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MODULATION OF RECURRENT INHIBITION FROM KNEE EXTENSORS TO ANKLE

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MODULATION OF RECURRENT INHIBITION FROM KNEE EXTENSORS TO ANKLE Powered By Docstoc
					Physiology in Press; published online on October 20, 2008 as 10.1113/jphysiol.2008.160630




     MODULATION OF RECURRENT INHIBITION FROM KNEE
   EXTENSORS TO ANKLE MOTONEURONES DURING HUMAN
                                              WALKING


  Jean-Charles LAMY1,2, Caroline IGLESIAS1,2, Alexandra LACKMY1,2, Jens Bo NIELSEN3, Rose
                           KATZ1,2 and Véronique MARCHAND-PAUVERT1,2


  1- INSERM, U731, F-75013, Paris, France

  2- UPMC Univ Paris 06, UMR_S731, F-75005, Paris, France

  3- Institute of Exercise and Sports, University of Copenhagen, Denmark




  Running title: Recurrent inhibition during walking

  Key words: Spinal interneurones, Human, Locomotion

  Total number of words (without references and figure legends): 6,428 words




  Corresponding author:

  Véronique Marchand-Pauvert, PhD
  U731 INSERM/UPMC Univ Paris 06
  Sce MPR, Hôpital Pitié-Salpêtrière, 47 bd de l’Hôpital, 75651 Paris cedex 13, France
  Tel: +33 1 42 16 11 20
  Fax: +33 1 42 16 11 02
  Email: veronique.marchand@chups.jussieu.fr




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ABSTRACT

            The neural control for muscle coordination during human locomotion
involves spinal and supraspinal networks, but little is known about the exact
mechanisms implicated. The present study focused on modulation of heteronymous
recurrent inhibition from knee extensors to ankle motoneurones at different times in the
gait cycle, when Quadriceps (Quad) muscle activity overlaps that in Tibialis Anterior
(TA) and Soleus (Sol). The effects of femoral nerve stimulation on ankle motoneurones
were investigated during treadmill walking and during tonic co-contraction of Quad and
TA/Sol while standing. Recurrent inhibition of TA motoneurones depended on the level
of background EMG, and was similar during walking and standing for matched
background EMG levels. On the other hand, recurrent inhibition in Sol was reduced in
early stance, with respect to standing, and enhanced in late stance. Reduced inhibition in
Sol was also observed when Quad was co-activated with TA around the time of heel
contact, compared to standing at matched background EMG levels in the two muscles.
The modulation of recurrent inhibition of Sol during walking might reflect central
and/or peripheral control of the Renshaw cells. These modulations could be implicated
in the transition phases, from swing to stance to assist Sol activation during the stance
phase, and from stance to swing, for its deactivation.




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INTRODUCTION

            During human walking, the activity of muscles acting at different joints
must be well synchronised to ensure upright posture and the ongoing locomotor rhythm.
Given their organisation and their control by peripheral and descending inputs, this may
be achieved by modulation of the activity of spinal neural networks (see Nielsen, 2003).
Two of the neural pathways, which likely make an important contribution to muscle
coordination during walking, are monosynaptic excitation and recurrent inhibition. They
are produced in spinal motoneurones by group Ia afferents and motor axon discharge,
respectively, and are more widely distributed in the human lower limb (Meunier et al.,
1993; 1994) than in the cat and baboon hindlimb (Eccles et al., 1957; Eccles &
Lunderg, 1958; Hultborn et al., 1971; Hongo et al., 1984). It has been suggested that
these trans-joint connections have evolved to assist bipedal stance and gait (see Pierrot-
Deseilligny & Burke, 2005).

            Quadriceps (Quad) group Ia afferents and recurrent collaterals from its
motoneurones have been shown to influence the activity of both Tibialis Anterior (TA)
and Soleus (Sol) motoneurones (Fig. 1A; Meunier et al., 1994). This antagonistic
muscle pair thus receives common inputs from Quad and the question then arises as to
how the motor command is focused on the relevant motoneurone pool when activity in
Quad overlaps successively TA (around the time of heel contact) and Sol (stance phase)
activity during walking; Ia monosynaptic excitation and recurrent inhibition from
Renshaw cells are of special interest. During walking, modulation of the activity of
interneurones mediating presynaptic inhibition of group Ia terminals (Hultborn et al.,
1987a; b; see Rudomin, 2002) could help to gate monosynaptic Ia excitation to the
different ankle motoneurones, and thus facilitate their respective activation with Quad.
Cat and human experiments suggest that presynaptic inhibition is generally enhanced
during locomotion keeping homonymous monosynaptic Ia excitation low (Gossard,
1996; Morin et al., 1982; Capaday & Stein, 1986); less is known on heteronymous
pathways (Faist et al., 1996a), in particular whether there is a specific modulation of the
monosynaptic Ia excitation of ankle dorsiflexors from knee extensors at the time of co-
activation. In cats, Renshaw cell activity changed during fictive locomotion, but it is
unclear whether this simply reflects the motoneuronal discharge or whether there is a




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possibility of selectively modulating the amount of recurrent inhibition in different parts
of the step cycle (Pratt & Jordan, 1980). In humans, it has been shown that recurrent
inhibition may be both facilitated and inhibited during various voluntary movements
(see Katz & Pierrot-Deseilligny, 1999), and there is some evidence to suggest a
reduction of heteronymous recurrent inhibition during postural tasks (from Quad to
ankle muscles; Barbeau et al. 2000) and locomotion (from Sol to Quad; Iles et al.,
2000).

            In the present study, we investigated the modulation of heteronymous Ia
excitation and recurrent inhibition from Quad to ankle motoneurones. The effect of
femoral nerve (FN) stimulation on TA and Sol motoneurones was assessed by studying
the modulation of rectified EMG averages and the size of motor evoked potentials
(MEPs), at the end of the swing phase (effect of FN stimulation on TA motoneurones)
and during the stance phase (effect on Sol motoneurones) of treadmill walking, when
Quad activity overlaps that in TA and Sol, respectively. The FN-induced inhibition of
Sol H-reflex was investigated around the time of heel strike, when Quad and TA are co-
activated, to test the modulation of recurrent inhibition of Sol motoneurones during
activation of its antagonist. The results were compared to those obtained during tonic
co-contraction of Quad to either TA or Sol while standing.


METHODS

            The experiments were carried out in 14 healthy volunteers (22-45 yrs) who
all gave written informed consent to the experimental procedures. The study was
performed according to The Code of Ethics of the World Medical Association
(Declaration of Helsinki), and was approved by the local ethics committees of the Pitié-
Salpêtrière Hospital.

   Recordings

            The EMG activity was recorded with bipolar surface electrodes (EMG
sensors DE-2.1; Delsys Inc., Boston, Massachusetts, USA) placed over the muscle belly
of Vastus Lateralis (VL; lateral head of Quad), Tibialis Anterior (TA) and Soleus (Sol).
EMG activity was amplified (x 1,000-10,000; Delsys Bagnoli System 4 Ch), and
filtered (EMG bandwidth 20-450 Hz) before being digitally stored (2-kHz sampling




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rate) on a personal computer for later off-line analysis (Notocord-hem 3.4; Notocord
SA, Croissy s/Seine, France). Recordings were done during treadmill locomotion
(Biodex Medical Systems Inc., Shirley, New York, USA), and a pressure transducer
was placed on the heel of the shoe in order to detect the time of heel strike. At the
beginning of the experiment, the subjects walked on the treadmill for 5-10 minutes
before recordings, to accustom themselves to treadmill walking, and to determine their
preferred speed (3-4 km/h). Recordings were also done during tonic co-contraction of
Quad and TA and of Quad and Sol while standing with EMG levels within the same
range to those recorded during walking.

  Peripheral stimulations

           Peripheral stimulations consisted of rectangular electrical pulses of 1-ms
duration delivered at fixed intervals after heel strike (triggered by the pressure
transducer under the heel) or during tonic co-contraction while standing. The maximal
amplitude of the M response (Mmax) in each corresponding EMG activity was first
measured during both tasks, and at each investigated interval during walking. Femoral
nerve (FN) was stimulated between cathode (2.5-cm diameter brass hemisphere) placed
in the femoral triangle and anode on the back of the thigh (40-cm2 plate), and stimulus
intensity was adjusted i) so as to produce a constant M response of 30 % Mmax in VL
EMG, which was monitored throughout the experiment, and ii) at ~0.8 x the threshold
for M response (MT) determined during walking and tonic contraction while standing
(and below H-reflex threshold). The comparison between the two intensities was done
to check if EMG suppression was evoked only if Quad motor axon discharged.
Common peroneal nerve (CPN) was stimulated through bipolar surface electrodes
(Maersk Medial Ltd, Redditch, UK; proximal cathode) at the level of the neck of the
fibula to measure TA H-reflex latency. Posterior tibial nerve (PTN) stimulation was
applied between cathode (2.5-cm diameter brass hemisphere) placed in the popliteal
fossa and anode above the patella (40-cm2 plate), and stimulus intensity was adjusted so
as to produce H-reflexes in Sol EMG of similar size during the two motor tasks (5-10 %
Mmax; Crone et al., 1990).

  Cortical stimulation

           Trans-cranial magnetic stimulation (TMS) over the primary motor cortex




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was used to produce MEPs in TA and Sol EMG. The magnetic field was generated
through a double cone-coil (Magstim Rapid, Whitland, UK) held at the optimal position
for evoking an MEP in one of the ankle muscles, which was determined during tonic
ankle plantarflexion (for Sol) and dorsiflexion (for TA) while standing on the treadmill;
activities in TA and Sol were simultaneously recorded to control that the response was
evoked in the target muscle and was not caused by cross-talk of an MEP produced in its
antagonist. A custom-made prosthesis, with the same shape as the coil, was used to fix
the coil over the head; a band was used to tighten the coil and prosthesis over the head.
The coil cable was held by an elastic restraint, which was fixed to the treadmill body-
weight support system. This setup reduced the weight of the coil and the cable. The coil
position was thus stable, despite the up-and-down oscillations during walking, which
were softened by the elastic restraint. This was checked by asking subjects if they felt
the coil moving while walking, and by monitoring the MEP threshold, its shape and test
size throughout the duration of the experiment. Recordings during walking and tonic co-
contraction while standing were done during the same experiment to ensure that the coil
position was the same. TMS intensity was adjusted so as to produce test MEP within the
same proportion of Mmax (15-25 % in TA and 5-15 % in Sol) during both motor tasks.

   Experimental protocols

      Stimulus trigger delay after heel strike

            At the beginning of the experiment, the subject was asked to walk for 1-2
min. at his preferred speed (3-4 km/h) to determine the stimulus trigger delays after heel
strike according to his walking EMG pattern (Figs. 1BC). At this speed, the step cycle
was reasonably stable, and on average, the variability was 5 ± 1 % the mean cycle
duration. FN stimulation was delivered when ankle muscle activity overlapped that in
VL (dotted area in Fig. 1C) and that in Rectus femoris (another head of Quad, grey area
in Fig. 1C; Nene et al., 2004). TA EMG modulations could not be explored at the
beginning of the swing phase since FN stimulation, evoking an M response of 30 %
Mmax, perturbed the gait cycle, which made a comparison between control and
conditioned TA EMG impossible. Indeed, the tip of the toe scraped the treadmill belt,
due to the FN-induced knee extension, which delayed the ankle dorsiflexion. Therefore,
the effect of FN stimulation was not investigated during the first TA EMG burst (~600




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ms after heel strike; Fig. 1C) corresponding to the TA shortening contraction but only
during the second EMG burst (~1000 ms after heel strike) corresponding to the TA
lengthening contraction (den Otter et al., 2004).

                                               Figure 1 about here


              In each subject, FN stimulation was thus delivered (see vertical arrows in
Fig. 1C) i) for TA investigation: in the ascending phase of the second EMG burst (onset
TA; 850-1000 ms after heel strike, depending on the subject), at the peak of activity
(middle TA; 900-1150 or 0 ms after heel strike), and within the descending phase of the
EMG burst (late TA; 1050 or 0-50 ms after heel strike), and ii) for Sol: in the ascending
phase of the EMG burst (onset Sol; 60-150 ms after heel strike), at the beginning of the
plateau (early Sol; 100-180 ms after heel strike), and before the EMG burst descending
phase (late Sol; 300-480 ms after heel strike).

      Tonic co-contraction while standing

              Subjects stood on the treadmill and performed tonic co-contraction of TA
and Quad and of Sol and Quad. EMG activities were displayed on the screen of the
computer for visual feedback to help subjects to produce EMG activity similar to those
recorded during walking. Sol EMG activity was also recorded when subjects sustained
their Maximal Voluntary Contraction (MVC) for a few seconds, while standing on the
tip of their toes and one of the investigators exerted a resistance on their shoulders. The
EMG activity produced during walking and tonic co-contraction while standing was
expressed as a percentage of the EMG activity produced during MVC.

      Assessment of the FN effect on TA and Sol motoneurones

              The effect of the FN stimulation on TA (10 subjects) and Sol (11 subjects)
motoneurones was first investigated in stimulus-triggered averaging of rectified EMG
activity. Recordings with stimulation (conditioned EMG; N = 50) were randomly
alternated (~0.8 Hz) with recordings without stimulation (control EMG; N = 50; Figs.
1D, 2 & 5).

              Since presynaptic inhibition can contribute to FN-induced EMG suppression
and since the MEP is not sensitive to presynaptic inhibition (Nielsen & Petersen, 1994),




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the FN stimulation was used to condition MEPs in TA and Sol (5 subjects; Fig. 4) at
inter-stimulus intervals between -12 to 50 ms (depending on the subject). Test MEPs
(without FN stimulation; N = 12) were randomly alternated (~0.8 Hz) with conditioned
MEP (with FN stimulation; N = 12). During walking, TA MEPs were investigated at
delays corresponding to the onset and middle TA activity, and Sol MEPs were studied
at the onset of Sol activity and later in the EMG burst, before its deactivation (see
above).

           Lastly, we wondered whether recurrent inhibition from Quad to one of the
ankle muscle could be modified during the activation of its antagonist. This was only
possible by testing the effect of FN stimulation on Sol H-reflexes (5 subjects; Fig. 6)
during TA activation (1000 or 0 ms after heel strike and during Quad and TA co-
contraction while standing). Test H-reflexes (without FN stimulation; N = 20) were
randomly alternated (~0.3 Hz) with conditioned H-reflexes (with FN stimulation; N =
20). Intervals between 5 and 35 ms were investigated in each subject.

           To compare measurements in both tasks, it was ensured that test MEPs and
H-reflexes had similar size (see above).

  Quantitative and statistical analysis

           Figure 1D shows that FN stimulation increased TA EMG activity at 24.5 ms
before long lasting EMG suppression, and similar modulations have been described in
Sol EMG activity (Meunier et al., 1996; Barbeau et al., 2000). The areas of rectified
control and conditioned EMG were analysed within two windows to assess the amount
of FN-induced facilitation and inhibition. The beginning of the windows was
determined according to the H-reflex latency in VL, TA and Sol, and conduction
velocity in group Ia afferents in FN, CPN and PTN. The method used is more detailed
in previous studies (Meunier et al., 1990; Meunier et al., 1996; Barbeau et al., 2000),
and only appears in figure legend in the present study (see Fig. 1D). Window duration
for facilitation was limited to the duration of the peak in EMG (e.g. dotted area between
24.5 and 30 ms in Fig. 1D). This duration was mainly determined during tonic co-
contraction since FN stimulation produced less facilitation during walking (see left part
of Figs. 2 & 5). The analysis window for inhibition started 10 ms after the facilitation,
and its duration was fixed to 12 ms in order to limit the analysis to spinal transmission




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(e.g. dotted area between 34.5 and 46.5 ms in Fig. 1D; see Nielsen et al., 1997; Barbeau
et al., 2000). The same analysis window was used for each motor task, and for each
delay during walking. The resulting mean control EMG and the difference between
conditioned EMG and mean control EMG, reflecting the amount of facilitation and
inhibition, were expressed as a percentage of Mmax in TA and Sol for inter-individual
comparison. MEPs in TA and Sol (with and without FN stimulation) were rectified for
surface analysis within a window corresponding to their latency and duration. The Sol
H-reflex amplitude was used to assess the effect of the FN stimulation. The conditioned
responses were expressed as a percentage of the corresponding mean test response
whose size was similar between the two motor tasks (see above).

            Conditioned and test responses (EMG areas, MEP and reflex sizes) were
compared in each individual by using paired t test. EMG grouped data were analysed
using Pearson’s correlation (pooling multiple subject data for linear analysis; Poon,
1988) to test the relation between control EMG and the amount of facilitation and
inhibition; the difference between motor tasks (tonic vs. different times in the gait cycle)
was tested using ANCOVA. Conditional on a significant F value, Post hoc Newman-
Keuls tests analyses were performed for comparisons of two means. Given the data
distribution and heteroscadicity, mean conditioned MEPs and H-reflexes were
compared between the various motor tasks using Kruskal-Wallis tests. Conditional on a
significant H value, Wilcoxon tests were performed for comparisons of two means. For
all tests, the significance level was 0.05. Mean data are indicated ± 1 standard error of
the mean (S.E.M.).


RESULTS

   Effects on TA motoneurones

      Rectified TA EMG averaging

            Figure 2 shows that FN stimulation significantly increased (paired t test; P <
0.01) TA EMG activity at 24 ms during tonic co-contraction of Quad and TA while
standing (A) but not (onset TA C and late TA G) or hardly during walking (middle TA
EI) in one subject. On the other hand, significant FN-induced long lasting EMG




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suppression was observed during both tasks, and whatever time in the gait cycle, when
FN stimulation was adjusted so as to evoke a constant M response in VL EMG of 30 %
Mmax (BDFH). No EMG suppression was evoked when stimulus intensity was adjusted
below M response and H-reflex threshold (0.8 x MT, IJ). In all the 10 subjects, FN
depressed TA EMG activity only when FN stimulation produced M and/or H-reflex in
VL EMG (checked during tonic and walking contraction).

                                             Figure 2 about here


           On average, FN stimulation produced EMG facilitation at 23.7 ± 0.2 ms,
which was very weak (0.38 ± 0.17 % Mmax) and rarely significant during standing (5/10
subjects). During walking, FN-induced facilitation was almost absent (-0.05 ± 0.13 %
onset TA and -0.25 ± 0.20 % middle TA), and reached statistical significance in only
one subject in late TA (mean 0.29 ± 0.28 %).

           FN stimulation suppressed TA EMG activity while standing in all the 10
subjects (significantly in 9/10 subjects) and grouped data were analysed to compare the
amount of inhibition between tasks. The mean control EMG activity in TA during tonic
co-contraction was between those recorded at the delays corresponding to onset and
middle TA during walking. Group data illustrated in Figure 3A show a significant
correlation between the control EMG and the amount of inhibition (Pearson’s
correlation, r = 0.68, P < 0.001), whatever the motor task. ANCOVA was then used to
test if the correlation between the level of control EMG and the amount of inhibition
changed depending on the motor task. The amount of inhibition was thus compared
between tasks using the control EMG as covariate, and the result was not significant (P
= 0.14; Fig. 3C). This suggests that the FN-induced inhibition in TA EMG depended on
its background activity while the subjects were standing or walking.

                                             Figure 3 about here



     TA MEPs

           Figure 4A shows that conditioned TA MEPs in one subject were
significantly smaller (paired t test, P < 0.01) than test MEPs when FN stimulation
preceded TMS by 20 ms during tonic and walking. Full time course of the effect in the




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same subject is illustrated in B showing similar FN-induced changes during tonic and
walking (at two delays) with facilitation at short interval (-5 ms) and inhibition at longer
intervals (20-30 ms).

                                              Figure 4 about here


            On average, test MEPs had similar size (19.1 ± 2.6 % Mmax during tonic vs.
19.1 ± 3.3 onset TA vs. 21.3 ± 2.9 middle TA; Kruskal-Wallis, P = 0.70) and were
evoked with TMS outputs within the same range (40.8 ± 3.5 % maximum output during
tonic vs. 43.2 ± 3.9 onset TA vs. 41.2 ± 3.5 middle TA; P = 0.85). FN stimulation
significantly increased the MEP size in 4/5 subjects (between -12 and 0 ms, depending
on the subject) during tonic co-contraction, and in only one subject during walking. The
mean amount of facilitation tended to be larger during standing (120.4 ± 3.8 % test size)
as compared to walking (105.9 ± 8.2 and 100.9 ± 8.8 %, at onset and middle TA,
respectively) but the difference did not reach statistical significance (Fig. 4E, Kruskal-
Wallis, P = 0.08). At longer intervals (between 10 and 40 ms), FN significantly reduced
the MEP size in 3/5 subjects during tonic and middle TA during walking, and in 4/5 at
onset TA during walking. On average, this long-interval inhibition did not significantly
change between tasks (Fig. 4E; P = 0.81).

   Effects on Sol motoneurones

      Rectified Sol EMG averaging

            Figure 5 shows that FN stimulation significantly increased (paired t test, P <
0.01) Sol EMG activity at 28.5 ms (peaking at 32.5 ms) during tonic co-contraction of
Quad and Sol while standing (A) but not or hardly during walking (onset C, early E, and
late Sol G) in one subject. This facilitation was followed by significant long lasting
EMG suppression during tonic co-contraction, which was also observed when FN
stimuli were delivered at the end of the walking stance phase (G) but hardly when
triggered earlier (CE). Such EMG suppression was only produced when FN stimulation
was adjusted so as to evoke a constant M response in VL EMG of 30 % Mmax (BDFH).
No EMG suppression was evoked when stimulus intensity was adjusted below M
response and H-reflex threshold (0.8 x MT, IJ). In all the 11 subjects investigated the




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same way, FN depressed Sol EMG activity only when FN stimulation produced M
and/or H-reflex in VL EMG (checked during tonic and walking contraction).

                                              Figure 5 about here


            On average, FN-induced Sol EMG facilitation was observed at 26.6 ± 0.7
ms. It was very weak (0.62 ± 0.24 % Mmax) and rarely significant during standing (4/11
subjects). During walking, FN-induced facilitation was even more difficult to evoke
(0.18 ± 0.09 % onset Sol), and reached statistical significance only in 2/11 subjects in
early Sol (mean 0.27 ± 0.11 %), and in 3/11 in late Sol (mean 1.03 ± 0.52 %).

            FN stimulation suppressed Sol EMG activity while standing in all the 11
subjects (significantly in 9/11 subjects) and grouped data were analysed to compare the
amount of inhibition between tasks. Figure 3B shows the significant correlation
between the control EMG and the amount of inhibition (Pearson’s correlation, r = 0.55,
P < 0.001), whatever the motor task. ANCOVA, by using the control EMG as covariate,
revealed highly significant change in FN-induced inhibition between tasks (P < 0.01;
Fig. 3D), which suggests that its level was task- and walking phase-dependent. Post hoc
analyses revealed significant (Newman-Keuls, P < 0.05) decrease of inhibition at the
onset of Sol activity during walking (as compared to tonic and late Sol) and significant
(P < 0.05) increase at the end of stance (late Sol as compared to onset Sol).

            The mean control EMG activity in Sol during tonic co-contraction
corresponded to that recorded in early stance during walking (onset and early Sol), i.e.
15-20 % the mean EMG level recorded during MVC. At the end of the stance phase
(late Sol), the mean control EMG reached 35-40 % that of MVC. FN stimulation
produced H-reflex in VL EMG in 9/11 subjects. The size of the reflex was within the
same range whatever the motor task: 19.6 ± 3.5 % Mmax in tonic vs. 22.7 ± 4.0 % for
onset Sol vs. 19. ± 4.7 % for early Sol vs. 12.5 ± 6.3 % for late Sol (ANOVA, P = 0.62).
At the end of stance (late Sol), the VL H-reflex was larger in 3 subjects and smaller in 3
other subjects, as compared to early stance or during tonic co-contraction.

      Sol MEPs

            Figure 4C shows that conditioned Sol MEPs in one subject were




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significantly smaller (P < 0.01, paired t test) than test MEPs when FN stimulation
preceded TMS by 20 ms during tonic contraction and at the end of the stance phase
(Late Sol) but larger at the onset of Sol activity during walking. Full time course of the
effect in the same subject is illustrated in D showing that FN stimulation similarly
increased MEP size during tonic and walking at short interval (-10 ms). At longer
intervals (10-20 ms), FN stimulation similarly reduced the MEP size during tonic
contraction and at the end of the stance phase (Late Sol), but tended to enhance the
MEP size at the onset of Sol activity during walking.

            On average, test MEPs had similar size (6.9 ± 2.3 % Mmax during tonic vs.
7.7 ± 3.3 % onset Sol vs. 7.9 ± 1.8 % late Sol; Kruskal-Wallis, P = 0.77), and were
evoked with TMS outputs within the same range (51.2 ± 2.9 % maximum output during
tonic vs. 50.4 ± 3.1 % onset Sol vs. 48.6 ± 2.2 % late Sol; P = 0.45).

            FN stimulation significantly increased the MEP size in 3/5 subjects
(between -10 and -5 ms, depending on the subject) during tonic co-contraction, in only
one subject in early stance, and in 2/5 in late stance. The mean amount of facilitation
tended to be larger during standing (119.8 ± 6.7 % test size) compared to walking (93.2
± 12.3 and 107.2 ± 5.1 % at onset and late Sol, respectively) but the difference did not
reach statistical significance (Fig. 4E; Kruskal-Wallis, P = 0.18). At longer intervals
(between 10 and 30 ms), FN significantly reduced the MEP size in all the 5 subjects
during tonic co-contraction and in late stance but in only 2 in early stance. On average,
this long-interval inhibition significantly changed depending on the motor task (Fig. 4F;
P < 0.05) with significant decrease of inhibition at the onset of Sol activity during
walking, as compared to tonic (Wilcoxon, P < 0.05) or late stance (Late Sol; P < 0.05).

      FN-induced inhibition of Sol H-reflexes during TA activation

            Figure 6 shows that FN stimulation significantly (paired t test, P < 0.01)
reduced Sol H-reflex size at intervals between 5 and 35 ms in one subject during tonic
co-contraction of Quad and TA while standing and to a lesser extent at the end of the
walking swing phase, when TA was strongly activated (Middle TA, A).

                                              Figure 6 about here




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            The mean Sol H-reflex test size was similar during the two motor tasks (4.0
± 1.0 % during walking vs. 5.1 ± 1.0 % Mmax during tonic contraction; Wilcoxon, P =
0.08). Grouped data obtained by averaging results at intervals between 10 and 25 ms
(B) revealed significant decrease of FN-induced Sol H-reflex inhibition in end swing
and beginning of stance (1000-1075 ms and 0 ms after heel strike), as compared to tonic
contraction while standing (Wilcoxon, P < 0.05).


DISCUSSION

            The main result of the present study is that FN-induced inhibition in Sol
motoneurones was modulated during walking. When Quad and Sol activity overlapped
during the gait cycle (early and late stance phase), the inhibition was smaller at the onset
of Sol activity in early stance, as compared to standing, and was stronger at the end of
stance, as compared to early stance. Moreover, around the time of heel strike, when
Quad was activated with TA during walking, the FN-induced inhibition in Sol
motoneurones decreased as compared to tonic co-contraction of Quad and TA while
standing.

   Pathways mediating FN-induced changes in TA and Sol motoneurones

            FN-induced facilitation. FN-induced monosynaptic group Ia excitation in
TA and Sol motoneurones was first shown by studying single motor unit post-stimulus
histograms (Meunier et al., 1990; 1993). Since FN stimulation can modify rectified
EMG averaging, H-reflex and MEP size with similar characteristics, it has been
suggested that the resulting facilitation could be mediated through the same pathway
(Meunier et al., 1996; Barbeau et al., 2000; Fig. 1A). In the present study, FN
stimulation hardly evoked excitation (with similar characteristics) in TA and Sol
motoneurones during walking, and our results are thus consistent with previous studies
showing a decrease in group Ia excitation during walking, as compared to tonic
contraction while standing, which has been attributed to increased presynaptic inhibition
of group Ia terminals mediated by PAD interneurones (Fig. 1A; Morin et al., 1982;
Capaday & Stein, 1986; Faist et al., 1996a).

            FN-induced inhibition. A long lasting inhibition in TA and Sol
motoneurones has been observed after FN-induced monosynaptic group Ia excitation in




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several previous studies (Meunier et al., 1990; 1994; 1996). In these studies, it was
suggested that Renshaw cells, activated by Quad motor axon recurrent collaterals, likely
mediate the inhibition; ischemia experiments have further supported this hypothesis
(Barbeau et al., 2000). It has also been proposed that FN-induced EMG suppression
should be analysed within an analysis window starting 10 ms after group Ia excitation to
exclude possible contribution of group Ib inhibition, and during 12 ms to limit the
analysis to spinal transmission (Barbeau et al., 2000). Similar to the previous studies,
FN-induced EMG suppression was evoked in the present study only when producing
Quad motor axon discharge during both tasks, and given the analysis window and inter-
stimulus intervals for changes in MEP and H-reflex size, we assume that the amount of
inhibition compared during the two motor tasks mainly reflected heteronymous
recurrent inhibition from Quad to TA and Sol motoneurones.

   Modulation of recurrent inhibition during walking

            To our knowledge, modulation of recurrent inhibition during human
walking has been investigated to a lesser extent than monosynaptic Ia excitation (Iles et
al., 2000). However, a preliminary study reported in abstract form revealed modulations
of the FN-induced inhibition in TA and Sol motoneurones during the gait cycle;
inhibition was reduced in the transition phases, as compared to tonic contraction (Faist
et al., 1996b). In the present study, changes in the amount of inhibition in TA
motoneurones paralleled those in the TA background EMG activity, and only inhibition
in Sol motoneurones was task- and phase-dependent (independent of its background
EMG activity). In the former study, supra-maximal FN stimulation was used to evoke
EMG suppression, which could lead to occlusion. Such saturation could then have
masked distinct modulation between TA and Sol motoneurones. In addition, it seems
that EMG suppression was analysed in all its duration, which might reflect changes at
both spinal and supra-spinal levels (cf. Barbeau et al., 2000).

            The present study revealed a distinct modulation of recurrent inhibition
from Quad to TA and Sol motoneurones during walking. Only inhibition to Sol
motoneurones changed during walking, with depressed inhibition at the onset of Sol
activity in early stance and enhanced inhibition in late stance. These modulations are
different from those reported during isolated Sol contractions. Indeed, recurrent




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inhibition (homo- and heteronymous pathways) has been shown to decrease with the
level of muscle activity during tonic contraction (Hultborn & Pierrot-Deseilligny, 1979;
Iles & Pardoe, 1999), whereas recurrent inhibition increased with the level of muscle
activity during walking (15-20 and 35-40 % MVC in early and late stance,
respectively). Moreover, recurrent inhibition is reduced towards the end of ramp-and-
hold ankle plantarflexion (Nielsen & Pierrot-Deseilligny, 1996) but during walking,
inhibition increased with Sol activity. Lastly, homonymous recurrent inhibition has
been reported to be enhanced during antagonist contraction (Katz & Pierrot-Deseilligny,
1984), while heteronymous recurrent inhibition is not modified (Iles & Pardoe, 1999).
During walking, the heteronymous recurrent inhibition from Quad to Sol motoneurones
was reduced when Quad was co-activated with TA around heel strike, as compared to
tonic co-contraction of TA and Quad while standing.

  Possible mechanisms underlying changes in recurrent inhibition to Sol
motoneurones

           Activation of Renshaw cells. Recurrent inhibition from Quad results from
the activation of its motor axons by the direct M-wave, the reflex discharge, and its
background activity during movement. Any change at one of these levels could
influence the amount of heteronymous recurrent inhibition produced in Sol
motoneurones but: i) M-wave: attention was paid to keep the M response in VL EMG
within the same proportion of Mmax measured for each condition, which suggests that
the electrically-evoked motor axon discharge was the same during each motor task, ii)
Reflex discharge: the VL H-reflex size (see Fig. 5) was on average within the same
range in the various conditions, and iii) VL background activity: it has been shown that
recurrent inhibition to Sol motoneurones does not depend on the level of Quad
contraction (Pierrot-Deseilligny et al., 1977), and in heteronymous pathways, the
contraction of the test muscle (Sol in the present study) influences more the level of
recurrent inhibition than that of the source muscle (Quad; Iles et al., 2000). Moreover,
although variations in Quad activity occurred during both TA and Sol activation, only
recurrent inhibition in Sol motoneurones was modified during walking.

           From the present experiments, it is difficult to draw any conclusion as
regards the mechanisms responsible for the changes in recurrent inhibition of Sol




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motoneurones during walking. Nevertheless, some of the possibilities should be
mentioned:

             Descending control on Renshaw cells. Recurrent inhibition is depressed
during weak voluntary contraction (Hultborn & Pierrot-Deseilligny, 1979; Rossi &
Mazzocchio, 1991) and, accordingly, TMS over the primary motor cortex decreased
recurrent inhibition (Mazzochio et al., 1994). Motor cortex contributes to both Sol and
TA activation during walking (Petersen et al., 1998; 2001; Christensen et al., 2001), and
heteronymous recurrent inhibition was modified only in Sol motoneurones. Our results
might thus suggest a differential corticospinal control on Renshaw cells, with specific
inhibition of those projecting on Sol motoneurones. The vestibular influence is most
important around the time of heel strike and during the double support phase (Bent et
al., 2004), i.e. when recurrent inhibition of Sol motoneurones decreased during walking.
The vestibulospinal inputs to Renshaw cells (Rossi et al., 1987) may thus account for
the depression of recurrent inhibition during walking at that time in the gait cycle. The
vestibular system is involved in foot placement during walking (Bent et al., 2004),
which requires a precise control of both ankle flexors and extensors (Iles et al., 2007),
and recurrent inhibition was only depressed in extensor motoneurones. This might thus
reflect a specific vestibulospinal control on Renshaw cells controlling Sol motoneurones
during walking.

             Changes in peripheral inputs. Peripheral afferents of various origins are
involved in the control of human walking (see Zehr & Stein, 1999). Well-known
example is the reversal control of cutaneous afferents on ankle muscles during walking
(Duysens et al., 1990; Van Wezel et al., 2000). On the other hand, unloading Sol during
walking causes a drop in its EMG activity, which is thought to reflect the contribution
of peripheral afferents to motoneurone activation; this contribution is maximal at the
onset of the stance phase and involves muscle spindle group Ib and group II afferents
(Sinkjaer et al., 2000). Accordingly, partial removal of the body weight during walking
reduces EMG activity in ankle extensors, but activity in flexors is enhanced (Finch et
al., 1991; Bastiaanse et al., 2000). This suggests that muscle afferents (group Ib/group
II) might contribute to TA activation to a lesser extent than Sol during walking (see
Zehr & Stein, 1999), which could account for the different modulation of recurrent
inhibition between ankle muscles. Moreover, since afferents from single- and multi-




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joint muscles may be differentially interpreted, peripheral inputs from the
gastronecmius muscles (acting at both ankle and knee level) may also account for the
specific control of Renshaw cells controlling extensor motoneurones during locomotion
(Sturnieks et al., 2007).

Cutaneous & muscle spindle group II hypotheses: In cats, cutaneous and muscle spindle
group II inputs inhibit Renshaw cell activity (Wilson et al., 1964; Fromm et al., 1977),
with specific depression of recurrent inhibition of extensor motoneurones for the latter.
This may account for the depression of recurrent inhibition during walking, and if an
analogous mechanism exists in humans, the control by group II afferents would account
for the specific depression of recurrent inhibition from Quad to Sol at the onset of the
walking stance phase. Accordingly, we have shown that group II excitation is
particularly enhanced at the beginning of stance (Marchand-Pauvert & Nielsen, 2002a),
and might contribute to the gait posture (Marchand-Pauvert et al., 2005; Iglesias et al.,
2008). However, Renshaw cells are not inhibited during cat fictive locomotion (Pratt &
Jordan, 1980).

Group Ib hypothesis: Group Ib inputs produce excitation in extensor motoneurones
during cat fictive locomotion (Pearson & Collins, 1993; Gossard et al., 1994), and there
are some evidences for similar mechanisms in humans (Stephens & Yang, 1996;
Marchand-Pauvert & Nielsen, 2002b; Faist et al., 2006). Since short (oligosynaptic
pathway) and long latency (polysynaptic pathway; see McCrea, 1998; McCrea &
Rybak, 2008) group Ib EPSPs occur at motoneurone level, it is thus conceivable that the
summation (whether linear or not) of excitatory and inhibitory inputs at motoneurone
level makes them more or less susceptible to Renshaw inhibition in early stance, which
could thus account for the modulation of recurrent inhibition of Sol motoneurones
during locomotion (Burke et al., 1971; Segev & Parnas, 1983; Powers & Bender, 2000).
Similar mechanisms of synaptic integration might also account for the decrease in
recurrent inhibition of Sol motoneurones around the time of heel contact, when Quad is
co-activated with TA, as compared to standing, since potent group Ib excitation is
evoked during the flexor phase to initiate the transition between swing to stance
(Conway et al., 1987; Gossard et al., 1994). Lastly, changes in load on extensors during
locomotion might contribute to the increase in recurrent inhibition at the end of the
stance phase by influencing group Ib transmission (Gossard et al., 1994; Faist et al.,




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2006). Alternatively, changes in recruitment gain and/or activation of fast motor units,
which increases the discharge in recurrent collaterals (Wand & Pompeiano, 1979), may
also account for the enhanced recurrent inhibition in late stance.

            In decerebrated cats, Renshaw cell activation is not modified during fictive
locomotion, and there is a linear relationship between motoneurone firing rate and the
amount of recurrent inhibition (Pratt & Jordan 1980; McCrea et al., 1980; Noga et al.,
1987). This might account for the parallel changes of FN-induced recurrent inhibition in
TA and of its background EMG activity at the end of the swing phase.

   Functional significance

            The decrease in recurrent inhibition from Quad to Sol around the time of
heel strike, and in early stance, may help initiate the transition from swing to stance and
thus favours ankle extensor activation. In addition, since Renshaw cells also inhibits
interneurones mediating reciprocal group Ia inhibition (Hultborn et al., 1971; Baret et
al., 2003), the decrease in recurrent inhibition of Sol motoneurones may favour
reciprocal inhibition of TA motoneurones at the same time. In contrast, at the end of
stance, the enhanced recurrent inhibition of Sol motoneurones could help release TA
motoneurone from reciprocal inhibition and thus could initiate the transition from stance
to swing. This has been suggested as one of the possible roles of Renshaw cells during
cat fictive locomotion (McCrea et al., 1980; Noga et al., 1987), and such a control is
thought to assist muscle synergies also in humans (Hultborn & Pierrot-Deseilligny,
1979; Nielsen & Pierrot-Deseilligny, 1996). Moreover, given the distribution of
heteronymous recurrent inhibition in the human lower limb (Meunier et al., 1994), the
enhanced inhibition from Quad to Sol at the end of the stance phase must result in
decreased activity of the Renshaw cells activated by Sol motoneurones, and thus
reduced recurrent inhibition from Sol to Quad at the end of the walking stance phase
(Iles et al., 2000). This mechanism may assist hip flexion by favouring Rectus Femoris
(another head of Quad) activation at this stage of the gait cycle (Nene et al., 2004).
Lastly, since the ability to modulate recurrent inhibition appropriately during movement
is lost in patients with movement disorders (see Pierrot-Deseilligny & Burke, 2005),
abnormal recurrent inhibition during locomotion might be involved in aberrant muscle
synergies during pathological gait.




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ACKNOWLEDGEMENTS

             This work was supported by Institut pour la Recherche sur la Moelle
Epinière (IRME) and Assistance Publique - Hôpitaux de Paris (AP-HP). Dr Lamy was
supported by a grant from the French Research Government Dpt and Dr Iglesias, by the
University of Milan and the French-Italian University.


FIGURES AND LEGENDS

Figure 1: Experimental design

A. Diagram of the spinal pathways controlling TA and Sol motoneurones, fed by group
Ia afferents (interrupted line) and motor axon recurrent collaterals (continuous line)
from Quadriceps (Q). The open circle and Y-shaped ending represents the motoneurone
soma and excitatory synapses, and the filled circles, the inhibitory neurones (Renshaw




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cells). Arrows indicate presynaptic inhibition of group Ia terminals mediated by PAD
(primary afferent depolarisation) interneurones. BC. Raw (B) and rectified (averaging of
20 step cycles; C) EMG activity in VL, TA and Sol (traces from top to bottom) in one
subject walking at 4 km/h. Dots in B indicate the heel contact, which was used as
trigger for EMG averaging in C (transition between swing 0 and stance 1). D.
Difference (in V) between TA EMG activity conditioned by FN stimulation (30 %
Mmax) and its mean control value (plotted against the latency after FN stimulation; ms)
in one subject during tonic co-contraction of TA and Quad while standing; vertical bars
are ± 1 S.E.M. In this subject, the distance between L2 vertebra and FN and CPN was
respectively 23 and 68.5 cm, and given their conduction velocity (60 and 70 m/s in FN
and CPN, respectively), the afferent delay for group Ia fibres after FN and CPN
stimulation to reach spinal motoneurones was respectively 3.8 (23 / 60) and 9.7 ms
(68.5 / 70). The TA H-reflex latency (after CPN stimulation) was 30.3 ms and FN
increased EMG activity at 24.5 ms, so 5.8-ms difference, which almost corresponds to
the theoretical difference (5.9 = 9.7 - 3.8) suggesting that the FN-induced increase in
TA EMG activity was mediated by monosynaptic group Ia pathway. Similar
calculations were done in each subject, and for EMG modulations in Sol (see Meunier
et al., 1990).

Figure 2: FN-induced modulation of rectified and averaged TA EMG

ACEGI. Control (grey line) and conditioned (black line) TA EMG (V), in one subject,
during tonic co-contraction of Quad and TA while standing (A) and walking (3.6 km/h),
at the end of the swing phase (1100 ms after heel strike, Onset TA, C and 1150 ms after
heel strike, Middle TA, EI) and at the beginning of stance (0 ms after heel strike, Late
TA, G), are plotted against the latency (ms) after FN stimulation adjusted so as to evoke
M response of 30 % Mmax (ACEG) and at 0.8 x MT (I). Vertical bars are ± 1 S.E.M.
BDFHJ. Mean VL EMG activity after FN stimulation, recorded simultaneously with
TA EMG, during tonic (B) and walking (D-J), is expressed as a percentage of Mmax in
VL, which was estimated for each situation.

Figure 3: Task related changes in the FN-induced EMG suppression

AB. The difference between conditioned and control EMG (% Mmax), used to estimate




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                                            Recurrent inhibition during walking - Lamy et al. - 26/27



the amount observed in TA (A) and Sol (B), is plotted against the control EMG (surface
estimated within the same analysis window than the conditioned EMG, and expressed
as a % Mmax). Results obtained in each subjects during tonic co-contraction and during
walking (3 delays) are represented in the same scatter diagram, so 4 dots by subject.
CD. Mean amount of inhibition observed in TA (10 subjects; C) and Sol (11 subjects;
D) during tonic (white column) and walking (light grey for Onset TA and Sol, middle
grey for Middle TA and Early Sol, and dark grey for Late TA and Sol). Vertical bars are
± 1 S.E.M. * P < 0.05 post hoc Newman-Keuls.

Figure 4: FN-induced changes of MEP size

A & C. Mean test (grey line) and conditioned (black line) MEPs after FN stimulation
adjusted so as to produce M response in VL of 30 % Mmax. Test and conditioned MEPs
are expressed as % Mmax (estimated in each situation), and the interval between FN
stimulation and TMS was 20 ms. A, TA MEPs evoked in one subject during tonic co-
contraction of Quad and TA while standing (Tonic), and during walking (4 km/h), when
TMS was delivered 950 ms (Onset TA) and 1025 ms after heel strike (Middle TA). C,
Sol MEPs evoked in one subject during tonic co-contraction of Quad and Sol while
standing (Tonic), and during walking (4 km/h), when TMS was delivered 100 ms
(Onset Sol) and 300 ms after heel strike (Late Sol). B & D. Full time course of the
effects evoked in the same subjects as in A & C respectively. Conditioned MEPs
(expressed as a percentage of its test size) are plotted against the interval between FN
stimulation and TMS (ms) combined during tonic contraction (open circles and
interrupted line) and during walking: grey circles and continuous grey line for Onset TA
(B) or Sol (D), and black circles and continuous black line for Middle TA (B) or Late
Sol (D). In B, at -5 ms and 50 ms, the filled circles overlap the open circles. EF.
Grouped data showing the mean conditioned MEPs (% the test size) obtained at long
intervals (between 10 and 40 ms for TA in E, and between 10 and 30 ms for Sol in F)
during tonic (white column) and walking (light grey for Onset TA and Sol and dark
grey for Middle TA and Late Sol). Vertical bars are ± 1 S.E.M. * P < 0.05 Wilcoxon.

Figure 5: FN-induced modulation of rectified and averaged Sol EMG

Same legend as in Fig. 2. Walking speed was 3.6 km/h and FN stimulation was
delivered during tonic co-contraction of Quad and Sol while standing (Tonic, AB), and




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                                           Recurrent inhibition during walking - Lamy et al. - 27/27



during walking 80 (Onset Sol, CD), 100 (Early Sol, EF) and 320 ms (Late Sol, G-J)
after heel strike. FN stimulation was adjusted so as to produced M response of 30 %
Mmax (A-H) and at 0.8 x MT (IJ).


Figure 6: FN-induced inhibition of Sol H-reflex during TA activation

A. Mean Sol H-reflexes (% its test size), conditioned by FN stimulation (evoking an M
response in VL of 30 % Mmax), are plotted against the interval between FN and PTN
stimulation (ms), in one subject during tonic co-contraction of Quad and TA while
standing (Tonic, open circles and interrupted line) and during walking (4 km/h), when
PTN stimulation was delivered 1075 ms after heel strike, i.e. during maximum TA
activity EMG in end swing (Middle TA, black circles and continuous line). B. Grouped
data (6 subjects) obtained at intervals between 10 and 25 ms during tonic contraction
(white column) and in middle TA activity during walking (grey column). Vertical bars
are ± 1 S.E.M. * P < 0.05 Wilcoxon.




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A                Group Ia
                                                                         Q
                                                                                             B
PAD                                                                                               40 µV                                                VL
                                                            Renshaw
        TA         Sol                                                        Femoral
                                                                               nerve              200 µV                                               TA


                                                                                                  100 µV                                               Sol

                                                                                                                                                    Contact
                                                                                                                                                  1s




       C
                                                                                                                                          VL
      5 µV




                                                                                                                                          TA
    10 µV

                                                            late                                                              onset middle


    10 µV                                                                                                                                 Sol
                                                                   onset early             late                                200 ms

                 Swing 0                                                      Stance 1                              Swing 1

             D
                   Conditioned - mean control TA EMG (µV)




                                                                                         Latency (ms)



                                                                                                                                  Lamy et al. - Figure 1



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               TA EMG                                                            VL EMG
           A                        Control              B                                              Tonic
                                    Conditioned




           C                                            D                                           Onset TA




           E                                             F                                         Middle TA
EMG (µV)




           G                                            H                                            Late TA




           I                                             J
                                                                                        Middle TA - 0.8xMT




                                                                                                    10 % Mmax
                                                                                           10 ms

               Latency (ms)

                                                                                       Lamy et al. - Figure 2




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                                                  TA                                                                  Sol
                                      A                                                           B
Conditioned - control EMG (% Mmax)




                                                                             Control EMG (% Mmax)




                                     Tonic   Onset TA/Sol      Middle TA/Early Sol         Late TA/Sol


                                      C                                                           D


                                                                                                                 *




                                                                                                                                       *




                                                                                                                          Lamy et al. - Figure 3




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                                           Test MEP     Conditioned MEP

                                           A                                                            B       Tonic         Onset TA          Middle TA
                                                      Tonic
10 % Mmax




                                                      Onset TA


                                                      Middle TA

                                                                         Conditioned MEP (% test MEP)
                                                      5 ms



                                                                                                                Tonic         Onset Sol         Late Sol
                                           C          Tonic                                             D
8 % Mmax




                                                      Onset Sol



                                                      Late Sol



                                                      5 ms
                                                                                                                FN - TMS interval (ms)




                                                 E                                                          F                     *
            Conditioned MEP (% test MEP)




                                                                                                                                  Lamy et al. - Figure 4




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               Sol EMG                                                           VL EMG
           A                        Control              B                                             Tonic
                                    Conditioned




           C                                            D                                          Onset Sol




           E                                             F                                          Early Sol
EMG (µV)




           G                                            H                                            Late sol




           I                                             J                                Late Sol - 0.8 x MT




                                                                                                   10 % Mmax
                                                                                           10 ms

               Latency (ms)

                                                                                       Lamy et al. - Figure 5




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                                         A
                                                                                              Tonic              Middle TA
Conditioned H-reflex (% test H-reflex)




                                                                FN - PTN interval (ms)


                                                   B               Inhibition

                                                                                    *




                                                                                                                  Lamy et al. - Figure 6




                                             Downloaded from J Physiol (jp.physoc.org) by guest on May 7, 2011

				
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