DEVELOPMENTAL DISABILITIESRESEARCH REVIEWS 15: 112 – 116 (2009)

ACTIVITY-BASED RESTORATIVE THERAPIES:
CONCEPTS AND APPLICATIONS IN SPINAL CORD
INJURY-RELATED NEUROREHABILITATION
Cristina L. Sadowsky1* and John W. McDonald2
1

International Center for Spinal Cord Injury, Department of Physical Medicine and Rehabilitation,
Kennedy Krieger Institute, Johns Hopkins School of Medicine, Baltimore, Maryland

2

International Center for Spinal Cord Injury, Department of Neurology, Kennedy Krieger Institute,
Johns Hopkins School of Medicine, Baltimore Maryland

Physical rehabilitation following spinal cord injury-related paralysis
has traditionally focused on teaching compensatory techniques, thus enabling the individual to achieve day-to-day function despite significant
neurological deficits. But the concept of an irreparable central nervous
system (CNS) is slowly being replaced with evidence related to CNS plasticity, repair, and regeneration, all related to persistently maintaining
appropriate levels of neurological activity both below and above the area
where the damage occurred. It is now possible to envision functional
repair of the nervous system by implementing rehabilitative interventions.
Making the transition from ‘‘bench to bedside’’ requires careful analysisof existing basic science evidence, strategic focus of clinical research, andpragmatic implementation of new therapeutic tools. Activity, defined asboth function specific motor task and exercise appears to be a necessity
for optimization of functional, metabolic, and neurological status inchronic paralysis. Crafting a comprehensive rehabilitative intervention
focused on functional improvement through neurological gains seems
logical. The terms activity-based restorative therapies, activity-based
therapies, and activity-based rehabilitation have been coined in the last
10 years to describe a new fundamental approach to deficits induced byneurological paralysis. The goal of this approach is to achieve activationof the neurological levels located both above and below the injury level
using rehabilitation therapies. This article reviews basic and clinical science evidence pertaining to implementation of physical activity and exercise as a therapeutic tool in the management of chronic spinal cord' 2009 Wiley-Liss, Inc.
related neurological paralysis.
Dev Disabil Res Rev 2009;15:112–116.

Key Words: activity; paralysis; restorative therapies; spinal cord injuries

INTRODUCTION
he field of neurorehabilitation is changing. After yearsof evidence from the basic science data, the old, deeprooted rehabilitative principles of compensation andadaptation are slowly starting to change. Strategies for stimulating the nervous system are being used to optimize functional recovery and eliciting abilities thought to be lost foreverat the time of injury.
From basic science/animal model we have learned thatthe adult injured central nervous system (CNS) is capable ofreorganization at multiple levels, thus allowing for significant
improvement following injury. The reorganization occurs at

T' 2009 Wiley -Liss, Inc.

all different levels: cortical, subcortical, spinal cord, and in the
peripheral nervous system. The repair process can happen
through various mechanisms: synaptic plasticity in preexisting
connections (peripheral and central), sprouting, and formationof new connections. Remyelination and new cell birth also
occurs, correcting, restoring, and replacing the damaged
nervous system. Both reorganization and repair seem to be
dependent on maintaining an optimal level of neurologicalactivity.
Thus, the basic science evidence suggests that optimizing
the activity of cellular processes, including synapse formation,remyelination, new cell birth, and reorganization and repair,can provide a rationale for fueling a clinical trend in neurorehabilitation based on attempting to achieve optimal activity
following damage to the nervous system. The field of spinal
cord injury allows for an easier exploration of activity-based
concepts because the spinal cord is a ‘‘simpler’’ neurologicalstructure, traditionally responsible for reflexogenic, preprogrammed-type activity.
Assuming most of basic science proven changes related
to activity can be applied to the human spinal cord, activitybased restorative therapies (ABRT) is essentially an arsenal ofpreviously extensively used evidence-based rehabilitative interventions utilized under the premise that impairment repair
leads to improvement in disability and handicap.
ABRTs tools can simply be described as follows: (a) patterned motor activation (i.e., locomotor training, functional
electrical stimulated (FES) ergometry), (b) nonpatterned motor
activation (i.e., recruitment and strengthening, task specifictraining), and (c) sensory stimulation (i.e., sensorimotor therapy).

*Correspondence to: Cristina Sadowsky, International Center for Spinal Cord
Injury, Kennedy Krieger Institute, 707 North Broadway, Suite 518, Baltimore, MD
21205. E-mail: sadowsky@kennedykrieger.org
Received 13 February 2009; Accepted 2 April 2009
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI: 10.1002/ddrr.61

This article predominantly describes studies in animals and humans
with neurologic injuries related to spinal cord injuries. Although the effect ofdifferent forms and amounts of physicalactivity on recovery has been evaluatedin other adult and pediatric neurologicalconditions, like stroke and cerebral palsy(CP), this information will not be
reviewed in this report due to the difficulty of assessing the results of intervention in the context of new onset neurologic damage superimposed on ongoingdevelopmental changes. Thus this articleemphasizes the importance of ABRT toadvancing thinking and practice in thefield of neurorehabilitation, specificallyas it applies to the potential restorationof function in spinal cord injury relatedparalysis.
ROLE OF ACTIVITY IN
NEURORESTORATION: THE
BASIC SCIENCE ARGUMENT
Effect of Activity on Synaptogenesis
Synapses are specialized junctions
between multiple neurons or between
neurons and other cells they interact
with. Synapse formation, strength, andmodulation are all dependent on membrane electrical activity generated byrelease of chemical neurotransmitters.
For example, N-methyl D-aspartate(NMDA) receptor activation induces
synaptogenesis by driving the formationof dendritic spines through intracellular
calcium elevation [Ciani and Salinas,
2008]. Brief presynaptic activity rapidly
converts early nonfunctional contacts
between cultured hippocampal neurons
into functional synapses by enhancing
presynaptic glutamate release [Shenet al., 2006].
Uncontested, activity plays a critical role in development and plasticity
within the nervous system, including
activity-dependent gene expression[Mingo et al., 1997; Ono et al., 1997;
Sgambato et al., 1997; Karlsson andHallbook, 1998; Muslimov et al., 1998].
Activity is also essential for normal synaptic function [Howe, 2003], modification of synaptic strength [Daoudal and
Debanne, 2003; Zhou and Poo, 2004],
homo and heterosynaptic plasticity[Riegle and Meyer, 2007], and synapse
elimination [Zhou and Poo, 2004].
Effect of Activity on Myelination/
Remyelination
Myelination and remyelination areachieved by wrapping a myelin sheatharound an axon. In the peripheral nervous system, myelination and remyelina-

tion is achieved by Schwann cells whilein the CNS the process is done byoligodendrocytes. One Schwann cell
wraps one myelin sheath around a single
axonal segment. One oligodendrocyte
can myelinate up to 40 axons. Axonal
loss, disruption of astro-glial interactions, oligodendroglial default, and dysregulation of cellular environment allplay important roles in remyelination
failure.
Both myelination and remyelination are dependent on neuronal impulse
activity. A significant amount of thebasic science data that supports the roleof activity in myelin formation comesfrom the visual system. Mice reared in
the dark develop fewer myelinatedaxons in the optic nerve compared withnormally reared mice [Gyllensten andMalmfors, 1963]. Myelination is highly
decreased in the optic nerve of blind
cape mole rats [Omlin, 1997], whereaspremature opening of eyelids accelerated the process of myelination in the
optic nerve of rabbit [Tauber et al.,1980].
Other cellular processes involved
in myelination and axonal growth arealso activity dependent. For example,
myelination of the peripheral sciatic
nerve in newborn rats is regulated by
activity controlled potassium exchanges[Wilson and Chiu, 1990]. NMDA dependent axonal growth [Cantallops andRouttenberg, 1999] and adequate dendritic neuronal network development[van Ooyen and van Pelt, 1994] are all
highly regulated by neural activity.
Effect of Activity on New
Cell Birth
Under normal conditions, neurogenesis only occurs in two ‘‘privileged’’
regions of the human adult brain: hippocampus and olfactory system. In the
hippocampus, physical activity stimulates neurogenesis by acting on the proliferation of neuronal stem cells [Kempermann et al., 2000]. In addition tostimulating neurogenesis, exercise andactivity also reverses the decline in neurogenesis commonly associated withaging [van Praag et al., 2005]. Activation of neighboring axons plays a majorrole in the proliferation of oligodendrocyte precursor cells in the developing
rat optic nerve [Barres and Raff, 1993].
Effect of Activity on
Reorganization and Repair
The widespread dependence ofdevelopment and plasticity in the CNS
on neural activity suggests that opti-

mized neural activity might also be important for neural repair.
Activity modulated release ofbrain-derived
neurotrophic
factor(BDNF) seems to occur in both the
CNS [Neeper et al., 1996] and the
peripheral nervous system [Al-Majedet al., 2000]. Beaumont et al. [2008]
compared sedentary T10 spinal cord
injured rats with rats gait trained
through stepping in voluntary wheelcages, then measured lumbar spinal cord
BDNF levels and recorded electromyographic (EMG) tracings from the tibial
motor neuron pool. Trained rats had
significantly decreased stance/swing duration and decreased number of limbs
simultaneously activated in the stancephase. Their lumbar BDNF level waselevated, and there was significant
increase in the amplitude of EMG
extracellular recordings from the tibial
motor neuron pool in response to descending neuronal drive.
There is further evidence of activity dependent neural reorganization andrepair supported by modulation of multiple components of spontaneous regeneration by increasing and decreasingneural activity. Spinalized rats (T10level) underwent motor-driven bicycling of the hind legs starting 2 and 5days after the injury and continuing for
2 weeks. Gene expression of BDNF
and glial cell line-derived neurotrophic
factor (GDNF) was elevated 11- and
14-fold, respectively, in soleus muscle
after one bout of exercise performed 5days after spinal cord transection. When
exercise was started 2 days after the
injury, the changes in gene expression
were not observed. Long-term exercise
for 4 weeks attenuated muscle atrophy
equally well in rats started at 2 days or
5 days after injury [Dupont-Versteegden
et al., 2004]. Mice that underwent 3
weeks of preinjury activity (wheel running) recovered locomotor function significantly better following T9 contusion
injury than mice that were sedentarypreinjury [Engesser-Cesar et al., 2005].
The ability of the adult rat spinal
cord to reorganize through regenerationof lesioned fibers has also been demonstrated. After incomplete spinal cord
injury in rats, transected hindlimb corticospinal tract (CST) axons sprouted into
the cervical gray matter to contact longpropriospinal neurons, which in turnarborized on lumbar motor neurons, creating a new intraspinal circuit relaying
cortical input to its original spinal targets[Bareyre et al., 2004]. In another experiment in rats, the rubrospinal tract reorganized, invading the ventral horn and

Dev Disabil Res Rev  ACTIVITY-BASED RESTORATIVE THERAPIES  SADOWSKY AND MCDONALD

113

connecting to motor neurons normally
innervated by the CST following bilateral
CST transection at its entry into the pyramidal decussation [Raineteau and
Schwab, 2001; Raineteau et al., 2002].
ROLE OF ACTIVITY IN
NEURORESTORATION: THE
CLINICAL SCIENCE
ARGUMENT
Effect of Activity on Function
Optimization
There is no doubt that spinal cord
injuries induce a dramatic decrease in
the amount of physical activity that anindividual exerts [van den Berg-Emonset al., 2008].
Maintaining an adequate level ofphysical activity is undoubtedly helpful
with numerous anatomic, physiological,
and functional characteristics related to
the normal human body, such as cardiovascular function, muscle and bone mass,
longevity [Paffenbarger et al., 2001], cognition [Angevaren et al., 2008] quality oflife [Kell et al., 2001]. Regular physicalactivity can significantly reduce the riskof coronary heart disease [Thompson
et al., 2003], colon cancer, diabetes, andhigh blood pressure. Regular physical activity also helps to: (1) control weight, (2)contribute to healthy bones, muscles, andjoints, (3) reduce falls among the elderly,(4) reduce the pain of arthritis, (5) reduce
symptoms of anxiety and depression, (6)reduce the need for medication, and (7)reduce hospitalizations and physician visits [Fernhall et al., 2008].
Although there is an abundance ofliterature pertaining to the effects ofphysical activity in general population,
the literature pertaining to the SCI population is, understandably, more limited.
However, data related to cardiovascularfunction is plentiful. Individuals withparalysis related to SCI have an added
degree of cardiovascular challenge on
top of deconditioning; their autonomic
nervous system is markedly affectedby the spinal injury, especially if the
injury is above T6-T9 level, where themajor splanchnic autonomic outflow
emerges.
It is well recognized that cardiovascular conditioning can be achieved
and maintained in individuals with SCIrelated paralysis utilizing FES ergometry.
This intervention utilizes a robotic device that delivers a quantified amountof workload. Bhambhani and Maikala[2000] reported that acute FES exercise
produced a 2-fold increase in the oxygen uptake, a 3-fold increase in ventilation rate and a five beats/min increase114

in heart rate from the resting value inseven volunteers with C5 to T12 spinal
cord injury. Kakebeeke et al. [2008]
reported 103% increase in peak oxygen
uptake and 113% increase in maximum
power output after 1 year of homebased FES ergometry training in an
individual with C6 motor complete
SCI. This case study also demonstrated
a significant level of compliance withthe home-based exercise regimen(22.9–82.9%) and the feasibility ofundergoing a sustained, home-based
program, with interventional guidancefrom a trained physical therapist. Faghri
et al. [1992] showed significant decreasein heart rate and blood pressure duringsubmaximal exercise and significant
increase in stroke volume and cardiac
output after completion of a 3 months(three sessions/week) FES training program in 13 individuals with SCI. Raymond et al. [2002] compared low
power output FES training in six individuals with SCI-related paralysis with

Cardiovascularconditioning can beachieved and maintained
in individuals with SCI
related paralysis utilizing
FES ergometry.
voluntary leg cycling in able bodied
individuals and found similar changes inseveral cardiovascular parameters (oxygen uptake, heart rate, and stroke volume).
The role of physical activity andexercise in maintenance of muscle andbone mass in SCI is also well documented. Mohr et al. [1997] reported on
the effect of 1 year FES training in 10
individuals with chronic C6 to T4 SCI.
Their proximal tibia bone mineral density increased by 10% and the bone massgain was reversed after 6 months of subsequent inactivity. Belanger et al. [2000]
reported recovery of 30% lost bone massat the proximal tibia level and significant
muscle strength gains following a 24
weeks resisted quadriceps strengthening
utilizing electrical stimulation. The factthat the bone and muscle gains disappear
after discontinuation of activity [Chenet al., 2005] point to the need for sustained, preferably home-based intervention to maintain physiological gains.

Effect of Activity in
Neurorestoration
Exercise becomes an important
tool when used in individuals withneurological paralysis. It is a treatment thatenhances neurological function by affecting musculoskeletal and neural plasticity.
McDonald et al. [2002] reports ina prospective single case study significant improvement of neurological function in an individual with severe
chronic spinal cord injury after instituting 3 years of patterned neural activity
utilizing FES ergometry. Harness et al.
[2008] reports a prospective study
involving 21 individuals with motor
complete (American Spinal Injury Association (ASIA) impairment A and B)
SCI individuals performing a 6 months
intense exercise program that significantly improved their motor scores(total ASIA motor score, ASIA lower
extremity motor score LEMS) whencompared with a matched group (n 59) that performed a self regulated exercise program. Shields and Dudley-Javoroski [2006] report on significant muscle
properties changes following a 2-yeartraining program utilizing electricallystimulated strengthening of one sided
ankle plantarflexors muscle group whencompared with the untrained, internal
control opposite leg. Significant gains intorque (24%), torque-time integral(27%), fatigue index (50%), torque risetime (45%), and between-twitch fusion(15%) were recorded in the group that
underwent the 2 year training (with a
83% compliance rate). Other studies
showed preservation of muscle fiber
type when electrical stimulation wasapplied shortly (less than 4 weeks) after
acute injury [Crameri et al., 2000].
Long-term FES training reverses muscle
atrophy even in cases of lower motor
neuron injury, universally accepted as‘‘unresponsive’’ to electrical stimulation
and FES [Kern et al., 2005].
THE ROLE OF TASK SPECIFIC
TRAINING (QUALITY) AND
SPINAL CENTRAL PATTERN
GENERATORS ACTIVATION(QUANTITY)
The role of task specific training
is an essential concept in the field of
rehabilitation (‘‘practice makes perfect’’).
But it might not be the only factor
accounting for the success of a therapeutic intervention when rehabilitating
individuals with neural paralysis. In one
cross over design study, eight subjects
with chronic (more than 3 years) ischemic stroke and severe hand dysfunction
underwent two different types of neuro-

Dev Disabil Res Rev  ACTIVITY-BASED RESTORATIVE THERAPIES  SADOWSKY AND MCDONALD

muscular electrical stimulation (NMES).
One was ‘‘active’’ (resulting in grasping
and release of a tennis ball) and one‘‘passive,’’ consisting of sequential wrist
flexion and extension. Both groups had
significant improvements in sensorimotor score and spasticity, with the‘‘active’’ group having also significant
functional gains [Santos et al., 2006].
Beekhuizen and Field-Fote [2008] studied the effect of different patterns ofinterventions (specific task training andsomatosensory peripheral nerve stimulation, specific task training, peripheral
nerve stimulation and no intervention)on the hands of 24 subjects withincomplete tetraplegia. All three intervention groups had functional improvements, but only the group undergoing
specific task training and somatosensory
peripheral nerve stimulation had significant changes in sensory score as well.
The literature supporting specificity in locomotor training following
SCI, using mostly supported gait training on treadmills, is abundant [Barbeau
et al., 2006; Behrman et al., 2006;
Hicks and Ginis, 2008]. As for pediatric
literature, Behrman et al. [2008] reports
the case of a 4 1/2 year old wheelchairdependent child with cervical spinal
cord injury and a lower extremities
motor score of 4/50, 16 months postinjury, who was able to ambulate in thecommunity following 76 sessions oflocomotor training utilizing bodyweight support (BWS) and treadmill
training. The improved ambulatory ability was achieved despite no change inlower extremities muscle strength.
Recent clinical work suggests that
passive or FES-assisted lower extremities
ergometry in pediatric population improvesbone mineral density, muscle volume,
stimulated quadriceps strength, and lowers
the resting heart rate [Johnston, 2008]
The combination of task specificlocomotor training with FES ergometry
may deliver high quality motor activation in sufficient quantity to stimulate
functional restoration in spinal cord
injury. FES ergometry and gait training
both activate the central pattern generators (CPG) located in the lumbar
region of the spinal cord (approximately
L2-5) [Kiehn and Kjaerulff, 1998; Nishimaru and Kudo, 2000]. Very limited
input can cause activation of the CPG
as well as produce interlimb CPG activation [Kiehn and Kjaerulff, 1998; Frigon and Rossignol, 2006]. For example,
focal sensory activation or stimulation as
well as nonfocal activation (e.g., epidural stimulation or intrathecal delivery of
NT-3 or BDNF) can produce complex
lower limb cycling like movements.

There are pragmatic advantages
and disadvantages for both specific gait
training and FES ergometry. Gait training is center-based and can only bedone under direct supervision of rehabilitation specialists. FES ergometry canbe done in a home-based setting, withremote monitoring of compliance (viainternet) (RT 300 ES cycling for adults
and pediatric population; Restorative
Therapies, Baltimore, MD). Gait training is limited by endurance (patient andtherapist alike), while FES ergometry is
only limited by patient’s endurance.
Gait training is operator dependent andrequires highly trained therapists utilizing a standardized technique that suffersfrom significant inter-practitioner variance; FES is delivered by a robotic
device, ensuring repetitive accuracy.
Robotic gait training devices have beenstyle modifications. In the case of paralysis, exercise and physical activity is not aluxury, but needed therapy to manage
the condition. The paralysis ‘‘cure,’’much like the cure for diabetes or hypertension, is still to come. It could evencome from those stem cell trials that weso fondly and ardently talk about. Activity-based interventions are not ‘‘the cure’’for paralysis and might indeed appear expensive at societal level, but they areneeded. The challenge presented here is
to view paralysis like any other devastating disease, where results of standard
treatment are poor (e.g., nonsmall celllung cancer), but patients are stillencouraged to become candidates forstudies evaluating new forms of treatment. ABRTs are evidence-based rehabilitative interventions that are applied
according to a new conceptual paradigm
that uses activity as a tool for neurological recovery, and not only as a means toachieve compensatory function. n

Passive or FES assisted
lower extremities
ergometry in pediatricpopulation improves bonemineral density, muscle
volume, stimulated
quadriceps strength, andlowers the resting heart
rate.

ACKNOWLEDGMENTS
We wish to acknowledge the editorial help provided to us by Ms. Stephanie Fels, Patama Gariensripongsa,
Mollie Lange, and Grethlyn Orr. Also,
my thanks to Ms. Heather Whiting forher invaluable help with the End Notebibliography.

built: the Lokomat and Pediatric Lokomat (Hocoma AG, Switzerland), theAutoambulator (HealthSouth, Birmingham, AL), REOAmbulator (Motorika
Ltd.) but in clinical practice they do not
yet deliver the same results like therapist
guided gait training [Edgerton and Roy,
2009; Hidler et al., 2008].
FUTURE DIRECTIONS AND
THOUGHTSThis article is intended to support
the idea of utilizing physical activity andexercise as a therapeutic intervention in
spinal cord injury, and eventually otherdisorders of the CNS like stroke and CP.
Much like other chronic diseases (i.e.,diabetes mellitus, hypertension), paralysis
is associated with a multitude of complications that ultimately increase morbidity
and mortality. Paralysis does not have acure per se just as diabetes or hypertension are not yet ‘‘curable.’’ We manage
these conditions, utilizing drugs and life

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Dev Disabil Res Rev  ACTIVITY-BASED RESTORATIVE THERAPIES  SADOWSKY AND MCDONALD