Progress in brain research, volume 218

Joseph AlarconBiophotonics and Bioengineering Laboratory, Department of Electrical and Computer Engineering, Ryerson University, Toronto, ON, Canada Olivier Alluin Department of Neurosci

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Vincent WalshInstitute of Cognitive NeuroscienceUniversity College London

17 Queen SquareLondon WC1N 3AR UK

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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

School of Rehabilitation, Universite´ de Montre´al, and Centre for Interdisciplinary

Research in Rehabilitation of Greater Montreal, Institut de re´adaptation

Gingras-Lindsay de Montre´al, SensoriMotor Rehabilitation Research Team of the

Canadian Institute of Health Research, Montreal, Canada

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

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Hugo Delivet-Mongrain

Department of Neuroscience and Groupe de Recherche sur le Syste`me NerveuxCentral (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 ofCalifornia, Los Angeles, CA, USA

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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),

Research, Montreal, Quebec, Canada

Parag Gad

Departments of Integrative Biology and Physiology, University of California,

Los Angeles, CA, USA

Helen Genis

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

Matthew Jeffers

Jamil Jivraj

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

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Aritra Kundu

Department of Neuroscience and Groupe de Recherche sur le Syste`me NerveuxCentral (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, andMontreal Centre for Interdisciplinary Research in Rehabilitation (CRIR),

SensoriMotor Rehabilitation Research Team of the Canadian Institute of HealthResearch, Montreal, Quebec, Canada

Faculty of Medicine, Department of Rehabilitation, Universite´ Laval; Centreinterdisciplinaire de recherche en re´adaptation et inte´gration sociale (CIRRIS),Institut de re´adaptation en de´ficience physique de Que´bec (IRDPQ), andSensoriMotor Rehabilitation Research Team of the Canadian Institute of HealthResearch, Quebec, Canada

Sylvie Nadeau

Ecole de re´adaptation, Universite´ de Montre´al, Centre de recherche

interdisciplinaire en reádaptation de Montreál me´tropolitain (CRIR), Institut dereádaptation Gingras-Lindsay-de-Montreál (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

viii Contributors

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Carine Nguemeni

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

Research, Quebec, Canada

Serge Rossignol

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),

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

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Biophotonics and Bioengineering Laboratory, Department of Electrical andComputer Engineering, Ryerson University; Physical Science—Brain SciencesResearch 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, CanadaBoubker Zaaimi

Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UKEphrem 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

x Contributors

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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

Transla-tional 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

sci-entists, 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

ner-vous 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

re-covery On each day, we designed the sessions to discuss clinical impairments,

on-going 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

impor-tantly, the infrastructures to handle future changes of practice are much improved

Clinical research has also been thriving with the improvement of noninvasive

imag-ing 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

ques-tions 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

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to produce activity-dependent stimulation of the brain, spinal cord, or muscles Suchmethods 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 lated populations just a few years ago, our Symposium, as reflected in this collection

iso-of contributions from our speakers, sends the clear message that translation is ing much more a reality than a vague concept Our discussions highlighted theremarkable consistency in the key conclusions between basic and clinical research

becom-as well becom-as between the fields of SCI and stroke Perhaps the strongest take-homemessage was that each individual, either after stroke or SCI, is different Plasticitybetween patients varies with, for example, lesion size and location, initial impair-ments resulting from the lesion, prelesion lifestyle, and cardiovascular conditionand neuropsychological profiles In these heterogeneous populations, it is unlikelythat 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 factorsaffect plasticity and recovery With this knowledge, perhaps some day, it will be pos-sible to individualize the treatment of each patient based on his or her clinical profileand surrogate markers of postlesion plasticity We believe this colossal task will beachieved through close collaboration between basic and clinical scientists, some-thing that must be nurtured through events such as this symposium

We wish to acknowledge Manon Dumas and Rene´ Albert of the GRSNC for theirdaily implication in the organization of this meeting as well as Claude Gauthier andTania Rostane for their support Many thanks also to reviewers who took the time toassess the abstracts and to comment on the manuscripts

Finally, our special thanks to the funding organizations: CIHR, FRQ-S, RickHansen Institute, Wings for Life, Eli Lilly, Institute of Neurosciences and MentalHealth and Addiction of CIHR, the Universite´ de Montre´al, and the Faculty ofMedicine as well as the Quebec Rehabilitation Research Network (REPAR) forthe student poster Awards

N Dancause

S Nadeau

S Rossignol

xx Preface

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Comprehensive assessment

of walking function after

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: lawai@paralab.balgrist.ch

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

un-derlying motor impairment and locomotor recovery Clinical scores inform on functional

out-comes 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

acti-vation 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

mea-sures 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

com-plex 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),

insuf-ficient hip extension during stance, and excessive plantar flexion during swing (van

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, http://dx.doi.org/10.1016/bs.pbr.2014.12.004

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muscles (Ditunno and Scivoletto, 2009) Thus, a multimodal and comprehensive proach to study normal and altered gait and its recovery is required for elucidatingunderlying mechanisms of gait control.

ap-The majority of clinical studies that monitor recovery processes or training fects during different interventions after spinal cord injury (SCI) chose measures

ef-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 reflectmotor 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

• Time [s]

• Distance [m]

• Mobility

• Type of assistive device

Subjective gait quality

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 ofwalking function during rehabilitation or interventions Clinical scores (e.g., walking indexfor 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 personperform 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 discretetime 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 CHAPTER 1 Walking after SCI

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outcomes may not be well compared across studies and remain nonconclusive at

explaining mechanisms of recovery Even the examination of highly selected

mea-sures (e.g., changes in single joint angles), although presenting very concise

infor-mation, 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

high-return clinical trials (phase I/II studies), investigators should consider any possible

efforts to search for complementary information (including surrogate markers)

be-yond 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

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

in-jury 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

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

mus-cle 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

recom-mended (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.,

cor-relate best with walking speed, distance, and ambulatory capacity in chronic iSCI

subjects compared to unilateral LEMS of the individual lower limb muscles (Kim

performance (speed and distance) but may not have an influence on movement

qual-ity It was shown that iSCI patients have preserved movement accuracy in the lower

limbs despite diminished muscle strength, which distinguished them from stroke

pa-tients 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

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2.2 FUNCTIONAL ASSESSMENTS

The SCIM was developed as a scale to score disability in patients with SCI (Catz

appro-priate performance with respect to specific psychometric properties (i.e., reliability,validity, reproducibility, responsiveness) when compared to other measures such asFunctional Independence Measure, Walking Index for Spinal Cord Injury (WISCI),Modified Barthel Index, Timed Up & Go, 6-minute walk test (6MinWT), or10-meter walk test (10MWT) (Furlan et al., 2011) Compared to measures of walkingcapacity (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 theaim of a study, the appropriate outcome measures should be chosen If walking func-tion and its recovery are to be investigated and the question of whether or not patientsimprove locomotor function and by what means they might improve their walkingcapacity, the SCIM score might not be a sensitive tool while it does inform on to whatextent a patient can perform activities of daily living independent of aids or supportfrom third parties

Recovery of walking function is routinely assessed by functional outcome sures 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.,

walk-ing speed and distance (endurance) are evaluated (Fig 1) Walking capacity (speedand distance) are important prerequisites for successful community ambulation

Despite improvements in walking speed during rehabilitation, iSCI patients ically show a reduced velocity compared to a healthy control cohort, especially whenasked to walk at their maximally possible walking speed (Awai and Curt, 2014;

dis-cussed the question as to whether the 10MWT and 6MinWT actually bear mentary information (Forrest et al., 2014; van Hedel et al., 2007).van Hedel et al

when performed at a comfortable walking speed, while the results at maximal speedrevealed additional information However, these studies did not aim at answering thequestion of why patients may or may not walk faster or longer distances Limitations

in walking speed, particularly pronounced at maximal speed, may indicate a limitedaccess to supraspinal drive (Bachmann et al., 2013) while endurance might be cor-rupted as a consequence of the increased energy expenditure found in iSCI patients

Different training approaches that all include some sort of walking (e.g., on atreadmill, overground, robot-assisted, body-weight supported, FES-supported) allfound improvements in walking function as assessed by walking speed, distance,

or WISCI II (Alexeeva et al., 2011; Dobkin et al., 2006; Fote, 2001; Fote and Roach, 2011; Harkema et al., 2012; Postans et al., 2004; Thomas and

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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,

geneti-cally 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;

Interestingly, SCI patients may improve their ambulatory capacity in the absence of

concomitant improvements of corticospinal conduction velocity assessed via the

la-tencies of motor- and somatosensory-evoked potentials (MEPs and SSEPs) (Curt

by improved walking function (Curt and Dietz, 1997; Curt et al., 1998; Petersen

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

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;

reflex responses shifted from exhibiting a predominant late component to a

predom-inant early component, suggesting that neural pathways mediating nonnoxious spinal

reflexes are also involved during locomotion (Hubli et al., 2012) A similar

phenom-enon was reported by another group (Thompson and Wolpaw, 2014; Thompson

showed that iSCI subjects could improve their walking ability after 30 sessions of

voluntary soleus H-reflex downconditioning, supporting the idea of common

path-ways for rather simple reflex responses and more complex motor behaviors

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Even in complete human SCI, muscle activity could be elicited during steppingmovements and increased during training when appropriate afferent input was pro-vided (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 inten-sive and long-lasting training In a distinct set of patients, limited voluntary lowerlimb control and manually assisted locomotion could be elicited during epidural spi-nal cord stimulation in motor complete spinal cord injured patients following inten-sive training (Angeli et al., 2014; Harkema et al., 2011) These findings suggest thatcurrent 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 substantiatedthe general assumption that human subjects, to a larger extent than animals, requireinput from supraspinal centers in order to walk How strongly humans rely on braininput and to what extent locomotor activity is controlled on a rather autonomous spi-nal level remains to be elucidated Certain phases of the gait cycle (i.e., initial swingphase) and specific muscle groups (i.e., distal leg muscles) obviously receive inputvia the corticospinal tract (CST), as revealed by TMS studies (Calancie et al., 1999;

synergistic muscles reveals the amount of common synaptic drive to motor outputand the coherence frequency within a specific range (i.e., 8–20 Hz) possibly indi-cates supraspinal origin of walking (Halliday et al., 2003; Hansen et al., 2005;

4 GAIT ANALYSIS

With the aim of disentangling the mechanisms underlying motor recovery and motor control of normal and pathological gait, the assessment of walking speed anddistance is insufficient Furthermore, additional measures are of need to reveal fac-tors contributing to recovery of walking and gait control In addition to gait-cycleparameters (e.g., stance/swing phase, single/double limb support, step length, ca-dence), kinematic data objectively reveal information on the quality of walking.The gait of SCI patients is particularly characterized by muscle weakness on theone hand and an elevated muscle tone on the other hand These conditions lead tolimited knee mobility expressed by a reduced knee excursion and knee angular ve-locity as reported byKrawetz and Nance (1996), while greater knee flexion duringswing and increased total hip excursion were reported byPepin et al (2003) Addi-tionally, 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 di-minished CST drive (Barthelemy et al., 2010, 2013) Only few studies investigatedfeatures of gait quality such as the interplay of lower limb joint angles (hip–kneecyclograms) revealing information on intersegmental coordination (Field-Fote and

coordina-tion is believed to offer insights into control mechanisms underlying locomotor havior that are not revealed by gait-cycle parameters or measures of speed and

be-6 CHAPTER 1 Walking after SCI

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distance These latter measures were even shown to be well modulated in iSCI

pa-tients (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

config-uration 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

How-ever, 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;

spontane-ously 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

improve-ments observed in SCI patients (Curt et al., 1998, 2008) It is therefore most probable

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Subj2

−40

−20 0 20 40 60

Subj3

−40

−20 0 20 40 60

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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

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

Motor-evoked potentials (MEPs) Somatosensory-evoked potentials (SSEPs)

Nerve conduction studies (NCS)

Spinal neural circuits

Spinal reflexes H-reflex Electromyogram (EMG)

Cortex Brain stem Spinal cord Motoneurons Muscle properties

Neural control

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

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

6 CONCLUSION

A comprehensive assessment framework reveals different aspects of locomotion

specific tasks (i.e., activities of daily living), while measures of speed and distancemay decide on whether or not regained function enables a patient to achieve com-munity ambulation Electrophysiological procedures assess neural and/or muscularsignal propagation, which may be differentiated into central and peripheral conduc-tion 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 andreveal the plasticity of neural circuits Kinematic outcome measures representingcomplex coordinative movements and their responsiveness to speed modulationreveal the integration of a multitude of signals involved in locomotion Measures

of intralimb coordination may be used to stratify patients with respect to their gaitimpairment enhancing targeted patient interventions and reduction of outcome var-iability Only an elaborate assessment battery including complementary measuresprovides sufficient information for a profound understanding of an existing disorder

To tackle the amount and diversity of data, a multivariate approach (e.g., principalcomponents analysis) may be the method of choice

ACKNOWLEDGMENTS

This study was partly funded by the European Commission’s Seventh FrameworkProgram (CP-IP 258654, NEUWalk) and the Clinical Research Priority Program CRPPNeurorehab UZH

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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: michael.fehlings@uhn.on.ca

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

de-compression, hemodynamic control, and methylprednisolone However, these early

treat-ments are associated with modest functional recovery Some treattreat-ments currently being

investigated for use in SCI target neuroprotective (riluzole, minocycline, G-CSF, FGF-2,

and polyethylene glycol) or neuroregenerative (chondroitinase ABC, self-assembling

pep-tides, and rho inhibition) strategies, while many cell therapies (embryonic stem cells, neural

stem cells, induced pluripotent stem cells, mesenchymal stromal cells, Schwann cells,

olfac-tory 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, http://dx.doi.org/10.1016/bs.pbr.2014.12.007

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cell therapy, clinical translation, neuroprotection, neuroregeneration, spinal cord injury

1 INTRODUCTION

Spinal cord injury (SCI) refers to traumatic injury to the spinal cord that is not theresult of disease In recent years, advances in health care and rehabilitation haveresulted in greater survival after injury However, it is still the case that betweenone and two thirds of patients die on the way to the hospital (Bydon et al., 2014;

The reported incidence of SCI ranges from 9.2 to 246 cases per million of thepopulation a year depending on the area surveyed (Furlan et al., 2013) The incidence

of SCI is highest among people in their late teens to early 20s and the elderly (Carroll,

28.3 years in the 1970s to 37.1 years in 2005–2008 and it is expected to rise further asthe population ages (DeVivo and Chen, 2011) The global prevalence ranges from

236 to 1298 per million of the population with the rate increasing over the last

30 years (Furlan et al., 2013) SCI occurs three to four times more often among malesthan females, however, the proportion of females is rising as the population ages

Approximately half of SCI cases in the United States occur due to motor vehiclecrashes (Putzke et al., 2003; DeVivo and Chen, 2011; Price et al., 1994) Other causesinclude violence (12%), sports (10%), and trips/falls (DeVivo, 2010) Among the el-derly, falls are the leading cause of SCI and the incidence of this has been increasing

as the population ages (Acton et al., 1993; DeVivo, 2012) Over half of SCIs occur atthe cervical level of the spinal cord (Burney et al., 1993; DeVivo, 2010; Sekhon and

develop better treatments that will help to improve the survival rate and quality oflife of patients after injury

The pathophysiology of SCI is a biphasic process that consists of a primary phase thatinvolves the initial mechanical injury followed by a delayed secondary phase thatinvolves processes such as vascular disruption, inflammation, and excitotoxicity

1.2.1 Primary Phase

The primary phase of injury is mainly due to the spinal column exerting force on thespinal cord resulting in disruption of axons (Rowland et al., 2008) This is most com-monly the result of a compressive/contusive injury that causes shearing, laceration,

or acute stretching (Baptiste and Fehlings, 2006; Dasari et al., 2014; Sekhon and

16 CHAPTER 2 Mechanisms of neuroprotection, regeneration, and repair

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connections are spared (Rowland et al., 2008) These spared but demyelinated axons

are most commonly found at the subpial rim (McDonald and Belegu, 2006; Nashmi

animal studies have shown significant neurological recovery with as little as 10%

of the original axons being preserved (Fehlings and Tator, 1995; Kakulas, 2004)

There is much interest in therapies that optimize recovery using existing connections

1.2.2 Secondary Phase

The secondary phase of injury is characterized by ischemia, excitotoxicity, vascular

dysfunction, oxidative stress, and inflammation that leads to cell death (Braughler

the secondary injury are often harmful to surviving bystander neurons and the injury

of these neurons can lead to poor functional recovery (McDonald and Sadowsky,

an inhibitory environment is created that impairs endogenous regeneration and

remyelination (Dasari et al., 2014) The secondary phase is made up of subphases

that are divided temporally into the immediate, acute, subacute, intermediate, and

chronic stages of SCI (Fig 1)

FIGURE 1

Timeline summarizing the phases after spinal cord injury and the therapeutic aims best

suited for that phase The events that occur after spinal cord injury are divided into the

immediate (first 2 h), acute (2–48 h), subacute (48 h–14 days), intermediate (14 days–6

months), and chronic (6 months and beyond) phases These phases are characterized by

changes in inflammation, hemorrhage, apoptosis, the blood-spinal cord barrier (BSCB),

and the extracellular matrix Some therapeutic aims are shown to be beneficial in certain

phases of SCI since they target the events that occur in that phase

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1.2.2.1 Immediate Phase

The immediate phase lasts for approximately the first 2 h of injury and constitutes theimmediate aftermath of the injury (Norenberg et al., 2004) The rapid death of neu-rons and glia accompanies spinal shock that results in the immediate loss of function

at and below level of the injury (Boland et al., 2011; Ditunno et al., 2004) The firstsign of the immediate phase is the necrotic cell death of neurons due to ischemia,hemorrhaging, edema, and mechanical disruption of the cell membrane (Kakulas,

TNF-a and IL-b (Davalos et al., 2005; David and Kroner, 2011; Donnelly and

minutes of SCI is the rise of extracellular glutamate to excitotoxic levels (Park et al.,

48 h after injury A hallmark of the secondary injury in the acute phase is the vasculardisruption and hemorrhage that result in ischemia (Tator and Fehlings, 1991; Tator and

ische-mia is not fully understood, it is thought that disruption of the microvascular, sion, and increased interstitial pressure leads to hypoperfusion of the cord after injury

The process of hemorrhage and ischemia is closely related to the permeability ofthe blood–brain-barrier (BBB)/blood-spinal cord barrier (BSCB) SCI results in thepermeability of the BBB/BSCB due to the direct mechanical disruption of the vas-culature and the effect of inflammatory mediators on endothelial cells (Rowland

contusive/clip compression SCI and returns to control levels around 2 weeks afterinjury (Figley et al., 2014; Noble and Wrathall, 1989) BSCB permeability may

be affected by inflammatory cytokines that are commonly upregulated by SCI

perme-ability of the BBB/BSCB after SCI is seen as a deleterious event, the permeperme-abilitymay provide an opportunity to introduce cell treatments and drugs that normally maynot be able to cross the BBB/BSCB

The leakiness of the BBB/BSCB permits the infiltration of immune cells, such as

T cells, neutrophils, and monocytes, into the CNS The resident microglia continue toproliferate and become activated into the subacute stage Microglia attract peripheralleukocytes and other immune cells through production of cytokines that upregulateproduction of chemokines (Donnelly and Popovich, 2008; Mueller et al., 2006;

where they produce cytokines, MMPs, superoxide dismutase, and myeloperoxidase

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(Donnelly and Popovich, 2008; Fleming et al., 2006; Guth et al., 1999; Noble et al.,

extrav-asation, as well as the activation of glia and mediation of the respiratory burst which

may be harmful to neurons (Carlson et al., 1998; Tzekou and Fehlings, 2014) The

monocytes begin to be recruited as the levels of neutrophils stop increasing at 48 h

be-gin to differentiate into macrophages and produce glutamate, TNF-a, IL-1 and IL-6,

and prostanoids which may exacerbate secondary injury (Leskovar et al., 2000;

injury, but the activation of microglia can persist for weeks after injury (Donnelly

to be a double-edged sword where activation of certain immune cells and

inflamma-tory cytokines has been shown to have both beneficial and detrimental roles

Micro-glia and macrophages have also shown to have beneficial and detrimental effects

after CNS injury, partly due to the fact that they may have proinflammatory

(M1) and neuroprotective (M2) activation states (David and Kroner, 2011; Kigerl

Ischemia and immune infiltration can lead to the production of oxidative stress

and free radical production Reactive oxygen (ROS) and nitrogen (NO) species can

be produced by macrophages/microglia after SCI or even as a result of ischemia and

reperfusion (Chatzipanteli et al., 2002; Sakamoto et al., 1991) The levels of ROS

peak 12 h after injury and remain elevated for 1 week (Donnelly and Popovich,

2008) Inhibition of NO production has been shown to have neuroprotective effects

after CNS injury (Chatzipanteli et al., 2002; Koeberle and Ball, 1999; Lo´pez-Vales

the formation of peroxynitrite radical generated from the reaction between nitric

ox-ide and superoxox-ide which is involved in the initiation of neuronal apoptosis after

ex-perimental SCI (Bao and Liu, 2003; Xiong et al., 2007)

Ionic dysregulation and excitotoxicity immediately follow SCI and contribute to

the cellular damage and loss The proper regulation of calcium is an important

pro-cess in preventing cell death, and its dysregulation leads to cell death through

mito-chondrial dysfunction, production of free radicals, and activation of calpains

glu-tamate rise after injury as a direct consequence of disruption of membrane

trans-porters which maintain homeostasis of ions and glutamate (Llado´ et al., 2004)

This results in overactivation of the glutamate receptor leading to an increased influx

of sodium and calcium ions through the NMDA and AMPA receptors, dysregulation

of metabolic and mitochondrial activity, and loss of osmotic balance that ultimately

results in excitotoxic cell death (Agrawal and Fehlings, 1997; Gerardo-Nava et al.,

there has been great interest in using drugs to control it through antagonism of

NMDA and other receptors

The ultimate consequences of the processes described earlier during the acute

phase are cell death and demyelination The majority of neuronal cell death after

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SCI occurs through necrosis, although apoptosis also plays an important role (Beattie

occurs through apoptosis, partially dependent on activation of the Fas receptor andthrough p75 receptor signaling (Ackery et al., 2006; Casha et al., 2001, 2005; Chu

spinal cord are found on oligodendrocytes and expressed by activated microgliaand lymphocytes (Austin and Fehlings, 2008; Casha et al., 2001, 2005) The inter-action between the two leads to apoptosis through the activation of caspases (Austin

cell death can lead to functional recovery and be used in the treatment of SCI

The subacute phase lasts from approximately 2 days to 2 weeks after SCI cytes initially go through necrotic cell death but, in the subacute phase, become hy-pertrophic and proliferative (Rowland et al., 2008) The large cytoplasmic processescome together to become the gliotic scar that forms a physical and chemical barrier toregeneration (Fawcett and Asher, 1999; Hagg and Oudega, 2006; Karimi-

in scar tissue release inhibitory molecules, such as chondroitin sulfate proteoglycans(CSPGs) (Fawcett and Asher, 1999; Fitch and Silver, 2008) To combat the inhibition

to regeneration from the glial scar, there is interest in developing therapeutics thatcan remove the glial scar to promote regeneration

1.2.2.3 Intermediate Phase

The immediate phase begins approximately 2–3 weeks after injury and continues to 6months after injury During this phase, reactive gliosis continues as the scar begins tomature There is also axonal sprouting of the corticospinal tract and the reticulospinalfibers (Hill et al., 2001) during this stage Although this endogenous attempt atsprouting axons does not translate to significant functional recovery, it presents

an attractive target for therapeutic intervention

1.2.2.4 Chronic Phase

The last phase in SCI is the chronic phase which begins at around 6 months injury and lasts for the lifetime of the patient During the chronic phase, the lesionbegins to stabilize with scar formation and cyst/syrinx development (Li and Lepski,

and macrophages due to progressive loss of neural tissue (Basso et al., 1996;

the rim of the cysts but the cysts present a physical barrier to neuronal tion (Kramer et al., 2013) In addition, Wallerian degeneration of the axonscontinues and years for the cell bodies and axons to be removed (Beattie et al.,

stage aim to promote regeneration, promote plasticity, or to improve function ofspared axons

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2 CLINICAL INTERVENTION

Historically, patients with SCI had a poor prognosis and were left unmonitored in

hospital wards until their vertebrae healed However, modern medical advances have

led to improvements in patient care The use of spineboards and the practice of

immobilizing patients at the site of injury have acted to reduce injury and mortality

becom-ing more common

Surgical decompression helps to restore spinal stability and maintains cord perfusion

includes various procedures intended to relieve symptoms caused by pressure, or

compression, on the spinal cord There is controversy about the role and timing of

surgical decompression after an acute SCI (Fehlings et al., 2001) Numerous

exper-imental studies of decompression after SCI have been performed in various animal

models including primates, dogs, cats, and rodents These studies have consistently

shown that neurological recovery is enhanced by early decompression (Fehlings and

per-forming decompression, our center was part of the “Surgical Timing in Acute Spinal

Cord Injury Study” (STASCIS) on a multicenter, international, prospective cohort of

patients The results demonstrate a more favorable neurologic recovery among those

treated with early (defined as<24 h after injury) rather than late surgical

decompres-sion (Fehlings et al., 2012) Having demonstrated the potential for improved

neuro-logical outcomes with early surgical decompression, we recommend urgent

decompression of bilateral locked facets in patients with SCI Urgent decompression

in acute cervical SCI is a reasonable practice option and can be performed safely

One of the symptoms of SCI above T1–T4 is hypotension as the heart receives its

sympathetic supply from this region and SCI leads to decreased myocardial

contrac-tility and heart rate (Ploumis et al., 2010; Stevens et al., 2003) Hypotension can arise

from the loss of central supraspinal sympathetic control that occurs in complete

cer-vical cord injury (Furlan and Fehlings, 2008; Raw et al., 2003) Hypotension can lead

to decreased cord perfusion that can result in further ischemic injury (Anon, 2002b)

It is recommended that arterial pressure be maintained at a minimum of 85 mmHg

replace-ment followed by vasopressors (Stratman et al., 2008) Crystalloids are first used for

volume replacement, followed by colloids (Ploumis et al., 2010) The Consortium for

Spinal Cord Medicine recommends that injuries above T6 use a vasopressor that has

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inotropic, chronotropic, and vasoconstrictive characteristics, such as dopamine andnorepinephrine (Anon, 2002b; Nockels, 2001; Wing, 2008) However, use of dopa-mine or phenylephrine has not resulted in any neurological functional improvement

as phenylephrine and dobutamine (Anon, 2002b; Ball, 2001; Nockels, 2001) Usingheparin for the first 3 months following SCI is also recommended for thrombopro-phylaxis to target venous thromboembolism and establish hemodynamic control

Methylprednisolone is a corticosteroid that is given as a sodium succinate (MPSS)and is thought to work by reducing peroxidation of membranes and lessening inflam-mation MPSS has an immunomodulatory effect, inhibiting infiltration of neutro-phils and macrophages into the spinal cord (Bartholdi and Schwab, 1995) whichmay improve functional outcomes There have been three major clinical trials done

to investigate the use of MPSS after SCI The National Acute Spinal Cord InjuryStudy (NASCIS) I was the first double blind, randomized control trial that was done

to establish the neuroprotective role of MPSS after SCI (Bracken, 2001; Bracken

deter-mined that there were no significant differences in motor or sensory scores betweenthe treatment groups There were also no reported differences in mortality betweenthe groups, however high doses were associated with increased risk of infection Thelack of proper controls made it difficult to determine the safety of MPSS In addition,preclinical studies suggested that the serum concentrations needed for neuroprotec-tion were not met in the NASCIS I trial The NASCIS II trial used a higher dose(30 mg/kg bolus) at time of admission and 5.4 mg/kg/h for the following 23 h

II found some neurological improvements (light touch and pinprick sensation) 6months after SCI when administered within 8 h of the injury However, results indi-cated that there may be worse motor recovery if MPSS was administered after 8 h ofinjury The use of MPSS is controversial since it can lead to some serious side effectssuch as infection and pneumonia (Hall and Springer, 2004; Wilson et al., 2013) Inaddition,Nesathurai (1998)suggested that there was no significant difference in out-come between the treatment group and placebo in NASCIS II (Nesathurai, 1998).The NASCIS III trial was done to see if an administration time of 48 h would haveany additional benefit (Bracken, 2001; Bracken and Holford, 2002) There somemotor recovery when MPSS was administered for 48 h, and a subanalysis showedthat the best time to administer may be between 3 and 8 h postinjury Initially,the AANS/CNS Joint Guidelines Committee in 2002 recommended the use of MPSS

24 or 48 h after SCI but cautioned that it should be “undertaken only with the edge that the evidence suggesting harmful side effects is more consistent than anysuggestion of clinical benefit” (Hadley, 2002) However, in 2013, they issued alevel 1 recommendation that MPSS not be used (Hurlbert et al., 2013) The use of

knowl-22 CHAPTER 2 Mechanisms of neuroprotection, regeneration, and repair

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MPSS remains controversial evidence from the STASCIS trial showed synergistic

effects of early decompression and MPSS after acute cervical SCI (Fehlings

recommendation are nonrandomized trials that have a risk of bias and show

mixed results There may be incidences where the use of MPSS is appropriate;

however, the new recommendation may deter physicians from its use (Fehlings

steroids in SCI

3 REHABILITATION

Several studies have shown that rehabilitation after SCI has beneficial effects and

that longer stays at rehabilitation facilities are associated with increased functional

recovery (Spivak et al., 1994; Sumida et al., 2001) However, rehabilitation

pro-grams differ among centers and there is limited research evidence regarding the

ef-fectiveness of many of the treatments that are provided in SCI rehabilitation Many

programs have relied, in the past, on expert opinion but evidence-based approaches

are becoming more apparent One review of the literature has suggested that patients

with SCI should engage in at least 20 min of moderate to vigorous aerobic exercise

twice a week and strengthening exercises twice a week to exercise the major muscle

groups (Ginis et al., 2011) Overall, it is out of the scope of our chapter to cover

rehabilitation in detail, but it is recognized that rehabilitation will be

complemen-tary to neuroprotective, reparative, or regenerative strategies as treatments move

forward

4 NEUROPROTECTIVE STRATEGIES

Currently, there is a lack of clinically accepted neuroprotective treatments for SCI

Neuroprotective therapies aim to limit the secondary injury after the initial damage

through modulation of inflammation, reduction of cell death, and protection against

excitotoxicity (Fig 2)

Riluzole is an FDA-approved sodium channel blocker that has neuroprotective

prop-erties and is used clinically for neurodegenerative disorders, such as amyotrophic

lateral sclerosis (ALS) (Grossman et al., 2014; Hurlbert et al., 2013; Miller et al.,

2007) It has been shown to reduce symptoms in animal models of neurodegeneration

and traumatic injury by modulating glutamate release through blocking the

overac-tivation of sodium channels (Bellingham, 2011; Doble, 1996; Schwartz and

the stimulation of neurotrophic factor expression (Katoh-Semba et al., 2002;

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Mizuta et al., 2001; Palace, 2008) In preclinical studies, riluzole promote functionalrecovery after SCI and decrease the extent of cavitation (Schwartz and Fehlings,

greater preservation of white matter, mitochondrial function, somatosensory-evokedpotentials, and motor neurons (Tator et al., 2012) One study showed tissue preser-vation, improved neurobehavioral outcomes, reduced inflammation, improved axo-nal conduction, and decreased apoptosis after repeated doses of 6 mg/kg riluzolewithin the first 3 h after SCI in rats (Wu et al., 2013)

The Riluzole in Spinal Cord Injury Study (RISCIS) is a clinical trial, undertaken

by our center and others, to determine the safety and pharmacokinetics of riluzoleafter acute SCI (Grossman et al., 2014) This Phase I study included 36 patients thathad SCI with ASIA grades A–C (28 cervical and 8 thoracic) Patients were given

50 mg of riluzole twice a day within 12 h of injury for 14 days No additional plications and side effects were noted in patients treated with riluzole There weresome functional improvements in mean motor scores of 24 cervical patients treatedwith riluzole 90 days after admission The RISCIS trial is now recruiting patients for

com-a Phcom-ase II/III registered cliniccom-al tricom-al (ClinicalTrials.govidentifier: NCT01597518)

to determine the effects of riluzole with more explicit endpoint measures

FIGURE 2

Strategies that therapeutics use to promote neuroprotection after spinal cord injury.Neuroprotective strategies, such as riluzole, minocycline, granulocyte colony stimulatingfactor (G-CSF), fibroblast growth factor (FGF), and polyethylene glycol (PEG), targetneuroprotection by modulating inflammation, protecting against excitotoxicity, and blockingapoptotic processes Many of these compounds under investigation have multiple actionsand their main mode of action is summarized above

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4.2 MINOCYCLINE

Minocycline is a broad spectrum tetracycline antibiotic that may have

neuroprotec-tive effects through the inhibition of M1 microglia (Festoff et al., 2006; Kobayashi

sta-bilization, metalloproteinase inhibition, neutralization of oxygen radials, and

cal-cium regulation (Yong et al., 2004)

Minocycline is an attractive drug for use in clinical trials because it is known to be

well tolerated in humans, where it has been used for treatment of acne for decades

rare (1/10,000–1/1,000,000 patients) and occur mainly after long-term use (Cunliffe,

diseases show encouraging results, although one randomized trial in ALS showed

that minocycline resulted in clinical deterioration (Chaudhry et al., 2012; Gordon

showed that the use of minocycline resulted in a trend toward improved motor

re-covery, although this result was not statistically significant (Casha et al., 2012)

The study also showed that minocycline was safe to use after SCI (Casha et al.,

2012) Even though the efficacy of minocycline treatment after SCI was not strongly

supported, the study has progressed to a Phase III trial that combines minocycline

treatment with spinal perfusion augmentation

Granulocyte colony stimulating factor (G-CSF) is a small glycoprotein (19.6 kDa)

that is able to cross the BBB/BSCB (Pitzer et al., 2008; Welte et al., 1985; Zhao

differentiation and inhibit neutrophil apoptosis (Welte et al., 1985) It is particularly

expressed on microglia where it has an immunomodulatory role by increasing the

expression of M2 phenotype markers (Arg 1 and CD206) and promoting the

expres-sion of neurotrophic factorsin vitro (Guo et al., 2013) G-CSF also inhibits

proin-flammatory markers (TNF-a, IL-1b, iNOS) and promotes neuroprotection through

the inhibition of NF-kB (Guo et al., 2013) G-CSF has been shown to inhibit neuronal

apoptosis, degeneration of myelin, apoptosis of oligodendrocytes, and expression of

inflammatory cytokines, as well as having angiogenic effects (Kawabe et al., 2011;

From the success of G-CSF in preclinical studies and due to its mild side effects,

the treatment has entered into clinical trials for SCI Some reported side effects of

G-CSF are lower back and pelvic pain, listeriosis, nausea, headaches, urinary tract

infection, and vomiting (Anderlini et al., 1996; Murata et al., 1999; Takahashi et al.,

2012) However, most of these symptoms subside after discontinuation of the drug or

use of antibiotics In a Phase I/IIa clinical trial of G-CSF, 5 and 10mg/kg/day doses

were well tolerated (Takahashi et al., 2012) The drug was administered

intrave-nously within the first 48 h postinjury for 5 days There were significant increases

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in the ASIA motor and sensory scores in patients after cervical (15 patients) and racic (1 patient) injuries 10mg/kg/day doses (Takahashi et al., 2012) There was also

tho-a trend noted for higher ASIA motor scores in ptho-atients tretho-ated with 10mg/kg/daydoses as opposed to those treated with MPSS (Takahashi et al., 2012) This clinicaltrial shows great promise for further clinical studies and use of this drug in the treat-ment of SCI

Fibroblast growth factor-2 (FGF-2; or basic fibroblast growth factor) is a protein thathas been shown to have neuroprotective properties that decrease cell death in excito-toxic environments (Guo et al., 1999; Jin et al., 2005; Mattson et al., 1993; Meijs et al.,

2004) FGF-2 can promote the proliferation of spinal cord neural stem and progenitorcells (Shihabuddin et al., 1997) The use of FGF-2 promotes functional recovery inmodels of SCI by promoting neuronal survival, angiogenesis, and reduction in cavi-tation (Kang et al., 2013; Lee et al., 1999; Rabchevsky et al., 2000; Teng et al.,

scar formation, and astrogliosis after SCI in the mouse model (Goldshmit et al., 2014).This is due to the reduction in macrophage infiltration and cytokine levels Thereduction in macrophage infiltration may be due to the ability of FGF-2 to reducethe leakiness of the BBB/BSCB after SCI (Kang et al., 2010) Not only is astrogliosisreduced, but FGF-2 promotes the formation of radial bipolar glial cells that help sup-port regenerating neuronal processes (Goldshmit et al., 2014) Intrathecal infusion ofFGF-2 is associated with improvements in hind limb function in animal models of SCI

shown any functional recovery benefits after FGF-2 treatment (Kang et al., 2013)

A closely related FGF, (FGF-1; or acidic FGF), is in clinical trials for SCI

FGF-1 with fibrin glue was administered surgically approximately 25.7 months afterinjury, followed by FGF-1 injections via lumbar puncture 3 and 6 months postsur-gery (Wu et al., 2011) There were significant improvements in the ASIA motorscores and ASIA sensory scores (light touch and pinprick) in both cervical and thor-acolumbar groups at the 24 month follow up There was also an associated improve-ment in the ASIA impairment scales, neurological levels, and functionalindependence measure (Wu et al., 2011) The use of FGF-1 was also deemed safesince no serious side effects were reported in this trial Although there are improve-ments noted in this study, one should be cautious in the interpretation of these resultswithout a control group In addition, it is possible that the improvements are due tointrinsic recovery ability and rehabilitation protocols (Fehlings and Wilson, 2011)

Polyethylene glycol (PEG) is a hydrophilic polymer that may have neuroprotectiveproperties such as aiding in repairing damaged axons (Kwon et al., 2011) It has beenshown to decrease NF200 degradation and apoptosis, as well as increasing tissue

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sparing (Baptiste et al., 2009) PEG may also protect against mitochondrial

dysfunc-tion after SCI, which can reduce oxidative stress and apoptosis (Luo and Shi, 2004,

prevent extracellular calcium and other ions from entering, ultimately protecting the

mitochondria from swelling (Luo and Shi, 2007) This inhibits cytochromec release

and caspase activation (Luo and Shi, 2007) PEG-treated animals show some

func-tional improvement and reduction in allodynia but no improvement on the inclined

plane test (Baptiste et al., 2009; Ditor et al., 2007) Some long-lasting hind limb

re-covery was seen when PEG with a matrix was used (Estrada et al., 2014) However,

PEG alone may not be sufficient to confer any significant neuroprotection after

in-jury (Ditor et al., 2007; Kwon et al., 2009) The addition of magnesium (Mg) to PEG

increased tissue sparing and BBB scores 6 weeks post-SCI (Ditor et al., 2007; Kwon

the safety, tolerability, and pharmacokinetics of the drug in patients that have SCI

5 CELL-BASED THERAPIES

Cell therapies for treating SCI have shown a great deal of promise Cell therapy uses

the regenerative ability of cells to repopulate areas of damage that result from SCI

A wide range of cells been studied for treatment of SCI These studies show that the

beneficial effects of cell therapies for SCI are attributable to different mechanisms

depending on cell sources including neurotrophic support, cell replacement,

immu-nomodulation, or scaffold support (Fig 3;Vawda et al., 2012) Clinical trials are now

underway in North America for cell therapy in SCI, including the Phase I/II trial

which our center is involved in, in collaboration with Stem Cells, Inc The trial

is currently enrolling spinal cord injury patients at three centers: the University of

Toronto, the University of Calgary, and the Balgrist University Hospital in Zurich

This trial treated its first patient in Toronto in February 2014 Despite these advances,

stem cell therapy for SCI is limited by differences in pathophysiology associated

with the anatomical level of injury and also the continued search for the ideal cell

source This increases the critical need for extensive preclinical studies to explore

different aspects of the mechanisms and safety of different cell types

Schwann cells (SCs) are the main glial cells of the peripheral nervous system which

wrap around axons of motor and sensory neurons to form the myelin sheath SCs

are one of the first cell types that have been tested for the treatment of SCI

SCs can be easily harvested from the sural nerve of the patients for an autologous

transplantation approach (Saberi et al., 2008) The main contribution of SCs in

SCI recovery after transplantation is attributed to axon remyelination (Park et al.,

2010) Upon transplantation into the spinal cord, SCs also improve the recovery

of behavioral and electrophysiological function, by producing several neurotrophic

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factors (Park et al., 2010) that contribute to survival and the intrinsic regenerationability of damaged neurons.

SCs have also been used in clinical trial for the treatment of SCI In trial, SCswere purified from the sural nerves of the patients, cultured and transplanted intothe injured spinal cord after 1 year This study demonstrated that SC transplantationdoes not result in any adverse effects One patient showed improvements in motorand sensory functions combined with extensive rehabilitation (Saberi et al., 2008)

Embryonic stem cells (ESCs) are pluripotent cells derived from the inner cell mass ofblastocysts ESCs are distinguished by their ability to replicate indefinitely and todifferentiate into any one of three primary germ layers and, eventually, all cell types

FIGURE 3

Mechanisms by which cell therapy works to treat SCI Transplanted cells exerts theirtherapeutic effects in the treatment of SCI via different mechanisms Some transplantedcells, such as NPCs, can replace lost or damaged cells through differentiation or

transdifferentiation into mature neurons and oligodendrocytes (1) Some cell types like MSCs,NPCs, SCs, and OECs provide neurotrophic factors (like GDNF, NGF, BDNF, and CNTF)which are crucial to enhance neuronal regeneration and survival (2) Some other cell types,such as MSCs, SCs, and OECs, are beneficial to SCI through downregulating inhibitorymolecules, immunomodulation (3), or modulating the environment and providing a scaffoldsupport for the regeneration of axons (4) Therefore, cotransplanting different cell typeswith different mechanisms of action can evoke more functional and anatomical recovery byproviding a synergistic effect

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in the body Due to high risk of teratoma formation, it is not common to use ESCs

directly for the treatment of SCI and typically ESCs are differentiatedin vitro into

progenitor cells before being used for treatment

Transplantation of cells derived from ESCs such as neural progenitor/stem cells,

motor neurons, oligodendrocyte progenitor cells, and olfactory ensheathing cells

(OECs) are much more promising for treatment of SCI Several studies have shown

the beneficial effects of “neuralized ESCs” in partial functional recovery rat-SCI

model (Cui et al., 2011; Harper et al., 2004; Kimura et al., 2005; McDonald

rela-tively safe and can only differentiate into neuronal lineagesin vivo Transplantation

of ESC-derived motor neuron progenitor cells into the spinal cord of an adult rat

model of SCI increased the sprouting of endogenous serotonergic projections,

sur-vival of endogenous neurons, and gross tissue sparing It also decreased

phosphor-ylation of stress-associated protein kinase which can result in apoptosis, immune

activation, and inflammation (No´gra´di et al., 2011; Rossi et al., 2010)

Extensive research on the application of ESC-derived oligodendrocyte precursor

cells (OPCs) has been performed These experiments showed that transplantation of

ESC-OPCs resulted in remyelination of spared axons (Keirstead et al., 2005; Sharp

2010), restore forelimb motor function, improved forelimb stride length, reduce in

cavity, and white and gray matter sparing (Keirstead et al., 2005; Sharp et al.,

2010) These exciting results led to the approval of the world’s first human ES cell

human trial by the FDA for a Phase I clinical trial by Geron Corporation for

trans-plantation of hESC-derived OPCs into spinal cord-injured individuals on January 23,

2009 In the following year, Geron initiated the Phase I study to test the safety of

hESC-OPCs in patients who were suffering from complete thoracic level paraplegia

with loss of motor and sensory function hESC-OPCs were administered into the

le-sion site within 14 days of injury with a low dose of 2 million cells However in

No-vember 2011, Geron announced that it had ended its SCI stem cell research program

Induced pluripotent stem cells (iPSCs) are adult cells that have been genetically

repro-grammed to an ESC-like state They display important characteristics of pluripotent

stem cells, including expressing stem cell markers and forming tumors-containing

cells from all three germ layers (Takahashi et al., 2007) Different differentiated

adult cells types can be reprogrammed to iPSCs upon exogenous expression of

repro-gramming transcription factors (Takahashi et al., 2007) Since iPSCs can be derived

directly from adult tissues, they can be made in a patient-matched manner that

circum-vents ethical and religious concerns, while allowing for autologous transplantation

The efficiency of cell reprogramming varies among different cell types For example,

human keratinocytes from skin biopsies can be reprogrammed to pluripotency at much

higher frequency and faster speed than fibroblasts (Colman and Dreesen, 2009)

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Transplantation of cells derived from iPSCs is increasingly recognized as a ising strategy for SCI NPCs derived from iPSCs represent an easily accessible cellsource Experiments from our laboratory and others demonstrated that transplantediPSC-NPCs differentiated into neurons and glia in vivo, enhanced remyelinationaxon regeneration, supported the survival of endogenous neurons and promoted lo-comotor recovery and sensory responses (Hatami et al., 2009; Nutt et al., 2013;

Neural stem cells and neural progenitor cells (NPCs) are self-renewing, multipotentcells that primarily differentiate into neurons, astrocytes, and oligodendrocytes.NPCs have attracted great interest as a potential source for replacing damaged or lostneurons in SCI (Tetzlaff et al., 2011) In the adult CNS, NPCs can be isolated fromthe subventricular zone of the forebrain, subgranular zone of the dentate gyrus, andalso from the spinal cord (Emga˚rd et al., 2014; Gage, 2000; Weiss et al., 1996) Onthe other hand, NPCs can also be derived from more primitive stem cells includingESCs and iPSCs However, the logistics and ethical issues surrounding the use ofeach source of NPCs are quite significant For example, ESC-NPCs present ethicalchallenges and the risk of tumorigenicity Though adult NPCs, derived from theCNS, are attractive for SCI due to their neural commitment and lack of tumorigenic-ity (Karimi-Abdolrezaee et al., 2006), derivation of adult NPCs for autologous trans-plantation is not feasible More recently, we have been able to generate safe andeffective NPCs derived from iPSCs, which is clinically more attractive (Salewski

Our laboratory and others have shown that transplantation of rodent and humanNPCs into the spinal cord improves neural repair and regeneration and functionalrecovery following traumatic SCI in rodents (Alexanian et al., 2011; Emga˚rd

transplanted NPCs are via cell replacement and plasticity, remyelination, nutrientsecretion, increasing axon regeneration, and immunomodulatory effects The resultsfrom our lab and others have shown that the main functional recovery after NPCtransplantation is attributable to remyelination of host axons by myelinating oligo-dendrocytes differentiated from NPCs (Hawryluk et al., 2014; Karimi-Abdolrezaee

into the lumbar cord of an SCI rat model showed large-scale differentiation into rons, axon regeneration, and extensive synaptic contact reformation with host motorneurons The newly differentiated neurons integrated into the host neural circuits

were grafted into the T3 transection rat SCI Seven weeks after transplantation, NPCsconsistently filled the complete transection site The implanted cells differentiatedinto neurons, astrocytes, and oligodendrocytes in roughly equal proportions Mostimportantly, grafted neurons extended very large numbers of axons into the host spi-nal cord both rostral and caudal direction to the lesion (Lu et al., 2012)

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