Hubli and Dietz Journal of NeuroEngineering and Rehabilitation 2013, 10:5
http://www.jneuroengrehab.com/content/10/1/5

JNER

REVIEW

JOURNAL OF NEUROENGINEERING
AND REHABILITATIONOpen Access

The physiological basis of neurorehabilitation locomotor training after spinal cord injury
Michèle Hubli* and Volker Dietz

Abstract
Advances in our understanding of the physiological basis of locomotion enable us to optimize theneurorehabilitation of patients with lesions to the central nervous system, such as stroke or spinal cord injury (SCI).
It is generally accepted, based on work in animal models, that spinal neuronal machinery can produce a
stepping-like output. In both incomplete and complete SCI subjects spinal locomotor circuitries can be activated byfunctional training which provides appropriate afferent feedback. In motor complete SCI subjects, however, motor
functions caudal to the spinal cord lesion are no longer used resulting in neuronal dysfunction. In contrast, in
subjects with an incomplete SCI such training paradigms can lead to improved locomotor ability. Appropriate
functional training involves the facilitation and assistance of stepping-like movements with the subjects’ legs andbody weight support as far as is required. In severely affected subjects standardized assisted locomotor training isprovided by body weight supported treadmill training with leg movements either manually assisted or moved by adriven gait orthosis. Load- and hip-joint related afferent input is of crucial importance during locomotor training as
it leads to appropriate leg muscle activation and thus increases the efficacy of the rehabilitative training. Successful
recovery of locomotion after SCI relies on the ability of spinal locomotor circuitries to utilize specific multisensory
information to generate a locomotor pattern. It seems that a critical combination of sensory cues is required togenerate and improve locomotor patterns after SCI. In addition to functional locomotor training there are numbersof other promising experimental approaches, such as tonic epidural electrical or magnetic stimulation of the spinal
cord, which both promote locomotor permissive states that lead to a coordinated locomotor output. Therefore, acombination of functional training and activation of spinal locomotor circuitries, for example by epidural/flexor
reflex electrical stimulation or drug application (e.g. noradrenergic agonists), might constitute an effective strategy
to promote neuroplasticity after SCI in the future.
Keywords: Locomotion, Neurorehabilitation, Neuronal plasticity, Spinal cord injury

Introduction
A spinal cord injury (SCI) is a devastating event that, depending on the level and severity, impacts sensorimotor
and autonomous function. In affected subjects the goalof rehabilitative interventions is the regaining of independence and thus a good quality of life. From thepatients perspective this is probably best achieved by targeting restoration of bladder and bowel function, and in
tetraplegic subjects upper limb function [1]. However,recovery of locomotor ability is also of high priority by
SCI subjects independently from the severity, time after
injury and age at the time of injury [2]. It is now widely* Correspondence: mhubli@paralab.balgrist.ch
Spinal Cord Injury Center, Balgrist University Hospital, University of Zurich,
Forchstrasse 340, 8008, Zurich, Switzerland

accepted that the central nervous system is able to recover locomotor function following incomplete SCI withfunctional training on a treadmill combined with partial
body weight support [3-5]. However, the physiologicalrequirements for training effects remain vague. A century of research into the organization of the neuronalprocesses underlying the control of locomotion in mammals has demonstrated that the basic neuronal circuitries responsible for generating efficient stepping patterns
are embedded within the lumbosacral spinal cord [6,7].
These spinal locomotor circuitries appear to play a crucial role in stepping ability in animal models and in
human SCI. This review covers the physiological basis ofeffective locomotor training after SCI. Several studies
in animal models, especially in rats and cats, have© 2013 Hubli and Dietz; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of theCreative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.

Hubli and Dietz Journal of NeuroEngineering and Rehabilitation 2013, 10:5
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unraveled the neuronal principles underlying neurorehabilitation of locomotion after SCI. The role of neuronalplasticity will be discussed in this review. After SCI neuroplasticity in the cortex, brainstem and spinal cord canbe exploited by rehabilitative approaches. This review
will mainly focus on studies of neuroplastic changes atthe spinal level as the knowledge gained from thesestudies is used to create novel translatory neurorehabilitative approaches with the aim to restore and improve
locomotor ability after human SCI.

Neuronal basis of human locomotion

The question, how does the central nervous system coordinate limb movements during locomotion in a seemingly“simple” and automatic manner challenges neuroscientists
for more than a century. At the beginning of the last century (1911) Graham-Brown postulated his “half-center”
hypothesis which demonstrated the intrinsic capacity ofthe mammalian spinal cord to generate rhythmic motor
patterns without descending or sensory input [8]. Subsequently Grillner called these spinal neuronal circuitries
central pattern generators (CPGs). CPGs are embedded
within the lumbosacral spinal segments and are capable ofgenerating stepping-like activation patterns [6]. However,a CPG alone does not appear to be sufficient for overground walking. Locomotion represents the interaction
between the innate pattern and an appropriate modulationof leg muscle activation which has to continuously adapt
to the present requirements, e.g., to the over-ground conditions. Feedback from a variety of sources, e.g., visual,vestibular and proprioceptive systems, is interpreted byand then integrated into the activity of the CPG [9]. The
CPG can open and close reflex pathways in a context- andtask-dependent manner. The sensory feedback and thecontext-specific requirements of the motor task determine
the mode of organization of muscle synergies [10]. Additionally, supraspinal control is needed to provide both thedrive for locomotion as well as the coordination to interact with a complex environment. Corticospinal access tolocomotion control in humans is phase-dependent [11].
Brain centers can initiate CPG activity but the fundamental rhythmicity is hard-wired. For example, in the cat, it
was shown that application of clonidine, a substance mimicking the action of long descending pathways, results indistinct and consistent alternating bursts of electromyographic (EMG) activity which induce spinal stepping [12].
In humans, neuroimaging methods have revealed that
distinct cortical areas, e.g., both the medial primarysensory-motor cortices and the supplementary motor
areas, become activated during locomotion [13,14] andthe size of the activated areas is related to the subjects’walking speed [15]. In addition, more demanding tasks,
such as walking over obstacles, require more cortical

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control, especially during swing phase of stepping inhumans [16] and the cat [17].
Quadrupedal locomotion is characterized by the coordination of forelimb and hindlimb rhythmic activities generated by common spinal neuronal control mechanisms,
i.e., long propriospinal neurons coupling the cervical andlumbar segments [18,19]. This neuronal coupling and coordination of upper and lower limbs that is present inquadrupedal locomotion is preserved in bipedal gait. Unilateral tibial nerve stimulation during locomotion, but notduring sitting or standing, leads to reflex responses in leg
muscles and in the proximal muscles of both arms [20,21].
Such task-dependent coupling of thoraco-lumbar and cervical locomotor centers is flexible and allows humans to
use the upper limb for fine, skilled movements, or alternatively for locomotor tasks, such as swimming or crawling,or for the control of body equilibrium during stepping,e.g., arm swing as a residual function of quadrupedal locomotion [22].
It is important that the neuronal mechanisms underlying human locomotor control in the normal andpathophysiological condition are understood, as it is only
then that it is possible to maximize the recovery of locomotion in patients following central nervous systemdamage.
Focusing on neuronal plasticity brought about by
locomotor training

Modern neurorehabilitation no longer aims to simply
compensate for disabilities in SCI subjects, rather it aims
to functionally regain locomotor ability by exploiting
neural plasticity and/or neural repair. A first question to
ask is, “What is neuronal plasticity?” An example ofneuronal plasticity is the spontaneous reorganizationthat is observed after SCI at the cortical level which canoccur over one year [23]. Next to spontaneously occurring neuronal plasticity, it can also be induced by locomotor training at cortical level [24]. Plastic changes insensorimotor cortex activity are related to functional locomotor recovery after an SCI [25]. Besides cortical plasticity
it seems that other supraspinal centers, such as the cerebellum and brainstem are also important sites of neuronalplasticity in humans receiving locomotor training after
SCI [24]. In humans, it is assumed that supraspinal plasticity is associated with plasticity of spinal neuronal circuits,
but the evidence for this is predominantly from animalmodels of SCI [26].
Spinal neuronal circuits below the level of lesion canbe activated by an appropriate afferent input, and this isconsidered important to sustain functional recovery after
an SCI [9]. In contrast, typical movement disorders after
SCI, e.g., spastic movement disorder, are due to the defective utilization of afferent input in combination withsecondary compensatory mechanisms [27]. It has been

Hubli and Dietz Journal of NeuroEngineering and Rehabilitation 2013, 10:5
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shown that neuronal networks underlying the generationof locomotor patterns of cats [28] and humans [29,30]
have an impressively high level of flexibility after SCI.
Rehabilitative interventions after SCI should therefore
focus on exploiting the plasticity of neuronal circuits,i.e., at supraspinal and/or spinal level, rather than focusing on improving isolated clinical signs, such as muscle
tone or reflex excitability.
The plasticity of spinal neuronal circuits is taskspecific and use-dependent as shown in several earlier
experiments in cats with complete SCI. For example,
after several months of daily step training, spinal catsregained full weight-bearing locomotion on a treadmill[31,32]. If a spinal cat is intensively trained to stand it
develops the ability to support its body weight for up to anhour, but stepping ability on the treadmill remains poor
[33]. These findings suggest that spinal neuronal circuits
learn the sensorimotor task that is specifically practiced
and trained [34]. The repetitive activation of particularsensorimotor pathways by task-specific training canreinforce circuits and synapses used to successfully perform the practiced movement [35,36]. Therefore, the outcome of a neurorehabilitative approach strongly depends
upon the type, the repetition and the quality of the trained
motor function.
Neuronal plasticity is not always positive, anatomical
and neurophysiological observations in animals suggestthat after SCI severed axons degenerate and create freesynaptic territories which could become re-occupied bysprouting of intraspinal fibres [37]. The new neuronal
circuits may be aberrant and can lead to inappropriate
movement patterns or pain in rats [38] and humans [39].
This can largely be prevented by a combination of locomotor training, electrical and pharmacological stimulations of the region of the spinal cord that is deprived ofsupraspinal input which leads to a weight-bearing locomotor capacity in spinal rats [38]. For human SCI, it will
be important to make sure that future neurorehabilitatitive
approaches direct the spontaneous and/or experimentallyinduced (e.g., stem cells or Nogo-A antibodies) neuronalplasticity towards functional synaptic connections that areassociated with an improved locomotor performance.
The decline in supraspinal and peripheral input inhumans after a severe SCI is suggested to be responsible
for the development of a neuronal dysfunction below
the level of lesion [40,41]. Characteristic changes inneuronal behavior occur up to approximately one year
after SCI. At one year post-injury complete and severe
but incomplete SCIs are characterized by an exhaustionof leg muscle activity during assisted locomotion whichis associated with changes in polysynaptic spinal reflexes[42]. Neuronal dysfunction after SCI is assumed to be
dependent more on the subjects’ loss of mobility, i.e.,decreased appropriate afferent information to the CPG,

Page 3 of 8than on the completeness of the injury [43]. Consequently, the better the stepping ability of SCI subjects,
the less the neuronal dysfunction. The functional stateof spinal locomotor circuitries is not fixed after an SCI
and neuronal dysfunction can be improved by intensive
locomotor training over one month, but only in incomplete SCI subjects [43].
Locomotor capacity after spinal cord injury
Locomotor pattern generation: from animal to humanCats with a complete spinal cord transection at thoracic
segments gradually improve hindlimb locomotion on atreadmill following 2–3 weeks of daily locomotor training [31,33]. The spinal cat can relearn walking with alternating steps in the hindlimbs, body weight support
and plantar foot placement. Under such circumstancesthe EMG activity of the hindlimbs was remarkably similar before and after the spinal cord transection. However,the EMG amplitudes of leg extensors were smaller,
whilst the timing between flexor muscles, such as hipand knee joint flexors, was changed and lead to footdragging early in the swing phase [44]. With ongoingtraining it has been shown that the body support can be
decreased and this is associated with improved locomotor capacity until a complete support of body weight
and well-coordinated hindlimb stepping movements are
possible [45]. Experiments in cats as well as non-humanprimates with complete spinal cord lesions have shownthat the isolated spinal cord has the capacity to produce
stepping patterns [46].
There are several indications for the existence of spinal
neuronal circuitries for locomotion generation in humans.
For example, step-like leg movements are present at birthand can be initiated spontaneously or by peripheral stimuli[47]. It is likely that the EMG activity underlying this newborn stepping is produced at the spinal level, as corticospinal projections are not fully grown and myelinated innewborns. In addition, rhythmic: coordinated leg movements have been observed in motor complete SCI subjects,
during sleep [48] and after spinal cord stimulation [49,50].
Effect of locomotor training after SCI

In motor complete and incomplete SCI subjects a coordinated leg muscle activation pattern in both legs can be
induced following partial unloading standing on a moving treadmill (Figure 1) [4,51]. In complete SCI subjects
with no voluntary motor control below the level of lesion leg movements have to be assisted manually or by arobotic device during the whole training period. These
subjects cannot relearn the ability to perform unsupported stepping movements on solid ground, but following such training they experience positive effects on
cardiovascular and musculo-skeletal systems, such as a
reduction of muscle spasms.

Hubli and Dietz Journal of NeuroEngineering and Rehabilitation 2013, 10:5
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Figure 1 Two examples of locomotor activity during assisted
walking in the driven gait orthosis Lokomat in (A) an acute(3 months after SCI) and (B) a chronic (41 months after SCI)
paraplegic subject. Both SCI subjects suffered a motor complete
spinal cord lesion and leg muscle activity was assessed in rectus
femoris (RF), biceps femoris (BF), tibialis anterior (TA) andgastrocnemius medialis (GM) (modified from [42]).

In the early phase of rehabilitation after a severe incomplete SCI, the main limitations for overground ambulation
are usually reduced coordination, leg paresis, and impairedbalance. Therefore, at the beginning of the training program locomotor training has to be assisted either by physiotherapists or a robotic device (e.g. Lokomat). Duringassisted locomotion in incomplete SCI subjects theinduced leg muscle EMG activity is modulated over the
step cycles in a similar way to as observed in healthy subjects. However, the amplitude of leg muscle activity is considerably smaller and corresponds to the degree of paresis
probably due to a diminished noradrenergic input to spinal
locomotor circuitries [45]. Providing full body unloading
during robotic assisted walking in complete paraplegic subjects does not lead to significant leg muscle activation [52],i.e., ground contact is essential for leg muscle activation.
During the course of an assisted locomotor training program, the EMG amplitudes of gastrocnemius activity increase during the stance phase, while inappropriate tibialis

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anterior activation decreases [53]. This leads to an improvement in weight bearing function during stance phaseand thus allows a decrease of body unloading duringassisted treadmill locomotion. The successive reloading of
the SCI subjects might be an important stimulus for extensor load receptors which are essential for leg extensor activation during locomotion in cats [54] and humans [55,56].
The general rehabilitation strategy to regain locomotor
ability after SCI or stroke is based on the principles ofmotor learning, such as task-specificity, task-variability,
feedback information and the intensity of training. So far
training paradigms for robotic assisted treadmill training
in human SCI rely on suggestions by experts and single
observational studies. However, no study has so far
determined the essential components required for a
locomotor training setup in individuals with SCI or inanimal models of SCI. Several questions remain to beanswered, for example, how early should the training therapy start, how intensive should it be, e.g., 30 min or morethan 1 hour and how many times a week? It is not yet
clear whether a longer duration of training results in an
improved outcome or if certain endpoints, in terms ofwalking capacity, can be achieved within shorter periodsof time. This question has so far only been addressed instroke subjects where a longer duration of early onset augmented locomotor training, i.e., 16 hours within the first
6 months after insult, was correlated with improved walking performance (positive dose–response relationship)[57]. Whether this relationship is also applicable to the
SCI community will be investigated by a controlled randomized multicenter study [58]. In addition, it remains to be
determined which training paradigms fit the best to which
SCI subjects and how this training could be adapted in difficulty, e.g., by the amount of body weight support, guidance force, treadmill speed. In stroke subjects higher
treadmill speeds lead to better locomotor recovery thanlower treadmill speeds [59]. It is assumed that these training principles which were applied in stroke subjects arealso reasonable for successful training in SCI subjects. In
general, locomotor training should always be challenging
for patients with only minimal support provided by therapists or robotic devices.
Appropriate sensory cues

After an incomplete SCI, spared corticospinal and/or propriospinal pathways can play an active role in the recovery
of locomotion. However, under these circumstances theintrinsic capacity of spinal locomotor circuitries and thesensory feedback information still remains as the basis forgenerating a locomotor pattern. The spinal locomotor circuitries interact dynamically with specific afferent inputs
from receptors located in muscles, joints, and skin, andthis interaction shapes the locomotor output (for review
see [9]). The sensory input most relevant for locomotion

Hubli and Dietz Journal of NeuroEngineering and Rehabilitation 2013, 10:5
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comes primarily from stretch- and load-sensitive mechanoreceptors located in the muscles and skin. Afferent information from hip flexors and ankle extensors is particularly
important for the stance to swing transition phase in cats[60]. Furthermore, sensory input from the skin mechanoreceptors of the paw are involved in positioning the paws
and, therefore, become increasingly important during
complex locomotor tasks in which precise paw placement
is required, e.g., ladder walking in the cat [61]. Skin receptors on the dorsal foot play a role during the swing phaseof walking over obstacles in both cats [62] and humans[63] and cutaneous input from the plantar surface of thepaw reinforces extensor activity in decerebrated cats walking on a treadmill [64]. Group II hip flexor afferents,group I ankle extensor afferents, and low-threshold cutaneous afferents from the cat paw are assumed to have direct access to spinal locomotor circuitries with the ability
to reset or entrain fictive locomotion in adult decerebrated
cats [65].
Afferent inputs from load and hip joint receptors are essential for the activation of leg muscle activity during locomotion in paraplegic subjects in a corresponding way to incats, [52,66]. Load information is provided for proprioceptive input from leg extensor muscles, namely Ib afferent
signals from Golgi tendon organs, and probably also frommechanoreceptors in the foot sole (see Figure 2) [67]. This
information is thought to be integrated into polysynaptic
spinal reflex pathways that adapt the autonomous locomotor pattern to the actual ground condition and it isassumed that the Ib afferent input from leg extensors

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during the stance phase inhibits the flexor activity. This isfunctionally meaningful because loading of the stance limb
has to decrease before swing can be initiated and leg extensor activity is reinforced during the stance phase bypositive feedback [68]. In addition, the role of hip joint
afferents is assumed to control phase transition andreinforce ongoing activity as it has been shown in decerebrated cats [65]. The observations that in motor complete
paraplegic subjects assisted stepping movements within adriven gait orthosis and restricted movements of the hips
(blocked knees) induces a patterned leg muscle EMG activity, highlights the significance of hip joint receptors in
the generation of locomotor activity [52]. Such thatassisted stepping movements restricted to imposed ankle
joints were followed by no, or only focal reflex responses
in the stretched muscles [52].
Modulation of spinal neuronal excitability

The importance of appropriate afferent information fromperipheral receptors as a source of controlling locomotion
became obvious from experiments, during the last decades, in completely transected animals. The inability to
produce locomotor patterns after a severe SCI is, to a large
extent, due to the depressed functional state of spinal
locomotor circuitries [69]. It is believed that reduced sensory feedback after SCI has a negative impact on locomotor recovery. Therefore, there is a need to develop
tools to artificially activate spinal cord pattern generators.
Besides the essential sensory cues provided during locomotor training, i.e., from body loading and hip joint

Figure 2 Influence of body loading on leg muscle EMG activity. Loading/unloading effects on the EMG activity of the left tibialis anterior (TA,ankle flexor) and gastrocnemius medialis (GM, ankle extensor). EMGs are the averages from seven healthy subjects. Three walking conditions areshown: normal body loading (NBL), 30% body loading (BL), and 60% body unloading (BU). In all subjects, there was a strong reduction of GM
EMG activity during BU compared with NBL and 30% BL walking (modified from [67]).

Hubli and Dietz Journal of NeuroEngineering and Rehabilitation 2013, 10:5
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afferents, there has been much effort spent in developing
additional strategies to increase the excitability of spinal
neuronal circuitries in order to tune the physiologicalstate of these circuitries to a level that leads to a facilitation of the locomotor patterns in humans. These
approaches include continuous vibration of the quadriceps
and hamstring muscle groups [70], continuous electricalstimulation of the peroneal or sural nerve [71], and magnetic stimulation of the spinal cord [72]. The latter approach of repetitive electromagnetic stimulation shows
positive effects on spastic muscle tone in patients with diverse neurological diseases [73-75]. So far only one study
investigated the effect of repetitive magnetic stimulation
applied at the thoracolumbar vertebral level on spinal locomotor circuitries in healthy subjects [72]. The mostfavourable stimulation parameters to induce stepping-like
activity in the legs placed in a gravity-neutral position wereobserved to be 3 Hz, 1.3 -1.82 tesla at the T11-12 vertebrae[72]. However, there is no proof that this kind of magnetic
stimulation is able to evoke sufficient leg muscle activation
to lead to load-bearing locomotion in SCI subjects.
In contrast to the low frequency (3 Hz) for thoracolumbar levels, higher frequencies (20–30 Hz) are necessary for
peripheral nerve stimulation to decrease spastic muscle
tone [74] and also for electrical epidural stimulation(~ 40 Hz) at the lumbar spinal cord in complete SCI subjects to induce stepping-like activity [49,76,77]. In addition
to electrical or magnetic stimulation approaches, diverse
pharmacological agents, such as serotonergic and noradrenergic agonists, can activate spinal locomotor circuitries in
rats, cats and mice [38,78,79]. However, so far there is only
limited evidence about whether pharmacological agentsfacilitate locomotor recovery following human SCI (for review see [80]). Recently, two new noninvasive methods,
namely transcutaneous spinal direct current stimulation(tsDCS) [81-83] and paired spinal associative stimulationsof H-reflexes and transcranial magnetic stimulation [84],have been applied to modulate spinal excitability andmight be a promising tool for the modulation of sensorimotor pathways underlying functional movements.
TsDCS is a method derived from transcranial direct
current stimulation and it influences neuronal excitability
by anodal or cathodal polarization. Anodal stimulation typically increases neuronal firing rates in stimulated corticalareas, whereas cathodal stimulation evokes the opposite
effect, i.e., inhibition. Depending on the duration andstrength of polarization, these changes can persist for morethan one hour after stimulation [85]. For the spinal approach the electrode positions are changed from the scalp
to one electrode at T11 vertebral level and the other electrode on a shoulder region [81-83,86,88]. The polarizationof the stimulation (anodal or cathodal) refers to the spinal
electrode. TsDCS is applied for 15 min with a stimulation
intensity of 2.5 mA. Depending on the electrode size

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(between 35 and 40 cm2) these stimulation parameters result in a total delivered charge of 0.056 and 0.064 C/cm2
respectively [81-83,86,87]. The dispersion and density of
the current is, however, hard to predict due to the large
volume of the conductor surrounding the target tissue. So
far tsDCS has only been applied in healthy subjects as atool to modulate trans-synaptic efficacy in monosynaptic[82,86] and polysynaptic reflex pathways [83], dorsal column function [81] or pain thresholds [87]. The effect on
the excitability of spinal locomotor circuitries, especially in
SCI subject, needs to be addressed in the future.

Conclusion
Designing effective neurorehabilitation after SCI depends
on having knowledge about the neuronal mechanisms
involved in normal and pathological movement conditions, such as the interactions between central programs
and afferent feedback as well as the quadrupedal coordination of human locomotion. Task-specific rehabilitation to
improve locomotor function after SCI is well established[51,88]. In addition, there is growing evidence that theenhanced application of afferent input to the spinal cord,for example by electrical epidural stimulation of the spinal
cord, can lead to a facilitation of standing and steppinglike activity during assisted leg movements in human SCI[77]. Consequently, it is argued that specific multipronged neurorehabilitative approaches will pave the way
for more efficient therapeutic strategies to improve locomotor function in severely affected SCI subjects [89]. The
aim of new neurorehabilitative approaches should be to
optimize the use of task-specific sensory cues in order tofacilitate locomotor pattern generation involving arm
movements and the provision of approaches favouring therecruitment of both spinal circuitries and spared supraspinal connections during rehabilitation.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
MH structured the content of the review and wrote the draft of themanuscript. VD made the revisions of the whole article. Both authors readand approved the final version of the manuscript.
Acknowledgements
This review has been carried out with financial support from the Wings forLife foundation. A special thank goes to Michelle Starkey for her editorial
help.
Received: 27 March 2012 Accepted: 7 January 2013
Published: 21 January 2013
References
1. Anderson KD: Targeting recovery: priorities of the spinal cord-injured
population. J Neurotrauma 2004, 21(10):1371–1383.
2. Ditunno PL, Patrick M, Stineman M, Ditunno JF: Who wants to walk?
Preferences for recovery after SCI: a longitudinal and cross-sectional
study. Spinal Cord 2008, 46(7):500–506.

Hubli and Dietz Journal of NeuroEngineering and Rehabilitation 2013, 10:5
http://www.jneuroengrehab.com/content/10/1/5

3.

4.
5.

6.
7.
8.
9.
10.

11.

12.

13.

14.

15.

16.

17.
18.

19.
20.

21.
22.
23.

24.

25.

26.
27.
28.

Barbeau H, McCrea DA, O'Donovan MJ, Rossignol S, Grill WM, Lemay MA:
Tapping into spinal circuits to restore motor function. Brain Res Rev 1999,
30(1):27–51.
Dietz V, Colombo G, Jensen L: Locomotor activity in spinal man.
Lancet 1994, 344(8932):1260–1263.
Wernig A, Muller S: Laufband locomotion with body weight support
improved walking in persons with severe spinal cord injuries. Paraplegia
1992, 30(4):229–238.
Grillner S: Neurobiological bases of rhythmic motor acts in vertebrates.
Science 1985, 228(4696):143–149.
Sherrington CS: Flexion-reflex of the limb, crossed extension reflex, andreflex stepping and standing. J Physiol (Lond) 1910, 40:28–121.
Graham-Brown T: The intrinsic factors in the act of progression in the
mammal. Proc R Sopc Lond B Biol Sci 1911, 84:308–319.
Rossignol S, Dubuc R, Gossard JP: Dynamic sensorimotor interactions inlocomotion. Physiol Rev 2006, 86(1):89–154.
Horak FB, Nashner LM: Central programming of postural movements:
adaptation to altered support-surface configurations. J Neurophysiol 1986,
55(6):1369–1381.
Schubert M, Curt A, Jensen L, Dietz V: Corticospinal input in human gait:
modulation of magnetically evoked motor responses. Exp Brain Res 1997,
115(2):234–246.
Edgerton VR, Roy RR, Hodgson JA, Prober RJ, de Guzman CP, de Leon R:
Potential of adult mammalian lumbosacral spinal cord to execute andacquire improved locomotion in the absence of supraspinal input.
J Neurotrauma 1992, 9(1):119–128.
Miyai I, Tanabe HC, Sase I, Eda H, Oda I, Konishi I, Tsunazawa Y, Suzuki T,
Yanagida T, Kubota K: Cortical mapping of gait in humans: a near-infrared
spectroscopic topography study. Neuroimage 2001, 14(5):1186–1192.
Fukuyama H, Ouchi Y, Matsuzaki S, Nagahama Y, Yamauchi H, Ogawa M,
Kimura J, Shibasaki H: Brain functional activity during gait in normal
subjects: a SPECT study. Neurosci Lett 1997, 228(3):183–186.
Suzuki M, Miyai I, Ono T, Oda I, Konishi I, Kochiyama T, Kubota K: Prefrontal
and premotor cortices are involved in adapting walking and runningspeed on the treadmill: an optical imaging study. Neuroimage 2004,
23(3):1020–1026.
Schubert M, Curt A, Colombo G, Berger W, Dietz V: Voluntary control ofhuman gait: conditioning of magnetically evoked motor responses in a
precision stepping task. Exp Brain Res 1999, 126(4):583–588.
Armstrong DM: The supraspinal control of mammalian locomotion.
J Physiol 1988, 405:1–37.
Cazalets JR, Bertrand S: Coupling between lumbar and sacral motor
networks in the neonatal rat spinal cord. Eur J Neurosci 2000,
12(8):2993–3002.
Nathan PW, Smith M, Deacon P: Vestibulospinal, reticulospinal anddescending propriospinal nerve fibres in man. Brain 1996, 119:1809–1833.
Michel J, van Hedel HJ, Dietz V: Obstacle stepping involves spinal
anticipatory activity associated with quadrupedal limb coordination.
Eur J Neurosci 2008, 27(7):1867–1875.
Dietz V, Fouad K, Bastiaanse CM: Neuronal coordination of arm and leg
movements during human locomotion. Eur J Neurosci 2001, 14(11):1906–1914.
Dietz V: Do human bipeds use quadrupedal coordination? Trends Neurosci
2002, 25(9):462–467.
Jurkiewicz MT, Mikulis DJ, McIlroy WE, Fehlings MG, Verrier MC:
Sensorimotor cortical plasticity during recovery following spinal cord
injury: a longitudinal fMRI study. Neurorehabil Neural Repair 2007,
21(6):527–538.
Winchester P, McColl R, Querry R, Foreman N, Mosby J, Tansey K, Williamson
J: Changes in supraspinal activation patterns following robotic
locomotor therapy in motor-incomplete spinal cord injury. Neurorehabil
Neural Repair 2005, 19(4):313–324.
Lundell H, Christensen MS, Barthelemy D, Willerslev-Olsen M, BieringSorensen F, Nielsen JB: Cerebral activation is correlated to regional
atrophy of the spinal cord and functional motor disability in spinal cord
injured individuals. Neuroimage 2011, 54(2):1254–1261.
Tansey KE: Neural plasticity and locomotor recovery after spinal cord
injury. Pm R 2010, 2(12):220–226.
Dietz V, Sinkjaer T: Spastic movement disorder: impaired reflex function
and altered muscle mechanics. Lancet Neurol 2007, 6(8):725–733.
Pearson KG: Neural adaptation in the generation of rhythmic behavior.
Annu Rev Physiol 2000, 62:723–753.

Page 7 of 8

29. Dietz V: Proprioception and locomotor disorders. Nat Rev Neurosci 2002,
3(10):781–790.
30. Edgerton VR, Tillakaratne NJ, Bigbee AJ, de Leon RD, Roy RR: Plasticity ofthe spinal neural circuitry after injury. Annu Rev Neurosci 2004, 27:145–167.
31. Barbeau H, Rossignol S: Recovery of locomotion after chronic
spinalization in the adult cat. Brain Res 1987, 412(1):84–95.
32. Lovely RG, Gregor RJ, Roy RR, Edgerton VR: Effects of training on therecovery of full-weight-bearing stepping in the adult spinal cat. Exp
Neurol 1986, 92(2):421–435.
33. De Leon RD, Hodgson JA, Roy RR, Edgerton VR: Full weight-bearing
hindlimb standing following stand training in the adult spinal cat.
J Neurophysiol 1998, 80(1):83–91.
34. Tillakaratne NJ, de Leon RD, Hoang TX, Roy RR, Edgerton VR, Tobin AJ: Usedependent modulation of inhibitory capacity in the feline lumbar spinal
cord. J Neurosci 2002, 22(8):3130–3143.
35. Edgerton VR, Courtine G, Gerasimenko YP, Lavrov I, Ichiyama RM, Fong AJ,
Cai LL, Otoshi CK, Tillakaratne NJ, Burdick JW, Roy RR: Training locomotor
networks. Brain Res Rev 2008, 57(1):241–254.
36. Cai LL, Courtine G, Fong AJ, Burdick JW, Roy RR, Edgerton VR: Plasticity offunctional connectivity in the adult spinal cord. Philos Trans R Soc Lond B
Biol Sci 2006, 361(1473):1635–1646.
37. Hou S, Duale H, Cameron AA, Abshire SM, Lyttle TS, Rabchevsky AG:
Plasticity of lumbosacral propriospinal neurons is associated with thedevelopment of autonomic dysreflexia after thoracic spinal cord
transection. J Comp Neurol 2008, 509(4):382–399.
38. Courtine G, Gerasimenko Y, van den Brand R, Yew A, Musienko P, Zhong H,
Song B, Ao Y, Ichiyama RM, Lavrov I, et al: Transformation of nonfunctional
spinal circuits into functional states after the loss of brain input.
Nat Neurosci 2009, 12(10):1333–1342.
39. Maegele M, Muller S, Wernig A, Edgerton VR, Harkema SJ: Recruitment of
spinal motor pools during voluntary movements versus stepping after
human spinal cord injury. J Neurotrauma 2002, 19(10):1217–1229.
40. Hubli M, Bolliger M, Dietz V: Neuronal dysfunction in chronic spinal cord
injury. Spinal Cord 2011, 49(5):582–587.
41. Dietz V: Behavior of spinal neurons deprived of supraspinal input. Nat
Rev Neurol 2010, 6(3):167–174.
42. Dietz V, Grillner S, Trepp A, Hubli M, Bolliger M: Changes in spinal reflex
and locomotor activity after a complete spinal cord injury: a common
mechanism? Brain 2009, 132(8):2196–2205.
43. Hubli M, Dietz V, Bolliger M: Spinal reflex activity: a marker for neuronal
functionality after spinal cord injury. Neurorehabil Neural Repair 2012,26(2):188–196.
44. Belanger M, Drew T, Provencher J, Rossignol S: A comparison of treadmill
locomotion in adult cats before and after spinal transection.
J Neurophysiol 1996, 76(1):471–491.
45. Barbeau H, Rossignol S: Enhancement of locomotor recovery following
spinal cord injury. Curr Opin Neurol 1994, 7(6):517–524.
46. Vilensky JA, O'Connor BL: Stepping in nonhuman primates with acomplete spinal cord transection: old and new data, and implications forhumans. Ann N Y Acad Sci 1998, 860:528–530.
47. Forssberg H: Ontogeny of human locomotor control. I. Infant stepping,supported locomotion and transition to independent locomotion. Exp
Brain Res 1985, 57(3):480–493.
48. Lee MS, Choi YC, Lee SH, Lee SB: Sleep-related periodic leg movements
associated with spinal cord lesions. Mov Disord 1996, 11(6):719–722.
49. Dimitrijevic MR, Gerasimenko Y, Pinter MM: Evidence for a spinal
central pattern generator in humans. Ann N Y Acad Sci 1998,
860:360–376.
50. Rosenfeld JE, Sherwood AM, Halter JA, Dimitrijevic MR: Evidence of apattern generator in paralyzed subject with spinal cord stimulation.
Soc Neurosci Abstr 1995, 21:688.
51. Dietz V, Harkema SJ: Locomotor activity in spinal cord-injured persons.
J Appl Physiol 2004, 96(5):1954–1960.
52. Dietz V, Muller R, Colombo G: Locomotor activity in spinal man:significance of afferent input from joint and load receptors. Brain 2002,
125(12):2626–2634.
53. Dietz V, Colombo G, Jensen L, Baumgartner L: Locomotor capacity ofspinal cord in paraplegic patients. Ann Neurol 1995, 37(5):574–582.
54. Pearson KG, Collins DF: Reversal of the influence of group Ib afferents
from plantaris on activity in medial gastrocnemius muscle duringlocomotor activity. J Neurophysiol 1993, 70(3):1009–1017.

Hubli and Dietz Journal of NeuroEngineering and Rehabilitation 2013, 10:5
http://www.jneuroengrehab.com/content/10/1/5

55. Dietz V, Colombo G: Effects of body immersion on postural adjustments
to voluntary arm movements in humans: role of load receptor input.
J Physiol 1996, 497:849–856.
56. Dietz V, Gollhofer A, Kleiber M, Trippel M: Regulation of bipedal stance:
dependency on "load" receptors. Exp Brain Res 1992, 89(1):229–231.
57. Kwakkel G, van Peppen R, Wagenaar RC, Wood Dauphinee S, Richards C,
Ashburn A, Miller K, Lincoln N, Partridge C, Wellwood I, Langhorne P: Effects
of augmented exercise therapy time after stroke: a meta-analysis. Stroke
2004, 35(11):2529–2539.
58. Wirz M, Bastiaenen C, de Bie R, Dietz V: Effectiveness of automatedlocomotor training in patients with acute incomplete spinal cord injury:
a randomized controlled multicenter trial. BMC Neurol 2011, 11:60.
59. Pohl M, Mehrholz J, Ritschel C, Ruckriem S: Speed-dependent treadmill
training in ambulatory hemiparetic stroke patients: a randomized
controlled trial. Stroke 2002, 33(2):553–558.
60. Pearson KG: Role of sensory feedback in the control of stance duration inwalking cats. Brain Res Rev 2008, 57(1):222–227.
61. Bouyer LJ, Rossignol S: Contribution of cutaneous inputs from thehindpaw to the control of locomotion. I Intact cats J Neurophysiol 2003,
90(6):3625–3639.
62. Forssberg H: Stumbling corrective reaction: a phase-dependentcompensatory reaction during locomotion. J Neurophysiol 1979,
42(4):936–953.
63. Schillings AM, van Wezel BM, Mulder T, Duysens J: Muscular responses andmovement strategies during stumbling over obstacles. J Neurophysiol
2000, 83(4):2093–2102.
64. Duysens J, Pearson KG: The role of cutaneous afferents from the distal
hindlimb in the regulation of the step cycle of thalamic cats. Exp Brain
Res 1976, 24:245–255.
65. Frigon A, Sirois J, Gossard JP: Effects of ankle and hip muscle afferent
inputs on rhythm generation during fictive locomotion. J Neurophysiol
2010, 103(3):1591–1605.
66. Harkema SJ, Hurley SL, Patel UK, Requejo PS, Dobkin BH, Edgerton VR:
Human lumbosacral spinal cord interprets loading during stepping.
J Neurophysiol 1997, 77(2):797–811.
67. Bastiaanse CM, Duysens J, Dietz V: Modulation of cutaneous reflexes byload receptor input during human walking. Exp Brain Res 2000,
135(2):189–198.
68. Prochazka A, Gillard D, Bennett DJ: Positive force feedback control ofmuscles. J Neurophysiol 1997, 77(6):3226–3236.
69. Harkema SJ: Plasticity of interneuronal networks of the functionallyisolated human spinal cord. Brain Res Rev 2008, 57(1):255–264.
70. Gurfinkel VS, Levik YS, Kazennikov OV, Selionov VA: Locomotor-likemovements evoked by leg muscle vibration in humans. Eur J Neurosci
1998, 10(5):1608–1612.
71. Selionov VA, Ivanenko YP, Solopova IA, Gurfinkel VS: Tonic central andsensory stimuli facilitate involuntary air-stepping in humans.
J Neurophysiol 2009, 101(6):2847–2858.
72. Gerasimenko Y, Gorodnichev R, Machueva E, Pivovarova E, Semyenov D,
Savochin A, Roy RR, Edgerton VR: Novel and direct access to the humanlocomotor spinal circuitry. J Neurosci 2010, 30(10):3700–3708.
73. Nielsen JF, Sinkjaer T, Jakobsen J: Treatment of spasticity with repetitive
magnetic stimulation; a double-blind placebo-controlled study. Mult Scler
1996, 2(5):227–232.
74. Krause P, Edrich T, Straube A: Lumbar repetitive magnetic stimulation
reduces spastic tone increase of the lower limbs. Spinal Cord 2004,
42(2):67–72.
75. Nielsen JF, Sinkjaer T: Long-lasting depression of soleus motoneurons
excitability following repetitive magnetic stimuli of the spinal cord in
multiple sclerosis patients. Mult Scler 1997, 3(1):18–30.
76. Minassian K, Persy I, Rattay F, Pinter MM, Kern H, Dimitrijevic MR: Human
lumbar cord circuitries can be activated by extrinsic tonic input togenerate locomotor-like activity. Hum Mov Sci 2007, 26(2):275–295.
77. Harkema S, Gerasimenko Y, Hodes J, Burdick J, Angeli C, Chen Y, Ferreira C,
Willhite A, Rejc E, Grossman RG, Edgerton VR: Effect of epidural stimulationof the lumbosacral spinal cord on voluntary movement, standing, andassisted stepping after motor complete paraplegia: a case study.
Lancet 2011, 377(9781):1938–1947.
78. Rossignol S, Giroux N, Chau C, Marcoux J, Brustein E, Reader TA:
Pharmacological aids to locomotor training after spinal injury in the cat.
J Physiol 2001, 533(1):65–74.

Page 8 of 8

79. Lapointe NP, Guertin PA: Synergistic effects of D1/5 and 5-HT1A/7
receptor agonists on locomotor movement induction in complete spinal
cord-transected mice. J Neurophysiol 2008, 100(1):160–168.
80. Domingo A, Al-Yahya AA, Asiri YA, Eng JJ, Lam T: A systematic review on
the effects of pharmacological agents on walking function in people
with spinal cord injury. J Neurotrauma 2012, 29(5):865–879.
81. Cogiamanian F, Vergari M, Pulecchi F, Marceglia S, Priori A: Effect of spinal
transcutaneous direct current stimulation on somatosensory evoked
potentials in humans. Clin Neurophysiol 2008, 119(11):2636–2640.
82. Winkler T, Hering P, Straube A: Spinal DC stimulation in humans
modulates post-activation depression of the H-reflex depending on
current polarity. Clin Neurophysiol 2010, 121(6):957–961.
83. Cogiamanian F, Vergari M, Schiaffi E, Marceglia S, Ardolino G, Barbieri S,
Priori A: Transcutaneous spinal cord direct current stimulation inhibits
the lower limb nociceptive flexion reflex in human beings. Pain 2010,
152(2):370–375.
84. Cortes M, Thickbroom GW, Valls-Sole J, Pascual-Leone A, Edwards DJ: Spinal
associative stimulation: a non-invasive stimulation paradigm tomodulate spinal excitability. Clin Neurophysiol 2011, 122(11):2254–2259.
85. Nitsche MA, Fricke K, Henschke U, Schlitterlau A, Liebetanz D, Lang N,
Henning S, Tergau F, Paulus W: Pharmacological modulation of corticalexcitability shifts induced by transcranial direct current stimulation inhumans. J Physiol 2003, 553(1):293–301.
86. Lamy JC, Ho C, Badel A, Arrigo RT, Boakye M: Modulation of Soleus
H-reflex by spinal DC stimulation in humans. J Neurophysiol 2012,
doi:10.1152/jn.10898.2011.
87. Truini A, Vergari M, Biasiotta A, La Cesa S, Gabriele M, Di Stefano G, Cambieri
C, Cruccu G, Inghilleri M, Priori A: Transcutaneous spinal direct current
stimulation inhibits nociceptive spinal pathway conduction andincreases pain tolerance in humans. Eur J Pain 2011, 15(10):1023–1027.
88. Wirz M, Zemon DH, Rupp R, Scheel A, Colombo G, Dietz V, Hornby TG:
Effectiveness of automated locomotor training in patients with chronic
incomplete spinal cord injury: a multicenter trial. Arch Phys Med Rehabil
2005, 86(4):672–680.
89. Musienko P, Heutschi J, Friedli L, van den Brand R, Courtine G: Multi-systemneurorehabilitative strategies to restore motor functions following
severe spinal cord injury. Exp Neurol 2012, 235(1):100–109.
doi:10.1186/1743-0003-10-5
Cite this article as: Hubli and Dietz: The physiological basis ofneurorehabilitation - locomotor training after spinal cord injury. Journalof NeuroEngineering and Rehabilitation 2013 10:5.

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