Interaction of corticospinal and dorsal root inputs to human leg muscles

Interaction of corticospinal and dorsal root inputs
to human leg muscles
François D. Roy1, Grady Gibson2, Richard B. Stein2
Departments of Surgery1 and Physiology2, University of Alberta, Edmonton, Canada
Abstract
Spinal cord stimulation is a technique that has been introduced to monitor and study spinal cord circuitry and
potentially to improve function after spinal cord injury. In this study we have examined the interaction between spinal
cord and motor cortex stimulation. EMG was recorded from the tibialis anterior (TA) and soleus muscles under
conditions of rest and weak voluntary contraction. When the cortical stimulation occurred about 15 ms before the
spinal stimulation, the soleus EMG response was facilitated. This was more dramatic with doublets applied to the
spinal cord at 50 ms intervals. Normally, the second response would be almost completely suppressed (homosynaptic
depression), but motor cortex stimulation in 4 of 6 subjects showed a marked facilitation of the depressed response. In
the TA muscle the most marked facilitation occurred when a spinal stimulation was delivered 80-200 ms before a
cortical stimulation. This is probably because of rebound excitation after the post-spike hyperpolarization, but was
observed in both the resting (no EMG) and weakly contracted TA muscle.
Keywords: spinal root stimulation, transcranial magnetic stimulation, dorsal roots, corticospinal tract
Introduction
Spinal root stimulation has shown some promise to
improve motor function after injury to the central
nervous system (CNS). Two individuals with a chronic
spinal cord injury showed motor benefits that were
unachievable when the stimulation was turned off [1, 2].
Epidural stimulation can preferentially target dorsal
roots to elicit a monosynaptic reflex response [3].
However, surgical implantation is required, which limits
applicability. A non-invasive percutaneous approach is
also available [3, 4]. This technique has been useful for
studying spinal circuitry during locomotion [5, 6],
though to our knowledge, little is known about how it
interacts with corticospinal neurons to facilitate
movement.
We and others have shown that sensory input from the
legs can modify corticospinal excitability, both
transiently [7-9] and chronically [10]. Activation of the
corticospinal tract using transcranial magnetic
stimulation (TMS) elicits motor evoked potentials
(MEPs). The size of the MEP is correlated with motor
function [11, 12] and a sustained increase provides
evidence for stronger pathways [10, 13]. In the present
study, we characterized the interaction of the MEP with
dorsal root inputs activated using percutaneous spinal
stimulation. We show that spinal root inputs regulate
descending motor pathways, and describe the nature of
the interaction.
Materials and Methods
Eight able-bodied volunteers participated in the study.
Subjects gave informed consent for the protocol which
was approved by the Health Research Ethics Board at
the University of Alberta. Subjects were screened for
potential contraindications to the stimulations, which
included: back pain, spine surgery, metal implants in the
head and history of seizures.
Recording and stimulation:
Subjects were comfortably seated with the left leg
secured to a metal brace that maintained the ankle and
knee at angles of 100°. Electromyography (EMG) was
recorded from the tibialis anterior (TA) and soleus
muscles (Sol) using Ag-AgCl electrodes (3.52.2 cm;
Vermont Medical Inc., Bellow Falls VT). The EMG
was amplified (1000 times; Octopus, Bortec
Technologies, Calgary, Canada) and digitized (5 kHz
using Axoscope hardware and software (DigiData 1200
series, Axon Instruments, Union City CA). EMG from
the target muscle was also full-wave rectified, smoothed
using a 3-Hz first-order low-pass filter and displayed on
an oscilloscope so the subjects could monitor their
activity. The spinal levels were marked following
palpation by a physiotherapist. The cathode (5 x 5 cm;
WalkAide premium electrode; Innovative Neurotronics,
Austin TX) was placed over the midline of the vertebral
column. The site was identified as the position that
produced a large, low-threshold reflex response. This
root evoked potential (REP) has also been referred to as
a multisegmental monosynaptic response (MMR [5])
and a posterior root-muscle reflex (PRM [14, 15]). The
anode (7.5 x 13 cm; Axelgaard Manufacturing Co.,
Fallbrook, California) was placed on the ipsilateral
anterior superior iliac spine [3]. Electrical stimulation
(1-ms pulse) was provided with a constant current
stimulator (Digitimer DS7A). The corticospinal tract
was activated using TMS over the motor cortex
(MagStim, Dyfed, UK). Pulses were delivered using a
double cone coil connected to a MagStim2 stimulator.
The coil was orientated to induce postero-anterior
currents in the brain and the optimal site was identified
during voluntary contraction: 15-20% of the maximum
voluntary contraction (MVC).
Experimentation
Experiments targeted either the TA or the Sol muscle.
Six subjects participated in each experiment, and data
were collected both at rest and during a tonic
contraction (i.e. dorsiflexion or plantarflexion at 1520% MVC). For each condition, the intensity of the
spinal stimulation and TMS were set to produce half
maximal responses. The intensities were determined
after performing recruitment curves. The interaction of
spinal stimulation on the motor evoked potential (MEP)
produced by a TMS pulse was examined at selected
inter-stimulus intervals (-35 to 200 ms). At intervals of 35 to -20 the TMS pulse will reach the spinal cord
before the spinal stimulation (TMS conditions spinal
stimulation). At intervals of -15 to -10 the two stimuli
will sum at the spinal cord (spinal summation). Finally,
at intervals of -5 to 200 ms spinal stimulation occurs
before the TMS pulse reaches the spinal cord (spinal
stimulation conditions TMS). Four responses were
collected at each interval, intermixed with 12 responses
with TMS alone and 12 with spinal stimulation alone.
Since homosynaptic depression is known to suppress a
second reflex response [5, 15, 16], we also examined the
interactions in the presence of this suppression. This
was done by combining TMS with a pair of spinal
stimuli delivered 50 ms apart. The TMS pulse was
timed with respect to the second REP, which was
suppressed by homosynaptic depression.
Analysis
The REP traces collected with only spinal stimulation
were averaged, shifted according to the various
interstimulus intervals and subtracted from the MEP
traces (see Fig. 1). This ensured that the contribution of
the REP and/or the background EMG was removed
from the interaction. The onset and offset of the MEP
was determined by visual inspection of the data
collected from the recruitment curves. The MEP was
then quantified as the mean rectified EMG over this
interval. This same interval was used to evaluate the
trials in which the MEP immediately preceded the REP
(see Fig. 1). Values were considered statistically
significant if P<0.05 using a t-test.
Results
The soleus muscle produced a large REP, but a small
MEP (Fig. 1A; MEP scaled 20x). The opposite was true
in the TA muscle (Fig. 1C; REP scaled 10x).
Corticospinal and afferent inputs arriving at the
motoneurons pool within a few milliseconds of each
other produced a net increase to the MEP (see
Combined trace in Fig. 1A). The summation was more
than linear, since subtracting the REP (C-B) and the
MEP (C-B-A) still leaves a substantial positive response.
During voluntary plantarflexion, the interaction
increased the Sol MEP by 206 ± 131% (mean ± S.D.) at
grouped intervals of -10 to -15 ms (symbol  in region
of Fig. 2A between vertical dashed lines; P = 0.003).
Some temporal facilitation was observed in the TA
Figure 1. Average rectified traces showing three
distinct interactions. A, Spinal summation of the REP
and the MEP at the spinal cord. B, Interaction when the
MEP immediate precedes the second REP. On its own,
the second REP (i.e. see #2) was greatly suppressed, but
the response is markedly enhanced when combined with
an MEP. Both (A&B) are from the Sol muscle during a
tonic contraction. C, Facilitation of the TA MEP when
the spinal stimulus was delivered 100 ms before the
TMS pulse. Traces in (C) were collected during
dorsiflexion to highlight the recovery of the EMG
following the spinal stimulation. Five traces are shown
for each condition: 1) A = MEP alone, 2) B = REP
alone (shifted according to the time interval), 3)
measured interaction C = MEP+REP, 4) difference of
the measured interaction after subtracting the REP (C B), and 5) also subtracting the MEP ( C - B - A). An
increase in the bottom traces indicates that the
interaction is greater than the linear sum. Three traces
have been amplified (10x or 20x) to show the small Sol
MEP and the level of background EMG.
muscle, though the effects did not reach statistical
significance.
When the Sol MEP arrived before the REP (e.g., -25 ms
interval), the motor response was facilitated (Fig. 1B).
This interaction was only evident in the Sol muscle and
was most striking during spinal doublets. The first REP
is large (#1 in Fig. 1B) while the second REP 50 ms
later is almost abolished (#2), presumably by
homosynaptic depression. However when the MEP is
timed to coincide with the second REP at the spinal
cord, the second REP is not abolished and is actually
considerably larger than the first (see Combined trace in
Fig. 1B). Again, subtracting the REP alone (C-B) and
the MEP alone (C-B-A) leaves a large positive response,
indicating a much greater than linear summation. In this
study, 4 out of the 6 subjects produced marked
facilitation (i.e. 46 to 460%) of the motor response. The
shape of the waveform is consistent with an abolition or
even reversal in homosynaptic depression. The
interaction was specific to the Sol muscle and was most
prominent during tonic plantarflexion (compare
symbols in Fig. 2C).
In contrast to the mechanisms in the Sol muscle, the
interactions in the TA muscle were dominated by
resetting motoneuronal activity following the REP.
Conditioning motoneurons with a spinal stimulus 80200 ms before TMS markedly increased the MEP. The
facilitation was similar in both resting and active states,
and paralleled the rebound excitation observed in the
contracted muscle. When the muscle was at rest, the
rebound excitation of the motoneurons remained below
firing threshold as evidenced by the absence of
spontaneous EMG. Given that the spinal doublets
tended to produce increases over a larger range of
intervals, greater activation of dorsal root inputs may
add to the overall rebound effect. This late-interval
facilitation tended to be weaker in the Sol muscle, and
may be related to the stronger period of post-activation
inhibition that follows the large Sol REP or because its
smaller MEP.
When the motoneuron pool was refractory, the MEP
tended to be suppressed. This occurred as the MEP
trailed the REP and was most pronounced in the Sol
muscle. During contraction, the effect was significant
for grouped intervals of 0 to 40 ms ( symbols in Fig.
2A&C; P < 0.05). In the TA muscle, the most dominant
interaction was seen at longer intervals. An REP,
generated 80-200 ms before an MEP, could greatly
facilitate the MEP in both relaxed and contracted
muscles (Fig. 2B&D P<0.05). During contraction the
preceding stimulus evoked a period of rebound
excitation that mirrored the profile of facilitation (see B
= REP 100ms trace in Fig. 1C). However, the facilitation
was still evident when no spontaneous EMG was
generated in the resting muscle (see  symbols in Fig.
2B&D).
Discussion
The present study investigated the interaction of dorsal
root and corticospinal responses in human leg muscles.
Facilitation of the Sol MEP was largest when the two
inputs arrived at the spinal cord at nearly the same time.
Two specific interactions were noted: 1) the summation
of EPSPs at the motoneuron pool (-10 to -15 ms
intervals), and 2) removal of the homosynaptic
depression caused by successive spinal stimuli (intervals
near -20 ms). We have previously shown that
heterosynaptic inputs from corticospinal neurons and Ia
muscle afferents can sum at the motoneurons to
facilitate the Sol MEP [17]; the present results confirm
and extend these findings. With electrical stimulation of
the tibial nerve in the popliteal fossa, several studies
have shown that corticospinal excitation can reduce
homosynaptic depression of Ia fibres [18, 19]. The
effect is strongest during a plantarflexion [20] and is
therefore reminiscent of the current findings done with
spinal stimulation. The effect has been attributed to
presynaptic disinhibition.
Figure 2. Conditioning of the MEP by spinal root
stimulation. Responses are from the Sol (A&C) and TA
muscles (B&D), each in 6 subjects. Data is shown at rest
( symbols) and during a voluntary contraction (
symbols). Points show the size of the mean rectified
MEP collected at the different interstimulus intervals
from -35 to 200 ms. Negative intervals indicate that the
TMS pulse was delivered before the conditioning spinal
stimulus. The interactions are shown for single pulse
(A&B) and double pulse spinal stimulation (50 ms interpulse interval; C&D). The horizontal dotted lines
represent the size of the unconditioned MEP. The
vertical dashed lines show the period when the TMS
and spinal stimulation produce responses that should
sum at the spinal cord.
Conclusions
Increasing corticospinal excitability may improve motor
function after injury to the CNS, and may also facilitate
MEP generation during general anesthesia, as routinely
administered during human spine surgery. The present
study was aimed at characterizing the interaction of
corticospinal and dorsal root inputs to human leg
muscles. Here, we show that percutaneous spinal
stimulation modulates the MEP in a manner that is
partly muscle and task specific. Future work will be
done investigating whether the profiles are maintained
in individuals with a chronic CNS injury.
[11]
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Acknowledgements
This research was supported in part by the Canadian
Institutes for Health Research. We thank Dr. Monica
Gorassini for the loan of some equipment.
Author’s Address
François D. Roy
Neurophysiologist & Assistant Adjunct Professor
Department of Surgery, University of Alberta
3B5.02 WMC, 8440 112 St
Edmonton, AB T6G 2B7
E-mail: francois.roy@ualberta.ca