Hindawi Publishing Corporation
Neural Plasticity
Volume 2012, Article ID 254948, 13 pages
doi:10.1155/2012/254948

Review Article
Plasticity of Corticospinal Neural Control after
Locomotor Training in Human Spinal Cord Injury
Maria Knikou1, 2, 3, 4
1 Graduate Center and Physical Therapy Department, College of Staten Island, City University of New York,Staten Island, NY 10314, USA
2 Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
3 Sensory Motor Performance Program, Rehabilitation Institute of Chicago, Chicago, IL 60611-2654, USA
4 Electrophysiological Analysis of Gait and Posture Laboratory, Rehabilitation Institute of Chicago, Chicago, IL 60611, USA

Correspondence should be addressed to Maria Knikou, maria.knikou@csi.cuny.edu
Received 14 February 2012; Revised 9 April 2012; Accepted 10 April 2012
Academic Editor: Marie-Hélène Canu
Copyright © 2012 Maria Knikou. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Spinal lesions substantially impair ambulation, occur generally in young and otherwise healthy individuals, and result indevastating eﬀects on quality of life. Restoration of locomotion after damage to the spinal cord is challenging because axonsof the damaged neurons do not regenerate spontaneously. Body-weight-supported treadmill training (BWSTT) is a therapeutic
approach in which a person with a spinal cord injury (SCI) steps on a motorized treadmill while some body weight is removed
through an upper body harness. BWSTT improves temporal gait parameters, muscle activation patterns, and clinical outcome
measures in persons with SCI. These changes are likely the result of reorganization that occurs simultaneously in supraspinal andspinal cord neural circuits. This paper will focus on the cortical control of human locomotion and motor output, spinal reflex
circuits, and spinal interneuronal circuits and how corticospinal control is reorganized after locomotor training in people with
SCI. Based on neurophysiological studies, it is apparent that corticospinal plasticity is involved in restoration of locomotion after
training. However, the neural mechanisms underlying restoration of lost voluntary motor function are not well understood andtranslational neuroscience research is needed so patient-orientated rehabilitation protocols to be developed.

1. Introduction
Spinal cord injuries (SCIs) cause substantial social, economic, and health burdens. In the majority of cases, thespinal cord is not completely severed and thus some fiber
tracts and segmental spinal cord circuits remain intact [1],which determine the preserved functions and provide thebasis for functional restoration. In incomplete SCI persons,recovery of sensorimotor function increases progressively
during the first year [2], with reorganization of sensory andmotor cortices [3] to lead to recovery of function and maladaptive behavior. In para- and tetraplegic patients, the cortical hand area was expanded towards the cortical leg area andwas diﬀerent based on the lesion level [4]. Further, in paraplegic patients the representation of the nonimpaired upper
limb muscles was modified showing an increased activation in the corresponding primary motor cortex (M1), in

the parietal cortex, supplementary motor area, and cerebellum [5]. An fMRI study in rats showed that after midthoracic
spinal cord transection, deaﬀerented hindlimb territories in
S1 exhibited responses to electrical stimulation of the unaffected forepaw, presumably mediated by both spinothalamicand dorsal column nuclei pathways [6]. Evidence suggeststhat functional plasticity of motor cortical representations ismediated by an anatomical framework of preexisting projections that transverse representation borders [7].
In addition to spontaneous reorganization of the brain
after SCI, spinal cord circuitries have the capacity to alter
their structure and function with motor training [8], as
supported by the physiological leg muscle activation patterns
observed after locomotor training in spinalized animals [9–14]. Body weight-supported treadmill training (BWSTT) isa therapeutic approach in which a person with SCI steps ona motorized treadmill while some body weight is removed

2
through an upper body harness [15] and repetitive rhythmic
leg movement patterns are promoted either through manual
assistance provided by therapists or through a robotic
exoskeleton system. Evidence that supports this intervention
has been derived largely from studies conducted in spinalized
animals [16–19]. Specifically, treadmill training increases
axonal regrowth and collateral sprouting proximal to thelesion site in mice [20], phosphorylation of Erk1/2 in the
motor cortex as well as the spinal cord injury area [21],expression of brain-derived neurotrophic factor (BDNF) in
the spinal cord [22], ameliorates muscle atrophy in moderatecontused SCI rats [23], and alters properties of spinal motor
neurons [24]. These changes are only a small representationof activity-dependent plasticity located at the synaptic terminals of a variety of systems, that involves physiological,
structural, and biochemical changes (see more in [25, 26]).
In humans, BWSTT improves lower extremity motorscores, increases the amplitude of muscle activity in the ankle
extensors during the stance phase of walking, and improves
walking ability and clinical outcome measures [27–31].
A recent single-blind, randomized clinical trial involving
BWSTT with manual assistance, stimulation, over-groundtraining with stimulation and treadmill training with robotic
assistance showed improvements in walking speed anddistance [31]. Walking speed was not significantly diﬀerent
between groups, but distance gains were greatest with overground walking training. Further, lower extremity motorscores increased in all groups, regardless the type of intervention [31].
Based on the aforementioned findings, it is apparent that
BWSTT contributes to restoration of locomotion. Because
remodeling of neuronal circuits as a result of plasticity occurs
at multiple sites of the central nervous system [8, 32] restoration of movement after training is anticipated to be theresult of neural reorganization that occurs simultaneously insupraspinal and spinal cord circuits. The aim of this paper is
to focus on the corticospinal neural plasticity after locomotor
training in SCI.

2. Cortical Control of Locomotion
The corticospinal tract is the most direct pathway between
the cerebral cortex and spinal cord with corticospinal axonsmonosynaptically synapsing onto spinal motor neurons.
Even though neurons of the motor cortex are not required
for simple locomotion, they exhibit a profound step-related
frequency modulation in the cat [33–35]. This modulation
is driven by a combination of signals from the spinal
central pattern generators and sensory aﬀerent feedbackreflex mechanisms that support interlimb coordination [36].
The modulation of motor cortex neurons is necessary for
accurate stepping on uneven terrain when adjustments of
the limb trajectory are required to overstep an obstacle orto place the foot on a definite spot on the ground [37–39]. However, pyramidal tract stimulation evokes disynaptic
excitatory postsynaptic potentials (EPSPs) in flexor motor
neurons that are much bigger in the locomotor state than in
the resting state, which are rhythmically modulated so thatthe facilitation occurs in the flexor-active phase [40]. While

Neural Plasticity
the spinal cord of vertebrates possesses the neural structures
for genesis of the locomotor rhythm [41–43] and the spinal
pattern generator plays a decisive role in the recovery of
locomotion after incomplete SCI [12], lesions of the dorsolateral funiculi at Thoracic T13 level in the cat induced longterm deficits on the locomotor pattern [44], supporting thatthe corticospinal tract plays a prominent role in the neuralcontrol of locomotion.
The involvement of supraspinal neural control in humanwalking can be assessed by a variety of techniques utilized inisolation or in combination, including electroencephalography (EEG), electromyography (EMG), transcranial magnetic
and electric stimulation (TMS and TES), and neuroimaging[45, 46]. Single-photon emission tomography and nearinfrared spectroscopic topography have shown that the sensorimotor and supplementary motor cortices are activatedduring real and imagined locomotion [47, 48], while theprefrontal and premotor cortices were involved in adapting
the locomotor speed on the treadmill [49]. A recent study
postulated a significant coupling between EEG recordings
over the leg motor area and EMG from the tibialis anterior(TA) muscle in the frequency band of 24–40 Hz prior to heel
strike during the swing phase of walking [50], supportinga cortical involvement in human gait function [51]. (Time(cross-correlation) and frequency (coherence) domain techniques for the detection of coupling between signals provide
an analytical framework from which functional coupling
between localized cortical activity (measured by MEG or
EEG) and motor output (EMG) can be identified in humansubjects [52].)
A single stimulus of TMS produces a synchronizeddischarge of cortical interneurons and pyramidal neurons
that travel down the corticospinal tract. Epidural electrodesin the spinal cord detect several waves following TMS,
termed direct (D) and indirect (I) waves. I waves originate
in the motor cortex most likely through activation of corticocortical projections onto corticospinal neurons [53], while
D waves are thought to result from direct depolarization of
the initial axon segment of the corticospinal neuron [46].
Recordings from the peripheral muscles demonstrate compound muscle action potentials known as motor evoked
potentials (MEPs), which are a summation of multiple motor
units depolarizing in response to D and I waves arriving onto
the spinal motor neurons [54].
However, the MEP amplitude is not a reliable measureof corticospinal excitability. This is because TMS-induced
action potentials in cortical axons spread transynaptically tomany other neurons [55] that activate diﬀerent descending
pathways which are diﬀerently regulated during human
movement [56]. Further, in order to support cortical excitability changes based on alterations of MEP amplitude due tomotor plasticity, both need to be mediated by the same motor
neurons and caused exclusively by direct monosynaptic projections from the motor cortex without any contamination
through indirect interneuronal relays. The peaks in theperistimulus time histogram of the discharge probability of
motor units induced by TMS have the same duration as thoseinduced by Ia stimulation, and thus there is ample time fornonmonosynaptic eﬀects to influence the MEP amplitude asNeural Plasticity
is the case for the H-reflex [57, 58]. Lastly, because MEPs
are facilitated on average 12 ms before the reaction time
to contraction during which antagonists are concomitantly
facilitated by subcortical circuits [59, 60], it is apparent thatthey are sensitive to the excitability state of spinal α-motor
neurons and interneurons [61].
The aforementioned limitations can be counteracted by
reducing the TMS intensity below the MEP threshold. Direct
recordings in awake human subjects have shown that TMS
at subthreshold MEP intensities, which does not evoke any
descending corticospinal volleys, depresses the MEP evokedby a subsequent suprathreshold TMS [62] and the EMG
activity of ankle extensor muscles during the stance phase ofwalking, while the TA ongoing EMG activity is facilitated at ashort-latency at early swing phase [63]. At subthreshold TMS
intensities the excitability of spinal motor neurons at shortlatencies is influenced by intracortical inhibitory circuits
and mechanisms [62, 64], including but not limited to
intracortical and interhemispheric inhibition [65–70], thatin turn influence soleus or TA coupled corticomotoneuronalcells. These findings support that cortical excitability changes
can be assessed in awake humans and that cortical cells withdirect motoneuronal connections change their excitability
during human walking. Corticospinal drive of human locomotion is further addressed in Sections 3 and 4, whereas thecortical control of spinal reflex and interneuronal circuits is
discussed.
2.1. Reorganization of Cortical Control of Motor Output afterTraining. Various training protocols in uninjured subjects
induce reorganization of corticospinal actions on lumbosacral motor neurons. For example, balance training
decreased the TA and soleus MEP amplitudes [71], while
32 min voluntary ankle dorsi- and plantar-flexion training
increased the TA MEP amplitude regardless of the stimulation intensity level [72]. Repeated visuomotor skill training
increased the maximal MEP and decreased the stimulation intensity needed to evoke an MEP, while opposite
results were obtained after strength training [73], suggestingthat reorganization of corticospinal actions on lumbosacral
motor neurons depends on the type of training.
In motor incomplete SCI subjects at rest, MEPs are either
absent or very small in amplitude with prolonged latencies,
which are considered signs of impaired transmission of thefastest conducting corticospinal neurons [74–77]. Further,
the absent or small TA MEPs prevail in SCI persons withincreased foot drop [75]. Further, the peak coherence in the
10 to 20 Hz frequency band and synchronization within anarrow time band between paired TA EMG recordings taken
during the swing phase were absent during the swing phaseand were positively correlated to the degree of foot drop [75].
Because coherence in the frequency and time domain reflects
the common synaptic drive, which may be corticospinal inorigin, behavioral deficits in ambulatory SCI persons are
driven by impaired corticospinal excitability.
Reorganization of corticospinal actions with training inneurological disorders has been shown in few studies. In 4
male SCI subjects with tetraparesis, f MRI showed a greater
activation in sensorimotor cortical and cerebellar regions

3
following 36 BWSTT sessions [78] consistent with thechanges observed in the activation patterns of both hemispheres in poststroke subjects after 4 weeks of BWSTT [79].
Three-to-5 month BWSTT enhanced the MEP amplitudein 9 out of 13 muscles tested, increased the maximal MEP,
and changed the slope of the MEP input-output curve inthe majority of SCI subjects tested while seated [80]. Furthermore, in incomplete SCI participants whom their locomotor function improved following treadmill training, thecoherence (24–40 Hz) of EMG activity, which is thought toindicate a common drive from corticospinal inputs, between
antagonist muscles acting at the knee joint was increased andremained unaltered in participants that the locomotor ability
was not improved [81]. The lower-frequency coherence (5–18 Hz), which is thought to contain common synaptic drivefrom spinal inputs, remained unchanged in both groups[81].
One person (49 yo female, 5 years after-injury) withan American Spinal Injury Association (ASIA) Impairment
Scale (AIS) D at Thoracic 5–7 received 60 BWSTT sessions(1 h/day; 5 days/week) with a robotic exoskeleton device(Lokomat). Before training, the patient stepped at 0.5 m/swith 50% body weight support (BWS), and after training thepatient stepped at 0.89 m/s with 20% BWS. Electrophysiological tests, illustrated as a schema in Figure 1, were conducted
before and after training in the same patient while seated aswell as during BWS assisted stepping. Data presented in thispaper are original, have not been published elsewhere, andare from the same patient. Experiments and training wereconducted following the written consent of the subject. All
experimental procedures were approved by the Institutional
Review Board of the Northwestern University IRB committee
and were conducted in compliance with the 1964 Declarationof Helsinki.
The TA MEPs evoked at 1.3 TA MEP threshold duringassisted stepping before and after training are shown in
Figure 2. (The TA MEP threshold was established with thesubject standing at equivalent BWS levels to that utilized
during stepping. During stepping, TA MEPs were evoked
randomly at diﬀerent phases of the step cycle every 3 to 5
steps based on the signal from the ipsilateral foot switch. The
step cycle of the right leg was divided into 16 equal time windows or bins.) Before training, the TA MEP amplitude wasincreased during early swing (bins 10–13) when compared tothat observed at midstance (bins 3–5), but an MEP was not
evocable from mid stance (bin 6) until swing phase initiation(bin 9). After training, the TA MEP amplitude increased
significantly compared to that observed before training andwas modulated in a phase-dependent pattern; that is, it was
progressively depressed during the stance phase (bins 1–7) and was facilitated during the swing phase (bins 9–14)(Figure 2). This TA MEP modulation pattern during assisted
stepping is consistent with that reported in uninjured
subjects, which is generally increased when the muscle fromwhich it is recorded is active and small when the antagonist
muscle is active [82–84]. Although the findings reported in
Figure 2 are from a single case, the altered MEP modulation pattern supports the notion that locomotor training
alters the eﬃcacy of corticospinal descending motor volleys

4

Neural Plasticity

TMS

Corticospinal+ −Soleus α
motor
neurons+ −+ −Ia INsTA α motor
neurons

Soleusgroup
Ia aﬀ.
TA
group Iaﬀ.

Figure 1: Schematic illustration of cortical control of spinal reflex circuits and spinal interneuronal circuits investigated after 60 sessionsof locomotor training in the same SCI subject. The soleus H-reflex evoked by posterior tibial nerve stimulation, tibialis anterior (TA)muscle motor evoked potential (MEP), soleus H-reflex conditioned by subthreshold transcranial magnetic stimulation (TMS) deliveredat an optimal site (“hot spot”) for evoking an MEP in the right soleus muscle, soleus H-reflex depression by common peroneal nerve
stimulation that is mediated by Ia inhibitory interneurons (Ia INs; reciprocal inhibition), and the reciprocal inhibition conditioned bysubthreshold TMS delivered at an optimal site (“hot spot”) for evoking an MEP in the right TA muscle were all investigated in the same
patient at rest and/or during assisted stepping after locomotor training. Open triangles indicate excitatory synapses, while the filled circle
indicates inhibitory synapses. The cortical control on these spinal circuits is indicated as a synapse that may increase (+) or decrease (−)
actions of flexor-extensor α motor neurons and/or Ia inhibitory interneurons.

synapsing with TA spinal motor neurons in a manner that
supports a physiologic gait pattern. It is apparent that morestudies are needed on the neuronal mechanisms mediating
improvement of locomotor function after training in spinal
lesions of diﬀerent segmental levels and types, in order thatcurrently available rehabilitation strategies are optimized.

3. Cortical Control of Spinal Reflex Circuits
The spinal cord constitutes the final common pathway
for segmental and supraspinal pathways underlying motor
behavior. Electrical stimulation of a mixed peripheral nerve

at low intensities activates primary (Ia) aﬀerent axons which
synapse in the spinal cord. Alpha motor neurons activatedmonosynaptically by Ia aﬀerent volleys induce a synchronized reflex response known as the Hoﬀmann-(H-) reflex[85], which is the electrical analogue of the monosynaptic
stretch reflex. When the H-reflex is used as a test reflex,
the eﬀects of conditioning volleys from other aﬀerents ordescending tracts on the motoneuron pool and synaptic
actions from diﬀerent sources in health and disease can beassessed [85, 86].
Cortical control of spinal reflex circuits has been extensively investigated in awake humans by means of TMS.

Neural Plasticity

5

TA MEP amplitude (mVs)

350
300
250
200
150
100
50
0
1

2

Heel
strike3

4

5 6
Stance78

9 10 11 12 13 14 15 16
Swing
Swing-toSwing
stanceinitiation

Step cycle divided into 16 equal time windows (or bins)
Before BWSTT
After BWSTT

Figure 2: TA MEP modulation during stepping before and after
locomotor training in SCI. The tibialis anterior (TA) motor
evoked potential (MEP) amplitude before (dashed line) and after(solid line) 60 body weight-supported treadmill training (BWSTT)
sessions is indicated as a function of the step cycle during bodyweight-supported (BWS) assisted stepping for one patient with
American Spinal Injury Association (ASIA) Impairment Scale (AIS)
D (49 yo female, 5 years after injury, T5–7). The TA MEP was evoked
randomly every 3 to 4 steps at 1.3 times TA MEP threshold while
stepping at 0.5 m/s with 50% BWS before training and at 0.89 m/swith 20% BWS after training. MEP threshold was establishedwith subject standing at equivalent levels of BWS utilized during
stepping. The step cycle was divided into 16 equal time windows
or bins. Stance phase duration is identified by the grey region.
Bin 1 corresponds to heel strike. Bins 8, 9, and 16 correspond
approximately to stance-to-swing transition, swing phase initiation,and swing-to-stance transition, respectively.

Subthreshold TMS produces a short-latency inhibition on
the soleus H-reflex followed by a period of facilitation[56, 87–89] with subjects at rest. In contrast, the TA
H-reflex is facilitated at an early conditioning-test (C-T)
interval [87]. Superficial peroneal or sural nerve stimulation
potentiates the presumably monosynaptic facilitation of the
TA H-reflex evoked by brain stimulation [90]. The corticalmodulation of the soleus H-reflex depends largely on theposition of the ankle joint, with subthreshold TMS to
induce an early long-lasting facilitation or depression of thesoleus H-reflex during tonic plantar flexion and dorsiflexion,
respectively [87, 91]. Similar findings have been reported for
pyramidal monkeys, cats, and baboons during which corticalinhibition predominated on the soleus and gastrocnemiusmonosynaptic reflex, while cortical facilitation influenced
largely flexor motor neurons [92, 93]. It should be noted,
however, that a single cortical D wave could produce changes
in segmental motor neurons in the primates but not in thecat that required D and I waves or multiple D-waves [93].
In addition to the H-reflex, the TA long-latency (orM3) ankle stretch reflex was facilitated when the MEP
arrived in the spinal cord at the same time [94]. However,subthreshold TMS intensities delivered 55–85 ms prior to

the M3 depressed the long-latency TA stretch reflex [95].
Because the long-latency response was reduced in size following subthreshold TMS while the short-latency response
remained unchanged [95, 96], it provides evidence thatthe long-latency stretch reflex is mediated in part by atranscortical path that can be aﬀected by subthreshold TMS.
During human walking, subthreshold TMS induces a shortlatency, presumably monosynaptic, facilitation of the soleus
H-reflex followed by a long-lasting inhibition [94]. Because
potentiation of TA MEPs was synchronized with the peakTA ankle stretch reflex, corticospinal pathways are partly
involved in the generation of spinal stretch reflexes during
human walking [97, 98]. In human SCI, the conditioned
H-reflex profile by subthreshold TMS varied significantly
based on the AIS scores [99, 100]. In patients with severe
paralysis (AIS A-B) an early or late soleus H-reflex facilitation
by TMS was absent [99], suggesting for a nonphysiologicalinteraction between descending inputs and spinal reflex
excitability in patients with spastic paraparesis [100].
3.1. Reorganization of Cortical Control of Spinal Reflexes afterTraining. Persistent changes in H- or stretch reflex amplitudes may be regarded as signs of learning and plasticity asa result of training, which have been shown after various
training protocols. For example, 30 min ankle cocontraction
training decreased the ratio of maximal H-reflex versus maximal M wave (Hmax/Mmax) and improved motor performance defined as the diﬀerence between the maximum andminimum torque displacements within 1 min [101]. The
soleus H-reflex amplitude was enhanced after 3 week isometric maximal plantar flexion training when measured at 20%
and 60% of maximal voluntary contraction (MVC) [102],
with similar results to be reported after 14 week of resistancetraining that involved heavy weight-lifting exercises forthe leg muscles with reflexes measured during maximal
isometric ramp contractions [103]. In contrast, 18 sessions
eccentric strength training of the plantar flexor muscles fora 7 week period increased the Hmax/Mmax ratio during
eccentric MVC but not during isometric or concentric
contractions [104], suggesting that spinal reflex excitability
is adjusted based on the type of exercise training protocol.
Nonetheless, the aforementioned changes in H-reflex
amplitude can result from modifications of interneuronal
circuits interposed in the spinal pathway or by changes on
the strength of descending pathways, since the latter is potent
regulator of spinal reflex circuits behavior [105–107]. Thisis supported by the failed operant conditioning of the Hreflex in rats when the corticospinal tract was transected at
the spinal cord level [108, 109].
Limited evidence exists on plastic changes of the cortical control of spinal reflexes after locomotor training inneurological disorders. Forty BWSTT sessions in 29 patientswith incomplete SCI reestablished the TMS-induced longlatency soleus H-reflex facilitation with subjects at rest [110].
It should be noted that BWS improves the eﬃcacy of thesensorimotor cortex function [111], decreases the TA MEP
threshold, and increases the map size for the TA in bothhemispheres of stroke patients [112]. Nonetheless, when
TMS eﬀects on spinal reflexes are assessed with patients at

6

Neural Plasticity

70

50

Soleus H-reflex(% of the maximal M-wave)

Soleus H-reflex(% of the maximal M-wave)

60

40
30
20
10

60
50
40
30
20
10
0

0
1

2

3

4

5 6 7 8 9 10 11 12 13 14 15 16
Bin number of the step cycle

1

2

3

4

5 6 7 8 9 10 11 12 13 14 15
Bin number of the step cycle

Before BWSTT
After BWSTT

Before BWSTT
After BWSTT
(a)

(b)

Figure 3: Soleus H-reflex modulation during assisted stepping before and after locomotor training in SCI. The unconditioned soleus Hreflex modulation before (dashed lines) and after (solid lines) 60 sessions of body weight-supported treadmill training (BWSTT) (a) and theconditioned soleus H-reflex by subthreshold TMS at the conditioning-test interval of 1 ms (b) are indicated as a function of the step cycle.
The mean amplitude of the unconditioned and conditioned soleus H-reflexes evoked at each bin is expressed as a percentage of the maximal
M-wave evoked 80 ms after the test H-reflex. TMS was delivered at 0.95 times MEP threshold for the soleus muscle at a conditioning-test
interval of 1-ms. Unconditioned and conditioned soleus H-reflexes were accepted when the associated M-waves ranged from 4 to 8% of the
maximal M-wave evoked at each bin. H-reflex values are not indicated for some of the bins after BWSTT because they were not accepted
based on the M-wave amplitude as a percentage of the maximal M-wave, which is diﬀerent from not being evocable as was the case for
before BWSTT. The step cycle was divided into 16 equal time windows or bins. Stance phase duration is identified by the grey region. Bin 1
corresponds to heel strike. Bins 8, 9, and 16 correspond approximately to stance-to-swing transition, swing phase initiation, and swing-tostance transition, respectively.

a resting state, it cannot be assumed that corticospinal
changes due to training are transferrable at a locomotor state
and thus be functional relevant. This is largely based on that(1) short-latency ankle or quadriceps extensor reflexes (H- or
stretch reflexes) are modulated in a phase-dependent patternin uninjured subjects [113–115], (2) the phase-dependent
modulation of these reflexes is aﬀected substantially inindividuals with an SCI [115–117], and (3) cortical control
constitutes one of the sources for the phasic patterned reflex
excitability during human walking [86].
In Figure 3(a), the soleus H-reflex recorded during BWS
assisted stepping according to methods described in detail[115, 118, 119], before and after 60 BWSTT sessions, isindicated for the same patient whose TA MEP modulation
pattern was described in Figure 2. After 60 BWSTT sessions,the maximal reflex excitability shifted, with respect to thestep cycle phase, from mid- to early stance (bins 1–3),
while a maintained H-reflex excitability commonly observed
throughout the stance phase in uninjured subjects [115] wasabsent before and after training (Figure 3(a)). However, after
60 BWSTT sessions the soleus H-reflex amplitude increased
during the late swing phase (bins 12–16), consistent to areflex behavior observed in some control subjects [120]. The
eﬀects of subthreshold TMS on the soleus H-reflex at a C-T
interval of 1-ms during BWS assisted stepping are indicatedas a function of the step cycle before and after 60 BWSTT sessions in Figure 3(b). It is clear that, after 60 BWSTT sessions,subthreshold TMS aﬀected substantially the soleus H-reflex
during the stance phase resulting in a progressive increaseof the soleus H-reflex amplitude. The soleus H-reflex
amplitude was maintained throughout the stance phase(compare bins 1–8 in Figures 3(a) and 3(b)). Modifications
in synaptic actions of cortical inhibitory circuits exerted onsoleus motor neurons might be the source of these changes
since the phasic soleus H-reflex excitability during BWS
assisted stepping with or without leg assistance by a robotic
exoskeleton remains unaltered [115, 118].

4. Spinal Interneuronal Inhibitory Circuits:
Reciprocal Ia Inhibition
One of the spinal interneuronal circuits with paramountcontribution to the neural control of movement is thatof disynaptic reciprocal Ia inhibition. Reciprocal inhibitionrefers to an automatic antagonist motor neuron inhibition when an agonist muscle contracts. Following an SCI,
the reciprocal inhibition is either reduced or replaced byreciprocal facilitation [121–124] leading to coactivation ofantagonist ankle muscles, spasticity, and poor movement
performance.
Regulation of locomotion by reflexly mediated spinal
circuits that integrate sensory inputs is well established.
The contribution of muscle aﬀerents mediating information
about the amplitude and rate of muscle stretch is easily
recognized by the phase-dependent modulation of shortlatency spinal reflexes during walking. The short-latencysoleus and quadriceps extensor reflexes (stretch, tendon, or
H-reflex) in humans are modulated in a way that promotes

Neural Plasticity

4.1. Cortical Control of Reciprocal Ia Inhibition. Animalstudies through intracellular recordings provided a detailed
knowledge of the pathway and integration of segmental andsupraspinal convergence at the interneuronal level [132–135]
with volleys in the corticospinal tract to exert an excitatoryeﬀect over Ia inhibitory interneurons [136]. In monkeys,
intracortical stimulation revealed that the same interneurons
mediate the disynaptic inhibition of motor neurons evokedby corticospinal fibers and the disynaptic inhibition of
motor neurons evoked by group Ia aﬀerents of antagonist
muscles [137]. Further, motor neurons and Ia inhibitory
interneurons were activated in parallel by supraspinal centersin order to secure a coordinated contraction of agonists andrelaxation of antagonists [138, 139].
Descending control of reciprocal inhibition has clearly
been postulated in humans. In particular, the reciprocal
inhibition exerted from common peroneal nerve group I
aﬀerents on soleus motor neurons was observed 50 ms before
the onset of TA EMG activity [140]. Further, when subjects
attempted to dorsiflex the ankle after the common peroneal
nerve was blocked with a local anesthetic a strong soleus Hreflex depression was still evident [141]. The test H-reflex
facilitation, induced by TES applied to the scalp below theintensity needed to produce a motor response, was quickly
terminated by subsequent arrivals of IPSPs at the motor
neurons [88]. These IPSPs might be produced by activity
in Ia inhibitory interneurons, which in monkeys receivemonosynaptic tract projections [142]. Single subthreshold
TES reduced the inhibition of the flexor carpi radialis
H-reflex evoked by radial nerve stimulation at a latency
compatible with a monosynaptic or disynaptic corticospinal
projection to Ia inhibitory interneurons [143]. Descending∗ P < 0.05

120
Responses (% of control H-reflex)

bipedal gait. The ankle stretch and soleus H-reflexes increaseprogressively from mid- to late stance in parallel withthe soleus EMG activity and are significantly depressed orabolished during the swing phase of gait [113–115, 125]. A
phase-dependent modulation has been demonstrated for the
ankle stretch reflex in the high decerebrate mesencephalic cat[126].
The soleus H-reflex depression during the swing phase in
humans has been partly ascribed to reciprocal Ia inhibition
exerted from common peroneal nerve group I aﬀerents
on soleus motor neurons, which is regulated in a similarmanner to that reported in animals and corresponds largely
to absent reciprocal inhibition in the stance phase andmaximal in the swing phase [127, 128]. During fictive locomotion in cats without brainstem connections, simultaneous
extracellular recordings from Ia inhibitory interneurons andintracellular recordings from lumbar motor neurons revealed
that hyperpolarization of soleus α motor neurons coincidedwith activity of Ia inhibitory interneurons [129, 130]. Ia
inhibitory interneurons were rhythmically active due toperiodic excitation and not due to periodic inhibition byother spinal inhibitory interneurons [130]. Recent evidence
obtained from spinalized animals verified that reciprocal
Ia inhibition contributes to hyperpolarization of motor
neurons during the inactive (flexion) phase of locomotion[131].

7

∗

100

∗
∗

80
60
40
20
0

Control
H-reflex

RCI

TMS +
H-reflex

TMS + RCI

Before BWSTT
After BWSTT

Figure 4: Cortical control of spinal reflex circuits after locomotor
training in SCI. Mean size (n = 20) of soleus H-reflex conditioned
by common peroneal nerve stimulation at the conditioningtest interval of 3 ms, which reflects the amount of reciprocal
Ia inhibition (RCI), soleus H-reflex conditioned by subthreshold
TMS (TMS + H-reflex) at a C-T interval of 1 ms, and reciprocal
inhibition conditioned with subthreshold TMS (TMS + RCI) at CT intervals of 1 and 3 ms, respectively. Data are from the same
patient. The size of the conditioned H-reflexes is expressed as apercentage of the mean amplitude of the control soleus H-reflex.
Error bars indicate the SEM, and asterisks denote a statisticallysignificant diﬀerence (paired t-test, P < 0.05) for conditioned Hreflexes recorded before and after 60 BWSTT sessions.

facilitation of Ia inhibitory interneurons has also been
documented for the human leg [87, 89].
4.2. Reorganization of Cortical Control of Reciprocal Ia
Inhibition after Training. Findings on the reorganization ofreciprocal inhibition as a result of motor training in healthand disease are limited. Stimulation of the common peroneal
nerve with a train of 10 pulses at 100 Hz with and without
motor cortex stimulation potentiated reciprocal inhibition incontrol subjects [144]. Reciprocal inhibition was potentiatedafter 12 sessions of ankle dorsiflexion strength training whenmeasured at the onset of ankle dorsiflexion but remained
unchanged when measured with subjects at rest [145].
In Figure 4, the mean amplitude of the soleus H-reflex
conditioned by stimulation of common peroneal nervegroup I aﬀerents at a C-T interval of 3 ms and establishedaccording to methods outlined in detail [146], which represents the amount of reciprocal inhibition (RCI), before andafter 60 BWSTT sessions with subject seated (same patientfor data previously described in Figures 2 and 3 is indicated asa percentage of the control H-reflex). Further, the soleus Hreflex conditioned by subthreshold TMS at a C-T interval of
1 ms and the reciprocal inhibition conditioned by subthreshold TMS (C-T intervals: 3 and 1 ms, resp.) as a percentageof the control H-reflex is indicated. It is apparent that
locomotor training reestablished the reciprocal inhibition

8

Neural Plasticity
control of reciprocal inhibition after locomotor training
supports that changes of corticospinal neuronal pathways
interacting with Ia interneurons are possible in people with achronic SCI, although altered corticospinal interactions withother spinal inhibitory interneurons, such as Renshaw cells
and presynaptic inhibitory interneurons, cannot be excluded[85, 148, 149].

20

Net modulation (%)

10
0
−10
−20
−30

5. Conclusion

−40
−50
−60

0

1

2

3

4

5

6

7

8

9 10 11 12 13 14 15 16

Bin number of the step cycle
Before BWSTT
After BWSTT

Figure 5: Changes in the cortical control of reciprocal Ia inhibition
after locomotor training in SCI. Net eﬀects of subthreshold transcranial magnetic stimulation (TMS) on reciprocal Ia inhibition
during BWS assisted stepping before and after 60 body weightsupported treadmill training (BWSTT) sessions. The net eﬀects
of subthreshold TMS on reciprocal inhibition were estimated ateach bin of the step cycle based on the equation (D-C)-(B-A)
whereas A is the test H-reflex during stepping, B is the soleus
H-reflex conditioned by subthreshold TMS during stepping at aconditioning-test (C-T) interval of 1 ms, C is the soleus H-reflex
conditioned by common peroneal nerve stimulation (i.e., reciprocal
inhibition) at a C-T interval of 3 ms during stepping, and D is thereciprocal inhibition conditioned by subthreshold TMS (3 and 1 ms
C-T intervals). Positive values indicate potentiation of reciprocal
inhibition and negative values indicate attenuation of reciprocal
inhibition by cortical inputs.

SCI changes the human body homeostasis leading to myriadchanges of multiple systems. In most cases, the spinal
cord is not completely severed and thus some fiber tracts
and segmental spinal cord circuits remain intact. Based on
the plastic capabilities of the central nervous system, it isapparent that the adult lesioned motor system reorganization occurs spontaneously after an injury and after training. Electrophysiological studies have shown that BWSTT
increases the MEP amplitude, changes the common drive ofantagonist muscles from corticospinal inputs with subjects
seated, and alters the TA MEP modulation pattern during
BWS assisted stepping. Further, BWSTT reestablished the
TMS-induced long-latency soleus H-reflex facilitation andpotentiated the short-latency soleus H-reflex depression following subthreshold TMS with subjects at rest, while corticalmodulation of the soleus H-reflex during stepping changed
significantly. Lastly, BWSTT changed the cortical control ofreciprocal inhibition during BWS assisted stepping in a manner that promotes bipedal gait. These findings support thenotion that improvements in locomotor function fromtreadmill training are mediated, in part, by changes in thecorticospinal drive of spinal reflex circuits, spinal interneuronal circuits, and output of leg muscles during walking.

6. Perspective
exerted from flexor group I aﬀerents on soleus motor neurons, potentiated the soleus H-reflex depression following
subthreshold TMS, and potentiated the reciprocal inhibition
conditioned by subthreshold TMS, consistent with findings
reported in uninjured subjects (see Figure 4 in [147]).
The net eﬀects of subthreshold TMS on the reciprocal
inhibition during BWS-assisted stepping before and after
60 BWSTT sessions are indicated in Figure 5 for the same
patient. The net eﬀects (or net modulation) were estimated ateach bin of the step cycle based on the equation (D-C)-(B-A)
whereas A is the test soleus H-reflex (baseline soleus Hreflex modulation pattern during stepping), B is the soleus
H-reflex conditioned by subthreshold TMS, C is the soleus
H-reflex conditioned by common peroneal nerve stimulation(i.e., reciprocal inhibition), and D is the reciprocal inhibition
conditioned by subthreshold TMS. Positive values indicate
potentiation of reciprocal inhibition and negative values
indicate attenuation of reciprocal inhibition. Locomotor
training contributed significantly to attenuation of reciprocal
inhibition exerted from ankle flexor aﬀerents to extensor
motor neurons during the stance phase. Most importantly,
potentiation of reciprocal inhibition at swing phase initiation(i.e., bin 9 in Figure 5) was evident. Adaptation of cortical

Plasticity in the brain and spinal cord underlying restorationof lost function can be driven by appropriately designed
interventions [150, 151]. Development of such interventions
depends largely on gaining a detailed understanding of theunderlying neural mechanisms that support restoration of
motor function. Based on this brief paper it is clear that
there is a need for translational neuroscience research inorder that the neural mechanisms underlying restoration oflost voluntary motor function are outlined based on specificclinical cases. This body of knowledge will contribute significantly to the development of new rehabilitation strategies
and/or optimization of the currently available strategies,
and to patient-orientated rehabilitation protocols promoting
evidence-based rehabilitation.

Abbreviations
BWS:
Body weight support
BWSTT: Body weight-supported treadmill training
C-T:
Conditioning-test
EMG: Electromyographic
EPSPs: Excitatory postsynaptic potentials
IPSPs: Inhibitory postsynaptic potentials

Neural Plasticity
MEP: Motor evoked potentials
SCI: Spinal cord injury
TA: Tibialis anterior
TMS: Transcranial magnetic stimulation
TES: Transcranial electric stimulation.

Acknowledgments
Author’s work presented here was supported by the New YorkState Department of Health (NYSDOH), Wadsworth Center,
NY, USA, and the Craig H. Neilsen Foundation. The author
thanks Chaithanya K. Mummidisetty, Andrew C. Smith, andNupur Hajela for their help during data acquisition andthe subject for her dedication and patience during theexperiments and training.

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