these techniques may provide clinicians with more accurate information about the state of various motor pathways and may offer a method to more accurately target rehabilitation.
EXAMINATION OF PRESERVED MOTOR PATHWAYS IN PERSONS WITH MOTOR-COMPLETE SPINAL CORD INJURY by Jordan W. Squair B.Kin., The University of British Columbia, 2012 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Kinesiology) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) April 2014 © Jordan W. Squair, 2014 ii Abstract Previous work has demonstrated that mobility is consistently one of the most, if not the most important function persons with a spinal cord injury (SCI) desire following their injury. By increasing functional mobility, even slightly, there may be improved independence, leading to improved quality of life. While the current clinical examination for determining the level and severity of an SCI has proven to be very reliable and useful for standardizing SCI classification, it still has significant limitations that may limit a patient‟s future mobility. For example, the measures used to assess motor function in the limb following a SCI may not be sensitive enough to detect minimal levels of preserved motor function, as they are limited to manual palpation and/or visual inspection. Furthermore, the extent of preservation of trunk musculature and the vestibulospinal pathway following an SCI remains unclear. Therefore, there is a need for more sensitive measures of remaining motor activity and a need to examine the integrity of individual motor pathways. Using transcranial magnetic stimulation (TMS) and vestibular evoked myogenic potentials (VEMPs), this thesis examined the integrity of the cortico- and vestibulospinal pathways in 16 persons with a motor-complete SCI and 16 able-bodied (AB) matched controls. Despite being clinically classified as motor-complete, persons with an SCI showed some observable muscle activity to cortico- and vestibulospinal stimulation, as well as in response to voluntary contractions. In general, the corticospinal responses in the SCI group were delayed compared to their AB matched controls. The muscle activity detected using TMS related to voluntary activation; however, TMS appears to detect preserved muscle activity below that which can be voluntarily activated. Overall, the results from this thesis provide evidence for the use of TMS and VEMPs to assist in determining the neurophysiological integrity of various iii motor pathways in persons with a motor-complete SCI. Using these techniques may provide clinicians with more accurate information about the state of various motor pathways and may offer a method to more accurately target rehabilitation. iv Preface All data contained in this thesis were collected by Jordan Squair at the Biomechanics and Motor Control Laboratory within the Swedish School of Sport and Health Sciences, Stockholm, Sweden. Methodologies were reviewed and approved by both the UBC Clinical Research Ethics Board (Observing preserved motor tracts in motor complete spinal cord injury patients, H11-02467-003) as well as the Swedish Research Ethics Board (Identifiering av bevarad function I benmuskulaturen hos personer med motorisk komplett ryggmärgsskada, 2013/1393-32/2). The study contained in this thesis was not submitted for publication at the time of thesis submission. I was the lead investigator on the project, responsible for concept development, data collection and analysis, and manuscript composition. Dr. Anna Bjerkefors was involved in data collection. Dr. Tania Lam and Dr. J Timothy Inglis were involved in concept development. Dr. Mark G. Carpenter was the supervisory author on the project and was involved in concept formation and thesis revisions. v Table of Contents Abstract .......................................................................................................................................... ii Preface ........................................................................................................................................... iv Table of Contents ...........................................................................................................................v List of Tables .............................................................................................................................. viii List of Figures ............................................................................................................................... ix List of Abbreviations .....................................................................................................................x Acknowledgements ..................................................................................................................... xii Dedication ................................................................................................................................... xiii 1 General introduction and literature review ........................................................................1 1.1 Introduction to the population ......................................................................................................................... 1 1.2 Quality of life and functional desires .............................................................................................................. 2 1.3 Spinal cord anatomy ........................................................................................................................................ 4 1.4 The clinical examination for spinal cord injury ............................................................................................... 5 1.5 Neurophysiological assessments of preserved motor function in persons with spinal cord injury.................. 8 1.6 Transcranial magnetic stimulation and spinal cord injury ............................................................................. 11 1.7 Measuring vestibulo- and reticulospinal function in persons with a spinal cord injury ................................ 14 1.8 Functional significance.................................................................................................................................. 18 1.9 Purpose and hypotheses................................................................................................................................. 19 2 Methods .................................................................................................................................21 2.1 Participants .................................................................................................................................................... 21 2.2 Experimental design ...................................................................................................................................... 22 2.3 Measurements................................................................................................................................................ 22 2.3.1 Data collection ..................................................................................................................................... 22 2.3.1.1 Electromyography ...................................................................................................................... 22 vi 2.3.1.2 Transcranial magnetic stimulation ............................................................................................. 22 2.3.1.3 Maximal voluntary contractions ................................................................................................. 24 2.3.1.4 Vestibular-evoked myogenic potentials ..................................................................................... 24 2.3.1.5 Subclinical assessments .............................................................................................................. 25 2.3.2 Data analysis ........................................................................................................................................ 25 2.3.2.1 Motor evoked potentials ............................................................................................................. 25 2.3.2.2 Maximal voluntary contractions ................................................................................................. 26 2.3.2.3 Subclinical assessments .............................................................................................................. 26 2.3.2.4 Vestibular-evoked myogenic potentials ..................................................................................... 26 2.3.3 Statistical analyses ............................................................................................................................... 27 3 Results ...................................................................................................................................28 3.1 Participants .................................................................................................................................................... 28 3.2 Transcranial magnetic stimulation ................................................................................................................ 28 3.2.1 Motor evoked potentials ...................................................................................................................... 28 3.2.1.1 Muscle responses below the level of injury................................................................................ 29 3.2.1.2 Muscle responses above the level of injury ................................................................................ 30 3.2.2 Motor evoked potential peak to peak amplitudes ................................................................................ 30 3.3 Maximal voluntary contractions .................................................................................................................... 30 3.4 Vestibular evoked myogenic potentials ......................................................................................................... 31 3.4.1 Sternocleidomastoid responses ............................................................................................................ 32 3.4.2 Soleus responses .................................................................................................................................. 32 3.5 Subclinical assessments ................................................................................................................................. 33 3.5.1 Plantar-cutaneo withdrawal reflex ....................................................................................................... 33 4 Discussion..............................................................................................................................34 4.1 Motor evoked potentials ................................................................................................................................ 34 4.1.1 Frequency of motor evoked potentials ................................................................................................. 34 4.1.2 Frequency pattern of motor evoked potentials ..................................................................................... 37 vii 4.1.3 Inclusion of sartorius motor evoked potentials .................................................................................... 38 4.1.4 Latencies of motor evoked potentials .................................................................................................. 39 4.2 Maximal voluntary contractions .................................................................................................................... 44 4.3 Vestibular evoked myogenic potentials ......................................................................................................... 46 4.3.1 Sternocleidomastoid responses ............................................................................................................ 46 4.3.2 Soleus responses .................................................................................................................................. 48 4.4 Subclinical assessments ................................................................................................................................. 50 4.4.1 Plantar withdrawal reflex ..................................................................................................................... 50 4.5 Implications for classification and rehabilitation .......................................................................................... 51 4.6 Future directions ............................................................................................................................................ 54 4.7 Conclusions ................................................................................................................................................... 56 References .....................................................................................................................................65 Appendices ....................................................................................................................................83 Appendix A - ISNCSCI Exam Details .................................................................................................................... 83 Appendix B - ISNCSCI Exam Worksheet .............................................................................................................. 84 Appendix C - Pilot Data .......................................................................................................................................... 85 viii List of Tables Table 1 Detailed description of the participants with SCI ........................................................ 58 Table 2 Frequency of MEPs in response to TMS. The number of detectable MEPs was determined for each muscle. If a participant had 5 or more detectable MEPs out of 10 the response in that muscle was determined as “present” and included in subsequent analysis. Muscles with 1-4 detectable MEPs were defined as “inconsistent”. ............. 59 Table 3 Absolute onset latencies of MEPs elicited by TMS. Values are means ± standard deviation. “n” indicates the number of muscles with MEP responses defined as “present” in at least 5 out of 10 trials. .......................................................................... 60 Table 4 Frequency of MEPs and responses to MVC in persons with SCI. Participants were given a “T” if the participants‟ MEP response was defined as present and a “V” was given if the participants MVC response was defined as present. ................................. 61 ix List of Figures Figure 1 Experimental setup. Participants lay supine on a plinth. TMS was applied with a double cone coil above the leg area of the primary motor cortex. EMG was recorded from bilateral SAR, BF, RF, TA, SOL, MG, EH and unilaterally from TrA and OE. Participants were strapped down across the shoulders, hips, knees, and feet to ensure isometric contractions. ................................................................................................ 62 Figure 2 MEPs elicited by TMS over the vertex in A) one representative control, B) one participant (SCI14) with a T10 AIS A SCI, and C) one participant (SCI7) with a T3 AIS B SCI. Note: Responses are optimized for visual purposes. ............................... 63 Figure 3 VEMPs in the SOL ipsilateral to the side of stimulation. A) Seven AB participants had a detectable VEMP. An average trace of all 7 participants is shown in bold at the bottom for comparison purposes. B) Four SCI participants showing a detectable VEMP in SOL. From top to bottom the SCI participants are SCI7, SCI3, SCI1, and SCI14. Arrows denote the response peak. Grey boxes highlight the expected latency range for a detectable response. .................................................................................. 64 x List of Abbreviations  A/D: Analog-to-Digital  AB: Able-Bodied  ADL: Activities of Daily Living  ASIA: American Spinal Injury Association  AIS: ASIA Impairment Scale  BF: Biceps Femoris  EH: Extensor Hallucis  EMG: Electromyography  GVS: Galvanic Vestibular Stimulation  ISNCSCI: International Standards for Neurological Classification of Spinal Cord Injury  LEMS: Lower Extremity Motor Score  MVC: Maximal Voluntary Contraction  MG: Medial Gastrocnemius  MEP: Motor Evoked Potential  MSO: Maximal Stimulator Output  NLI: Neurological Level of Injury  OE: External Oblique  POE: Point of Optimal Excitability  RF: Rectus Femoris  SAR: Sartorius  SCM: Sternocleidomastoid xi  SD: Standard Deviation  SOL: Soleus  SCI: Spinal Cord Injury  TA: Tibialis Anterior  TrA: Transverse Abdominis  TMS: Transcranial Magnetic Stimulation  VEMP: Vestibular-Evoked Myogenic Potential  ZPP: Zone of Partial Preservation xii Acknowledgements I would like to express my appreciation and thanks to my supervisor Dr. Mark Carpenter for your exceptional support and guidance. Your passion for research and willingness to teach has inspired me to pursue new avenues and to gain experiences I may have never otherwise had. Without your patience and encouragement this thesis would not have been possible. I would also like to thank my committee members, Dr. Tim Inglis and Dr. Tania Lam, for your invaluable insight and contributions. I would like to extend a special thank you to Dr. Anna Bjerkefors for your dedication and support through this thesis. I owe an extensive amount of gratitude for your unwavering enthusiasm and commitment to this thesis. In addition, I would like to thank Dr. Maria Ekblom, Dr. Toni Arndt for their support and contributions. I would like to thank the past and present members of the Neural Control of Posture and Movement Lab who have supported and guided me through my thesis work. I also thank the University of British Columbia, the National Science and Engineering Research Council of Canada, and the Swedish School of Sport and Health Sciences for their financial support during this thesis. I would like to thank my family. Words cannot express how grateful I am for all the sacrifices you have made on my behalf. Lastly, I would like to express appreciation to my beloved fiancé, Catrina Nicholas who spent countless hours listening, reading, and supporting me through the entire process of this thesis. xiii Dedication To my family, whose love and support have never wavered, I dedicate this thesis to you. 1 1 General introduction and literature review 1.1 Introduction to the population The impact of traumatic spinal cord injury (SCI) on an individual‟s life can be devastating. An SCI can result in the partial or complete separation of the spinal cord from the brain, leading to a variety of symptoms. Among these symptoms are the loss of sensory, motor, and/or autonomic function, which have a significant effect on daily activities, quality of life, and the social status of the person affected (Simpson, Eng, Hsieh, Wolfe, & the Spinal Cord Injury Rehabilitation Evidence Research Team, 2012). SCIs are one of the oldest documented injuries and are described in what scholars argue is the first scientific document: the Edwin Smith papyrus, in which the author describes SCIs as “ailments not to be treated” (Hughes, 1988). Although much research has gone into the development of neuronal repair techniques, no “cure” has been found. Reported annual incidence rates for SCI in North America vary from 25 to 93 per million population (Dryden et al., 2003). Few studies have been conducted to examine the incidence rates in Canada and have been limited to provincial populations or indirect data (Couris et al., 2010; Dryden et al., 2003; Lenehan et al., 2012; Noonan et al., 2012; Pickett, Campos-Benitez, Keller, & Duggal, 2006). However, current estimates put the incidence of SCI in Canada around 53 per million population (Noonan et al., 2012). In comparison to incidence rates around the world, this suggests Canada is among the highest in SCI rates (Hagen, Rekand, Gilhus, & Grønning, 2012). In order to combat the incidence of SCI it is important to note the most common causes and characteristics of the injuries. Epidemiological evidence suggests SCIs are most often a result of a motor vehicle accident (51.4%) or falls (28.5%), and most common in 2 individuals aged 15-35 (Lenehan et al., 2012). An SCI may affect the cervical, thoracic, or lumbar spine, resulting in various levels of paralysis. In a recent retrospective study of British Columbians, cervical injuries represent close to 50% of all spinal cord injuries, followed by thoracic (27.4%) and lumbar (22.9%) injuries (Lenehan et al., 2012). As incidence rates of SCI continue to be high, costs associated with SCI are another important factor to consider. As surgical techniques improve, persons with an SCI are living longer. Consequently, the costs associated with their ongoing treatment are increasing. A recent study examined the cost of initial care following an SCI and subsequent follow up and found that each patient cost the Canadian health care system over $100,000 (Munce et al., 2012). Other studies have noted that the overall costs related to SCI are over 4 billion dollars annually in North America (Fehlings, Harris, & Cadotte, 2012). Therefore, there is a need for increased research into improving the quality of life, functional capabilities, and independence of this population, thereby reducing the overall cost to the health care system. 1.2 Quality of life and functional desires While research in the recent past has focused on the allusive task of finding a “cure” for SCI, this task is daunting and may take many years to complete. Therefore, a focus on improving the quality of life of persons living with an SCI and developing treatments that lead to partial functional recovery are crucial (Anderson, 2004). Several studies have examined the determinants of quality of life in persons with an SCI (see van Leeuwen, Kraaijeveld, Lindeman, & Post, 2012 for review). Despite the debate on the proper qualitative methods for measuring quality of life (Dijkers, 2005), it is currently established that an SCI significantly decreases the quality of life of the affected individual 3 (Dijkers, 2005). The explanation for this decrease in quality of life is complex, as an SCI results in much more than simply paralysis. Persons with an SCI also have autonomic impairments involving bladder function, sexual arousal, and respiratory functions (Anderson, 2004). Furthermore, social isolation may result from a lack of ability to participate in activities; there will be increased financial strain due to lifelong medical care costs; and persons with an SCI are commonly found to struggle with psychological problems such as depression and anxiety (Anderson, 2004). In order to improve the quality of life for persons with an SCI it is crucial for clinicians to be aware of patients‟ desires and priorities. Anderson (2004) sought to determine the greatest functional desires for persons with an SCI. Among these desires hand function was the most important to those with high cervical (quadriplegic) injuries. Across all injury severities bowel/bladder function, sexual function, and mobility were the next three most important functional desires. Following these were trunk stability, walking movement, relief of chronic pain, and normal sensation. Further work has demonstrated that mobility is consistently one of the most, if not the most, important function persons with an SCI desire following their injury (Brown-Triolo, Roach, Nelson, & Triolo, 2002; Ditunno, Patrick, Stineman, & Ditunno, 2008; Simpson et al., 2012; Snoek, Ijzerman, Hermens, Maxwell, & Biering-Sorensen, 2004). Furthermore, persons with an SCI do seem to have realistic expectations, as they would take any improvement in mobility, not necessarily full walking function (Brown-Triolo et al., 2002). The functional desires expressed in these studies also line up with the person‟s desire to see more research into functional mobility (Estores, 2003; Furlan & Fehlings, 2006). Collectively, these studies call for further research into enhancing the functional mobility of persons with an SCI. By increasing functional mobility, even slightly, there may be improved independence, leading 4 to improved quality of life (Anderson, 2004). This increased mobility may also improve the person‟s ability to perform transfers and to interact with and explore their environment. 1.3 Spinal cord anatomy The anatomy of the spinal cord is complex and damage to it leads to a variety of different symptoms, necessitating the need for a standardized assessment method. The spinal cord is the major medium by which nerve signals are transmitted from the brain to the body (Kirshblum, Burns, et al., 2011). The cord consists of both grey and white matter, both of which are oriented longitudinally. The grey matter is located in the deeper aspects of the cord and consists of nerve dendrites and cell bodies (Kirshblum, Burns, et al., 2011). Within the grey matter are segregations of sensory and motor nuclei (Kirshblum, Burns, et al., 2011). The white matter is located more superficially and mainly consists of mylenated axons (Kirshblum, Burns, et al., 2011). The spinal cord is separated into 30-32 segments depending on the individual (Kirshblum, Burns, et al., 2011). The cervical part of the cord consists of 8 segments, each with their own nerve root, which consists of motor and sensory branches. These nerve roots exit through the intervertebral foramina above the vertebra they are named after (Kirshblum, Burns, et al., 2011). For instance, the C7 nerve root exits above the C7 vertebra, that is, between the C6 and C7 vertebrae. The thoracic component of the cord consists of 12 nerve roots. These, and the 5 lumbar nerve roots, exit below the corresponding vertebra (Kirshblum, Burns, et al., 2011). That is, the L3 nerve root exits below the L3 vertebra, between L3 and L4. The spinal cord ends at the level of the L1-L2 vertebrae and this point is termed the conus medullaris (Kirshblum, Burns, et al., 2011). However, the remaining lumbar roots and 5 sacral nerve roots continue 5 down in what is known as the cauda equina and eventually exit through the intervertebral foramen of the lumbar vertebrae and the sacral foramina. There may also be 0, 1, or 2 coccygeal spinal nerve roots, but this will vary depending on the individual (Kirshblum, Burns, et al., 2011). 1.4 The clinical examination for spinal cord injury As recent as the early 1980s there was no standard method for determining the level and completeness of an SCI and, consequently, the results from many studies could not be compared. Therefore, there was a large push by the scientific community to address the need of a common classification method. In 1982 the American Spinal Cord Society developed a standardized method for classifying the level and completeness of an SCI (American Spinal Cord Injury Association [ASIA], 1982). This exam has seen many revisions over the past 20 years (e.g. Maynard et al., 1997; Waring et al., 2010), most recently in 2011 (Kirshblum, Burns, et al., 2011; Kirshblum, Waring, et al., 2011). Furthermore, it has now been endorsed by the international society for spinal cord injury (Kirshblum, Burns, et al., 2011) and is now the international standards for neurological classification of spinal cord injury (ISNCSCI) (Kirshblum, Burns, et al., 2011). This is the most widely used test around the world for the classification of the level and completeness of an SCI and has been thoroughly tested for reliability (Cohen, Ditunno Jr, Donovan, & Maynard Jr, 1998; Kirshblum et al., 2002; Priebe & Waring, 1991). The clinical exam combines a series of sensory, motor, and autonomic tests to determine the level and completeness of an SCI. Six “levels” are determined: left motor level, right motor level, left light touch level, right light touch level, left pin prick level, right pin prick level 6 (Kirshblum, Burns, et al., 2011; see Appendix B). Lastly, the completeness of injury is determined using the ASIA Impairment Scale (AIS) (Kirshblum, Burns, et al., 2011; see Appendix A). Sensory levels are determined by systematically evaluating dermatomes from C2 all the way through S4-5. Patients are given a score from 0 to 2 on each dermatome: zero being no sensation, 1 being altered sensation and 2 being normal sensation (Kirshblum, Burns, et al., 2011). The sensory score out of 112 is then calculated and the sensory level for each side and for each sensation is determined as the most caudal point a normal (2) sensory function is found. Patients then have their motor function assessed (Kirshblum, Burns, et al., 2011). The motor examination is crucial in determining a patient‟s remaining motor function and will greatly influence their rehabilitation prognosis (Kirshblum & O'Connor, 1998), independence, and quality of life (Anderson, 2004). Each motor level, or myotome, is assessed on a 5 point scale (Kirshblum, Burns, et al., 2011; see Appendix A). If a level is untestable due to immobilization or severe pain that level is given a score of “NT”, meaning not testable (Kirshblum, Burns, et al., 2011). Myotomes are assessed systematically beginning with the following cervical myotomes: C5 (elbow flexors), C6 (wrist extensors), C7 (elbow extensors), C8 (finger flexors), and T1 (small finger abductors). The exam then ignores the trunk musculature and skips down into the lumbar region where the following leg myotomes are assessed: L2 (hip flexors), L3 (knee extensors), L4 (ankle dorsiflexors), L5 (long toe extensors), and S1 (ankle plantar flexors). Thus, each segment is given a score out of 5 (see Appendix A), a total score out of 50 is calculated for the upper and lower limbs, and the motor level on each side is determined as the most caudal segment that has a score of at least 3, providing that all segments rostral to it have scores of 5. The most caudal sensory or motor level is then determined to be the single neurological level of injury (NLI). 7 Once the neurological levels of injury have been determined, the AIS is used to determine the completeness of injury. The AIS is a modified version of the Frankel scale originally put forward by Frankel et al. (1969) in which patients were classified as either “complete” or “incomplete” based on the presence or absence of motor or sensory function 3 levels below the neurological level of injury. One notable change to the definition of “complete” was made following the work of Waters, Adkins, and Yakura (1991). They argued conclusively that defining a patient as “complete” based on sacral sparing resulted in a more accurate long-term classification and avoided patients moving from “incomplete” to “complete”, as was a common issue based on the former definition of “complete”. Sacral sparing refers to the patient‟s ability to detect pressure, light touch or pin prick to anal stimulation, or to voluntary contract the anal sphincter (Waters et al., 1991). Preservation of any of these functions would suggest partial sparing of the S4-5 nerve roots and render the patient “incomplete”. The current AIS scale has been updated according to these results and its details can be found in Appendix A. For complete patients, the zone of partial preservation (ZPP) must also be determined. This is defined as the most caudal segment with some preservation of sensory or motor function (Kirshblum, Burns, et al., 2011). Current estimates of injury level and severity distribution show that complete injuries are the most common (AIS A = 45.3%), followed by AIS D (25.7%), AIS C (14.3%), and AIS B (9.6%) (Lenehan et al., 2012). While these statistics only reflect the status immediately after discharge and may change over time, persons with a complete SCI (AIS A) are quite common and their prognosis has been shown to be extremely negative (Kirshblum & O'Connor, 1998). Therefore, as persons with a motor-complete SCI make up such a large part of the SCI 8 population and their prognosis is the least favorable, research into improving the quality of life, independence, and functional capabilities for these people is crucial. While the current ISNCSCI has proven to be very reliable and useful for standardizing SCI classification, it still has significant limitations. For instance, motor function in the trunk muscles is not currently assessed due to the complexity of the muscle innervations. This makes the conclusions about motor function in the trunk imprecise since they are completely dependent on the sensory scores. Furthermore, the measures used to assess motor function in the limbs may not be sensitive enough to detect minimal levels of preserved motor function, as they are limited to manual palpation and/or visual inspection. Detecting any level of preserved motor function may provide persons with a motor-complete (AIS A/B) SCI an opportunity to perform more rigorous rehabilitation in order to retain/regain as much motor function as possible; however, rehabilitation efforts cannot be targeted to patients if their level of motor preservation is not correctly determined. 1.5 Neurophysiological assessments of preserved motor function in persons with spinal cord injury When there is damage to the spinal cord there is a disruption of the communication between the spinal cord and supraspinal structures such as the cerebral cortex, cerebellum, and brainstem. When this disruption involves motor pathways it is important to examine the effects this has on human motor control. With damage to the spinal cord, patients may present with clinical symptoms such as paraplegia or paralysis; however, there may also be residual motor control not detectable by common clinical tests, termed subclinical features (Dimitrijevic, 2012). Subclinical features may manifest themselves through reflex modulation or through other aspects of motor control modulation only detectable through the use of neurophysiological methods 9 (Dimitrijevic, 2012). The ability for persons with an SCI to recover motor function will be dependent on the remaining motor pathways intact and the rehabilitation program prescribed. The detection of subclinical motor preservation may be a strong indicator of preserved motor pathways and be used to tailor rehabilitation programs in order to retain/regain a maximal amount of motor control (Dimitrijevic, 2012). Various studies have examined three major subclinical motor features in persons with a motor-complete SCI. First, muscle activity in response to strong vibration to the Achilles and patellar tendons has been observed (Dimitrijevic, Spencer, Trontelj, & Dimitrijevic, 1977; Sherwood, Dimitrijevic, Bacia, & McKay, 1993). Strong evidence from cat experiments suggest that this muscle activity in response to vibration, termed the tonic vibratory reflex, is mediated by supraspinal structures, as it is abolished following spinal cord transection (Matthews, 1966). Therefore, presence of the response and subsequent modulation of it have been proposed as indicators for preserved bulbospinal pathways in persons with a motor-complete SCI (Dimitrijevic, McKay, & Sherwood, 1997; Dimitrijevic et al., 1977; Sherwood et al., 1993). Second, changes in muscle activation below the level of injury were observed following strong volitional contraction of nonparalyzed muscles above the injury (remote reinforcement maneuvers), which is thought to be a result of residual bulbospinal motor tract influence (Dimitrijevic, Dimitrijevic, Faganel, & Sherwood, 1984). Third, volitional inhibition of the cutaneomuscular plantar withdrawal reflex was found and strengthened the notion of subclinical features as patients were able to both facilitate and inhibit activity below the level of the lesion (Cioni, Dimitrijevic, McKay, & Sherwood, 1986). The results from these various studies have been used to determine the level of residual motor control in larger studies (McKay, Lim, Priebe, Stokic, & Sherwood, 2004; Sherwood, McKay, & Dimitrijević, 1996) and have been proposed as 10 an aspect of a neurophysiological exam for assessing motor control following an SCI (Kakulas, Tansey, & Dimitrijevic, 2012). The presence of residual motor control in persons with a motor-complete SCI has invariably led to the proposal of a third class of SCI patients: the “discomplete” patient (Dimitrijevic, 1987; Sherwood, Dimitrijevic, & McKay, 1992). Although this theoretically falls into the classification of incomplete, the lack of clinical features calls for a third and separate category. People may have remaining motor and/or sensory fibers crossing the site of the lesion, as evidenced in post-mortem studies (Kakulas, 1987, 1999); however, they do not produce any visible movement. While the tonic vibratory reflex, remote reinforcement maneuvers and inhibition of the withdrawal reflex may be useful tools in a clinical setting to detect preserved motor function, they are only indicators of preserved motor pathways and do not provide conclusive evidence that axons within the spinal cord are spared. Moving forward, various studies have examined the use of surface electromyography (EMG) in the detection of preserved motor function in persons with an SCI (Li et al., 2012; McKay et al., 2004; McKay, Ovechkin, Vitaz, Terson de Paleville, & Harkema, 2011a, 2011b; Sherwood et al., 1992; Sherwood et al., 1996). For instance, in 1989 the Brain Motor Control Assessment was developed. This assessment records surface EMG from various muscles, including those from the trunk and lower limbs, and can be used to compare the activity of persons with an SCI and controls (Sherwood & Dimitrijevic, 1989). Using this method, in conjunction with reflex facilitation, suppression, and reinforcement maneuvers (see above), several studies have validated the use of surface EMG in the detection of preserved motor function in persons with motor-complete SCIs (McKay et al., 2004; Sherwood et al., 1992; Sherwood et al., 1996). Although this method provides strong evidence of functional preserved 11 motor function, its limitation lies in its sensitivity. Prior evidence suggests surface EMG may miss preserved motor function, as evidenced by transcranial magnetic stimulation (TMS) (Calancie et al., 1999; Bjerkefors et al., in prep), Furthermore, this method lacks an ability to determine the mechanism by which persons with a motor-complete SCI may be voluntarily recruiting muscle activation and/or exhibiting other subclinical features. Therefore, there is a need for more sensitive measures of remaining motor activity and a need to provide a neuroanatomical mechanism by which patients may control their motor activity below the level of injury. 1.6 Transcranial magnetic stimulation and spinal cord injury In 1980 Merton and Morton developed a technique designed to directly stimulate the human cortex and termed it transcranial electric stimulation. By placing the electrodes over the primary motor cortex and providing a brief electrical stimulation they were able to observe a characteristic muscle twitch in the forearm, recorded using surface EMG, termed the motor evoked potential (MEP). This technique, while useful, posed some problems as it produced a large, uncomfortable twitch of facial and neck muscles due to stimulation of the scalp (Merton & Morton, 1980). A few years later, Barker, Jalinous, and Freeston (1985) sought to solve this problem and developed a tool capable of producing a strong magnetic field, which could cross the scalp and stimulate the cortex, therefore preventing the painful muscle twitches. This technique then came to be known as TMS. It was immediately evident that TMS would be a useful tool in studying the human nervous system. TMS works by releasing a high current electric pulse (5000A or more) that flows from a capacitor into a tightly wound coil (stimulating coil) (Nollet, Van Ham, Deprez, & 12 Vanderstraeten, 2003). Upon reaching the stimulating coil a magnetic field is produced with lines of flux perpendicular to the orientation of the coil (Hallett, 2007). A magnetic field of this magnitude will then cause an electrical current in any surrounding conductive tissue that will flow in the opposite direction of the current and have an amplitude in line with the magnetic field (1-20 milliamps/cm2) lasting for approximately 100 microseconds (Hallett, 2007). In our case, this conductive tissue is the human brain. Therefore, an electric current is produced perpendicular to the magnetic field; that is, parallel to the orientation of the coil (see Figure 1 in Hallett, 2007). Stimulation of the primary motor cortex using this method is thought to indirectly activate descending corticospinal neurons (Hallett, 2007) and thereby provides a way to assess the integrity of this major motor pathway. Numerous studies have examined motor control in persons with an SCI using TMS; however, these studies have been largely limited to incomplete SCIs. With regards to persons with a motor-complete SCI, the results from various studies using TMS stand in conflict and contain several limitations. Calancie et al. (1999) performed TMS on 97 patients with an SCI. Persons with an incomplete SCI were shown to have lower amplitude MEPs and delayed latencies compared to controls. However, the authors observed MEPs in 4 of 35 people who they had defined as motor-complete (Frankle scale, see above). Although the authors discount this by stating that the response is not important, as these participants were still not able to perform volitional movements, this provides evidence that persons with chronic injuries may still have preserved motor pathways years after injury. MEPs were also found in persons with a motor-complete SCI during attempted leg movement (Dimitrijevic, Eaton, Sherwood, & Van der Linden, 1988), while using H-reflex conditioning to reinforce lower motor neuron pool activity (Wolfe, Hayes, Potter, & Delaney, 1996), as well as in arm muscles of persons with a high 13 cervical SCI (Gianutsos, Eberstein, Ma, Holland, & Goodgold, 1987). Using various reinforcement maneuvers such as hand clenching and attempted focal muscle contraction, Hayes, Allatt, Wolfe, Kasai, and Hsieh (1991) also observed MEPs in persons with a motor-complete SCI. Furthermore, in a study observing SCI in the acute stages, Petersen et al. (2012) observed irregular responses in 4% of AIS A patients and 18% of AIS B patients (AIS score determined 1 year after injury). In contrast to these findings, Curt, Keck, and Dietz (1998) and Macdonell and Donnan (1995) performed similar protocols but were unable to elicit MEPs below the level of injury in persons with a motor-complete SCI. The results of the above studies point to the possibility of preserved motor pathways in persons with a motor-complete SCI. Furthermore, preliminary pilot data from our lab showed present rectus femoris MEPs in 3/5 persons with a motor-complete SCI (Appendix C). However, the limited and conflicting results make conclusions about motor preservation unclear. The conflicting results of previous work may be due to two limitations in the methodology. First, previous evidence demonstrates that remote and focal reinforcement maneuvers used in conjunction may be the most reliable way to facilitate MEPs in response to TMS (Kawakita et al., 1991; see McKay, Stokic, & Dimitrijevic, 1997 for review). In persons with an SCI, using remote facilitation may be even more crucial considering the evidence that persons with a chronic SCI show decreased cortical representation in paretic areas, making conclusions about their ability to produce focal facilitation unclear (Freund et al., 2011; Wrigley et al., 2009). Of the previous studies, only one (Hayes et al., 1991) used remote and focal reinforcement maneuvers in conjunction to facilitate the transmission of the MEP. Second, the use of a double cone stimulating coil has been shown to be most effective in producing reliable MEPs in the lower limbs, as it is able penetrate deeper into the longitudinal sulcus where the leg 14 representation of the primary motor cortex lies (Terao et al., 2000; Terao et al., 1994). Of the previous studies, only one (Calancie et al., 1999) used this coil. Without the use of a double cone stimulating coil and proper use of reinforcement maneuvers, the possibility of not detecting an MEP when preserved motor pathways are present may increase. Accordingly, there is a need to build upon previous studies by eliminating these two limitations and to provide an improved protocol by which motor preservation in persons with a motor-complete SCI can be determined. While TMS may provide us information about the integrity of the corticospinal pathway, previous work suggests other motor pathways may be preserved in persons with a motor-complete SCI (see Kakulas et al., 2012 for review). The preservation of subclinical features in the absence of volitional activity suggests the involvement of bulbospinal pathways. Specifically, the extent of preservation of the vestibulo- and reticulospinal pathways may also play a large role in a person‟s ability to display subclinical features (Sherwood et al., 1993) and to regain walking function (Fouad & Pearson, 2004). Therefore, it is crucial to determine the extent to which these other motor pathways are preserved in persons with a motor-complete SCI. 1.7 Measuring vestibulo- and reticulospinal function in persons with a spinal cord injury Descending vestibulo- and reticulospinal neurons are thought to have direct, excitatory monosynaptic connections to lower motor neurons (Grillner, Hongo, & Lund, 1970; Shapovalov & Gurevitch, 1970) that persist into lumbar segments of the spinal cord (Nathan, Smith, & Deacon, 1996), making their role in walking function and the presence of subclinical features a possibility. Furthermore, previous work has demonstrated descending connections from motor cortices onto vestibular and reticular formation nuclei (see Fukushima, 1997 for review; Keizer & Kuypers, 1984, 1989). Therefore, the volitional, subclinical features in persons with a motor-15 complete SCI may be mediated through cortico-vestibulo- and/or reticulospinal mechanisms. Moreover, the level of plasticity in the human nervous system is vast and the extent to which these smaller motor pathways may take over remaining motor function in persons with an SCI is unclear, yet possible (Raineteau & Schwab, 2001). There have been few studies investigating the role and preservation of vestibulospinal pathways in persons with an SCI (Iles, Ali, & Savic, 2004; Liechti, Müller, Lam, & Curt, 2008; Raffensperger & York, 1984; Wydenkeller, Liechti, Müller, & Curt, 2006). One tool used to stimulate the vestibulospinal pathway is galvanic vestibular stimulation (GVS) (Fitzpatrick & Day, 2004). GVS directly stimulates irregular firing afferents of the vestibulocochlear nerve, producing a characteristic muscle response (Fitzpatrick & Day, 2004). People with an incomplete SCI tend to show responses with increased latencies and decreased amplitudes, compared to controls, suggesting possible damage to the vestibulospinal pathway (Liechti et al., 2008; Wydenkeller et al., 2006). Iles et al. (2004) observed responses below the level of injury to GVS in persons with a motor-complete SCI; however, these responses were in the paraspinal muscles and may have been a result of multisegmental innervation from higher (above the injury) nerve roots (Ellaway et al., 2007). Lastly, Raffensperger and York (1984) did not observe any H-reflex amplitude modulation with caloric stimulation in persons with a motor-complete SCI, unlike controls. While these findings may suggest some preservation, the results are largely in persons with an incomplete SCI and the few results from people with a motor-complete SCI are confounded. Furthermore, responses to direct stimulation of the vestibulospinal pathway in persons with a motor-complete SCI have never been recorded in the lower limbs. Determining the preservation of the vestibulospinal pathway may provide a mechanism for the appearance of 16 subclinical features and improve our understanding of the relationship between preserved motor pathways and rehabilitation outcomes. Like the vestibulospinal pathway, very little work has been done to determine the integrity of the reticulospinal pathway in persons with a motor-complete SCI. Only two studies to my knowledge have examined the influence of the reticulospinal pathway following an SCI (Dobkin, Taly, & Su, 1994; Kumru et al., 2008). One method of probing the reticulospinal pathway is through the use of auditory startle tones (Davis, Gendelman, Tischler, & Gendelman, 1982). Kumru et al. (2008) observed increased amplitude and faster onsets of auditory startle responses above the level of the lesion in persons with a motor-complete SCI. However, responses in the lower limbs for these people were not reported. Dobkin et al. (1994) used the auditory startle response to condition H-reflexes in persons with an SCI and controls. In one person with a motor-complete SCI they observed facilitation of the H-reflex in the lower limb following auditory startle tones. These results suggest the reticulospinal pathway may be partially or completely preserved in this person. However, due to the nature of the startle response, reticulospinal pathway stimulation may possibly evoke major spastic events in persons with a motor-complete SCI and therefore this thesis did not use this technique. Due to the uncomfortable nature of GVS, as well as the complexity of collection and analysis, there has been a push in recent research to develop a new clinical tool to assess the vestibulospinal pathway. In an SCI population this becomes difficult as extensive evidence demonstrates vestibulospinal responses to GVS in lower limbs are absent in participants not performing a balancing task (Britton et al., 1993; see Fitzpatrick & Day, 2004 for review), which is an unavoidable reality when working with persons with an SCI. 17 Therefore, there is a need to develop a new technique whereby vestibulospinal responses can be measured in participants while in a seated or supine position. Vestibular evoked myogenic potentials (VEMPs) may be useful in this situation, as they are easily administrated in a supine position and measurable in a variety of muscles, including the lower limb (Colebatch, Halmagyi, & Skuse, 1994; Rudisill & Hain, 2008; Watson & Colebatch, 1998). VEMPs are often elicited through the use of high frequency tones (4-20ms) or clicks (0.1-0.5ms) (Rudisill & Hain, 2008; Watson & Colebatch, 1998). It is thought that the vibratory sound waves induced by the stapes force plate activate hair cells of the otolith end organs, primarily the saccule (Curthoys, 2010). Once stimulated, these organs send nerve impulses mainly through the inferior division of the vestibular nerve to the lateral vestibular nucleus (Curthoys, 2010). From there, projections of the efferent vestibulospinal pathway go caudal in the spinal cord and reach various levels of lower motor neuron pools. They then synapse onto interneurons and/or lower motor neurons to produce a muscle twitch. While studies have demonstrated that this type of vestibular stimulation preferentially activates descending vestibulospinal neurons (Kushiro, Bai, Kitajima, Sugita-Kitajima, & Uchino, 2008; Sato, Imagawa, Isu, & Uchino, 1997), there is also evidence the vestibular nuclei may also send collaterals to the reticulospinal neurons (Bolton et al., 1992). Therefore, in this thesis, inherent in any reference to vestibulospinal pathway is the assumption the reticulospinal pathway may be partially involved. Despite this limitation, stimulation of the vestibulospinal pathways through this method may, for the first time, provide a way to assess the pathway‟s integrity below the level of injury in persons with a motor-complete SCI. Additionally, it provides the opportunity to give a mechanistic explanation to reflex suppression and facilitation observed in these people (Cioni et al., 1986; Dimitrijevic et al., 1977; Sherwood et al., 1993). 18 1.8 Functional significance Despite a wealth of evidence showing the usefulness of neurophysiological testing in persons with an SCI, there is a lack of knowledge about the mechanisms underlying subclinical features and how these tests can be linked to the person‟s clinical classification and functional abilities. Few studies have been conducted in this nature and they have been largely limited to the trunk muscles. Bjerkefors, Carpenter, and Thorstensson (2007) as well as Bjerkefors and Thorstensson (2006) observed functional improvements in persons with a motor-complete (AIS A/B) high thoracic SCI following a kayak-training regime. Although they propose this may be neural adaptation, more neurophysiological evidence was needed. A further study by Bjerkefors, Carpenter, Cresswell, and Thorstensson (2009) described a case study of one individual with a motor-complete high thoracic SCI. The authors observed improvements in postural reactions to seated perturbations following a training protocol. In this study the authors took a step forward and recorded in-dwelling EMG from the trunk muscles. They observed activation similar to controls during postural perturbations, suggesting preserved motor pathways crossing the level of injury. Although strong evidence of preserved motor function in the trunk muscles was provided, a direct measure was needed. Therefore, a further study performing TMS on a small group of persons with motor-complete SCIs was conducted (Bjerkefors et al., in prep). We observed trunk MEPs in all people, were able to link this to voluntary function, and relate it to the person‟s current clinical classification. In addition to these trunk studies, there have been four case studies of persons with a clinically classified motor-complete SCI regaining some over-ground stepping ability (Behrman & Harkema, 2000; Manella, Torres, & Field-Fote, 2010; McDonald et al., 2002; Murillo et al., 19 2012). Preservation of corticospinal, vestibulo- and/or reticulospinal motor pathways may play a role in these people‟s ability to regain some over-ground stepping function. Thus, the functional importance of detecting any remaining motor pathways cannot be understated. These studies provide some groundwork and reveal a need to detect preserved motor function in persons with a motor-complete SCI. Therefore, it is necessary to extend this work into the muscles tested during the clinical examination and other motor pathways. 1.9 Purpose and hypotheses The inaccuracy of the ISCNSCI may persist beyond the untested muscles (trunk muscles) into muscles currently assessed during the examination (leg muscles). Previous results and pilot data (Appendix C) suggest motor preservation may continue down to leg myotomes in persons with a clinically classified motor-complete SCI (AIS A/B). A lack of sensitivity during the initial examination may result in unneeded muscle atrophy as a result of non-use. This non-use is a direct result of an inaccurate clinical exam and may be prevented by using more sensitive measures. Therefore, the purpose of this thesis is to determine the integrity of cortico- and vestibulospinal pathways in persons with a motor-complete SCI. I hypothesize that direct stimulation of corticospinal neurons using TMS will evoke motor activity in abdominal and leg muscles of persons with a motor-complete SCI and able-bodied (AB) controls (Bjerkefors et al., in prep). Furthermore, in persons with observable motor activity, I hypothesize persons with an SCI will have longer latency MEPs compared to AB controls (Calancie et al., 1999). Secondly, I hypothesize that stimulation of vestibulospinal neurons using VEMPs will evoke motor activity in leg muscles of persons with a motor-complete SCI and AB controls (Iles et al., 2004). Furthermore, in persons with observable motor 20 activity, I hypothesize persons with an SCI will have slower lower limb VEMP latencies compared to AB controls (Iles et al., 2004; Liechti et al., 2008). Lastly, I hypothesize that if an effect of plantar withdrawal reflex suppression is observed, it will be related to present motor activity. 21 2 Methods 2.1 Participants Sixteen individuals (4 Females, 44±13 years; 1.73±0.07m 67.3±14.9kg) with a stable (chronic) motor-complete (AIS A/B) SCI and 16 AB matched controls (4 Females, 42±14 years; 1.76±0.06m 77.7±11.0kg) volunteered for the study. The inclusion criteria for participants with an SCI were the following: sustained a cervical or thoracic SCI resulting in a motor-complete (AIS A/B) clinical classification at or above T12-level at least 1 year prior, with stable neurological and medical status and no cognitive impairments. Individuals with an SCI were excluded if they had: frequent experience with autonomic dysreflexia (uncontrolled, sudden rises in blood pressure), severe spasticity, personal history of epilepsy/seizure, and/or disturbances of the nervous system other than the SCI such as cauda equina syndrome (Bjerkefors et al., in prep). A detailed description of participants with an SCI can be found in Table 1. Exclusion criteria for all participants included any of the following contra-indications for TMS: recurring or severe headaches, skull fracture or head injury including concussion, head or brain surgery, hearing problems, psychiatric impairment and/or sleep deprivation, pregnancy, heart diseases, diabetes and electrodes implanted in the central or peripheral nervous system (Rossi, Hallett, Rossini, Pascual-Leone, & Safety of TMS Consensus Group, 2009). The University of British Columbia Clinical Research Ethics Board and the Swedish Central Ethical Review Board reviewed and approved this study. All participants received oral and written information describing the study and provided written consent prior to participating. 22 2.2 Experimental design This experiment was conducted in the Neural Control of Posture and Movement Laboratory at the University of British Columbia, as well as at the Biomechanics and Motor Control Laboratory at the Swedish School of Sport and Health Sciences. Persons with a motor-complete SCI and matched AB underwent the TMS and VEMP protocol over 3 hours. 2.3 Measurements 2.3.1 Data collection 2.3.1.1 Electromyography Muscle activity was recorded with surface EMG (Myosystem 1400A, Noraxon, USA) from left external oblique (OE), right transverse abdominus (TrA) and bilaterally from: sartorius (SAR), rectus femoris (RF), biceps femoris (BF), tibialis anterior (TA), soleus (SOL), medial gastrocnemius (MG), and extensor hallucis (EH) using belly-belly preparations. Electrodes were moved from the abdominal muscles (OE, TrA) to the left and right sternocleidomastoid (SCM) during the VEMP protocol. Signals were band-pass filtered between 10 and 1000Hz online, amplified 500x, A/D converted (Micro1401, CED, Cambridge, UK), and digitally collected at 5000Hz (Spike2, CED, Cambridge, UK). Prior to placing the electrodes, the skin was shaved and cleaned with alcohol. Pairs of self-adhesive electrodes (10mm diameter, BlueSensor, Ambu, Ballerup, Denmark) were attached with approximately 2cm inter-electrode separation. 2.3.1.2 Transcranial magnetic stimulation Participants laid in a supine position on a plinth with their arms folded and hips and knees bent (Figure 1). Participants wore a tight fitting swimming cap over the head and the location of 23 the vertex (CZ) was identified using the international 10/20 system. Magnetic stimulation was applied over the scalp site using a MagStim 2002 stimulator, Mono Pulse (The MagStim Company Ltd., Dyfed, UK) connected to a stimulating coil (Double cone coil, diameter 110mm). The coil was placed approximately 1cm anterior to the vertex, with the intersection of the coil placed over the stimulation site and point of optimal excitability (POE) over the primary motor cortex was determined. The stimulus intensity was initially set to 50% of maximal stimulator output (MSO), and then increased to 70-100% of MSO while the orientation of the coil and the location was slightly adjusted until the POE was localized and identifiable MEPs were recorded in both legs. Participants were asked to perform various sub-maximal contractions as previous studies have shown that the POE is easier to identify if the participant maintains a sub-maximal (or attempted) contraction, as MEP amplitude increases with facilitation (Hayes et al., 1991; Kawakita et al., 1991). The number of stimuli, the POE, and the percent of MSO were documented for all participants. Participants were then instructed to perform sub-maximal voluntary (or attempted) contractions during trunk rotation to the right, hip flexion, knee extension, plantarflexion, dorsiflexion, and great toe extension, while also performing a maximal hand-clench, as remote facilitation coupled with focal contraction has been shown to increase MEP amplitude to a greater extent than focal contractions alone (Kawakita et al., 1991). Participants then performed 1 trial using only remote facilitation and 1 trial at rest. Ten stimuli were delivered while participants performed each task using the same stimulation intensity as when the POE was defined. A 30s rest between trials and a 2min break between tasks were given. 24 2.3.1.3 Maximal voluntary contractions Following the TMS protocol, participants performed 6 different maximal muscle contractions while lying supine on a plinth: trunk rotation to the right, hip flexion, knee extension, plantarflexion, dorsiflexion, and great toe extension. The legs and trunk were secured to a plinth with straps placed over the shoulders, knees, and feet to minimize movements of the upper and lower body. Each task was preceded with a verbal explanation by the examiner. Participants performed two trials for each task, for each leg with a 30s rest between trials and a 2min break between tasks. 2.3.1.4 Vestibular-evoked myogenic potentials A sequence of 4ms short-tone burst (500Hz, 125dB) acoustic stimuli were presented to each participant monaurally, through Telephonics earphones via a stereo amplifier for 4 trials. Tones of this duration have been shown to preferentially activate the vestibulospinal system (Murofushi, Matsuzaki, & Wu, 1999). Each trial consisted of 2 blocks of 128 acoustic stimuli with an interstimulus interval of 0.2-1.8s. Stimuli were generated using a custom made sequencer (Spike 2 software) and calibrated to the correct amplitude. Participants‟ heads were turned contralateral to the side of stimulation. For participants with an SCI, the 4 trials were completed during hard (or attempted) contraction of SOL with and without vibration of the Achilles tendon. Stimulations were delivered to the left ear, and then repeated in the right ear. AB participants completed 2 trials during hard contraction of SOL with and without vibration and 2 trials during soft contraction of SOL with and without vibration. Hard and soft trials were always completed on opposite ears and the order of trials was randomized in both SCI and AB participants. Responses were recorded in the SCM and SOL EMG. In vibration trials, a bullet vibrator (80Hz) 25 driven by a constant voltage unit (#6214B Hewlett Packard, USA) was placed on the participants‟ Achilles tendon. Pilot data from our lab suggested constant vibration throughout the trial is sufficient to facilitate a VEMP in SOL, even in the absence of volitional activity. This may be a result of increased alpha motor neuron activity due to type II afferent entraining (Burke, Hagbarth, Löfstedt, & Wallin, 1976; Person & Kozhina, 1992), coupled with supraspinal reflex loops (Kanda, 1972). Each block was approximately 4mins with a 1-2min break between blocks, totaling approximately 10mins (256 stimulations) for each trial. 2.3.1.5 Subclinical assessments With participants lying on a plinth, the experimenter stroked the plantar surface of each foot in order to elicit a withdrawal reflex. A blunt end reflex hammer was used and stimulation began at the heel and proceeded along the lateral surface of the foot. Three stimulations were applied during rest and another three while the participant attempted to voluntarily suppress the response to stimulation. The participant was instructed to attempt to suppress the response as much as possible and the experimenter was blind to the trial order. 2.3.2 Data analysis 2.3.2.1 Motor evoked potentials MEP onset was calculated as the time at which the MEP exceeded 2SD above the average baseline EMG activity (100ms prior to the stimulation onset) and remained beyond this threshold for at least 2ms. All MEP onsets were visually confirmed by the experimenter. Muscles with detectable MEP onsets in at least 5 out of 10 trials were defined as “present” and used to calculate individual participant and group latency averages. Muscles with detectable MEP onsets 26 in less than 5 out of 10 trials were defined as “inconsistent” and not included in individual and group latency averages. Analysis was also performed to determine the number of participants with present and inconsistent responses for the target muscle, during each task. 2.3.2.2 Maximal voluntary contractions EMG recorded during voluntary tasks was used to calculate the root mean square (RMS) amplitude over a 500ms time period for each muscle and task during rest and voluntary contraction. If the average RMS of the two contraction trials for a given muscle and task exceeded 2SD above the mean resting value, the value was defined as “present” and included in subsequent analysis. Analysis was then performed to determine the number of subjects with present responses for the target muscle, during each task. 2.3.2.3 Subclinical assessments The reflex amplitude in TA (Cioni et al., 1986; McKay et al., 2004) in response to plantar stimulation was analyzed. The peak amplitude for TA was calculated over a 5s window starting from stimulus onset. Response amplitudes were collapsed across sides as no differences were expected (Cioni et al., 1986; McKay et al., 2004). Percent suppression was calculated by taking the average percent change from suppression to rest. Habituation was also calculated by taking the average percent change from the first (trial 1-3) and second (trial 4-6) blocks, regardless of the task. 2.3.2.4 Vestibular-evoked myogenic potentials VEMP responses were analyzed in a staged approach on the ipsilateral side to stimulation. Response latencies for the VEMP in SCM were determined from the ensemble 27 average of 256 trials for each participant. All data was baseline corrected prior to analysis. SCM VEMP latencies were determined as the point of peak amplitude of the first peak to exceed 2SD of background activity 250ms before the onset of stimulus and the following second peak in the unrectified signal (Eleftheriadou & Koudounarakis, 2011). Only muscles with a present SCM response on that side were included in the subsequent SOL analysis. As responses are more difficult to find in SOL unrectified signals, the data was rectified prior to the ensemble averaging (Luxon, 2013). SOL latencies were then determined as the first peak that exceeded 2SD of background activity (250ms prior to onset of stimulus) within a 40-120ms latency window (Luxon, 2013; Watson & Colebatch, 1998). Responses that passed the criteria were then included in a descriptive analysis to determine the number of participants with a detectable SOL VEMP. 2.3.3 Statistical analyses To compare MEP latencies with AB data, SCI MEPs were paired to their respective AB control (matched to the correct muscle and task) and included in a paired samples t-test. The number of present MEPs and responses to voluntary (or attempted) contraction in a given muscle, for a given task were descriptively compared across participants and groups. Latencies and amplitudes for SCM VEMPs were descriptively compared. Amplitude, duration, and number of muscles involved during subclinical assessments were descriptively analyzed. Significance was set at p≤0.05. 28 3 Results 3.1 Participants All participants completed the TMS protocol and were free from headaches or any other side effects from the TMS. Consistent with previous studies, the %MSO ranged from 45-80% in the AB group and 80-100% in the SCI group when stimulating over the leg region of primary motor cortex (Calancie et al., 1999). The number of stimulations ranged from 93-105 in the AB group and 93-102 in the SCI group and this number was well tolerated by all participants. All participants also completed the MVC protocol and all SCI participants completed the withdrawal reflex protocols. For the VEMP protocol, two of the AB participants were only able to complete 2 trials of stimulations due to muscle cramps and ear irritation. All SCI participants completed the VEMP protocol and tolerated it well. Of those participants who completed the VEMP protocol, they received all 4 trials of 256 stimulations. 3.2 Transcranial magnetic stimulation 3.2.1 Motor evoked potentials Biphasic MEPs were elicited by TMS in 100% of the target musculature for all AB participants (Table 3). In addition, TMS elicited MEPs in some abdominal and leg muscles of persons with a motor-complete SCI (AIS A/B) at or above T12 (Figure 2). BF and MG responses were excluded from the analysis due to a lack of true focal contraction and due to the position of the knee, respectively. 29 3.2.1.1 Muscle responses below the level of injury In persons with an SCI, biphasic “present” MEPs were elicited by TMS below the level of injury in 13 of 16 participants (9 AIS A, 4 AIS B). In 3 of 16 participants with SCI, no measureable MEPs were detected (2 AIS A, 1 AIS B). The probability of observing an MEP in response to TMS was similar between participants with AIS A (82%) and AIS B (80%) injuries. Of 13 SCI participants with MEPs, 8 had an injury above T6 (innervation to the abdominal muscles) and therefore abdominal muscle responses were considered as below the level of injury and 5 participants had injuries at or below T6. In the participants with injuries above T6, 5 showed a present MEP in OE only, 1 in TrA only, and 2 participants had an MEP in both OE and TrA. Furthermore, 2 of these 8 participants showed a present MEP in SAR. When considering the total number of MEPs in persons with an injury above T6, abdominal muscle MEPs across SCI participants were most common (n=10) and leg muscle MEPs less common (n=2). In the 5 participants with measureable MEPs and an injury at or below T6, abdominal muscle responses were classified as “above the level of injury” and are discussed in a following section. Of those 5 participants with injuries at or below T6, 2 showed MEPs in SAR only; 2 showed MEPs in SAR and in RF; and 1 participant showed MEPs in SAR, RF, TA, and SOL (Table 4). In participants with injuries at or below T6, leg muscle MEPs were more common (n=15) than in participants with injuries above T6, with the majority of those MEPs (n=14) found in persons with low thoracic injuries between T10-T12 (Table 4). In addition to “present” MEPs detected below the level of injury, 12 participants with SCI had “inconsistent” MEPs, having only 1-4 detectable MEPs out of 10 (Table 2). These MEPs were found in both the abdominal muscles (n=6) and in the leg muscles (n=18). 30 To examine latencies within participants with SCI, MEPs were collapsed across sides and across injury levels; although, abdominal muscle activity was only examined in persons with an injury level above T6. MEPs were observed in OE/TrA (n=10), SAR (n=11), RF (n=4), TA, (n=1), and SOL (n=1) with latencies of 22.8±3.2ms, 26.9±7.0ms, 30.2±7.4ms, 48.3ms, and 46.3ms, respectively (See Table 3 for summary). When individual muscle latencies were compared using paired sample t-tests no statistical differences between groups were found in OE/TrA (t(9)=2.05, p=0.07), SAR (t(10)=1.49, p=0.168) or RF (t(3)=1.82, p=0.166). 3.2.1.2 Muscle responses above the level of injury As noted in Table 2, 6 participants with an SCI had lesions between T6-T12. All participants had present MEPs in the abdominal muscles and their latencies (20.6±4.1ms) were similar to their matched AB controls (20.6±1.9ms). 3.2.2 Motor evoked potential peak to peak amplitudes For both abdominal and leg muscle responses, peak-to-peak amplitudes were, on average, smaller in the SCI group compared to the AB group. No statistical comparisons were done due to a lack of a reliable standardization (no peripheral nerve stimulation). 3.3 Maximal voluntary contractions All AB participants were able to elicit EMG activity above resting levels in all tasks. In persons with an SCI above T6, muscle responses defined as “present” (ie. exceeding 2SD above resting levels) were found in only 1 of 10 participants, both in the abdominal muscles (OE/TrA) and in SAR. In the participant‟s TrA and SAR, there was also a present TMS MEP; however, in the OE there was no present MEP (Table 4). 31 Leg muscle voluntary contractions defined as “present” were detected in 4 of 6 participants with injuries at or below T6. Of those 4 participants, 3 had present responses to MVC in SAR and 1 participant had detectable responses to MVC in SAR, RF, TA, and SOL. In 13 of 14 cases (Table 4), SCI participants with a present response to MVC also had a present response to TMS. Conversely, there were 16 cases where a response to MVC was absent in spite of a present MEP. Despite having an injury below the innervation of the abdominal muscles, 2 participants with injuries at or below T6 were not able to raise their muscle activity above baseline in their OE. 3.4 Vestibular evoked myogenic potentials Characteristic VEMPs were elicited by short-tone bursts in the SCM and SOL muscles of both AB and SCI participants. In AB participants, soft push trials were excluded as this was not a viable technique of eliciting a VEMP in the lower leg, with 0 of 16 participants showing a response during this type of facilitation. In addition, vibration was not found to be a useful technique in facilitating the SOL VEMP. Of 16 AB participants, only 7 showed a VEMP in SOL during hard pushing and of those 7, only 1 had a detectable SOL VEMP with vibration and 0 participants had a detectable VEMP during soft pushing with vibration. In 1 case a participant without a present SOL VEMP in the no vibration condition showed a detectable SOL VEMP in the vibration condition. In the SCI group the vibration posed more complications, often causing increased spasticity, aggravating sensitive skin, and even causing sores in 2 participants. The results in this section will therefore focus on the no vibration trials in the SCI group (both sides) and on the hard push trials in the AB group (one side). Thus, there are a total of 32 possible 32 muscle responses (left and right) in both SCM and SOL in the SCI group and 16 possible muscle responses (hard push side only) in both SCM and SOL in the AB group. 3.4.1 Sternocleidomastoid responses Present responses were found in 26 of 32 SCM muscles of persons with SCI and 12 of 16 SCM muscles of AB participants. Response latencies were found to be consistent, with average first peak latencies of 16.3±1.4ms and 16.2±2.2ms in the SCI and AB groups, respectively. Average second peak latencies were 25.0±2.4ms in the SCI group and 24.5±2.3ms in the AB group. No differences were observed between groups and the responses were similar in latency. Average peak-to-peak amplitudes were 81±48 µV and 142±63µV for the SCI and AB group, respectively. 3.4.2 Soleus responses SOL responses were more difficult to elicit than SCM responses in response to short-tone bursts. With participants in a supine position, present responses were found ipsilateral to the side of stimulation in 7 of 12 of the AB SOL muscles with an average latency of 84.6±7.9ms. Responses were detected in 4 of 26 SOL muscles in the SCI group with an average latency of 84.4±19.5ms. Of the 4 SCI participants, SCI14 had a present MEP in response to TMS and present voluntary activation in SOL and SCI01, SCI03, and SCI07 had no observable activation of SOL. Individual responses for the AB group (n=7) and the SCI group (n=4) can be found in Figure 3. 33 3.5 Subclinical assessments 3.5.1 Plantar-cutaneo withdrawal reflex Of the 16 participants with SCI (and 32 TA muscles), SCI1, SCI5, SCI6, and SCI15 had inconsistent or absent responses on both sides and SCI3, SCI10, SCI11, SCI12, and SCI13 had an inconsistent or absent response on 1 side. These 13 muscles were removed from the analysis, leaving a total of 19 TA reflex responses. The average percent change from suppression to rest was 1.54%±33.74%. When comparing the first (trial 1-3) and second (trial 4-6) block for habituation the average percent change was 2.12%±28.67%. 34 4 Discussion The aim of this thesis was to investigate the feasibility of using TMS and VEMPs to determine the integrity of cortico- and vesitbulospinal pathways in persons with a motor-complete SCI. In addition, this thesis aimed to a) compare any preserved muscle responses in the SCI group with those from matched AB controls, b) examine if preserved neural pathways predict voluntary motor activity, and c) determine if preserved neural pathways predict the presence of subclinical features. Despite being clinically classified with a motor-complete SCI at or above the T12 level, some participants showed observable responses below the level of their injury to cortico- and/or vestibulospinal stimulation. When examining preserved muscle activity in response to TMS, the MEPs in the SCI group were typically delayed compared to their matched AB controls. Muscle activity recorded using surface EMG in response to MVC was confirmed by a TMS MEP in all but one case; however, TMS was able to elicit muscle activity even in the absence of voluntary activation. Lastly, the examination of subclinical features and their relationship to neural preservation was inconclusive. Overall, these results highlight the need for more sensitive methods of determining motor function following SCI and provide an improved protocol for determining the neurophysiological integrity of cortico- and vestibulospinal pathways in persons with a motor-complete SCI. 4.1 Motor evoked potentials 4.1.1 Frequency of motor evoked potentials MEPs were elicited by TMS in all target muscles of every AB participant. This result confirms the reliability of TMS as a method to probe descending neural pathways. In addition, 35 persons with a motor-complete SCI showed present MEPs below the level of injury in response to TMS, confirming my first hypothesis. Previous studies have shown it is possible to record MEPs in response to TMS below the level of injury in persons with a motor-complete SCI; however, their detection rates have been, in general, lower than the detection rate in this thesis (13 of 16 persons with SCI). For example, when examining persons with a clinically defined motor-complete SCI, Calancie et al. (1999) detected MEPs in 4 of 35 participants, Dimitrijevic et al. (1988) reported 1 of 4, and Hayes et al. (1991) 4 of 26. Other experiments have reported even lower detection rates (6 of 107) (Petersen et al., 2012) or no responses (Curt et al., 1998; Macdonell & Donnan, 1995; Wolfe et al., 1996). Two studies reported higher detection frequencies with measureable MEPs detected in the arm muscles of 3 of 5 participants (Gianutsos et al., 1987) and in the abdominal muscles of 5 of 5 persons with a motor-complete SCI (Bjerkefors et al., in prep). The difference in detection frequency between previous work and this thesis can be partially explained by methodological differences between experiments. Firstly, abdominal and SAR MEPs were not analyzed by the majority of the discussed studies, with one exception (Bjerkefors et al., in prep). If this is taken into account, and the abdominal and SAR MEPs are ignored, the detection rate in this thesis would drop to 3 of 16. Secondly, many of these studies examined MEPs in only one (Petersen et al., 2012) or two (Curt et al., 1998; Macdonell & Donnan, 1995; Wolfe et al., 1996) lower limb muscles. Lastly, the analysis used to determine the presence of an MEP may also contribute to the differing detection rates observed between this thesis and previous work. However, previous studies have used more liberal detection criteria such as any detectable MEP (Calancie et al., 1999; Dimitrijevic et al., 1988; Hayes et al., 1991) or 1 of 4 (Petersen et al., 2012). If the criterion for a present MEP in this thesis was changed to 36 include “inconsistent” MEPs (≥1 of 10), the detection rate in the lower limbs would be 6 of 16 participants (Table 2). Applying a more liberal detection criterion to include inconsistent MEPs exposes an even greater difference in detection rate between this thesis and previous work. However, by using a more conservative detection criterion this thesis still demonstrates a high detection rate of consistent MEPs. Furthermore, the results from this thesis suggest a more comprehensive approach of including abdominal, SAR, and multiple lower limb MEPs evoked by TMS provides a more accurate assessment of preserved motor activity. Differences between this thesis and the results of previous work may also be attributable to neurophysiological methodology. Firstly, previous work provides evidence that using a double-cone stimulating coil is an exceptional method of stimulating deep into the longitudinal sulcus, where the leg region of the primary motor cortex lies (Terao et al., 2000; Terao et al., 1994). Of the discussed studies, only one used this type of coil (Calancie et al., 1999), increasing the possibility of false negatives in other experiments (Curt et al., 1998; Dimitrijevic et al., 1988; Hayes et al., 1991; Macdonell & Donnan, 1995; Petersen et al., 2012; Wolfe et al., 1996). Secondly, prior evidence suggests that using remote and focal contraction maneuvers in conjunction with each other lowers the stimulation threshold and increases the amplitude of the MEP (Hayes et al., 1991; Kawakita et al., 1991). Using these maneuvers is hypothesized to increase excitation levels at the cortical (Hayes et al., 1991) and also the spinal level, possibly through oligosynaptic mediation (Gregory, Wood, & Proske, 2001), thereby reducing the amount of stimulation needed in order to bring the lower motor neuron to threshold. Previous work has also speculated that increased cortical excitability, through both remote and focal contractions, may allow TMS to activate larger, faster corticospinal neurons (Hayes et al., 1991). Only one previous study used remote and focal contractions (Hayes et al., 1991), yet still had a detection 37 rate lower than that observed in this thesis. This thesis is the first study to date to use both a double-cone coil and remote and focal contractions, making direct comparisons with previous work difficult. However, the previous studies using a double-cone coil (Calancie et al., 1999) and remote and focal contractions (Hayes et al., 1991) report detection frequencies of 4 of 35 and 4 of 26, respectively, slightly higher than some other studies (Curt et al., 1998; Macdonell & Donnan, 1995; Petersen et al., 2012; Wolfe et al., 1996). Therefore, prior evidence suggests these individual techniques may improve the detection frequency of MEPs in the lower limb of persons with motor-complete SCI. Although the mechanism for the increased detection frequency demands additional study, the results from this thesis suggest that when these techniques are used in conjunction with each other, it may improve the detection frequency even further. 4.1.2 Frequency pattern of motor evoked potentials Though previous experiments have either excluded abdominal and SAR MEPs, attention has been given to the frequency and pattern of distribution in the current sample of persons with motor-complete SCI. As noted in Table 2, in persons with an injury level above T6, abdominal muscle MEPs were most common (n=10) and MEPs in the legs were least common (n=2). Conversely, in persons with an injury level at or below T6, MEPs in the leg were more common (n=15) with the majority of those MEPs (n=14) found in persons with injury levels between T10-T12. Previous work has demonstrated similar findings in the abdominal muscles (Bjerkefors et al., in prep); however, this is the first study to highlight the inaccuracy of the clinically determined motor level in injuries both above and below T6, specifically in the thoracic and L2-L3 myotomes. 38 4.1.3 Inclusion of sartorius motor evoked potentials Previous studies examining preserved motor activity in persons with SCI have removed hip flexor (SAR) MEPs from their analysis due to “inability to rule out cross-talk” (Calancie et al., 1999) or have not included them at all (Curt et al., 1998; Dimitrijevic et al., 1988; Gianutsos et al., 1987; Hayes et al., 1991; Macdonell & Donnan, 1995; Petersen et al., 2012; Wolfe et al., 1996). The MEPs observed in SAR in this thesis were more common than any other muscle in the leg (n=11) and were not removed from the analysis as they provide further insight into the extent of motor preservation. However, factors such as cross-talk from abdominal muscles, RF, and other pelvic muscles should be considered and will be discussed in the following paragraph. Firstly, the observed MEPs in SAR are unlikely to be a result of cross-talk from the abdominal muscles, as TrA/OI responses were measured, located very close to SAR, and the MEP latencies in the TrA/OI to TMS were on average 4ms faster than those observed in SAR (Table 3). A second confound is that the cross-talk may be coming from proximal segments of the RF. While I cannot be certain this is not the case, careful placement of small surface electrodes on SAR has been previously demonstrated to isolate SAR from RF, evidenced by task specific contributions while participants sit with different hip and knee angles (Andersson, Nilsson, Ma, & Thorstensson, 1997). Furthermore, some participants demonstrated MEPs in SAR but not RF, providing evidence the measurements are from different muscles; however, it is possible only proximal innervation was spared in RF. A third potential confound of the SAR MEPs is cross-talk from other pelvic muscles. While this study cannot conclusively rule this out, of note is that none of the pelvic muscles in the vicinity of SAR are innervated by segments above T12. For example, the most likely confounding pelvic muscles in the vicinity of SAR are 39 (innervation in parentheses): ilacus (L1-L3), psoas major (L2-L4), pectineus (L2-L4), the adductors (L2-L4), and tensor fasciae latae (L4-S1) (Blumenfeld, 2010). Therefore, the inclusion of SAR MEPs is warranted as the MEPs are unlikely a result of cross-talk from muscles innervated above the level of the lesion and, despite possible confounds from RF or other pelvic muscles (innervated L1 or below), the SAR MEPs provide more evidence for preserved muscle activity below the level of injury. 4.1.4 Latencies of motor evoked potentials The MEPs evoked by TMS in the AB population studied in this thesis are within the range of published values for the TrA/OE (Strutton et al., 2004; Tsao, Galea, & Hodges, 2008; Tsao, Tucker, & Hodges, 2011), RF (Furby, Bourriez, Jacquesson, Mounier-Vehier, & Guieu, 1992), TA (Terao et al., 1994), and SOL (Soto, Valls-Solé, Shanahan, & Rothwell, 2006). Latency comparisons for SAR and EH are difficult as there is a lack of published evidence concerning MEP latencies in these muscles; however, there was a clear rostro-caudal pattern of activation, as would be expected due to conduction distance for each muscle. While prior studies examining the latencies of MEPs in motor-complete SCI are scarce, Hayes et al. (1991) reported TA latencies of 38-42ms, slightly shorter than the single response in TA observed in this thesis (48ms). The latencies observed for RF, TA, and SOL were also comparable to the average latencies in persons with motor-incomplete SCI (Calancie et al., 1999). Although no statistical differences were observed between the SCI and AB control latencies, the mean difference in each muscle (Table 3), in addition to the effects observed in previous studies (Calancie et al., 1999), suggest the SCI latencies may be delayed, but that this is an underpowered sample. Further evidence for potential latency delays in SCI can be found by examining height 40 differences between the AB control and SCI group. Previous evidence demonstrates a correlation between height and latency in AB controls (Calancie et al., 1999), suggesting taller people should have longer latency MEPs. When comparing the mean height difference between AB controls and their SCI, AB controls were, on average, 5.25cm taller than their matched SCI. Therefore, based on height differences, AB controls should have, on average, longer latencies; however, the mean latency differences observed for each muscle suggest that, despite the height difference, the SCI group latencies are still longer. Thus, it is likely an effect of delayed latencies is present but could not be statistically demonstrated in this experiment due to small sample size. The following section will therefore discuss possible explanations for delayed latencies between the SCI and AB control groups. Although it represents a weakness in the study, absolute MEP latency was examined without height correction. Instead, values were compared only between SCI and their matched control to help account for this limitation. One method to better standardize MEP latency would be to measure central motor conduction time (Hallett, 2007). However, in order to measure central motor conduction time, spinal nerve root stimulation or peripheral nerve stimulation would be needed for each muscle examined. In the SCI population, instrumentation in the spinal cord to assist with fusion makes performing spinal nerve root stimulation inadvisable (Calancie et al., 1999). To conduct peripheral nerve stimulation for each muscle examined in the lower limb would have added a significant amount of time to the protocol and peripheral nerve stimulation in the trunk is not readily accessible due to the location of the peripheral nerves. As no peripheral nerve stimulation was conducted, peripheral neuropathy may have also contributed to the results. Previous evidence has examined the state of the peripheral nerves in persons with SCI, demonstrating that damage to these nerves is rare, with latencies of H-waves 41 (Alexeeva, Broton, & Calancie, 1998; Calancie et al., 1993) and F-waves (Brouwer, Bugaresti, & Ashby, 1992) being consistent with AB data. Prior studies have also ruled out peripheral nerve damage as it would likely result in a compounded effect of latency delay (Calancie et al., 1999). However, the difference in MEP latency between the SCI and AB groups in this thesis was not fixed, but rather increased from rostral to caudal (Table 3). Therefore, while there is evidence against this hypothesis, the current data are unable to conclusively rule out peripheral nerve damage as a cause for the delayed MEP latencies observed in the SCI group. This thesis is also unable to determine if all descending motor fibers are damaged equally or if total destruction of some descending fibers resulted in an insufficient amount of summation at the spinal motor neuron pool. This may result in a prolonged time to raise the lower motor neuron to threshold and possibly account for the observed delay. Previous evidence suggests insufficient summation is not responsible for the delayed latencies as TMS conditioning did not show early facilitation effects on H-reflex amplitudes but instead showed only delayed facilitation (Alexeeva et al., 1998). Specifically, the earliest interstimulus interval between the delivery of TMS and the H-reflex found to alter the SOL H-reflex amplitude in the incomplete SCI group was approximately 10ms later compared to AB controls (Alexeeva et al., 1998), comparable to the delay in MEP latency observed in SOL in this study (Table 3). This finding suggests there is no early arrival of neural potentials to condition the H-reflex, providing evidence that it is a central conduction problem and not a lack of summation at the lower motor neuron contributing to the observed MEP delays. However, H-reflexes were not done in this thesis and, due to the heterogeneous nature of the SCI population, insufficient summation may potentially contribute to the observed MEP delays. 42 The observed MEP delays may also be a result of focal myelin damage around the injury site (Calancie et al., 1999). This hypothesis has been extensively studied (see Plemel et al., 2014 for review) in both animal models (Blight & Young, 1989) and in human post-mortem studies (Kakulas, 1999). However, a large confound to previous work describing demyelination of axons around the injury site is that they did not exclude completely severed axons in their count of demyelinated versus myelinated axons (Plemel et al., 2014). When severed axons were excluded and only remaining axons were studied, those axons were observed to be extensively remyelinated in chronic SCI in both rats (Powers et al., 2012) and mice (Lasiene, Shupe, Perlmutter, & Horner, 2008). This finding is confirmed by human post-mortem studies, describing the majority of preserved fibers crossing the lesion as still myelinated (Kakulas, 1999). Thus, as recent evidence suggests demyelination is not common in preserved fibers crossing the lesion site, it is unlikely this theory accounts for the majority of the observed MEP delays observed in this thesis. However, small amounts of demyelination or improper remyelination may still affect the conduction rate and could account for a partial slowing of the action potential. Indirect activation of smaller, slower motor pathways through corticobulbar connections may also account for the observed MEP delays. While TMS is most often stated to stimulate corticospinal neurons, it has been demonstrated that TMS can also activate corticobulbar pathways, evidenced by TMS elicited responses in tongue and orofacial muscles, used to aid in the diagnosing of amyotrophic lateral sclerosis (Urban, Vogt, & Hopf, 1998; Vucic, Ziemann, Eisen, Hallett, & Kiernan, 2013). Furthermore, animal work has demonstrated that MEPs in response to TMS will persist following the abolishment of the corticospinal pathway; however, following the abolishment of both corticospinal and ventral pathways (reticulo- and 43 vestibulospinal) all MEPs are absent (Nielsen, Perez, Oudega, Enriquez-Denton, & Aimonetti, 2007). Human studies investigating early and late MEPs in response to TMS describe the early MEP as primarily activation of the corticospinal pathway (Dimitrijević et al., 1992). Conversely, late MEPs may be a result of indirect cortico-bulbo-spinal activation, possibly through the reticulo- and/or vestibulospinal pathways (Dimitrijević et al., 1992). In comparison to the late latency TA MEPs reported by Dimitrijević et al. (1992) in AB participants, the MEP elicited in the TA of one person with SCI in this thesis was early, with a latency of 48.3ms. This latency is more than 3SD outside the TA late MEP sample mean (79.1 ±9.8ms) reported by Dimitrijević et al. (1992), making the observed TA MEP in this thesis statistically unlikely (< 0.1%) to be a similar late latency MEP. Furthermore, the late latency MEPs reported by Dimitrijević et al. (1992) in quadriceps (64.6 ±8.1ms) are more than double the latency of those reported in the RF of the SCI group in this thesis (30.2 ±7.4ms). Therefore, the difference between previously reported late TMS MEPs (Dimitrijević et al., 1992) and the MEP latencies observed in this thesis make indirect activation of reticulo- and/or vestibulospinal pathways unlikely. In contrast, one experiment using vestibulospinal stimulation reports SOL latencies as short as 49 ±9.1ms in response to clicks (Watson & Colebatch, 1998). Responses in this range are in line with the TMS MEP latency reported in the SOL of one SCI participant (46.3ms) in this thesis. However, this participant also had a present SOL VEMP with a latency of 63.7ms. The latency difference between these two responses make it unlikely the TMS MEP is a result of indirect vestibulospinal activation. In addition, other studies using GVS report responses in SOL with short latencies of ~60-90ms (Dakin, Son, Inglis, & Blouin, 2007; Fitzpatrick & Day, 2004; Son, Blouin, & Inglis, 2008), which is in line with the vestibulospinal responses observed in the SCI (84.4 ±19.5ms) and AB (84.6 ±7.9ms) groups in this thesis. Therefore, the observation of a 44 later vestibulospinal response in the same participant, which is in line with previous work (Dakin et al., 2007; Fitzpatrick & Day, 2004; Son et al., 2008), makes indirect activation through reticulo- and/or vestibulospinal pathways an unlikely candidate to explain the delayed MEP latencies. While peripheral nerve damage, summation delays, focal myelin damage, and indirect activation of bulbospinal pathways are unlikely to, individually, account for the MEP latency delays observed in this thesis, the present data are unable to conclusively rule them out. Therefore, it may be a combination of these and other factors, such as preservation of only small, slow conducting corticospinal fibers, which account for the delayed MEP in response to TMS in persons with a motor-complete SCI. 4.2 Maximal voluntary contractions It was originally hypothesized that if a participant showed present EMG activity to MVC it would be supported by a present TMS MEP. EMG activity in response to MVC confirmed the TMS findings in 13 cases (Table 4) and in 1 case was present without a motor response to TMS. These results support those of previous work showing persons with a clinically classified motor-complete SCI may still be able to voluntarily alter their motor activity below the level of their injury, termed a „discomplete‟ SCI (Kakulas et al., 2012; Sherwood et al., 1992). Voluntary activation in the abdominal muscles was only observed below the level of injury in 1 participant with a motor-complete SCI. This finding is in contrast to previous work, which showed a much higher frequency of detection (Bjerkefors et al., in prep); however, this study only used 1 trunk task as opposed to 6 different trunk tasks. Although it is limited to a single participant, this result lines up with those of previous work, showing that EMG activity in 45 response to voluntary effort in the abdominal muscles of persons with a motor-complete SCI can be recorded using either in-dwelling electrodes (Bjerkefors et al., 2009) or surface electrodes (Bjerkefors et al., in prep). Furthermore, it is worth noting that in 2 cases individuals with an injury at or below T6 were not able to voluntarily activate their abdominal muscles to a measureable level. The lack of relationship between the level of injury and the ability to voluntarily activate the abdominal muscles further demonstrates that determining the motor level solely from the sensory level in the thoracic segments may lead to an inaccurate motor level. (Bjerkefors et al., 2009; Bjerkefors et al., in prep; Bjerkefors et al., 2007; Bjerkefors & Thorstensson, 2006). In contrast to the dearth of voluntary abdominal muscle responses, 5 participants showed present volitional EMG activation in leg muscles, below their level of injury. This activation was found in SAR only in 4 participants and in SAR, RF, TA, and SOL in 1 participant with a T10 lesion. This amount of preserved volitional activity has not been previously demonstrated in persons with motor-complete SCI. One major difference, as discussed above, was the inclusion of SAR responses, which are not included in previous work. Another limitation to comparisons between the data in this thesis and those of previous work is the classification technique. Some previous work has classified participants as motor-complete based on a lack of observable EMG activity (Calancie et al., 1999; Dimitrijevic et al., 1988), likely accounting for their lack of observable EMG in “motor-complete” participants. The results from this thesis also confirm TMS may be more sensitive compared to using MVC and surface EMG in its ability to detect preserved motor activity in persons with motor-complete SCI, demonstrated by a present TMS MEP in the absence of volitional activity (Table 3; Bjerkefors et al., in prep; Calancie et al., 1999; Edwards et al., 2013). While in a previous 46 study 5 MEPs in 4 persons with motor-complete SCI were disregarded as no volitional movement was observed (Calancie et al., 1999), more recent studies highlight the importance of detecting minimal preservation in the absence of volitional movement (Bjerkefors et al., in prep; Edwards et al., 2013), as it may have rehabilitation significance. Overall, the data from this thesis support the use of using EMG recordings during MVCs and TMS to assist in the detection of preserved motor pathways in persons with a motor-complete SCI. 4.3 Vestibular evoked myogenic potentials 4.3.1 Sternocleidomastoid responses To ensure the short-tone burst used in this thesis (4ms, 500Hz, 125dB) was able to elicit the robust SCM response, measurements were taken from the ipsilateral SCM. Responses were found in 26/32 persons with SCI (82%) and 12/16 AB (75%), with an overall detection rate of 79%. As no vestibular abnormalities were expected, a higher response rate was anticipated in the SCM in both the SCI and AB groups based on previous findings (Murofushi et al., 1999). Several factors need to be considered when putting these results in the context of previous work. Firstly, one limitation may be the duration of stimulus used. Previous studies comparing clicks (0.1ms duration) to short-tone bursts (4ms duration) demonstrated a higher response rate using clicks (98%) compared to short-tone bursts (88%) (Cheng, Huang, & Young, 2003). Similar work examining detection rates of the SCM VEMP reported rates as low as 70% (Wang & Young, 2006) using 4ms short-tone bursts, and 80.4% using a logon stimulus (Ozdek, Tulgar, Saylam, Tatar, & Korkmaz, 2009). However, other studies have demonstrated 100% response rates using 0.1ms (Cheng & Murofushi, 2001) and 4ms (Murofushi et al., 1999) tone durations. 47 Therefore, as the response rates vary a significant amount, it appears the duration of the stimulus is not the main determinant needed to explain the response rates observed in this thesis. Significant differences in SCM VEMP response rates have also been observed in a supine position when participants rotate their head to the side or elevate their head during stimulation. Participants in this thesis were all asked to rotate their head, as head elevation was extremely difficult to keep constant for the entire trial, which was limited by a slower stimulation rate (total time ~3min). This highlights a limitation to this study as previous work has demonstrated higher detection rates with head elevation (89-100%) in comparison to head rotation (80-85%) (Ozdek et al., 2009; Wang & Young, 2006). However, this may not always be the case, as another study using head rotation observed a 100% detection rate of the SCM VEMP (Murofushi et al., 1999). Due to the variability in the literature concerning SCM VEMP detection rates during head rotation, it is unlikely this factor solely accounts for the lower detection rates observed in this thesis and therefore other factors must be considered. Another factor that may have contributed to the lower detection rates observed in this thesis was the amplitude of SCM contraction. As the amplitude of the background contraction is linearly related to the response amplitude (Eleftheriadou & Koudounarakis, 2011), a comparison of the average peak-to-peak amplitude may give insight into whether a lack of background activity contributed to the lower response rate. Peak-to-peak amplitudes of the SCM VEMP were highly variable in this thesis, 81±48 µV and 142±63µV for the SCI and AB group, respectively. Unfortunately no measure (MVC) was collected to standardize these values; however, the peak-to-peak amplitude raw average values are in line with those reported in previous work, showing a mean of 109.3µV and a minimum of 52.1µV (Wang & Young, 2006). Despite this similarity, no 48 strong conclusions can be drawn from the comparison between studies as these are raw values and a host of variables may alter the amplitude of the EMG signal. The rate of stimulus delivery may have also limited the detection rate of the SCM VEMP. Previous studies have used a stimulus delivery rate of 5Hz (Cheng et al., 2003; Cheng & Murofushi, 2001; Murofushi et al., 1999; Wang & Young, 2006) and this rate has been recommended as optimal in a recent review (Eleftheriadou & Koudounarakis, 2011). Conversely, this thesis used an interstimulus interval of 0.2-1.8s, resulting in a trial time of ~3mins. This delivery rate was used to match the only previous study examining lower limb VEMPs in a supine position (Luxon, 2013) and to avoid possible mechanical perturbations at the lower leg. As a longer trial may result in fatigue to the SCM muscle, this limitation, in conjunction with the tone duration and head rotation method, may account for the decreased detection rate. 4.3.2 Soleus responses Determining the integrity of the vestibulospinal pathway to the lower legs in persons with a motor-complete SCI at or above T12 is one of the main findings of this thesis. This finding confirms my hypothesis that VEMPs are a viable technique for this purpose; however, I was not able to support my second hypothesis that responses would be delayed as the lack of consistent responses prevented a statistical comparison. Due to the nature of most vestibulospinal stimulations, no previous studies to my knowledge have been able to observe vestibulospinal responses in a muscle below the level of injury that could not be innervated by more rostral segments in persons with a motor-complete SCI. For instance, GVS responses are not able to be readily observed in persons not performing a balancing task, such as standing (Britton et al., 1993; Fitzpatrick & Day, 2004). When working 49 with persons with SCI this is an unavoidable reality. Using VEMPs I have been able to observe responses in the lower leg in response to 4ms short-tone bursts. A limitation to VEMPs can be observed in the frequency of SOL responses in the AB group. Assuming an intact vestibulospinal system, one would expect a much higher detection rate in the AB group. While a less than perfect detection rate in the AB group is expected, with previous studies detecting VEMPs in the lower leg in 6 of 8 muscles (Watson & Colebatch, 1998), 18 of 22 muscles (Rudisill & Hain, 2008), and 15 of 20 muscles (Luxon, 2013), the detection rate of the AB group in this thesis was lower, at 7 of 12 muscles (4 participants excluded based on lack of SCM VEMP). The duration of the tone may be one explanation for the differences between studies, as a variety of tone durations were used in these 3 other experiments, with 0.1ms, 18ms, and 7ms being used, respectively. Another difference is that of these 3 experiments, only 1 delivered the short-tone bursts in a supine position (Luxon, 2013). Therefore, a combination of being in a supine position and using a 4ms tone may have decreased the VEMP detection rate in the lower leg. While 15 of 20 muscles (Luxon, 2013) is slightly better than 7 of 12, the inability of this method to detect responses in 100% of the AB group in a supine position highlights a major limitation in its use as a clinical tool for persons with SCI as there may be some false negatives in the SCI group. The paucity of responses in both the AB and SCI group (4 of 26 muscles) highlight the need to further refine this technique in an AB population before extrapolating to a clinical population. However, as some SOL VEMPs were seen in the SCI group, the results from this thesis provide encouraging evidence to support this technique as a viable method to determine vestibulospinal integrity in persons with SCI. Another limitation to the SOL VEMPs observed in this thesis is the variability in response latency. Previous studies examining VEMPs in the lower leg report latencies of 50 49±9.1ms in SOL (Watson & Colebatch, 1998) and 49.5±2.7ms in MG (Rudisill & Hain, 2008). These responses are faster than those reported in the AB (84.6±7.9ms) and SCI (84.4±19.5ms) groups in this thesis, as well as those reported in response to GVS (Dakin et al., 2007; Fitzpatrick & Day, 2004; Son et al., 2008). In contrast, VEMPs recorded in the lower leg while participants are in a supine position were reported to be longer and more variable in response to 40ms (103.1±15.5ms) and 7ms (92.1±14.7ms) tones (Luxon, 2013). Therefore, placing participants in an upright position may decrease the mean latency and the variability of the SOL VEMP. Interestingly, SOL VEMPs were observed in the 3 persons with motor-complete SCI in the absence of observable background activity. In AB persons, responses are not readily observable without significant background activity (Watson & Colebatch, 1998). Therefore, it may be that the level of activation at the muscle (for example, the recorded response in the electrodes) is not the activation needed in order to elicit the VEMP. It may be that attempted volitional contraction activates the vestibular cell bodies via descending corticobulbar pathways in order to bring them closer to threshold and allow a larger descending volley down the spinal cord. (Fukushima, 1997; Keizer & Kuypers, 1984, 1989). 4.4 Subclinical assessments 4.4.1 Plantar withdrawal reflex The results from this thesis were not able to shed any light on the nature of subclinical assessments. The original hypothesis, that preserved neural pathways would predict the presence of subclinical features, could not be supported. This was due to an inability to replicate the suppression effect observed in previous studies (Cioni et al., 1986; McKay et al., 2004). While this was the first study to randomize the order of suppression and rest trials, there was no effect 51 of suppression or of habituation when examining the data for trial number as opposed to task. One major limitation to this study was that persons with an SCI were neither taken off baclofen, an anti-spasticity medicine, nor had their dose reduced. It is documented baclofen reduces neuronal excitability, likely through its effect on sub-cortical GABA-B receptors (Barry, Bunday, Chen, & Perez, 2013). A decrease in neuronal excitability may therefore have contributed to the lack of plantar reflex responses, as well as TMS MEPs and VEMPs observed in this thesis. 4.5 Implications for classification and rehabilitation The primary findings from this thesis, namely, the detection of preserved muscle activity below the level of injury in persons with a motor-complete SCI in two different motor pathways, have important implications for clinicians working in their respective fields. The detection of preserved motor pathways following an SCI is crucial to determine any remaining motor capabilities and the current ISNCSCI is not able to detect this minimal level of function (Kirshblum, Burns, et al., 2011). Due to the inability of the current clinical exam to detect minimal levels of preservation, preserved neurons crossing the level of the lesion and innervating muscle tissue may go unused, resulting in muscle atrophy. Conversely, being able to determine the full extent of motor preservation following an injury may provide a method to better target rehabilitation to those muscles which still hold their neural connection to various brain or brainstem centres. The observed abdominal muscle preservation in this thesis confirms previous findings (Bjerkefors et al., 2009; Bjerkefors et al., 2007; Bjerkefors et al., in prep; Bjerkefors & Thorstensson, 2006; Ellaway et al., 2007), highlighting the inaccuracy of determining motor 52 levels from sensory levels in the thoracic segments and emphasizing the need to include a trunk assessment in the current ISNCSCI. Further rigorous design of a controlled trunk assessment is needed in order to provide both persons with SCI and clinicians more information about the state of the abdominal musculature. Unlike previous studies which only examined preserved muscle activation in abdominal muscles (Bjerkefors et al., in prep) or limb muscles (Calancie et al., 1999) this study examined preserved muscle activation in both. It appears the inaccuracy of the ISNCSCI is not limited to the thoracic segments, as the results from this thesis demonstrate that persons with low-thoracic injuries may show activation of SAR, RF, and even SOL and TA in one case. Therefore, this thesis has provided evidence that it may be possible for both the lateral and anterior corticospinal pathways to be preserved following a motor-complete SCI. While the current data cannot determine which one may or may not be present in a given individual, some participants showed preservation of both abdominal and leg muscle function while others showed only abdominal muscle function, suggesting in some both pathways may be spared, while in others the lateral pathway may be completely destroyed. This is not surprising due to the more medial location of the anterior pathway in the cord, making it less likely to be damaged from a crush injury. Ultimately, clinical classification of SCI using the ISNCSCI may not be sensitive enough to detect underlying neural preservation and therefore, when possible, more sensitive neurophysiological methods should be used to detect minimal levels of motor activity. Based on the findings of this thesis and the current state of the literature it is recommended that, when possible and in combination with the ISNCSCI, TMS should be used with EMG recordings to determine minimal levels of motor activity. If TMS is not readily accessible or not able to be conducted due to exclusion criteria, surface EMG should be used to 53 measure voluntary muscle activation with an MVC. If neither of these techniques are available clinicians should, at the very least, attempt to determine the level of abdominal muscle activity remaining after injury using palpation (Bjerkefors et al., in prep). While determining the level of abdominal muscle activity may currently be somewhat subjective, future studies should attempt to standardize an easily accessible method to determine the level of motor preservation in the abdominal muscles. Correctly determining the amount and nature of neural preservation to muscles below the injury may also have important implications from a rehabilitation perspective. Previous work has shown that following rigorous rehabilitation on a kayak ergometer, persons with high-thoracic motor-complete SCI show improvements in sitting trunk stability, upper body coordination and functional performance (Bjerkefors et al., 2007; Bjerkefors & Thorstensson, 2006). While the mechanisms for this improvement can only be speculative, increases in neural drive through the anterior corticospinal tract and/or other motor pathways, past the lesion, may contribute to the observed improvements. This increased activation may then re-activate denervated and/or atrophied musculature. Furthermore, previous evidence demonstrating improvements in over-ground stepping abilities of persons with motor-complete SCI (Behrman & Harkema, 2000; Manella et al., 2010; McDonald et al., 2002; Murillo et al., 2012) may also be due, in part, to preserved corticospinal, vestibulospinal, and/or reticulospinal pathways to the musculature of the lower leg. These motor pathways have been extensively studied to determine their role in both maintaining upright stance through extensor activity (Matsuyama & Drew, 2000a) and in gait (Armstrong, 1986; Drew, Jiang, & Widajewicz, 2002; Matsuyama & Drew, 2000a, 2000b); however, their exact individual contributions are still debated. Therefore, when considering 54 rehabilitation for sitting posture, or gait, it is beneficial to know the extent of preservation of various motor pathways in order to better determine the potential for improvement. 4.6 Future directions There may be more advanced neurophysiological techniques to increase the excitability of the primary motor cortex and/or the spinal motor neuron pool in order to further reduce false negatives. For example, paired pulse stimulation has been demonstrated to produce intracortical facilitation if a subthreshold conditioning stimulus is delivered 6-25ms prior to the test stimulus, thereby increasing the amplitude of the MEP (Kujirai et al., 1993; Reis et al., 2008). Also, strengthening the synaptic transmission between the corticospinal tract and the lower motor neuron using a paradigm called spike timing-dependent plasticity may decrease any false negatives and possibly have beneficial functional consequences in persons with SCI (Bunday & Perez, 2012). Furthermore, some studies have used various sensory conditioning methods in an attempt to detect more subtle levels of preserved neural pathways (Hayes et al., 1991; Wolfe et al., 1996), methods which may be further refined and explored in future studies. TMS in conjunction with surface EMG has proven to be a valuable tool to provide a sensitive measure of neural preservation in persons with motor-complete SCI. However, TMS demands a time consuming procedure and may be difficult to conduct on persons following an SCI due to the strict exclusion criteria, some of which are commonly associated with SCI. Therefore, further studies are needed to determine more optimal ways of using MVCs and surface EMG to detect minimal levels of preserved motor activity as previous evidence shows this method may be more accurate than other non-invasive measures such as ultrasound (Bjerkefors et al., in prep). Measuring muscle activation with surface EMG in response to an 55 MVC provides a method that is non-invasive, less time-consuming, and with little to no exclusion criteria. However, as demonstrated in this thesis, it may not be as sensitive in its ability to determine minimal levels of motor activity compared to using TMS. Therefore, more rigorous experimental protocols should be designed to increase the sensitivity of this promising method. In addition to building on previous work using TMS and MVC to measure preserved muscle activity, this thesis provides the first experimental method to determine preservation of the vestibulospinal pathway in persons with a motor-complete SCI. While this is a strong first step in creating a more comprehensive neurophysiological assessment of motor pathways following an SCI, there are still necessary improvements to be made. For instance, VEMP responses in the lower leg cannot be detected all of the time in AB controls. Therefore, there is a need to improve the experimental methods of short-tone bursts so responses may be detected with more precision in AB controls. Improvements may include more optimal leg positions for activation of SOL and an increased delivery rate to reduce fatigue. Leg positions may be limited as persons with SCI cannot lie in certain positions but sitting up or being held up in a standing position may be possibilities. In addition, there is evidence that short-tone bursts may be delivered at rates of 5Hz or above (Rosengren, Welgampola, & Colebatch, 2010). This would reduce both central and muscle fatigue in AB persons and in persons with SCI. Using a longer tone may also increase the detection rate in SOL as previous work has demonstrated that 40ms tones are able to elicit responses in the SOL more readily (20 of 20) compared to 7ms tones (15 of 20) in a supine position (Luxon, 2013). In addition to improving the detection rate of vestibulospinal stimulation, future studies may also attempt to develop techniques to stimulate the reticulospinal pathway. While previous evidence has shown short-tone bursts preferentially activate the vestibular system (Kushiro et al., 56 2008; Murofushi et al., 1999; Sato et al., 1997), the results from this study cannot rule out indirect activation of the reticulospinal pathway via collaterals coming from the vestibular nuclei (Bolton et al., 1992). Therefore, future research might attempt to develop techniques to preferentially stimulate the vestibulospinal or reticulospinal pathways in isolation. Then, it may be possible to determine the individual integrities of the 3 main motor pathways to the lower leg. Targeting the abdominal musculature in rehabilitation may provide a good avenue to increase quality of life as well as mobility and stability functional outcomes. There is evidence to support improvements in sitting posture in both motor-complete and incomplete SCI as well as in high-thoracic and in low-thoracic injuries. While the mechanism is currently unclear, and may involve the corticospinal pathway, the vestibulospinal and/or reticulospinal pathways may also be contributing to unconscious aspects of sitting postural control. Therefore, using short-tone bursts, it may be possible to determine the preservation of these motor pathways to the abdominal muscles and thus provide a more comprehensive understanding of the motor innervation to the abdominal muscles in persons with an SCI and also better predict functional outcomes following rehabilitation. 4.7 Conclusions Despite being clinically classified with a motor-complete SCI above the T12 level, persons with SCI showed observable muscle activity below the injury level to cortico- and/or vestibulospinal stimulation. Overall, the results from this thesis provide evidence for the use of TMS and VEMPs to assist in determining the neurophysiological integrity of various motor pathways in persons with a motor-complete SCI. Using these techniques may provide clinicians 57 with more accurate information about the state of various motor pathways and may offer a method to more accurately target rehabilitation.58 Table 1 Detailed description of the participants with SCI Participant Age Height (m) Gender Years post injury NLI Sensory score LEMS AIS ZPP R & L Pin prick Light touch Traumatic Injury Spasticity Neg. Impact on ADL Medication SCI1 37 1.70 M 7 C4 12 13 0 A C5/C4 Yes Yes No Yes SCI2 27 1.61 F 5.5 C5 67 66 0 B - Yes Yes No Yes SCI3 55 1.78 M 13 C5 10 24 0 B - Yes Yes No No SCI4 36 1.73 M 10 C6 - - - A - Yes No No No SCI5 43 1.65 F 19 C7 28 40 0 B - Yes Yes Yes No SCI6 27 1.65 M 3 C8 28 33 0 B - Yes Yes No Yes SCI7 51 1.70 F 30 T3 50 68 0 B - Yes Yes No Yes SCI8 38 1.72 M 1.5 T3 42 43 0 A T4/T5 Yes No No No SCI9 70 1.73 M 16 T5 48 49 0 A T6/T5 Yes Yes No No SCI10 66 1.84 M 27 T5 48 54 0 A T7/T6 Yes Yes No No SCI11 44 1.83 M 25 T8 61 61 0 A T9/T9 Yes Yes No No SCI12 31 1.63 F 1 T10 66 67 0 A T11/T10 Yes Yes Yes Yes SCI13 53 1.83 M 29 T10 - - - A - Yes Yes No No SCI14 46 1.65 M 26 T10 74 78 2 A L3/L2 Yes Yes No Yes SCI15 48 1.79 M 28 T11 74 77 0 A L2/L1 Yes No No No SCI16 24 1.77 M 6 T12 77 79 1 A L1/L1 Yes Yes No No 59 Table 2 Frequency of MEPs in response to TMS. The number of detectable MEPs was determined for each muscle. If a participant had 5 or more detectable MEPs out of 10 the response in that muscle was determined as “present” and included in subsequent analysis. Muscles with 1-4 detectable MEPs were defined as “inconsistent”. Note: Trunk muscle responses in individuals with injuries below T5 are separated as they were not included in the averages for the latency analysis due to their injury being below the level of abdominal muscle innervation. Participant AIS Injury Level Trunk (T6-T12) SAR (L2) RF (L3) TA (L4) EH (L5) SOL (S1) OE TrA L R L R L R L R L R SCI1 A C4 5+ SCI2 B C5 SCI3 B C5 5+ 2 5+ 3 SCI4 A C6 5+ 5+ 3 1 SCI5 B C7 5+ 4 SCI6 B C8 5+ 5+ 3 4 1 SCI7 B T3 1 5+ 5+ 3 3 SCI8 A T3 5+ SCI9 A T5 3 3 1 SCI10 A T5 5+ 3 2 SCI11 A T8 5+ 5+ 4 5+ 1 SCI12 A T10 5+ 5+ 3 4 SCI13 A T10 5+ 5+ 5+ 5+ 5+ 5+ 1 1 SCI14 A T10 5+ 5+ 5+ 5+ 3 5+ 5+ 5+ SCI15 A T11 5+ 5+ 5+ 5+ SCI16 A T12 5+ 5+ 5+ 5+ 5+ 4 2 60 Table 3 Absolute onset latencies of MEPs elicited by TMS. Values are means ± standard deviation. “n” indicates the number of muscles with MEP responses defined as “present” in at least 5 out of 10 trials. Note: The dashed lines indicate no responses to TMS recorded for the muscle. *denotes significance with α=0.05 and Bonferonni correction. †Left=OE, Right=TrA as only Trunk Rotation to the RIGHT was performed. Left Side Right Side Collapsed SCI AB SCI AB SCI AB n Latency (ms) n Latency (ms) n Latency (ms) n Latency (ms) n Latency (ms) Latency (ms) MD ± SE p-value OE/TrA† 7 21.9 ± 3.2 16 20.9 ± 2.1 3 22.9 ± 1.8 16 21.0 ± 2.6 10 22.8 ± 3.2 20.8 ± 2.2 2.0 ± 1.0 0.07 SAR 5 27.2 ± 9.2 16 23.1 ± 2.0 6 26.6 ± 5.3 16 22.7 ± 2.6 11 26.9 ± 7.0 23.5 ± 2.9 3.4 ± 2.3 0.168 RF 2 30.1 ± 12.7 16 23.0 ± 1.6 2 30.2 ± 18.3 16 23.1 ± 1.9 4 30.2 ± 7.4 23.4 ± 1.4 6.8 ± 3.7 0.166 TA 0 16 37.9 ± 3.3 1 48.3 16 38.6 ± 4.3 1 48.3 33.3 EH 0 16 45.6 ± 3.9 0 16 45.0 ± 3.3 0 SOL 0 16 34.1 ± 2.6 1 46.3 16 33.9 ± 2.1 1 46.3 36.8 61 Table 4 Frequency of MEPs and responses to MVC in persons with SCI. Participants were given a “T” if the participants’ MEP response was defined as present and a “V” was given if the participants MVC response was defined as present. Note: Trunk muscle responses in individuals with injuries below T5 are separated as they were not included in the averages for the latency analysis due to their injury being below the level of abdominal muscle innervation. Participant AIS Injury Level Trunk (T6-T12) SAR (L2) RF (L3) TA (L4) EH (L5) SOL (S1) OE TrA L R L R L R L R L R SCI1 A C4 T SCI2 B C5 SCI3 B C5 T T SCI4 A C6 T T SCI5 B C7 T SCI6 B C8 T T SCI7 B T3 V T,V T,V SCI8 A T3 T SCI9 A T5 SCI10 A T5 T SCI11 A T8 T T,V T SCI12 A T10 T,V T,V SCI13 A T10 T T,V T,V T,V T T SCI14 A T10 T,V T,V T,V T,V T,V T,V T,V SCI15 A T11 T,V T,V T,V T,V SCI16 A T12 T,V T,V T,V T,V T 62 Figure 1 Experimental setup. Participants lay supine on a plinth. TMS was applied with a double cone coil above the leg area of the primary motor cortex. EMG was recorded from bilateral SAR, BF, RF, TA, SOL, MG, EH and unilaterally from TrA and OE. 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Exp Brain Res, 175(1), 191-195. doi: 10.1007/s00221-006-0688-z 83 Appendices Appendix A - ISNCSCI Exam Details 84 Appendix B - ISNCSCI Exam Worksheet 85 Appendix C - Pilot Data Individual subject responses to left hemisphere TMS (figure eight coil, 10mm diameter) over the trunk area of primary motor cortex for participants with an SCI and a representative Control. Responses were recorded in the contralateral rectus femoris during sub-maximal trunk bending. Present responses can be seen in SCI 3, SCI 4, and SCI5. The first vertical line denotes the stimulation onset and the second the average response onset.
Thesis/Dissertation
eng
Kinesiology
Vancouver : University of British Columbia Library
Attribution-NonCommercial-NoDerivs 2.5 Canada
Graduate
Examination of preserved motor pathways in persons with motor-complete spinal cord injury
Text