Progress in brain research, volume 218

Serial Editor

Vincent Walsh
Institute of Cognitive Neuroscience
University College London
17 Queen Square
London WC1N 3AR UK


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ISBN: 978-0-444-63565-5
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Contributors
Joseph Alarcon
Biophotonics and Bioengineering Laboratory, Department of Electrical and
Computer Engineering, Ryerson University, Toronto, ON, Canada
Olivier Alluin
Department of Neuroscience and Groupe de Recherche sur le Syste`me Nerveux
Central (GRSNC), Faculty of Medicine, Universite´ de Montre´al, and SensoriMotor
Rehabilitation Research Team of the Canadian Institute of Health Research,
Montreal, Quebec, Canada
Lea Awai
€rich, Switzerland
Spinal Cord Injury Center, Balgrist University Hospital, Zu
Stuart N. Baker
Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
Dorothy Barthe´lemy
School of Rehabilitation, Universite´ de Montre´al, and Centre for Interdisciplinary
Research in Rehabilitation of Greater Montreal, Institut de re´adaptation GingrasLindsay de Montre´al, SensoriMotor Rehabilitation Research Team of the
Canadian Institute of Health Research, Montreal, Canada
Fin Biering-Sørensen
Clinics for Spinal Cord Injuries, Rigshospitalet and Glostrup hospital, Hornbæk,

Denmark
Kathrin B€
osl
HELIOS Klinik Kipfenberg, Kipfenberg, Germany
David W. Cadotte
Division of Neurosurgery, Department of Surgery, Faculty of Medicine, University
of Toronto, and Toronto Western Hospital, University Health Network, Toronto,
ON, Canada
Jaehoon Choe
Departments of Integrative Biology and Physiology, and Department of
Neuroscience, University of California, Los Angeles, CA, USA
Julien Cohen-Adad
Institute of Biomedical Engineering, Ecole Polytechnique de Montre´al,
SensoriMotor Rehabilitation Research Team of the Canadian Institute of Health
Research, Montreal, QC, Canada
Dale Corbett
Heart & Stroke Foundation Canadian Partnership for Stroke Recovery and
Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa,
Canada

v


vi

Contributors

Armin Curt
€rich, Switzerland
Spinal Cord Injury Center, Balgrist University Hospital, Zu

Numa Dancause
De´partement de Neurosciences, and Groupe de Recherche sur le Syste`me
Nerveux Central (GRSNC), Faculty of Medicine, SensoriMotor Rehabilitation
Research Team of the Canadian Institute of Health Research, Universite´ de
Montre´al, Montre´al, QC, Canada
Hugo Delivet-Mongrain
Department of Neuroscience and Groupe de Recherche sur le Syste`me Nerveux
Central (GRSNC), Faculty of Medicine, Universite´ de Montre´al, Montreal,
Quebec, Canada
V. Reggie Edgerton
Departments of Integrative Biology and Physiology; Department of Neurobiology;
Department of Neurosurgery, and Brain Research Institute, University of
California, Los Angeles, CA, USA
Steve A. Edgley
Department of Physiology, Development and Neuroscience, Cambridge
University, Cambridge, UK
Manuel Escalona
Department of Neuroscience and Groupe de Recherche sur le Syste`me Nerveux
Central (GRSNC), Faculty of Medicine, Universite´ de Montre´al, Montreal,
Quebec, Canada
Hamza Farooq
Biophotonics and Bioengineering Laboratory, Department of Electrical and
Computer Engineering, Ryerson University, Toronto, ON, Canada
James W. Fawcett
Department of Clinical Neuroscience, John van Geest Centre for Brain Repair,
University of Cambridge, Robinson Way, CA, UK
Michael G. Fehlings
Department of Genetics and Development, Toronto Western Research Institute,
Toronto Western Hospital, University Health Network, Division of Neurosurgery,
Department of Surgery, Faculty of Medicine, Institute of Medical Sciences,

University of Toronto, Toronto, ON, Canada
Eberhard E. Fetz
Department of Physiology and Biophysics, Washington National Primate
Research Center, University of Washington, Seattle, WA, USA
Edelle C. Field-Fote
Crawford Research Institute, Shepherd Center, Atlanta, GA, USA
Karen M. Fisher
Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK


Contributors

Joyce Fung
School of Physical and Occupational Therapy, McGill University, Montreal;
Feil/Oberfeld Research Centre, Jewish Rehabilitation Hospital, Laval, and
Montreal Centre for Interdisciplinary Research in Rehabilitation (CRIR),
SensoriMotor Rehabilitation Research Team of the Canadian Institute of Health
Research, Montreal, Quebec, Canada
Parag Gad
Departments of Integrative Biology and Physiology, University of California,
Los Angeles, CA, USA
Helen Genis
Biophotonics and Bioengineering Laboratory, Department of Electrical and
Computer Engineering, Ryerson University, Toronto, ON, Canada
Yury Gerasimenko
Departments of Integrative Biology and Physiology, University of California,
Los Angeles, CA, USA; Pavlov Institute of Physiology, St. Petersburg, and Institute
of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
Mariana Gomez-Smith
Faculty of Medicine, and Canadian Partnership for Stroke Recovery, University of

Ottawa, Ottawa, Ontario, Canada
Monica A. Gorassini
Department of Biomedical Engineering; Faculty of Medicine and Dentistry, and
Neuroscience and Mental Health Institute, University of Alberta, Edmonton,
Alberta, Canada
Jean-Pierre Gossard
Department of Neuroscience and Groupe de Recherche sur le Syste`me Nerveux
Central (GRSNC), Faculty of Medicine, Universite´ de Montre´al, and SensoriMotor
Rehabilitation Research Team of the Canadian Institute of Health Research,
Montreal, Quebec, Canada
Matthew Jeffers
Faculty of Medicine, and Canadian Partnership for Stroke Recovery, University of
Ottawa, Ottawa, Ontario, Canada
Jamil Jivraj
Biophotonics and Bioengineering Laboratory, Department of Electrical and
Computer Engineering, Ryerson University, Toronto, ON, Canada
Dorsa Beroukhim Kay
Division of Biokinesiology and Physical Therapy, Ostrow School of Dentistry, and
Neuroscience Graduate Program, University of Southern California, Los Angeles,
CA, USA
Mohamad Khazaei
Department of Genetics and Development, Toronto Western Research Institute,
University Health Network, Toronto, Ontario, Canada

vii


viii

Contributors

Aritra Kundu
Department of Neuroscience and Groupe de Recherche sur le Syste`me Nerveux
Central (GRSNC), Faculty of Medicine, Universite´ de Montre´al, Montreal,
Quebec, Canada
Anouk Lamontagne
School of Physical and Occupational Therapy, McGill University, Montreal;
Feil/Oberfeld Research Centre, Jewish Rehabilitation Hospital, Laval, and
Montreal Centre for Interdisciplinary Research in Rehabilitation (CRIR),
SensoriMotor Rehabilitation Research Team of the Canadian Institute of Health
Research, Montreal, Quebec, Canada
Jessica Livingston-Thomas
Faculty of Medicine, and Canadian Partnership for Stroke Recovery, University of
Ottawa, Ottawa, Ontario, Canada
Jitka L€
udemann-Podubecka´
HELIOS Klinik Kipfenberg, Kipfenberg, Germany
Henrik Lundell
Department of Exercise and Sport Sciences; Department of Neuroscience and
Pharmacology, University of Copenhagen, Copenhagen, and Danish Research
Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging
and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
Francine Malouin
Faculty of Medicine, Department of Rehabilitation, Universite´ Laval; Centre
interdisciplinaire de recherche en re´adaptation et inte´gration sociale (CIRRIS),
Institut de re´adaptation en de´ficience physique de Que´bec (IRDPQ), and
SensoriMotor Rehabilitation Research Team of the Canadian Institute of Health
Research, Quebec, Canada
Babak K. Mansoori
De´partement de Biologie mole´culaire, Biochimie me´dicale et pathologie,

Universite´ Laval, Que´bec, QC, Canada
Marina Martinez
Department of Neuroscience and Groupe de Recherche sur le Syste`me Nerveux
Central (GRSNC), Faculty of Medicine, Universite´ de Montre´al, and SensoriMotor
Rehabilitation Research Team of the Canadian Institute of Health Research,
Montreal, Quebec, Canada
Sylvie Nadeau

Ecole
de re´adaptation, Universite´ de Montre´al, Centre de recherche
interdisciplinaire en re´adaptation de Montre´al me´tropolitain (CRIR), Institut de
re´adaptation Gingras-Lindsay-de-Montre´al (IRGLM), and SensoriMotor
Rehabilitation Research Team of the Canadian Institute of Health Research,
Quebec, Canada
Mandheeraj Singh Nandra
Department of Electrical Engineering, California Institute of Technology,
Pasadena, CA, USA


Contributors

Carine Nguemeni
Faculty of Medicine, and Canadian Partnership for Stroke Recovery, University of
Ottawa, Ottawa, Ontario, Canada
Jens Bo Nielsen
Department of Exercise and Sport Sciences, and Department of Neuroscience
and Pharmacology, University of Copenhagen, Copenhagen, Denmark
Dennis Alexander Nowak
HELIOS Klinik Kipfenberg, Kipfenberg, and Department of Neurology, University
Hospital, Philips University, Marburg, Germany

Carol L. Richards
Faculty of Medicine, Department of Rehabilitation, Universite´ Laval; Centre
interdisciplinaire de recherche en re´adaptation et inte´gration sociale (CIRRIS),
Institut de re´adaptation en de´ficience physique de Que´bec (IRDPQ), and
SensoriMotor Rehabilitation Research Team of the Canadian Institute of Health
Research, Quebec, Canada
Serge Rossignol
Department of Neuroscience and Groupe de Recherche sur le Syste`me Nerveux
Central (GRSNC), Faculty of Medicine, Universite´ de Montre´al, and SensoriMotor
Rehabilitation Research Team of the Canadian Institute of Health Research,
Montreal, Quebec, Canada
Francois D. Roy
Neuroscience and Mental Health Institute; Department of Physical Therapy, and
Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta,
Canada
Roland R. Roy
Departments of Integrative Biology and Physiology, and Brain Research Institute,
University of California, Los Angeles, CA, USA
Samir Sangani
School of Physical and Occupational Therapy, McGill University, Montreal;
Feil/Oberfeld Research Centre, Jewish Rehabilitation Hospital, Laval, and
Montreal Centre for Interdisciplinary Research in Rehabilitation (CRIR),
SensoriMotor Rehabilitation Research Team of the Canadian Institute of Health
Research, Montreal, Quebec, Canada
Ahad M. Siddiqui
Department of Genetics and Development, Toronto Western Research Institute,
University Health Network, Toronto, Ontario, Canada
Demetris S. Soteropoulos
Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
John D. Steeves

ICORD (International Collaboration On Repair Discoveries), Blusson Spinal Cord
Centre, Vancouver General Hospital, University of British Columbia (UBC),
Vancouver, BC, Canada

ix


x

Contributors

Yu-Chong Tai
Department of Electrical Engineering, California Institute of Technology,
Pasadena, CA, USA
Aiko K. Thompson
Department of Health Sciences and Research, College of Health Professions,
Medical University of South Carolina, Charleston, SC, and Helen Hayes Hospital,
NYS Department of Health, West Haverstraw, NY, USA
Boris Touvykine
De´partement de Neurosciences, Pavillon Paul-G-Desmarais, Universite´ de
Montre´al, Montre´al, QC, Canada
Barry Vuong
Biophotonics and Bioengineering Laboratory, Department of Electrical and
Computer Engineering, Ryerson University, Toronto, ON, Canada
Maria Willerslev-Olsen
Department of Exercise and Sport Sciences, and Department of Neuroscience
and Pharmacology, University of Copenhagen, Copenhagen, Denmark
Carolee J. Winstein
Division of Biokinesiology and Physical Therapy, Ostrow School of Dentistry;
Department of Neurology, Keck School of Medicine, and Neuroscience Graduate

Program, University of Southern California, Los Angeles, CA, USA
Jonathan R. Wolpaw
National Center for Adaptive Neurotechnologies, Wadsworth Center, NYS
Department of Health, Albany, NY, USA
Jaynie F. Yang
Faculty of Medicine and Dentistry; Department of Surgery, and Neuroscience and
Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada
Victor X.D. Yang
Biophotonics and Bioengineering Laboratory, Department of Electrical and
Computer Engineering, Ryerson University; Physical Science—Brain Sciences
Research Program, Sunnybrook Research Institute; Division of Neurosurgery,
Sunnybrook Health Sciences Centre, and Division of Neurosurgery, Department
of Surgery, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
Boubker Zaaimi
Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
Ephrem T. Zewdie
Department of Biomedical Engineering, and Faculty of Medicine and Dentistry,
University of Alberta, Edmonton, Alberta, Canada
Hui Zhong
Departments of Integrative Biology and Physiology, University of California,
Los Angeles, CA, USA


Preface
This book regroups the proceedings of a Symposium held in May 2014 in Montreal
entitled “Rehabilitation: At the Crossroads of Basic and Clinical Sciences.” This was
the 36th meeting of the Groupe de Recherche sur le Syste`me Nerveux Central funded
by the Fond de la Recherche du Que´bec-Sante´ (FRQ-S) and was jointly organized
with the SensoriMotor Rehabilitation Research Team funded by the Canadian
Institutes for Health Research (CIHR).

The Symposium was designed with two major goals in mind. First, we wanted to
bring together basic and clinical scientists interested in neurorehabilitation. Translational research should design models and conduct experiments that address pressing
clinical questions, while clinical researchers and clinicians integrate new knowledge
to design better treatments and platforms. A continuous dialogue between basic scientists, clinical researchers, and clinicians is necessary for these objectives to be
reached. Second, we wanted a meeting where scientists working on spinal cord injury
(SCI) and on stroke could share recent advances in their respective fields and find
commonality. Although these two fields are often separate in clinical and laboratory
settings, our thoughts were that the mechanisms of recovery following central nervous lesions, in the spinal cord or in the brain, follow similar rules and that emerging
treatments likely do as well. We devoted one day to SCI and one day to stroke recovery. On each day, we designed the sessions to discuss clinical impairments, ongoing clinical trials, the investigation of novel techniques currently being tested in
humans, and finally, potential mechanisms involved in spontaneous recovery and
how they can be best targeted through therapeutic approaches.
From our discussions, it was obvious that the treatments of both SCI and stroke
face important clinical challenges. The translation of findings from clinical research,
and even more from animal research, to patient care is not a trivial task. Despite
the challenges, we have seen great progress over the years. Perhaps most importantly, the infrastructures to handle future changes of practice are much improved.
Clinical research has also been thriving with the improvement of noninvasive imaging techniques and the development of stimulation methods. Both after SCI and
stroke, clinical scientists are developing promising treatments using transcranial
magnetic stimulation, transcranial direct current stimulation, or galvanic
stimulation. Although these are exciting times for neurorehabilitation, many questions remain. Our current understanding of principles of plasticity and mechanisms
of postlesion recovery is far from complete. Much of this knowledge can be more
efficiently and precisely obtained with research on animal models, which allow
better control of confounding factors and the use of invasive techniques and serve
to establish proofs of concepts. In the last decade, basic scientists have increasingly
directed their experiments toward providing complementary information to human
studies. In these animal models, potential treatments of the future, such as neural
prostheses, are conceived, developed, and improved. Our guest Plenary Speaker
(Eberhard E. Fetz) introduced concepts of closed-loop brain–computer interface

xix

xx

Preface

to produce activity-dependent stimulation of the brain, spinal cord, or muscles. Such
methods may eventually be used as therapeutic aids in several conditions and enable
us to further improve the recovery of patients with SCI and stroke.
Whereas basic and clinical research scientists represented two completely isolated populations just a few years ago, our Symposium, as reflected in this collection
of contributions from our speakers, sends the clear message that translation is becoming much more a reality than a vague concept. Our discussions highlighted the
remarkable consistency in the key conclusions between basic and clinical research
as well as between the fields of SCI and stroke. Perhaps the strongest take-home
message was that each individual, either after stroke or SCI, is different. Plasticity
between patients varies with, for example, lesion size and location, initial impairments resulting from the lesion, prelesion lifestyle, and cardiovascular condition
and neuropsychological profiles. In these heterogeneous populations, it is unlikely
that a single treatment will apply to all. Instead, to design better therapies, we need
a clear understanding of the basic mechanisms through which these different factors
affect plasticity and recovery. With this knowledge, perhaps some day, it will be possible to individualize the treatment of each patient based on his or her clinical profile
and surrogate markers of postlesion plasticity. We believe this colossal task will be
achieved through close collaboration between basic and clinical scientists, something that must be nurtured through events such as this symposium.
We wish to acknowledge Manon Dumas and Rene´ Albert of the GRSNC for their
daily implication in the organization of this meeting as well as Claude Gauthier and
Tania Rostane for their support. Many thanks also to reviewers who took the time to
assess the abstracts and to comment on the manuscripts.
Finally, our special thanks to the funding organizations: CIHR, FRQ-S, Rick
Hansen Institute, Wings for Life, Eli Lilly, Institute of Neurosciences and Mental
Health and Addiction of CIHR, the Universite´ de Montre´al, and the Faculty of
Medicine as well as the Quebec Rehabilitation Research Network (REPAR) for
the student poster Awards.
N. Dancause

S. Nadeau
S. Rossignol


CHAPTER

Comprehensive assessment
of walking function after
human spinal cord injury

1

Lea Awai1, Armin Curt
Spinal Cord Injury Center, Balgrist University Hospital, Z€
urich, Switzerland
1
Corresponding author: Tel.:+41-44-386-37-34; Fax: +41-44-386-37-31,
e-mail address:

Abstract
Regaining any locomotor function after spinal cord injury is not only of immediate importance
for affected patients but also for clinical research as it allows to investigate mechanisms underlying motor impairment and locomotor recovery. Clinical scores inform on functional outcomes that are clinically meaningful to value effects of therapy while they all lack the ability to
explain underlying mechanisms of recovery. For this purpose, more elaborate recordings of
walking kinematics combined with assessments of spinal cord conductivity and muscle activation patterns are required. A comprehensive assessment framework comprising of multiple
complementary modalities is necessary. This will not only allow for capturing even subtle
changes induced by interventions that are likely missed by standard clinical outcome measures. It will be fundamental to attribute observed changes to naturally occurring spontaneous
recovery in contrast to specific changes induced by novel therapeutic interventions beyond the
improvements achieved by conventional therapy.

Keywords

spinal cord injury, motor, walking, function, recovery, outcome measures, human

1 INTRODUCTION
In incomplete spinal cord injury (iSCI), walking is characterized by manifold complex alterations like a slower than normal speed (Awai and Curt, 2014; Pepin et al.,
2003), limited hip and knee flexion during swing (Perry and Burnfield, 2010), insufficient hip extension during stance, and excessive plantar flexion during swing (van
der Salm et al., 2005). These observed impairments of joint and limb movements
could be based on different underlying mechanisms such as limitations in hip flexion
during swing phase that were attributed to muscle weakness, while the reduced knee
flexion during swing was related to aberrant coactivation of antagonistic extensor
Progress in Brain Research, Volume 218, ISSN 0079-6123, />© 2015 Elsevier B.V. All rights reserved.

1


CHAPTER 1 Walking after SCI

Linear measures

muscles (Ditunno and Scivoletto, 2009). Thus, a multimodal and comprehensive approach to study normal and altered gait and its recovery is required for elucidating
underlying mechanisms of gait control.
The majority of clinical studies that monitor recovery processes or training effects during different interventions after spinal cord injury (SCI) chose measures
of walking performance (i.e., walking speed/distance) and functional independence
(e.g., type of required assistive device, performance during activities of daily living)
to reflect motor function (Fig. 1). However, “motor function” and “walking function”
are ill-defined terms as they rather nonspecifically refer to different aspects of gait
(i.e., speed and time-distance parameters, type of walking assistance), while such

• Mobility
• Type of assistive device

Subjective gait quality

Ordinal and discrete
measures

• Time [s]
• Distance [m]

Ordinal and subjective
measures

2

FIGURE 1
Measures of time and distance objectively assess the walking capacity or performance of
a person and represent continuous data. They are often used to monitor recovery of
walking function during rehabilitation or interventions. Clinical scores (e.g., walking index
for spinal cord injury (WISCI), spinal cord independence measure (SCIM)) assess the mobility
of a person (i.e., what type of assistive device does a person rely on, how well can a person
perform activities of daily living) and were often developed for a specific type of subjects (i.e.,
spinal cord injured patients, stroke patients). They are ordinal values assessed at discrete
time points. Gait quality is commonly assessed via subjective observation by trained persons
in a descriptive manner. The quality may then be scored and represented by an ordinal value.


2 Clinical assessments of recovery

outcomes may not be well compared across studies and remain nonconclusive at
explaining mechanisms of recovery. Even the examination of highly selected measures (e.g., changes in single joint angles), although presenting very concise information, is likely limited at elucidating underlying complex interactions. In order
to acquire more comprehensive evaluations to address questions of physiological

gait control as well as observed alterations and recovery profiles in iSCI, combined
multimodal assessments are required. Especially in high risk and potentially highreturn clinical trials (phase I/II studies), investigators should consider any possible
efforts to search for complementary information (including surrogate markers) beyond standard clinical outcome measures. These readouts may reveal more detailed
insights into different mechanisms of action that eventually may be important to
identify effects evoked by specific interventions (i.e., obvious as well as clinically
masked changes).

2 CLINICAL ASSESSMENTS OF RECOVERY
2.1 NEUROLOGICAL ASSESSMENTS
The completeness of lesion (i.e., the preservation of sensory function below the level
of lesion) is crucial for the clinical description and prediction of ambulatory outcome
(Maynard et al., 1979; Waters et al., 1994). Patients who are ASIA A early after injury have little chance of regaining functional ambulation, while ASIA B patients
may reach a functional level (Crozier et al., 1992; Maynard et al., 1979; Waters
et al., 1994). However, it is commonly accepted that the ASIA classification is
too crude to reveal functional changes (i.e., improved walking ability) that may occur
within one ASIA grade (i.e., ASIA D patients may increase walking speed and muscle strength without a conversion in ASIA grade).
For a general evaluation of motor function, the assessment of ASIA motor scores
as well as the spinal cord independence measure III (SCIM III) was strongly recommended (Labruyere et al., 2010). Even though the lower extremity motor scores
(LEMS) are assessed in a lying position while the respective muscles are activated
in a nontask specific manner (i.e., not during locomotion), LEMS were shown to be a
good predictor for ambulatory outcome after rehabilitation (van Middendorp et al.,
2011; Zorner et al., 2010). Furthermore, the LEMS of both legs were found to correlate best with walking speed, distance, and ambulatory capacity in chronic iSCI
subjects compared to unilateral LEMS of the individual lower limb muscles (Kim
et al., 2004). Thus, muscle strength seems to be an important determinant for walking
performance (speed and distance) but may not have an influence on movement quality. It was shown that iSCI patients have preserved movement accuracy in the lower
limbs despite diminished muscle strength, which distinguished them from stroke patients. The latter showed both diminished muscle strength in the affected leg as well
as bilaterally impaired movement accuracy (van Hedel et al., 2010), suggesting that
movement accuracy may not be corrupted by muscle weakness in iSCI.

3

4

CHAPTER 1 Walking after SCI

2.2 FUNCTIONAL ASSESSMENTS
The SCIM was developed as a scale to score disability in patients with SCI (Catz
et al., 1997). In acute patients, the SCIM III was evaluated to have the most appropriate performance with respect to specific psychometric properties (i.e., reliability,
validity, reproducibility, responsiveness) when compared to other measures such as
Functional Independence Measure, Walking Index for Spinal Cord Injury (WISCI),
Modified Barthel Index, Timed Up & Go, 6-minute walk test (6MinWT), or
10-meter walk test (10MWT) (Furlan et al., 2011). Compared to measures of walking
capacity (i.e., speed, WISCI), the SCIM also assesses improvements in ASIA A and
B patients who are wheelchair bound (van Hedel and Dietz, 2009). Depending on the
aim of a study, the appropriate outcome measures should be chosen. If walking function and its recovery are to be investigated and the question of whether or not patients
improve locomotor function and by what means they might improve their walking
capacity, the SCIM score might not be a sensitive tool while it does inform on to what
extent a patient can perform activities of daily living independent of aids or support
from third parties.
Recovery of walking function is routinely assessed by functional outcome measures such as the widely used 10MWT and 6MinWT (Alcobendas-Maestro et al.,
2012; Buehner et al., 2012; Hayes et al., 2014; Jayaraman et al., 2013; Kim et al.,
2004; Kumru et al., 2013; Petersen et al., 2012a; van Hedel et al., 2006), where walking speed and distance (endurance) are evaluated (Fig. 1). Walking capacity (speed
and distance) are important prerequisites for successful community ambulation
(Lapointe et al., 2001).
Despite improvements in walking speed during rehabilitation, iSCI patients typically show a reduced velocity compared to a healthy control cohort, especially when
asked to walk at their maximally possible walking speed (Awai and Curt, 2014;
Lapointe et al., 2001; Pepin et al., 2003; van Hedel et al., 2007). Several studies discussed the question as to whether the 10MWT and 6MinWT actually bear complementary information (Forrest et al., 2014; van Hedel et al., 2007). van Hedel et al.
(2007) found a certain redundancy in walking speed assessed by these two measures
when performed at a comfortable walking speed, while the results at maximal speed

revealed additional information. However, these studies did not aim at answering the
question of why patients may or may not walk faster or longer distances. Limitations
in walking speed, particularly pronounced at maximal speed, may indicate a limited
access to supraspinal drive (Bachmann et al., 2013) while endurance might be corrupted as a consequence of the increased energy expenditure found in iSCI patients
(Lapointe et al., 2001; Waters and Lunsford, 1985).
Different training approaches that all include some sort of walking (e.g., on a
treadmill, overground, robot-assisted, body-weight supported, FES-supported) all
found improvements in walking function as assessed by walking speed, distance,
or WISCI II (Alexeeva et al., 2011; Dobkin et al., 2006; Field-Fote, 2001; FieldFote and Roach, 2011; Harkema et al., 2012; Postans et al., 2004; Thomas and
Gorassini, 2005; Wirz et al., 2005). However, many of the studies that compared


3 Clinical neurophysiology

several training methods with respect to overground walking outcome did not find
any differences between training approaches. This may either imply that a specific
training method may not be superior to another or that the outcome measures are not
sensitive to capture differences.

3 CLINICAL NEUROPHYSIOLOGY
Due to the lack of more direct methods to investigate neural pathways underlying
certain behaviors (i.e., implantable electrodes, fiber tracking, optogenetics, genetically modified animals), alternative assessments need to be employed in humans.
Noninvasive or minimally invasive electrophysiological recordings can elucidate
the integrity and connectivity of central and peripheral sensory and motor pathways
in SCI patients either during a resting state (i.e., while subjects are lying; Chabot
et al., 1985; Curt and Dietz, 1996, 1997; Curt et al., 1998; Kirshblum et al., 2001;
Kovindha and Mahachai, 1992) or during activities such as locomotion
(Barthelemy et al., 2010; Capaday et al., 1999; Dietz et al., 1998, 2002, 2009;
Fung and Barbeau, 1994; Harkema et al., 1997; Schubert et al., 1997).

3.1 SPINAL CORD INTEGRITY
Interestingly, SCI patients may improve their ambulatory capacity in the absence of
concomitant improvements of corticospinal conduction velocity assessed via the latencies of motor- and somatosensory-evoked potentials (MEPs and SSEPs) (Curt
et al., 2008). At the same time, the amplitudes of the evoked potentials are paralleled
by improved walking function (Curt and Dietz, 1997; Curt et al., 1998; Petersen
et al., 2012a; Spiess et al., 2008), suggesting that remyelination of injured axons
or conduction velocity may not be the driving forces for functional recovery, but
rather an improved synchronization of action potentials or adaptations at the
neuromuscular site.

3.2 SPINAL NEURAL CIRCUITS
Alterations of spinal reflexes have been shown to reveal changes in spinal neuronal
(dys-)function and are related to walking ability in SCI patients (Dietz et al., 2009;
Hubli et al., 2011, 2012). Concomitant with an improved locomotor function, spinal
reflex responses shifted from exhibiting a predominant late component to a predominant early component, suggesting that neural pathways mediating nonnoxious spinal
reflexes are also involved during locomotion (Hubli et al., 2012). A similar phenomenon was reported by another group (Thompson and Wolpaw, 2014; Thompson
et al., 2013) via modulation of reflex circuits induced by operant conditioning. They
showed that iSCI subjects could improve their walking ability after 30 sessions of
voluntary soleus H-reflex downconditioning, supporting the idea of common pathways for rather simple reflex responses and more complex motor behaviors.

5


6

CHAPTER 1 Walking after SCI

Even in complete human SCI, muscle activity could be elicited during stepping
movements and increased during training when appropriate afferent input was provided (Dietz et al., 1994, 2002; Harkema et al., 1997). Yet, to date, no independent,
weight-bearing walking has been achieved after human complete SCI albeit intensive and long-lasting training. In a distinct set of patients, limited voluntary lower

limb control and manually assisted locomotion could be elicited during epidural spinal cord stimulation in motor complete spinal cord injured patients following intensive training (Angeli et al., 2014; Harkema et al., 2011). These findings suggest that
current clinical tests for the identification of completeness of injury are not sufficient
to detect a small number of spared fibers. Also, the results of this group substantiated
the general assumption that human subjects, to a larger extent than animals, require
input from supraspinal centers in order to walk. How strongly humans rely on brain
input and to what extent locomotor activity is controlled on a rather autonomous spinal level remains to be elucidated. Certain phases of the gait cycle (i.e., initial swing
phase) and specific muscle groups (i.e., distal leg muscles) obviously receive input
via the corticospinal tract (CST), as revealed by TMS studies (Calancie et al., 1999;
Schubert et al., 1997). Coherence analysis of two EMG signals within the same or
synergistic muscles reveals the amount of common synaptic drive to motor output
and the coherence frequency within a specific range (i.e., 8–20 Hz) possibly indicates supraspinal origin of walking (Halliday et al., 2003; Hansen et al., 2005;
Petersen et al., 2012b).

4 GAIT ANALYSIS
With the aim of disentangling the mechanisms underlying motor recovery and locomotor control of normal and pathological gait, the assessment of walking speed and
distance is insufficient. Furthermore, additional measures are of need to reveal factors contributing to recovery of walking and gait control. In addition to gait-cycle
parameters (e.g., stance/swing phase, single/double limb support, step length, cadence), kinematic data objectively reveal information on the quality of walking.
The gait of SCI patients is particularly characterized by muscle weakness on the
one hand and an elevated muscle tone on the other hand. These conditions lead to
limited knee mobility expressed by a reduced knee excursion and knee angular velocity as reported by Krawetz and Nance (1996), while greater knee flexion during
swing and increased total hip excursion were reported by Pepin et al. (2003). Additionally, iSCI walking is typically characterized by an excessive ankle plantar flexion
(foot drop) during the swing phase, which was considered to be an expression of diminished CST drive (Barthelemy et al., 2010, 2013). Only few studies investigated
features of gait quality such as the interplay of lower limb joint angles (hip–knee
cyclograms) revealing information on intersegmental coordination (Field-Fote and
Tepavac, 2002; Nooijen et al., 2009; Pepin et al., 2003). This lower limb coordination is believed to offer insights into control mechanisms underlying locomotor behavior that are not revealed by gait-cycle parameters or measures of speed and


5 Neural control of walking

distance. These latter measures were even shown to be well modulated in iSCI patients (Pepin et al., 2003, unpublished data from our own studies) in contrast to the

intralimb coordination that cannot be properly modulated according to speed (Fig. 2)
and even deviates further from healthy control subjects when increasing speed from
slow to preferred (Awai and Curt, 2014; Pepin et al., 2003, unpublished data from our
own studies). The deficient intralimb coordination was suggested to be a contributing
factor to the limited walking speed typically found in iSCI patients and upon visual
evaluation was stated to be unique for each patient (Pepin et al., 2003). Nevertheless,
specific characteristics of the cyclogram shared by several patients could be identified
and this measure was used to classify four groups of impairment (Awai and Curt,
2014). A meaningful patient stratification is required for tailored rehabilitation
programs as well as a homogenization of intervention groups for a more precise
investigation of treatment effects. Interestingly, even though the cyclogram configuration was not immediately responsive to an increase in speed, the cyclogram shape
reflected the preferred walking speed of the patients and could be quantified by
calculating the shape difference to a normal cyclogram (Awai and Curt, 2014).
Although the shape of the cyclogram did not normalize with increasing walking
speed, patients could actually increase the cycle-to-cycle consistency (i.e., angular
component of coefficient of correspondence). These distinct findings may allude
to the possible existence of a discretely organized control of specific gait features that
may be more or less affected by a SCI and reflect various recovery processes that are
differently amenable to therapeutic interventions.

5 NEURAL CONTROL OF WALKING
A reduction of walking speed is commonly observed in patients with a neurological
disorder but is an unspecific indicator of the underlying cause. A patient with a lower
limb bone fracture may also walk slower even in the absence of neural deficits. However, distinct recovery profiles and the way specific parameters are modulated with
respect to increasing speed may be more informative with respect to underlying
mechanisms of motor control. Given the complexity of bipedal locomotor control,
it is necessary to take into account numerous measures of different modalities that
explain specific characteristics of human gait and the underlying physiology (Fig. 3).
The incapacity of clinically complete SCI patients to spontaneously walk and the
studies that have shown that only a very limited locomotor pattern may be elicited in

the absence of supraspinal input (Dietz et al., 1994; Harkema et al., 1997) suggest
that compared to animals (Barbeau and Rossignol, 1987; De Leon et al., 1998)
humans depend more strongly on supraspinal input (Barthelemy et al., 2011;
Thomas and Gorassini, 2005) but have spinal neural centers capable of spontaneously producing rhythmic output (Calancie et al., 1994). The absence of recovering
MEP latencies in the first year after injury suggests that regeneration of disrupted
fibers or remyelination of injured axons are not the cause for functional improvements observed in SCI patients (Curt et al., 1998, 2008). It is therefore most probable

7


CHAPTER 1 Walking after SCI

Control subjects
Slow

6

Subj1

5
4
Subj2

3

Hip angle [°]

Pref

Hip angle [°]

Slow

1
Subj3

0
Slow

Hip angle [°]

2

Pref

Pref

60
40
20
0
−20
−40
60
40
20
0
−20
−40
60

40
20
0
−20
−40
0

50
100
Knee angle [°]

0

50
100
Knee angle [°]

0

50
100
Knee angle [°]

0

50
100
Knee angle [°]

Normalization of intralimb coordination

Walking speed

4

3
Pat2

2.5

Hip angle [°]

3.5

2
1.5
1

Pat3

0.5
0
Slow

Pref

60
40
20
0

−20
−40
60
40
20
0
−20
−40
60
40
20
0
−20
−40

No normalization of intralimb coordination

Pat1

4.5

Hip angle [°]

iSCI patients

Hip angle [°]

8

FIGURE 2

Intralimb coordination may be represented by so-called hip–knee cyclograms and
evaluates multisegmental lower limb coordination and therefore reveals information on
motor control. The cyclogram configuration may be rather heterogeneous at a slow speed
(0.5 km/h), while it normalizes to a very uniform shape at preferred walking speed in
healthy control subjects. In contrast, iSCI patients are unable to normalize their pattern when
walking at their respective preferred walking speed demonstrating their limited capacity to
modulate complex lower limb movements.


5 Neural control of walking

Neural control
Cortex
Brain stem
Spinal cord
Motoneurons
Muscle
properties

Walking capacity
Speed (10MWT)
Distance (6MinWT)
Type of assistive
device

Gait quality
Joint angles
Range of motion
(ROM)
Angular velocity

Limb coordination
Movement reliability

Mechanisms of
neural control of
walking
Mechanisms of
(motor) recovery

Neuromuscular innervation
Spinal cord integrity
Motor-evoked potentials (MEPs)
Somatosensory-evoked potentials
(SSEPs)
Nerve conduction studies (NCS)
Spinal neural circuits
Spinal reflexes
H-reflex
Electromyogram (EMG)

Gait-cycle parameters
Step length
Cadence
Stance/swing phase
Single/double limb support

FIGURE 3
In order to gain insight into mechanisms of neural control of walking and underlying processes
of motor recovery, it is important to integrate complementary information considering
different aspects of motor function. Measures assessing the anatomical and physiological

integrity of specific pathways as well as parameters quantifying performance and gait quality
are required for a comprehensive understanding of complex mutual interactions underlying
specific phenotypes.

that SCI patients regain locomotor capacity via detour connections or adaptations
that take place below the level of injury and therefore the control of walking might
shift significantly. Concomitant with improvements in functional measures patients
usually show increased MEP amplitudes and motor scores, which is most probably
not attributable to regenerative processes within the lesion site (Curt et al., 2008).
Moreover, most walking parameters increase during recovery while the gait quality
seems to remain largely pathological (Awai L., Curt A., unpublished data) suggesting
that compensatory mechanisms may not drive the recovery of complex movements as
reflected by the intralimb coordination, which may depend predominantly on intact
supraspinal input, making intralimb coordination a valuable measure for recovery
beyond spontaneous/conventionally induced improvements.
A clear segregation of motor control into spinal and supraspinal is probably
neither doable nor correct. It is most likely that locomotion depends on the intricate
temporal and spatial coordination of both feedforward and feedback control

9


10

CHAPTER 1 Walking after SCI

mechanisms performed at multiple levels of the neuraxis. Yet, knowledge about the
anatomical structures underlying specific phenotypes of motor behavior is of need if
outcome measures are to be correctly interpreted.

6 CONCLUSION
A comprehensive assessment framework reveals different aspects of locomotion
(Fig. 3). Clinical/functional measures inform on the performance of a patient during
specific tasks (i.e., activities of daily living), while measures of speed and distance
may decide on whether or not regained function enables a patient to achieve community ambulation. Electrophysiological procedures assess neural and/or muscular
signal propagation, which may be differentiated into central and peripheral conduction. Spinal reflexes were shown to reflect spinal cord excitability and may be used as
a simplified marker for locomotor function. These reflexes can be altered by and
reveal the plasticity of neural circuits. Kinematic outcome measures representing
complex coordinative movements and their responsiveness to speed modulation
reveal the integration of a multitude of signals involved in locomotion. Measures
of intralimb coordination may be used to stratify patients with respect to their gait
impairment enhancing targeted patient interventions and reduction of outcome variability. Only an elaborate assessment battery including complementary measures
provides sufficient information for a profound understanding of an existing disorder.
To tackle the amount and diversity of data, a multivariate approach (e.g., principal
components analysis) may be the method of choice.

ACKNOWLEDGMENTS
This study was partly funded by the European Commission’s Seventh Framework
Program (CP-IP 258654, NEUWalk) and the Clinical Research Priority Program CRPP
Neurorehab UZH.

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CHAPTER

Translating mechanisms
of neuroprotection,
regeneration, and repair
to treatment of spinal cord
injury

2

Ahad M. Siddiqui*, Mohamad Khazaei*, Michael G. Fehlings*,†,{,1
*Department of Genetics and Development, Toronto Western Research Institute, University Health
Network, Toronto, Ontario, Canada
†
Department of Surgery, University of Toronto, Toronto, Ontario, Canada
{
Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
1
Corresponding author: Tel.: +1-416-603-5229; Fax: +1-416-603-5745,
e-mail address:

Abstract

One of the big challenges in neuroscience that remains to be understood is why the central
nervous system is not able to regenerate to the extent that the peripheral nervous system does.
This is especially problematic after traumatic injuries, like spinal cord injury (SCI), since the
lack of regeneration leads to lifelong deficits and paralysis. Treatment of SCI has improved
during the last several decades due to standardized protocols for emergency medical response
teams and improved medical, surgical, and rehabilitative treatments. However, SCI continues
to result in profound impairments for the individual. There are many processes that lead to the
pathophysiology of SCI, such as ischemia, vascular disruption, neuroinflammation, oxidative
stress, excitotoxicity, demyelination, and cell death. Current treatments include surgical decompression, hemodynamic control, and methylprednisolone. However, these early treatments are associated with modest functional recovery. Some treatments currently being
investigated for use in SCI target neuroprotective (riluzole, minocycline, G-CSF, FGF-2,
and polyethylene glycol) or neuroregenerative (chondroitinase ABC, self-assembling peptides, and rho inhibition) strategies, while many cell therapies (embryonic stem cells, neural
stem cells, induced pluripotent stem cells, mesenchymal stromal cells, Schwann cells, olfactory ensheathing cells, and macrophages) have also shown promise. However, since SCI has
multiple factors that determine the progress of the injury, a combinatorial therapeutic approach
will most likely be required for the most effective treatment of SCI.

Progress in Brain Research, Volume 218, ISSN 0079-6123, />© 2015 Elsevier B.V. All rights reserved.

15