J Neurophysiol 113: 2447–2460, 2015.
First published January 21, 2015; doi:10.1152/jn.00872.2014.
Locomotor training improves reciprocal and nonreciprocal inhibitory control
of soleus motoneurons in human spinal cord injury
X Maria Knikou,1,3,4,5 Andrew C. Smith,2 and Chaithanya K. Mummidisetty1
1
Sensory Motor Performance Program, Rehabilitation Institute of Chicago, Chicago, Illinois; 2Northwestern University
Interdepartmental Neuroscience Program, Chicago, Illinois; 3Department of Physical Medicine and Rehabilitation,
Northwestern University Feinberg Medical School, Chicago, Illinois; 4Graduate Center/The City University of New York,
New York, New York; and 5Department of Physical Therapy, College of Staten Island, Staten Island, New York
Submitted 5 November 2014; accepted in final form 20 January 2015
locomotor training; neuromodulation; neuroplasticity; reciprocal inhibition; Ib inhibition; spinal cord injury
DURING WALKING, A MULTITUDE
of neuronal interactions at multiple spinal segments occurs simultaneously, with sensory
afferent feedback and descending inputs to adjusting amplitude, rate, and periodicity of motoneuron discharges based on
the demands of the motor task (Rossignol 2006; Knikou
2010a). Animal studies have provided clear evidence on the
contribution of the spinal nonreciprocal Ib and reciprocal Ia
inhibition to the reflex regulation of locomotion and the spinal
central pattern generator. Stimulation of group I afferents
mediating load information from ankle extensors potentiates
activity of extensor motoneurons at the stance phase, initiates
extension, and terminates or delays flexor bursts in the ipsilateral hind limb (Duysens and Pearson 1980; Conway et al.
Address for reprint requests and other correspondence: M. Knikou, Graduate
Center of The City Univ. of New York, School of Health Sciences, 2800
Victory Blvd., 5N-207, Staten Island, NY 10314 (e-mail: Maria.Knikou
@csi.cuny.edu or [email protected]).
www.jn.org
1987; Gossard et al. 1994; Guertin et al. 1995; Whelan et al.
1995). Similarly, recordings from Ia inhibitory interneurons
during fictive locomotion in complete spinally transected cats
showed that hyperpolarization of extensor alpha motoneurons
during the swing phase is directly related to their activity (Pratt
and Jordan 1987; Degtyarenko et al. 1996; Geertsen et al.
2011), which is determined largely by intraspinal rhythmic
processes (Feldman and Orlovsky 1975). Given the important
contribution of reciprocal and Ib inhibitory interneuronal circuits to spinal locomotor centers, in this study we sought to
determine the function of these circuits in people with spinal
cord injury (SCI) after locomotor training.
In uninjured humans, Golgi tendon group Ib afferents evoke
short-latency soleus H-reflex depression, which is reduced
when the triceps surae is voluntarily activated and the limb is
loaded and reverses to excitation during walking (PierrotDeseillingny et al. 1982; Stephens and Yang 1996; Faist et al.
2006). Both reciprocal and Ib inhibition are modulated in a
phase- and task-dependent manner in uninjured human subjects
(Capaday et al. 1990, 1995; Lavoie et al. 1997; Duysens et al.
2000; Ethier et al. 2003; Mummidisetty et al. 2013). In addition
to their online modulation to meet motor task demands, these
particular spinal circuits can be altered with operant conditioning (Chen et al. 2006), sensory stimulation (Perez et al. 2003),
and strength training (Geertsen et al. 2008). Reciprocal and
nonreciprocal Ib inhibition are heavily influenced by sensory
inputs (Lundberg et al. 1977; Rossi et al. 1988; Knikou 2006;
Mummidisetty et al. 2013) and are under descending control
(Fournier et al. 1983; Crone 1993; Crone and Nielsen 1994).
SCI in humans is associated with pathologic changes of these
spinal inhibitory circuits, with alterations in strength, timing,
and modulation at rest, during contraction, and during walking
being reported (Crone et al. 1994; Boorman et al. 1996; Morita
et al. 2001; Knikou and Mummidisetty 2011).
We have recently shown that locomotor training induces
plastic changes of flexor and extensor reflexes, presynaptic
inhibition of soleus Ia afferents, and soleus H-reflex habituation at rest and during stepping in individuals with SCI
(Knikou 2013; Knikou and Mummidisetty 2014; Smith et al.
2014, 2015). Most notable is the reemergence of the soleus
H-reflex phase-dependent modulation (Knikou 2013), which
can be viewed as a net plasticity of multiple spinal neuronal
circuits. Accordingly, the objective of this study was to assess
the plastic changes of reciprocal and nonreciprocal Ib inhibition in response to locomotor training in people with SCI. We
hypothesized that the pathologic behavior of these two spinal
0022-3077/15 Copyright © 2015 the American Physiological Society
2447
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Knikou M, Smith AC, Mummidisetty CK. Locomotor training
improves reciprocal and nonreciprocal inhibitory control of soleus
motoneurons in human spinal cord injury. J Neurophysiol 113: 2447–
2460, 2015. First published January 21, 2015; doi:10.1152/jn.00872.2014.—
Pathologic reorganization of spinal networks and activity-dependent
plasticity are common neuronal adaptations after spinal cord injury
(SCI) in humans. In this work, we examined changes of reciprocal Ia
and nonreciprocal Ib inhibition after locomotor training in 16 people
with chronic SCI. The soleus H-reflex depression following common
peroneal nerve (CPN) and medial gastrocnemius (MG) nerve stimulation at short conditioning-test (C-T) intervals was assessed before
and after training in the seated position and during stepping. The
conditioned H reflexes were normalized to the unconditioned H reflex
recorded during seated. During stepping, both H reflexes were normalized to the maximal M wave evoked at each bin of the step cycle.
In the seated position, locomotor training replaced reciprocal facilitation with reciprocal inhibition in all subjects, and Ib facilitation was
replaced by Ib inhibition in 13 out of 14 subjects. During stepping,
reciprocal inhibition was decreased at early stance and increased at
midswing in American Spinal Injury Association Impairment Scale C
(AIS C) and was decreased at midstance and midswing phases in AIS
D after training. Ib inhibition was decreased at early swing and
increased at late swing in AIS C and was decreased at early stance
phase in AIS D after training. The results of this study support that
locomotor training alters postsynaptic actions of Ia and Ib inhibitory
interneurons on soleus motoneurons at rest and during stepping and
that such changes occur in cases with limited or absent supraspinal
inputs.
2448
PLASTICITY OF POSTSYNAPTIC INHIBITION IN SCI
circuits observed in motor incomplete SCI (Knikou and Mummidisetty 2011; Knikou 2012) will be changed following
locomotor training. We will show that locomotor training
changes actions of Ia and Ib inhibitory interneurons on soleus
motoneurons at rest resembling that seen in neurological intact
humans and that their modulatory reflex actions are adjusted in
a phase-dependent pattern during assisted stepping in both the
motor complete and incomplete SCI conditions. These neurophysiologic changes suggest that task-dependent-mediated spinal neuronal reorganization occurs in humans with SCI.
METHODS
Subjects
Locomotor Training
Subjects received body weight support (BWS) assisted locomotor
training with a robotic exoskeleton system (Lokomat Pro, Hocoma,
Switzerland) and were trained 1 h/day, 5 days/wk. The protocol
employed to train individuals with SCI and progression of training has
been previously published in detail (see Fig. 1 and Table 2 in Knikou
Table 1. Characteristics of participants
ID
Gender
Age,
yr
Postinjury,
yr
Level
R04
R06
F
F
35
46
12
1.5
C3-C4
C5-C7
R07
R08
M
F
31
49
8
4
R09
M
44
3
R10
F
52
11
R11
R12
M
M
39
41
R13
F
R14
Cause of
SCI
ASIA
(motor)
AIS
Scale
Clonus
ASIA (light
touch)
ASIA (pin
prick)
LL
RL
MVA
MVA
C
B
1LL, 1RL
3LL, 3RL
72
77
72
77
4
0
4
0
C5-C7
T5-T7
MVA
Fall
A
D
3LL, 3RL
1LL, 1RL
76
75
40
75
0
22
0
14
C5-C6
Fall
D
0LL, 0RL
112
112
19
24
T7
Fall
D
1LL, 0RL
78
78
16
24
6
1.5
C4
C5-C6
GSW
MVA
D
D
3LL, 3RL
3LL, 3RL
106
54
106
54
24
19
22
16
39
7
T4
Transverse
myelitis
C
3LL, 3RL
112
74
9
2
M
25
0.5
C5-C6
Diving
D
1LL, 1RL
112
110
25
13
R15
M
37
1.0
C1
C
3LL, 2RL
64
64
12
5
R16
R17
M
M
49
21
2.5
3
C5
T10
Spinal
Tumor
MVA
GSW
C
D
0LL, 0RL
3LL, 3RL
64
105
34
105
17
13
12
15
R18
R19
R20
M
M
M
29
26
55
2
1
3
C7
C6
T6-T7
MVA
Diving
Blood clot
during
spinal
surgery
D
C
C
1LL, 1RL
3LL, 3RL
2LL, 3RL
86
112
82
86
97
82
25
21
33
21
8
34
Medication
#Training
Sessions
Not known
Baclofen: 10 mg
not frequent
None
None during the
study
Gabapentin: 3.6
g; Diazepam:
15 mg
Neurontin: 27
mg; Baclofen:
60 mg
Coumadin
None during the
study
Gabapentin: 0.3
g; Baclofen:
20 mg
None during the
study
Not known
57
53
Baclofen: 15 mg
Baclofen: 60 mg;
Gabapentin:
50.9 g
None
Dexapam: 10 mg
None
41
48
53
60
30
65
64
55
53
44
36
26
20
21
Level of spinal cord injury (SCI) corresponds to the neurological injury level. For each subject, the American Spinal Injury Association (ASIA) standard
neurological classification of SCI for sensation (sensory light touch and pin prick; out of 112 maximal points) is shown and evaluated as 0 ⫽ absent, 1 ⫽ impaired,
2 ⫽ normal. ASIA motor score (out of 50 maximal points for each leg) is indicated for the left leg (LL) and right leg (RL) based on the manual muscle test of
key muscles and evaluated as 0 ⫽ no contraction; 1 ⫽ flicker or trace of contraction; 2 ⫽ active movement, with gravity eliminated; 3 ⫽ active movement against
gravity; 4 ⫽ active movement against gravity and resistance; 5 ⫽ normal power. The ankle clonus for both legs leg is also indicated. Ankle clonus was clinically
assessed as follows: 0 ⫽ no clonus present; 1 ⫽ mild, clonus was maintained ⬍3 s; 2 ⫽ moderate, clonus persisted between 3 and 10 s; 3 ⫽ severe, clonus
persisted for ⬎10 s. Medication for each subject is indicated as total milligrams taken per day. C, cervical; T, thoracic; MVA, motor vehicle accident; GSW,
gunshot wound; M, male; F, female.
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Sixteen people with chronic SCI participated in the study. Study
participation varied depending on the number of locomotor training
sessions attended (Table 1) and ranged from 1.5 to 3.5 mo for each
subject. Data collection for this study lasted 3 yr. One participant had
neurological deficit grade A (no sensory or motor function preserved
below the lesion) on the American Spinal Injury Association Impairment Scale (AIS), one had AIS B (sensory but not motor function
preserved below the lesion), six had AIS C (more than half muscles
below the lesion level had muscle grade ⬍3), and nine had AIS D (at
least half key muscles below the lesion level had muscle grade ⱖ3)
(Table 1). The level of SCI ranged from Cervical 3 to Thoracic 10. All
participants signed an informed consent form before participation to
the study for neurophysiological tests, clinical evaluation, and locomotor training, which was approved by the Northwestern University
Institutional Review Board. Subjects’ consent was obtained according
to the Declaration of Helsinki. Subjects also participated in previous
studies (Knikou 2013; Knikou and Mummidisetty 2014; Smith et al.
2014, 2015) and are identified here with the same code. Subjects R09
and R20 did not participate in the Ib inhibition experiment. Data from
the reciprocal inhibition experiment from subject R10 were rejected
because the unconditioned M waves and H reflexes before and after
training had different amplitudes (%Mmax).
PLASTICITY OF POSTSYNAPTIC INHIBITION IN SCI
2013). Briefly, in AIS A-B subjects, training on the first day started
with 60% BWS at 1.58 km/h treadmill speed. At each subsequent
session, the treadmill speed was targeted to be adjusted by 0.07 km/h
and BWS to decrease by 5%. In AIS C-D subjects, when quadriceps
manual muscle test score was ⱖ3/5, training started with 40% BWS
at 1.98 km/h treadmill speed. At each subsequent session, the treadmill speed was targeted to be adjusted by 0.07 km/h and BWS to
decrease by 5%. When quadriceps and triceps surae strength was
increased by a full grade, then the BWS was decreased by 10%.
Treadmill speed and BWS were adjusted differently for each individual over the course of training based on the presence or absence of
knee buckling and toe dragging during the stance and swing phases,
respectively. In all subjects, the position of the ankle strap was
determined based on the tibialis anterior (TA) muscle strength, which
was assessed every five training sessions. The ultimate training goal in
AIS C-D subjects was to reach a treadmill speed of 2.98 km/h at the
lowest BWS possible without the ankle straps.
Posterior tibial nerve. With subject seated, a stainless steel plate
electrode of 4 cm in diameter was placed and secured proximal to the
patella (anode electrode). Rectangular single pulse stimuli of 1-ms
duration were delivered by a custom-built constant current stimulator
to the posterior tibial nerve at the popliteal fossa. A hand-held
monopolar stainless steel head electrode (cathode electrode) was used
as a probe (Knikou 2008) to locate the optimal stimulation site, at
which the M wave had a similar shape to that of the H reflex and the
H reflex could be evoked without an M wave at low stimulation
intensity levels (Knikou 2008). After the optimal stimulation site was
identified, the monopolar electrode was replaced by a pregelled
disposable electrode (SureTrace, Conmed, Utica, NY) that was maintained under constant pressure throughout the experiment with an
athletic wrap.
Common peroneal nerve. The common peroneal nerve (CPN) was
stimulated by a bipolar stainless steel electrode placed distal to the
head of the fibula. The optimal stimulation site corresponded to the
one that at increased levels of intensities the peroneus longus muscle
was silent, the TA motor threshold (MT) was always lower than that
of the peroneus longus muscle, and at increased stimulation intensities
selective ankle dorsiflexion without ankle eversion was induced
(Knikou 2005, 2008). The CPN was stimulated with a single shock of
1 ms in duration, generated by a constant current stimulator (DS7A,
Digitimer, UK). The stimulus to the CPN was delivered at 0.9 to 1.2
TA M-wave threshold across subjects. The TA M wave was monitored throughout the experiment to ensure consistency of the conditioning stimulation. For each subject, the conditioning stimulus after
training was delivered at similar multiples of TA M-wave threshold
utilized before training.
Medialis gastrocnemius nerve. The medialis gastrocnemius (MG)
nerve was stimulated with a bipolar electrode placed 7–10 cm distal
and medial to the cathode electrode for posterior tibial nerve stimulation where a clear contraction of the MG muscle could be evoked
(Knikou et al. 2006). The position of the bipolar stimulating electrode
was based on the criterion that an M wave or an H reflex in the soleus
muscle was not evoked at stimulation intensities above MG motor
threshold. The stimulus to the MG nerve was expressed in multiples
of MG MT and was delivered at 0.95 ⫻ MT to ensure that the
conditioning effects were not contaminated by recurrent inhibition
(Rossi et al. 1994).
Changes in Postsynaptic Inhibition of Soleus Motoneurons
The neurophysiological tests described below were conducted
before training and 2 days after training (both in the morning on
separate days). Recordings posttraining were conducted at similar
BWS levels, treadmill speeds, and M-wave amplitudes to those
utilized before training.
Experiment 1-reciprocal inhibition. Having established the most
optimal stimulation sites, the soleus maximal M wave (Mmax) was
evoked with subjects seated and saved for offline analysis. The
stimulation intensity was adjusted to evoke control H reflexes that
ranged from 20 to 40% of the Mmax (Crone et al. 1990). Twenty
reflexes elicited at 0.2 Hz were recorded with subjects seated. Then,
the effects of CPN stimulation on the soleus H reflex at the conditioning-test (C-T) intervals of 2, 3, and 4 ms were established. The
soleus H-reflex depression at these C-T intervals in uninjured humans
is exerted from flexor group Ia afferents on soleus ␣-motoneurons
involving the well described pathway of reciprocal inhibition because
the inhibition is strictly between antagonists, is evoked by pure Ia
volleys, and is reduced by recurrent inhibition (Pierrot-Desseilligny
and Burke 2012). The C-T interval during which the soleus H reflex
was depressed, remained unaltered, or was less facilitated with subjects seated was utilized during assisted stepping. The optimal stimulation site was rechecked with subjects during BWS standing, and
the TA MT was reestablished. During stepping, CPN stimulation was
delivered at 1.1–1.2 ⫻ TA MT, because the amount of reciprocal
inhibition depends on the conditioning stimulation strength (Petersen
et al. 1998, 1999).
Experiment 2-Ib inhibition. The preparation proceeded in the same
fashion as the reciprocal inhibition experiment. The effects of MG
nerve stimulation on the soleus H reflex at the C-T intervals of 4, 5,
and 6 ms were established with subjects seated (Knikou and Rymer
2002; Knikou 2005). In uninjured human subjects, the soleus H-reflex
depression at these C-T intervals is mediated by nonreciprocal Ib
inhibition (Bouaziz et al. 1975; Pierrot-Deseilligny et al. 1979). The
C-T interval during which the soleus H reflex was most depressed,
remained unaltered, or was less facilitated with subjects seated, was
utilized during assisted stepping.
Reciprocal and Ib Inhibition During Assisted Stepping
Each subject was transferred to the treadmill and wore an upper
body harness that was connected to overhead pulleys. Thigh and
shank segments of the exoskeleton were adjusted based on each
subject’s leg length and diameter, and both feet were secured into the
foot lifters. With the subject standing at a BWS similar to that utilized
during stepping, the stimulation sites were reevaluated, and the MG
and/or TA M-wave MT was reestablished. Then, 80 to 130 stimuli
were delivered at 0.2 Hz to assemble the soleus M-wave and H-reflex
recruitment curves (Knikou et al. 2009, 2011; Smith et al. 2015).
The orientation of the recording EMG electrode with respect to the
underlying muscle fibers changes during walking. The knee joint
during the swing phase moves the stimulating electrode away from the
tibial nerve, while knee extension during the stance phase has the
opposite effect. To counteract these confounding factors, a supramaximal stimulus to the tibial nerve was delivered at 60 ms after the
unconditioned or the conditioned H reflex at each bin of the step cycle
(Knikou et al. 2009, 2011; Knikou and Mummidisetty 2011, 2014).
The customized LabVIEW software measured the peak-to-peak amplitude of the M wave and Mmax recorded during stepping and used a
self-teaching algorithm to adjust the stimulus intensity at each bin of
the step cycle. Adjustment of stimulation intensity was based on two
criteria: the amplitude of the M wave as a percentage of the Mmax that
was set to range from 2 to 12% of the Mmax, and the stimulation
intensities that evoked H reflexes only on the ascending limb of the
recruitment curve (Knikou 2008, 2013; Knikou et al. 2009, 2011).
These criteria applied to both conditioned and unconditioned H
reflexes, which were randomly recorded during stepping. The experiment was concluded when at least five accepted conditioned and
unconditioned H reflexes were recorded at each bin of the step cycle.
During stepping, stimulation was triggered based on the signal
from the ipsilateral foot switch (MA153; Motion Lab Systems, Baton
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Peripheral Nerve Stimulation
2449
2450
PLASTICITY OF POSTSYNAPTIC INHIBITION IN SCI
Rouge, LA). In all subjects, the step cycle was divided into 16 equal
bins. Bin 1 corresponds to heel contact. Bins 8, 9, and 16 correspond
approximately to stance-to-swing transition, swing phase initiation,
and swing-to-stance transition, respectively. EMG and foot switch
signals (Motion Lab Systems) were filtered with a cut-off frequency
of 10 –1,000 Hz and sampled at 2,000 Hz using a data acquisition card
(NI PCI-6225; National Instruments, Austin, TX).
Data Analysis
A
Before training
After training
R07 – AIS A
2 ms
3 ms
4 ms
2 ms
3 ms
4 ms
300 mV
300 mV
3
R17 – AIS D
2 ms
3 ms
Conditioned soleus H-reflex amplitude (% of the unconditioned soleus H-reflex)
140
B
120
AIS B (n = 1)
AIS A (n = 1)
*
*
*
*
100
80
60
40
20
0
140
2
C
120
3
4
2
AIS C (n = 6)
*
3
4
*
100
80
60
Before
training
40
20
0
120
2
3
AIS D (n =7)
D
*
4
*
100
After
training
* P < 0.05
before vs. after
80
60
40
4 ms
75 ms
200 mV
Control H-reflex before
or after training
75 ms
200 mV
20
0
Conditioned H-reflex
before or after training
2
3
Conditioning – test interval
(ms)
4
Fig. 1. Reciprocal inhibition before and after locomotor training during seated. A: nonrectified waveform averages (n ⫽ 20) of conditioned soleus H reflexes
(black lines) by common peroneal nerve (CPN) stimulation at 2-, 3-, and 4-ms conditioning-test (C-T) intervals are shown superimposed on the associated
unconditioned (grey lines) soleus H reflexes recorded before and after locomotor training. Reflexes are indicated for motor complete [American Spinal Injury
Association Impairment Scale A (AIS A) R07] and motor incomplete (AIS C, R15; AIS D, R17) spinal cord injuries (SCIs). B–D: overall amplitude of the
conditioned soleus H reflex as a percentage of the unconditioned H reflex recorded in AIS A, B, C, and D subjects at 2-, 3-, and 4-ms C-T intervals before and
after training. *Statistically significant differences between the conditioned H reflexes recorded before and after training. Error bars denote the SE.
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Soleus M waves, H reflexes, and maximal M waves recorded
during seated and stepping were measured as peak-to-peak amplitudes
of the nonrectified waveforms. For each subject, the soleus H reflexes
recorded following CPN or MG nerve stimulation during seated were
expressed as a percentage of the mean amplitude of the unconditioned
(or control) H reflex. The mean normalized conditioned soleus H
reflex from each subject was grouped based on the C-T interval and
time of testing, and two factor repeated-measures ANOVA was used
to determine the effects of training across the C-T intervals tested for
each AIS group.
The conditioned and unconditioned soleus H reflexes during stepping were expressed as a percentage of the associated maximal M
wave evoked at each corresponding bin of the step cycle. This was
done separately for all reflexes recorded before and after training. The
mean amplitude of the conditioned and unconditioned soleus H
reflexes was estimated for each bin of the step cycle and grouped
based on time of testing and AIS scale. Three-way repeated-measures
ANOVAs (pre- and posttraining, conditioned/unconditioned H re-
flexes, 16 bins) were performed to determine the effects of training on
the amplitude of the H reflexes for each bin of the step cycle and
differences between conditioned and unconditioned H reflexes. Post
hoc Bonferroni tests were used to test for significant comparisons.
This analysis was also performed separately for the M waves of the
conditioned and unconditioned H reflexes in AIS C and AIS D
subjects before and after training. The percentage of change of the
conditioned H reflex after training from the conditioned reflex before
training following CPN and/or MG nerve stimulation was estimated,
and grouped separately based on the number of locomotor training
sessions attended (20 –50 and 51– 65) and time postinjury (0.5–1 yr,
1.5–3.0 yr, and more than 4.0 yr) for all subjects. A one-way ANOVA
was performed to determine whether the percentage of change
changed with varying sessions of training or time postinjury.
To determine the net modulation of reciprocal and/or Ib inhibition
before and after training during stepping, the unconditioned H reflex
at each bin of the step cycle was subtracted from the associated
conditioned H reflex (M waves for both reflexes ranged from 2 to 8%
of the Mmax), both normalized to the Mmax evoked at each bin
(Mummidisetty et al. 2013). This was done to counteract the soleus
H-reflex phase-dependent modulation (pathological or reorganized
after training) during walking. The mean amplitude of the subtracted
conditioned H reflex was grouped across subjects based on the bin
number and time of testing, and the overall amplitude was estimated.
A resultant positive value indicates a condition associated with decreased inhibition, while a negative value indicates increased inhibition (Mummidisetty et al. 2013). Two factor repeated-measures
PLASTICITY OF POSTSYNAPTIC INHIBITION IN SCI
before and after training is indicated, respectively. In AIS A
subject, the conditioned soleus H reflex was significantly
different before and after training at the C-T intervals of 2 and
3 ms (F1,2 ⫽ 10.87, P ⫽ 0.01; Fig. 1B). In the AIS B subject,
a significant change for the conditioned soleus H reflex was
found for the C-T intervals of 2 and 4 ms (F1,2 ⫽ 11.49, P ⫽
0.001). Similarly, in AIS C subjects, the conditioned soleus H
reflex varied significantly with respect to the time of testing (F1 ⫽
6.94, P ⫽ 0.015). Reciprocal inhibition increased at the C-T
interval of 2 and 4 ms after training compared with that
recorded before training (P ⬍ 0.05). In AIS D subjects, the
conditioned soleus H reflex varied significantly with respect to
the time of testing (F1 ⫽ 6.93, P ⫽ 0.01). Reciprocal inhibition
increased at the C-T intervals of 3 and 4 ms after training
compared with that recorded before training (P ⬍ 0.05). An
overall change of ⫺15.29 ⫾ 10.2% and ⫺18.13 ⫾ 6.1% (P ⫽
0.45) on the conditioned H reflex was observed for AIS C and
D subjects after training, respectively.
The mean normalized amplitudes of the conditioned and
unconditioned soleus H reflexes during assisted stepping before and after locomotor training for AIS C subjects are
indicated in Fig. 2, A and B, respectively. Before training, the
conditioned soleus H reflex was not significantly different from
the unconditioned soleus H reflex across all phases of the step
cycle (P ⬎ 0.05; Fig. 2A). After training, the conditioned
soleus H reflex was larger in amplitude from the unconditioned
H reflex at early stance phase (bins 1– 4; P ⬍ 0.05; Fig. 2B).
The conditioned H reflex recorded after training was significantly different from the conditioned soleus H reflex recorded
before training at midstance phase (bin 7) and at mid- and
late-swing phases (bins 11, 12, and 14; P ⬍ 0.05). The net
modulation of reciprocal inhibition before and after training in
AIS C subjects during assisted stepping is indicated in Fig. 2C.
Reciprocal inhibition was decreased at heel contact (bin 1; P ⬍
0.05) and at early stance (bins 2 and 3; P ⬍ 0.05) and was
RESULTS
Reciprocal Inhibition at Rest and During Stepping After
Locomotor Training in SCI
In both motor complete and incomplete SCI, the reciprocal
inhibition exerted from ankle flexor Ia afferents on soleus
motoneurons was reestablished with locomotor training (Fig.
1A). In all types of spinal injuries, reciprocal facilitation or
absent reciprocal inhibition before training was replaced by
reciprocal inhibition after training with subjects seated (Fig.
1A). Note that the control soleus H reflexes and M waves have
similar amplitude before and after training (Fig. 1A), supporting that the observed changes after training could not be due to
conditioning of different types of soleus motoneurons and that
stimulation and recording procedures were not different.
In Fig. 1, B–D, the overall amplitude of the conditioned H
reflexes for AIS A, B, C, and D subjects recorded in seated
Before training
70
60
60
50
50
40
40
30
30
20
10
*
*
*
§
§
3
4
5
6
7
8
9
10
11
stance
12
13
14
15
16
1
3
4
swing
AIS D
D
2
40
*
5
stance
7
8
9
10
11
12
13
swing
14
15
10
Unconditioned H-reflex
Conditioned H-reflex
stance
6
1
2
3
4
5
stance
7
8
9
10
11
12
13
swing
14
15
16
6
7
8
9
10
11
12
13
swing
14
15
16
Before
training
After * P < 0.05
training
F
*
10
*
*
5
*
*
0
-5
-15
0
0
5
0
-5
-10
Unconditioned H-reflex
Conditioned H-reflex
4
5
-20
16
20
20
3
*
10
-15
6
30
2
*
15
30
1
*
15
* P < 0.05 Unconditioned vs. Conditioned H-reflex
§ P < 0.05 Conditioned H-reflex before vs. after training
20
§
E
Hconditioned-Hunconditioned (% of Mmax)
-10
Conditioned H-reflex
0
2
C*
20
§
*
§
10
Conditioned H-reflex
1
Soleus H-reflex size (% of
maximal M-wave evoked at
each bin)
25
Unconditioned H-reflex
0
10
30
20
Unconditioned H-reflex
40
B
Modulation (%)
Soleus H-reflex size (% of
maximal M-wave evoked at
each bin)
After training
A
70
Modulation (%)
AIS C
-20
1
2
3
4
5
stance
6
7
8
9
10
11
12
13
14
15
16
swing
1
2
3
4
5
stance
6
7
8
9
10
11
12
13
14
15
16
swing
Fig. 2. Reciprocal inhibition before and after locomotor training during stepping. Mean amplitudes of the conditioned and unconditioned soleus H reflexes
recorded before and after locomotor training from AIS C (A and B) and AIS D (D and E) subjects during stepping as a percentage of the associated maximal
M wave. *Decreased conditioned H reflexes compared with the unconditioned H reflexes. §Statistically significant differences between the conditioned H reflexes
recorded before and after training. C and F: net modulation of reciprocal inhibition with positive values suggesting decreased reciprocal inhibition and negative
values suggesting increased reciprocal inhibition. Bin 1 corresponds to heel contact. Bins 8, 9, and 16 correspond approximately to stance-to-swing transition,
swing phase initiation, and swing-to-stance transition, respectively. Error bars in all graphs denote the SE.
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ANOVA was used to determine changes in the net modulation of
reciprocal and Ib inhibition after training during stepping.
The background activity of the ipsilateral soleus, MG, and TA
muscles for each bin of the step was calculated from the mean value
of the filtered and rectified EMG (band-pass filtered 20 – 400 Hz) for
50 ms beginning 100 ms before tibial nerve stimulation. The soleus,
MG, and/or TA background activity was then normalized to the
associated maximal locomotor EMG background activity for each bin
of the step cycle and was grouped based on bin number and time of
testing. Two factor repeated-measures ANOVA was applied to the
data. The mean amplitude of the conditioned soleus H reflexes
(normalized to the Mmax evoked at each bin) was plotted on the y-axis
(dependent variable) vs. the associated normalized soleus, MG, or TA
background activity (independent variable) on the x-axis, respectively.
The slope and the y-intercept from the linear least-square regression
were estimated for each subject, and changes before and after training
were established with a paired t-test. In all statistical tests, significant
differences were tested at 95% of confidence level. Results are
presented as means ⫾ SE.
2451
2452
PLASTICITY OF POSTSYNAPTIC INHIBITION IN SCI
0.99) or time of testing (F1 ⫽ 0.1, P ⫽ 0.74). A significant
interaction for the normalized M waves among bins, time of
testing, and type of H reflexes was not found (F1,15 ⫽ 0.13, P ⫽ 1.0;
Fig. 3, A and B). Similar results were also found for the soleus
M wave in AIS D subjects during stepping (across bins: F15 ⫽
0.55, P ⫽ 0.91; time of testing: F1 ⫽ 0.52, P ⫽ 0.47; Fig. 3,
C and D).
The normalized soleus background activity along with the
linear regression between the soleus and TA background activity and the associated conditioned H reflexes from all AIS C
and D subjects before and after training is indicated in Fig. 4.
The normalized soleus EMG background activity was similar
before and after training (F1 ⫽ 2.48, P ⫽ 0.11, two-factor
ANOVA; Fig. 4A, top). Linear regression analysis between the
soleus background activity and the conditioned H reflex from
each AIS C and D subject showed that the y-intercept reached
overall amplitudes of 10.21 ⫾ 3.17 and ⫺3.3 ⫾ 10.42 (P ⫽
0.11), and the slope reached overall amplitudes of 51.93 ⫾
12.07 and 55.99 ⫾ 17.37 (P ⫽ 0.42) before and after training,
respectively. The normalized TA EMG background activity
from all AIS C and D subjects was also similar before and after
training (two-factor ANOVA, F1 ⫽ 2.02, P ⫽ 0.15; Fig. 4B,
top). Linear regression analysis between the TA background
activity and the conditioned H reflex from each AIS C and D
subject showed that the y-intercept reached overall amplitudes
of 12.18 ⫾ 8.18 and 17.17 ⫾ 13.29 (P ⫽ 0.37), while the slope
Reciprocal Ia inhibition
AIS C
M-wave (% Mmax)
20
Before training
After training
20
A
15
15
10
10
5
5
0
0
1
2
3
4
5
6
7
8
9
10 11 12 13
stance
M-wave (% Mmax)
1
14 15 16
2
3
swing
AIS D
20
B
4
5
6
7
8
9
stance
13 14
15 16
M-wave of
20
D
unconditioned H-reflex
M-wave of
M-wave of
15
11 12
swing
M-wave of
unconditioned H-reflex
C
10
conditioned H-reflex
15
10
10
5
5
conditioned H-reflex
0
0
1
2
3
4
5
6
stance
7
8
9
10 11 12 13 14 15 16
swing
1
2
3
4
5
6
stance
7
8
9
10 11 12 13 14 15 16
swing
Fig. 3. Soleus M waves during stepping before and after training in SCI. Normalized M-wave amplitudes (as a percentage of the maximal M wave) recorded
during stepping before and after locomotor training for the unconditioned soleus H reflex and following common peroneal nerve stimulation (reciprocal Ia
inhibition) in AIS C (A and B) and in AIS D (C and D) subjects. For all cases, the M waves did not change across bins or time of testing.
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increased at late swing (bins 14; P ⬍ 0.05) after training
compared with that observed before training.
The mean normalized amplitudes of the conditioned and
unconditioned soleus H reflexes during assisted stepping for
AIS D subjects before and after training are indicated in Fig. 2,
D and E, respectively. Before training, the conditioned soleus
H reflex was smaller at midstance (bin 6; P ⬍ 0.05; Fig. 2D)
compared with the unconditioned soleus H reflex. After training, the conditioned soleus H reflex was not significantly
different from the unconditioned soleus H reflex across all
phases of the step cycle (P ⬎ 0.05; Fig. 2E). The conditioned
H reflex recorded after training was significantly different from
the conditioned soleus H reflex recorded before training at
midstance phase (bin 6; P ⬍ 0.05). The net modulation of
reciprocal inhibition in AIS D subjects before and after training
during assisted stepping is indicated in Fig. 2F. Reciprocal
inhibition was decreased at late stance phase (bins 6 and 7; P ⬍ 0.05)
and during the swing phase (bins 11, 12, and 14; P ⬍ 0.05)
after training compared with that observed before training (Fig.
2F), suggesting for a different reorganization pattern of reciprocal inhibition during walking in individuals with AIS C and
AIS D (compare Fig. 2, C and 2F).
Changes in reciprocal Ia inhibition during stepping were
observed at similar amplitudes of M waves before and after
training in all subjects (Fig. 3). For AIS C subjects, the
M-wave amplitudes of the conditioned and unconditioned
soleus H reflexes did not vary across bins (F15 ⫽ 0.29, P ⫽
PLASTICITY OF POSTSYNAPTIC INHIBITION IN SCI
Normalized EMG
background activity
0.6
A
B
0.7
0.6
0.5
0.5
0.4
0.4
0.3
0.3
0.2
0.1
40
35
0.2
Before training
0.1
After training
0
0
1
2 3 4 5 6
15 16 stance
7
8
1
9 10 11 12 13 14
25
25
20
20
6
7
8
9 10 11 12 13 14 15 16
swing
10
5
5
0
0.3
y =-125.4x+74.185
R² = 0.61 (after training)
15
y = 54.366x+9.3483
R² = 0.59 (after training)
0.2
5
35
30
0.1
4
40
30
10
3
stance
y = 75.45x+6.1714
R² = 0.6 (before training)
15
2
swing
0.4
Normalized SOL background activity
y = - 25.052X+34.52
R² = 0.03 (before training)
0
0.25
0.3
0.35
0.4
0.45
0.5
0.55
0.6
Normalized TA background activity
Fig. 4. Relationship between conditioned soleus H reflex and background EMG activity. A: normalized soleus background EMG activity (top) along with the
mean normalized soleus EMG background activity plotted against the conditioned soleus (SOL) H reflex recorded at each bin of the step cycle (bottom) before
and after locomotor training. B: normalized tibialis anterior (TA) background EMG activity (top) along with the mean normalized TA EMG background activity
plotted against the conditioned soleus H reflex recorded at each bin of the step cycle (bottom) before and after locomotor training. For both graphs at the bottom,
the 16 points correspond to the 16 bins of the step cycle.
reached overall amplitudes of 28.15 ⫾ 27.32 and ⫺8.54 ⫾
22.03 (P ⫽ 0.15) before and after training, respectively.
Ib Inhibition at Rest and During Stepping After Locomotor
Training in SCI
Locomotor training reestablished or potentiated the MGmediated short-latency soleus H-reflex depression during
seated in motor complete and incomplete SCI (Fig. 5A). Ib
inhibition was evident in R07 (AIS A) but was absent in R16
(AIS C) and R12 (AIS D) before training (Fig. 5A) and was
potentiated in all of them after training while seated (Fig. 5A).
In Fig. 5, B–D, the overall amplitude of the conditioned H
reflexes for AIS A, B, C, and D subjects recorded in seated
before and after training is indicated, respectively. In the AIS
A subject, the conditioned H reflex was significantly different
before and after training at all C-T intervals tested (F1 ⫽
487.06, P ⬍ 0.001), while the conditioned H reflex before
training was reduced from control H-reflex values at the C-T
interval of 6 ms (F3,71 ⫽ 33.29, P ⬍ 0.001; Fig. 5B). In the AIS
B subject, the conditioned H reflex was significantly different
before and after training at the C-T interval of 4 ms (F1 ⫽ 5.8,
P ⫽ 0.018; Fig. 5B), while again at the C-T interval of 5 ms the
conditioned H reflex before training was reduced from control
H-reflex values (F2 ⫽ 7.12, P ⫽ 0.02; Fig. 5B), suggesting the
presence of Ib inhibition in motor complete SCI.
In motor incomplete AIS C subjects, although there was a
trend for Ib excitation to be replaced by Ib inhibition after
training (Fig. 5C), a significant difference for the conditioned
soleus H reflexes as a function of time of testing (F1,2 ⫽ 3.58,
P ⫽ 0.07) or C-T interval tested (F1,2 ⫽ 0.09, P ⫽ 0.9) was not
found. Ib inhibition was not present only in one AIS C subject
(R15) after training, while in the remaining AIS C subjects an
overall change of ⫺26.72 ⫾ 20.8% on the conditioned H reflex
was observed. Ib facilitation before training was replaced by Ib
inhibition after training at the C-T interval of 4 ms in AIS D
subjects (F1 ⫽ 6.23, P ⫽ 0.018; Fig. 5D), and an overall
change of ⫺14.9 ⫾ 7.4% on the conditioned H reflex was
observed. When data from both AIS C and D subjects were
taken into consideration, the conditioned soleus H reflex was
decreased after training compared with that observed before
training at all C-T intervals tested (F1 ⫽ 10.28, P ⫽ 0.002).
The mean normalized conditioned and unconditioned H
reflexes during assisted stepping before and after training for
AIS C subjects are indicated in Fig. 6, A and B, respectively.
The conditioned soleus H reflex was not significantly different
from the unconditioned soleus H reflex across all phases of the
step cycle before and after training (P ⬎ 0.05; Fig. 6, A and B).
The conditioned soleus H reflex after training was reduced
compared with the conditioned soleus H reflex before training
at mid- and late-swing phases (bins 12, 14, and 16; P ⬍ 0.05;
Fig. 6B). The net modulation of Ib inhibition in AIS C subjects
during stepping before and after training is indicated in Fig.
6C. Ib inhibition was decreased at early swing phase (bin 10)
and increased at late swing phase (bin 14) and during the swing
to-stance transition phase (bin 16) after training compared with
that observed before training (Fig. 6C).
The mean normalized conditioned and unconditioned soleus
H reflexes in AIS D subjects during assisted stepping before
and after training are indicated in Fig. 6, D and E, respectively.
Before training, the conditioned soleus H reflex was not different from the unconditioned soleus H reflex across all phases
of the step cycle (P ⬎ 0.05; Fig. 6D). After training, the
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Soleus H-reflex amplitude
(% of the Mmax at each bin)
2453
2454
140
Before training
After training
R07 – AIS A
4 ms
5 ms
6 ms
500 mV
4 ms
6 ms
300 mV
4 ms
5 ms
B
120
AIS B (n = 1)
AIS A (n = 1)
*
*
*
100
§- *
§
80
60
40
20
0
180
160
140
120
100
80
60
40
20
0
140
4
5
6
4
5
6
AIS C (n = 5)
C
Before
training
After
training
* P < 0.05
before vs. after
4
D
*
5
6
AIS D (n =7)
120
100
§ P < 0.05
before
training:
Hcond vs.
Hcontrol
80
60
6 ms
400 mV
75 ms
75 ms
40
20
Control H-reflex
Conditioned H-reflex
before or after training before or after training
0
4
6
5
Conditioning – test interval (ms)
Fig. 5. Ib inhibition before and after locomotor training during seated. A: nonrectified waveform averages (n ⫽ 20) of conditioned soleus H reflexes (black lines)
by medialis gastrocnemius (MG) nerve stimulation at 4-, 5-, and 6-ms C-T intervals are shown superimposed on the associated unconditioned (grey lines) soleus
H reflexes recorded before and after locomotor training. Reflexes are indicated for motor complete (AIS A, R07) and motor incomplete (AIS C, R16; AIS D,
R12) SCIs. B–D: overall amplitude of the conditioned soleus H reflex as a percentage of the unconditioned H reflex recorded in AIS A, B, C, and D subjects
at 4-, 5-, and 6-ms C-T intervals before and after training. *Statistically significant differences between the conditioned H reflexes recorded before and after
training. §Statistically significant differences between the conditioned and the unconditioned H reflexes recorded before training. Error bars denote the SE.
conditioned soleus H reflex was decreased at midswing and at
swing-to-stance transition (bins 12 and 16) compared with the
unconditioned soleus H reflex (P ⬍ 0.05; Fig. 6E). Furthermore, the conditioned H reflex after training was decreased
compared with the conditioned soleus H reflex before training
at mid- and late-swing phases (bins 10, 11, 12, and 16; P ⬍
0.05). The net modulation of Ib inhibition in AIS D subjects
during stepping before and after training is indicated in Fig. 6F.
Ib inhibition was increased at the early stance phase (bin 4; P ⬍ 0.05)
after training compared with that observed before training and
remained unaltered during the swing phase (Fig. 6F).
Changes in nonreciprocal Ib inhibition during stepping were
observed at similar amplitudes of M waves before and after
training in all subjects (Fig. 7). For AIS C subjects, the M
waves of the conditioned and unconditioned soleus H reflexes
were not significantly different across the step cycle (F15 ⫽
0.29, P ⫽ 0.99) and time of testing (F1 ⫽ 0.09, P ⫽ 0.76). A
significant interaction for the M waves among bins, time of
testing, and type of H reflexes was not found (F1,15 ⫽ 0.13, P ⫽ 1.0).
Similar results were also found for the M waves in AIS D
subjects (across bins: F15 ⫽ 0.36, P ⫽ 0.98; time of testing: F1 ⫽
0.31, P ⫽ 0.57; Fig. 7C, D). A significant interaction for the
M-wave values among bins, time of testing, and type of H
reflexes was not found (F1,15 ⫽ 0.31, P ⫽ 0.99).
The normalized soleus EMG background activity along with
the linear regression between the SOL and MG background
activity and the associated conditioned H reflex from all AIS C
and D subjects before and after training is indicated in Fig. 8.
The normalized soleus EMG background activity was not
significantly different before and after training (F1 ⫽ 0.15, P ⫽
0.69; Fig. 8A, top). The y-intercept reached overall amplitudes
of 27.55 ⫾ 7.26 and 9.74 ⫾ 3.65 (paired t-test, P ⫽ 0.02), and
the slope reached overall amplitudes of 20.88 ⫾ 25.19 and
31.56 ⫾ 18.6 (paired t-test, P ⫽ 0.36) before and after training,
respectively. The normalized MG background activity during
walking from all AIS C and D subjects was also not significantly different before and after training (F1 ⫽ 0.14, P ⫽ 0.7;
Fig. 8B, top). Linear regression analysis between the overall
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5 ms
Conditioned soleus H-reflex amplitude (% of the unconditioned soleus H-reflex)
A
PLASTICITY OF POSTSYNAPTIC INHIBITION IN SCI
PLASTICITY OF POSTSYNAPTIC INHIBITION IN SCI
Before training
AIS C
After training
A
80
30
Modulation (%)
50
40
40
30
30
20
10
Unconditioned H-reflex
20
Conditioned H-reflex
10
1
2
3
4
5
6
7
8
9
10
11
stance
12
13
14
15
16
0
50
Unconditioned H-reflex
50
2
3
4
5
6
7
8
9
10
11
12
-20
*
*
-30
13
14
15
16
1
2
3
20
20
Unconditioned H-reflex
10
15
§
Unconditioned H-reflex
Conditioned H-reflex
Conditioned H-reflex
§
§
§*
2
3
4
5
6
stance
7
8
9
10
11
12
13
swing
14
15
16
7
8
9
10
11
F
12
13
14
15
16
swing
Before
training
After * P < 0.05
training
*
5
0
-5
-10
-15
0
0
6
-20
1
2
3
4
5
stance
6
7
8
9
10
11
12
13
swing
14
15
16
1
2
3
4
5
stance
6
7
8
9
10
11
12
13
14
15
16
swing
Fig. 6. Ib inhibition before and after locomotor training during stepping. The mean amplitudes of the conditioned and unconditioned soleus H reflexes recorded
before and after locomotor training from the right leg of AIS C (A and B) and AIS D (D and E) subjects during walking are shown as a percentage of the associated
maximal M wave. *Decreased conditioned H reflexes compared with the unconditioned H reflexes. §Statistically significant differences between the conditioned
H reflexes recorded before and after training. C and F: net modulation of Ib inhibition with positive values suggesting decreased Ib inhibition and negative values
suggesting increased Ib inhibition. Bins 8, 9, and 16 correspond approximately to stance-to-swing transition, swing phase initiation, and swing-to-stance
transition, respectively. Error bars in all graphs denote the SE.
amplitudes of MG background activity and the conditioned H
reflex from each AIS C and D subject showed that the y-intercept reached overall amplitudes of 19.92 ⫾ 12.38 and 15.13 ⫾
8.19 (P ⫽ 0.37), while the slope reached overall amplitudes of
21.63 ⫾ 21.45 and 20.19 ⫾ 17.6 (P ⫽ 0.47) before and after
training, respectively.
Changes in Magnitude of Spinal Inhibition as a Function of
Locomotor Sessions and Time Postinjury
The magnitude of reciprocal Ia inhibition (Fig. 9A) and
nonreciprocal Ib inhibition (Fig. 9B) during seated did not alter
when locomotor training sessions attended ranged from 20 to
50 or from 51 to 65 (reciprocal inhibition: F ⫽ 2.24, P ⫽ 0.14;
Ib inhibition: F ⫽ 0.43, P ⫽ 0.51). A similar result was also
found for the magnitude of spinal inhibition based on time
postinjury (Fig. 9, C and D; reciprocal inhibition: F ⫽ 3.03, P ⫽
0.06; Ib inhibition: F ⫽ 1.05, P ⫽ 0.36).
DISCUSSION
This is the first report on plastic changes of reciprocal Ia and
nonreciprocal Ib inhibition after locomotor training in people
with motor complete or incomplete SCI. One of the most
important findings was that locomotor training reversed reciprocal facilitation to reciprocal inhibition during seated regardless of the sensorimotor capacity before training (Fig. 1).
Similarly, Ib inhibition returned in 13 out of 14 subjects during
seated (Fig. 5) and increased at similar rates to that of reciprocal Ia inhibition. It should be noted that Ib inhibition was
present in motor complete SCI before training during seated
(Fig. 5B), a finding consistent with the physiologic behavior of
force-sensitive Ib afferents in untrained complete spinal cord
transected animal preparations (Conway et al. 1987; Pearson
and Collins 1993).
During stepping, reorganization of postsynaptic control of
soleus motoneurons occurred in a phase-dependent manner.
Reciprocal inhibition was decreased in AIS C at early stance
(bins 1–3) and in AIS D at late stance (bins 6 and 7) after
locomotor training (Fig. 2, C and D). In uninjured subjects,
cocontraction, which decreases reciprocal inhibition
(Nielsen and Kagamihara 1992), of ankle flexors and extensors at early stance is needed to stabilize the ankle and
ensure a physiological step progression (Misiaszek et al.
2000). The reduced reciprocal inhibition at early stance in
AIS C is thus functional and consistent with observations
during walking in uninjured humans (Petersen et al. 1999;
Mummidisetty et al. 2013). Furthermore, reciprocal inhibition was increased at midswing in AIS C (Fig. 2C) but was
decreased after training at midswing in AIS D (Fig. 2F).
These findings suggest that reciprocal inhibition during
stepping recovers at a greater level in AIS C than in AIS D
with training, and that for both subject groups, the modulation pattern was not the same compared with that we
reported under similar experimental procedures in healthy
control subjects (i.e., reciprocal Ia inhibition was increased
at stance-to-swing transition and throughout the swing
phase) (Mummidisetty et al. 2013). Decreased levels of
reciprocal inhibition in AIS D subjects are depicted by the
absent full soleus H-reflex depression after training (Fig. 2C
in Knikou 2013) and absent modulation of presynaptic
inhibition of Ia afferents (Fig. 2F in Knikou and Mummidisetty 2014) during the swing phase in these patients.
Based on the amplitude of the unconditioned and conditioned soleus H reflexes before and after training by MG nerve
stimulation, Ib inhibition was absent during the stance phase in
both AIS C and D (Fig. 6, B and E) and was decreased at early
stance after training in AIS D (Fig. 6F). These findings are
consistent with the reduced short-latency group I inhibition of
synergists at the stance phase of walking in healthy humans
and during fictive locomotion in spinal animals (McCrea et al.
1995; Stephens and Yang 1996) and the reduced Ib inhibition
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30
5
stance
*
30
4
swing
40
1
-10
* P < 0.05 Unconditioned vs. Conditioned H-reflex
§ P < 0.05 Conditioned H-reflex before vs. after training
E
*
0
10
40
10
Hconditioned-Hunconditioned (% of Mmax)
10
-40
1
stance
D
§
§
§
Conditioned H-reflex
swing
AIS D
C
20
60
50
0
Soleus H-reflex size (% of
maximal M-wave evoked at
each bin)
B
70
60
Modulation (%)
Soleus H-reflex size (% of
maximal M-wave evoked at
each bin)
70
2455
2456
PLASTICITY OF POSTSYNAPTIC INHIBITION IN SCI
Non-reciprocal Ib inhibition
AIS C
M-wave (% Mmax)
20
20
A
15
15
10
10
5
5
0
0
1
2
3
4
5
6
7
8
9
stance
M-wave (% Mmax)
C
10 11 12 13 14 15 16
1
2
3
4
M-wave of
unconditioned H-reflex
20
M-wave of
conditioned H-reflex
15
10
10
5
5
0
6
7
8
9
stance
swing
15
5
10
11 12 13 14 15 16
swing
M-wave of
unconditioned H-reflex
M-wave of
conditioned H-reflex
D
0
1
2
3
4
5
6
stance
7
8
9
10 11 12 13 14 15 16
swing
1
2
3
4
5
6
stance
7
8
9
10 11 12 13 14 15 16
swing
Fig. 7. Soleus M waves during stepping before and after training in SCI. Normalized M-wave amplitudes (as a percentage of the maximal M wave) recorded
during stepping before and after locomotor training for the unconditioned soleus H reflex and following medial gastrocnemius nerve stimulation (nonreciprocal
Ib inhibition) in AIS C (A and B) and in AIS D (C and D) subjects. For all cases, the M waves did not change across bins or time of testing.
during a rhythmic loading-unloading motor task in healthy
humans (Faist et al. 2006). Furthermore, Ib inhibition in AIS C
was decreased at early swing and increased at late swing (Fig.
6C), suggesting that synergistic group I afferents may contribute to the soleus H-reflex depression during the swing phase,
supported by previous findings reported for untrained SCI
subjects (Knikou 2012). Last, cyclic disinhibition of group Ib
excitatory spinal interneurons was weak compared with that
observed in animals (Angel et al. 1996), since locomotor
training did not induce an extra facilitation of soleus motoneuron responses by group Ib afferents during the stance phase
(Fig. 6, B and E).
The decreased reciprocal inhibition during the swing phase
in AIS D (Fig. 2F) and the weak Ib excitation during the stance
phase in AIS C and D (Fig. 6, C and F) may depend on the
number of training sessions, the number of steps per session
(de Leon et al. 2011), or even the BWS since loading can affect
the net EMG output (Dietz et al. 2002). The BWS during
training was adjusted separately for each participant based on
his/her ability to step without knee buckling or toe dragging,
and thus quantification of BWS effects is not possible. However, it should be noted that reciprocal inhibition at 27% BWS
is still modulated in a physiologic pattern in uninjured subjects
(Mummidisetty et al. 2013). Furthermore, the magnitude of
reciprocal Ia and nonreciprocal Ib inhibition was not affected
by the number of training sessions (Fig. 9, A and B) with
subjects seated. However, the number of training sessions may
affect differently the strength of postsynaptic inhibition during
stepping.
The neuroplastic changes described above occurred at similar levels of soleus and MG motoneuron gain before and after
training under control conditions and reflex conditioning during stepping (Figs. 4 and 8). The linear relationship between
the conditioned soleus H-reflex and soleus background activity
suggests that reflex actions of MG group I afferents on soleus
alpha motoneurons follow the soleus background excitability
pattern. However, because Ib inhibition is not affected by
triceps surae contraction (Pierrot-Deseilligny et al. 1982), and
reciprocal inhibition is not abolished following soleus muscle
voluntary contraction (Yang and Whelan 1993), although it is
modulated during ankle movement (Shindo et al. 1984), net
changes of soleus motoneuron excitability and duration of
hyperpolarization cannot account solely for the observed
changes.
Possible Mechanisms for Plasticity of Postsynaptic Inhibition
Posttraining
SCI in humans is characterized by extensive pathologic
reorganization of spinal neuronal circuits that gate sensory
afferent feedback and regulate amplitude and periodicity of
motoneuron discharges (Knikou 2010a; Tansey et al. 2012).
Reciprocal inhibition is replaced by facilitation (Crone et al.
1994; Morita et al. 2001; Okuma et al. 2002), attributed mostly
to altered cortical control of Ia inhibitory interneurons (Nielsen
J Neurophysiol • doi:10.1152/jn.00872.2014 • www.jn.org
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AIS D
20
B
Normalized
background activity
PLASTICITY OF POSTSYNAPTIC INHIBITION IN SCI
0.6
A
0.6
0.5
0.5
0.4
0.4
0.3
0.3
0.2
0.2
0.1
0.1
0
1
2
3
4
5
6
7
8
45
40
35
30
25
20
15
10
5
0
swing
y = 72.182x + 8.8073
R² = 0.32 (before training)
0.1
0.2
0.3
Before training
B
After training
0
1
2
3
4
5
6
stance
7
8
45
y = 111.69x – 9.6876
40 R² = 0.44 (before training)
35
30
25
20
15 y = 64.473x – 0.7412
y = 126.42x – 15.658
R² = 0.49 (after training) 10 R² = 0.05 (after training)
5
0
0.4
0.5
0.1
0.2
0.3
Normalized SOL background activity
9 10 11 12 13 14 15 16
swing
0.4
Fig. 8. Relationship between conditioned soleus H reflex and background EMG activity.
A: normalized soleus background EMG activity (top) along with the mean normalized
soleus background EMG activity plotted
against the conditioned soleus H reflex for
each bin of the step cycle (bottom) before and
after locomotor training. B: normalized MG
background EMG activity (top) along with
the mean normalized MG background EMG
activity plotted against the conditioned soleus
H reflex for each bin of the step cycle (bottom) before and after locomotor training. For
both graphs at the bottom, the 16 points
correspond to the 16 bins of the step cycle.
0.5
Normalized MG background activity
et al. 1995). Findings on Ib inhibition are conflicting, with both
physiologic and pathologic behaviors being reported (Downes
et al. 1995; Morita et al. 2006; Knikou 2012).
Because both reciprocal and Ib inhibition were potentiated
after training in complete SCI, direct descending inputs on
spinal inhibitory interneurons may not be a key source for
neuroplasticity but may be required for long-term support of
inhibitory synaptic transmission and regulation of the depth of
spinal inhibition. This is supported by the ability of the spinal
cord after complete spinalization to undergo functional reorganization with locomotor training (Rossignol 2006) and that
the plasticity of the glycinergic system, which mediates inhib-
itory neurotransmission, can occur independent of supraspinal
influences (Sadlaoud et al. 2010). Locomotor training normalizes the proportion of inhibitory and excitatory synaptic inputs
to spinal motoneurons (Ichiyama et al. 2011), improves synaptic inputs from Ia afferents (Petruska et al. 2007), alters the
concentration levels of Na⫹-K⫹-ATPase (Ilha et al. 2011), and
reverses disynaptic inhibition to polysynaptic excitation (Côté
et al. 2003) in animals. We have recently shown that locomotor
training changes the behavior of short- and long-latency flexion
reflexes, reestablishes a physiologic soleus H-reflex phasedependent modulation, increases presynaptic inhibitory control
of soleus motoneurons, modifies excitability properties of so-
Reciprocal Ia inhibition
0
0
-5
-5
% of change of the conditioned H-reflexes
-10
-10
-15
-20
-15
Fig. 9. Magnitude of spinal postsynaptic inhibition. A and B: percentage of change of the
conditioned H reflex during seated from all
subjects after training, reflecting the magnitude of reciprocal and nonreciprocal inhibition, is plotted against the number of locomotor training sessions attended. C and D:
percentage of change of the conditioned H
reflex during seated from all subjects after
training, reflecting the magnitude of reciprocal and nonreciprocal inhibition, is plotted
against the years postinjury.
-25
-20
-25
-30
A
-35
C
Non-reciprocal Ib inhibition
0
0
-5
-5
-10
-10
-15
-15
-20
-20
-25
-25
-30
-30
-35
-40
-35
B
-40
20-50
51-65
Number of locomotor training sessions
D
0.5-1.5 years
more than
4.0 years
Years post injury
1.5-3.0 years
J Neurophysiol • doi:10.1152/jn.00872.2014 • www.jn.org
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Soleus H-reflex amplitude
(% of the Mmax at each bin)
stance
9 10 11 12 13 14 15 16
2457
2458
PLASTICITY OF POSTSYNAPTIC INHIBITION IN SCI
Limitations
A limitation of this study is that data were acquired from one
person with AIS A and one person with AIS B, while the
sample sizes for AIS C and D subjects were small. Neurophysiological research studies in a larger number of patients receiving locomotor training are needed to further delineate the
neurophysiological mechanisms of locomotor training mediated plasticity in people with SCI. Patients who did not receive
locomotor training were not tested in this study. However, it is
unlikely that the observed changes were due to spontaneous
neuronal plasticity. Spontaneous plasticity is mostly observed
within the first 9 mo postinjury (Fawcett et al. 2007), and time
postinjury was less than 1 yr only in 3 of 16 patients tested
here. Furthermore, the BWS needed at the end of training was
decreased by as much as 280 ⫾ 66.6% and TA EMG activity
for example increased by as much as 243% in the left leg and
by 142% in the right leg (Knikou 2013; Knikou and Mummidisetty 2014), suggesting that stepping capabilities and full
body-weight bearing changed beyond that expected by spontaneous plasticity (de Leon et al. 1998).
Conclusion
We describe here, for the first time reported in the literature,
changes in the postsynaptic control of soleus motoneurons
from antagonistic Ia and synergistic Ib afferents in people with
chronic SCI after locomotor training. Our current and previous
findings from the same patients (Knikou 2013; Knikou and
Mummidisetty 2014; Smith et al. 2014, 2015) provide a comprehensive investigation on neurophysiological mechanisms
underlying locomotor training in people with SCI. Task-depen-
dent adaptation of neuronal and network excitability demonstrates that neuromodulation can express functional neuroplasticity and may be used as a biomarker of rehabilitation efforts
and recovery of motor dysfunction. However, more studies are
needed to establish to what extent neurophysiologic measures
of activity-dependent neuroplasticity can predict recovery of
motor function.
ACKNOWLEDGMENTS
We thank the research participants for participating in numerous experiments and training sessions and William Zev Rymer for support.
GRANTS
This work was supported by the New York State Department of Health,
Wadsworth Center, Spinal Cord Injury Research Board Grant C023690 and
The Craig Neilsen Foundation Grant 83607 (to M. Knikou). A. C. Smith is
supported by National Institute of Child Health and Human Development
Grant T32-HD-057845 and by the Foundation for Physical Therapy Promotion
of Doctoral Studies.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
Author contributions: M.K. conception and design of research; M.K.,
A.C.S., and C.K.M. performed experiments; M.K. analyzed data; M.K. interpreted results of experiments; M.K. and C.K.M. prepared figures; M.K. drafted
manuscript; M.K. and A.C.S. edited and revised manuscript; M.K., A.C.S., and
C.K.M. approved final version of manuscript.
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