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Motor Neurobiology of the Spinal Cord
5
Investigating the
Synaptic Control of
Human Motoneurons:
New Techniques,
Analyses, and Insights
from Animal Models
Randall K. Powers and Kemal S. Türker
CONTENTS
5.1
Introduction
5.2
Motor Unit Isolation
5.3
Stimulation Techniques
5.3.1
Electrical Stimulation
5.3.2
Mechanical Stimulation
5.3.3
Cortical Stimulation
5.3.4
Microneurography
5.4
Analyzing Afferent Effects on Motor Unit Discharge
5.4.1
Surface Electromyogram (SEMG)
5.4.2
Intramuscular Multi-Unit EMG
5.4.3
Single Motor Unit Discharge
5.4.4
Alternative Methods of Estimating Synaptic Effects on Single
Motor Units
5.5
Insights from Work on Animal Models
5.5.1
Relation of Synaptic Potential Time Course to Effects
on Firing Probability
5.5.2
Predictions from Threshold-Crossing Models
5.5.3
Using Injected Current Transients to Mimic Synaptic Potentials
5.5.3.1
Effects of Simulated Excitatory Synaptic Inputs on
Motoneuron Discharge
5.5.3.2
Effects of Simulated Inhibitory Synaptic Inputs on
Motoneuron Discharge
© 2001 by CRC Press LLC
5.5.3.3
Effects of Background Motoneuron Discharge Rate
5.5.3.4
Effects of Background Noise
5.5.4
White-Noise Analysis of Spike Encoding in Motoneurons
5.6
Summary
References
5.1 INTRODUCTION
The contraction of a group of muscle fibers is directly dependent upon the activity
of the motoneuron connected to those fibers, and there is a one-to-one relation
between the occurrence of action potentials in the motoneuron axon and those in its
innervated muscle fibers. For this reason, the effects of activity in afferents, inter-
neurons, and descending fibers on motor behavior are dependent upon their ability
to modulate the discharge of motoneurons. The unique importance of the motoneuron
in motor control was recognized by Sherrington,
1
who introduced the concept of the
motoneuron as the final common path between activity in the central nervous system
and movement. The one-to-one relation between the occurrence of action potentials
in a motoneuron and in the muscle fibers they innervate makes it possible to record
the discharge behaviour of single motoneurons using intramuscular electrodes. Con-
sequently, motoneurons are the only CNS neurons whose individual discharge behav-
iour can be recorded in human subjects during the execution of normal movements.
The ability to record the activity of human motor units has made it possible to
draw inferences regarding the organization of synaptic inputs to human motoneurons
during various motor tasks, in both healthy subjects and in subjects suffering from
a variety of nervous system disorders. These inferences are often based on the effects
of stimulating peripheral or descending afferents on motoneuron discharge proba-
bility. It is generally accepted that excitatory synaptic inputs lead to an increase in
discharge probability, whereas inhibitory synaptic inputs lead to a decrease in dis-
charge probability. However, the exact relation between the time course of a synaptic
potential and its effects on motoneuron discharge probability is still a matter of some
controversy. Nonetheless, there have been a number of methodological and theoret-
ical advances in the last 20 years that have led to an improved understanding of the
synaptic control of human motoneurons. In the following review, we focus on four
different advances related to measuring and interpreting synaptic effects on the
discharge of human motoneurons: (1) improvements in isolating the activity of single
motor units; (2) new techniques for stimulating different afferent inputs; (3) new
methods of analyzing afferent effects on motor unit discharge; and (4) recent insights
from animal models.
5.2 MOTOR UNIT ISOLATION
Although it is possible to record the activity of single motor units from the muscle
surface, the contribution of any motor unit to the surface electromyogram (SEMG)
depends upon its size and its distance from the surface electrodes. Therefore, whereas
action potentials from large motor units situated close to the electrodes appear as
© 2001 by CRC Press LLC
large spikes on the SEMG, action potentials from small motor units situated in the
deep portions of the muscle can be in the noise level.
Insertion of needle or wire electrodes into muscle is commonly used to record
the activity of a more limited sample of motor units. The number of motor unit
action potentials (MUAPs) recorded using intramuscular electrodes depends upon
the extent of the uninsulated (active) area.
2
As the size of the active area of recording
is increased, so do the number of units recorded. Recording from a large number
of motor units is a useful technique to get the overall picture of a muscle’s activity
patterns. Furthermore, quantification of multi-unit recording is easier and more
reliable than the SEMG records (see
5.3
)
. It is also possible to record the activity
of one or a few MUAPs using wire or needle electrodes with a smaller active
recording area.
2
From the few-unit record, it is possible to isolate one of the MUAPs
and study its response to a given stimulus.
Selection of a single MUAP from a few-unit record is not straightforward but
requires experience and special electronic circuits or computer programs. The most
common criterion used to discriminate the units is their peak amplitude. This is
achieved with simple level crossing circuitry. However, the units often may have
similar amplitudes but differ in the time taken to reach to the maximal amplitude
(frequency component of the MUAP). It is possible in some cases to produce an
amplitude difference between such units using bandpass filtering. In other cases, some
peculiarities of the MUAP shapes can be used to distinguish different units. Time-
amplitude window circuits can be used for selecting such units. This technique uses a
combination of the slope of the leading edge and the amplitude of the unit and may
require two experienced persons (four hands!) working very closely together.
The most powerful approaches for discriminating single motor units use some
sort of computer-based pattern recognition or template-matching algorithm to char-
acterize the entire MUAP waveform. This has been described by a number of
laboratories,
3–7
and commercial waveform discriminators are now widely available.
These various motor unit recognition programs often use the regular nature of motor
unit discharge together with interaction of the computer operator to minimize missed
or incorrectly classified MUAPs. One of the first approaches to sorting multiple
motor units utilized several different recording channels to improve discrimination,
3
since two motor units that exhibited similar shapes on a single channel often were easily
differentiated on one of the other channels. This approach has recently been used to
allow single unit discrimination based on an array of surface EMG electrodes.
8
Motor unit recognition is generally performed offline but in some cases
5
can be
used online based on a short epoch of previously collected data. In the latter case,
the operator first sets a threshold voltage for incoming unit signals. This threshold
needs to be above the noise level but below the peak of the MUAP of interest. Whenever
the input signal crosses this threshold, the system is triggered; i.e., it will now consider
a millisecond or so of data on each side of the threshold crossing as a potential spike.
The template/s is established before the experimental run begins by running a few
seconds of data containing MUAPs of interest. The operator chooses one (or a few)
MUAP waveforms and stores them in the computer’s memory as the templates.
During the experimental run, the system is triggered each time the incoming
signal exceeds the threshold. A millisecond of the incoming signal on each side of
© 2001 by CRC Press LLC
the trigger is then compared with the previously established templates. If any of the
templates match the incoming MUAP shape, the computer accepts that point as the
discharge of the unit. The discharge times of the motor unit can be saved and used
in variety of the analysis programs to estimate the synaptic potential that is developed
on a motoneuron by the stimulus (see
5.4
)
.
5.3 STIMULATION TECHNIQUES
Stimulating one afferent fiber type without affecting others has been a great challenge
for a number of years. Without invasive techniques, completely selective activation
of a single type of afferent fiber is generally not possible. However, given sufficient
attention to stimulus parameters, it is often possible to apply stimuli that predomi-
nantly activate one class of afferent fibers.
5.3.1 E
LECTRICAL
S
TIMULATION
Electrical stimuli can be applied with ease to the skin to study the synaptic connection
of the skin afferents to motoneurons. Usually, the sensory perception threshold (T)
of the subject is used to standardize the stimulus intensity. Intensities of 1 to 3T are
used to stimulate low-threshold afferents that convey information about touch sen-
sation.
9,10
When the stimulus intensity is increased, however, as well as stimulating
the low-threshold afferent fibers, the stimulus current begins to activate the higher
threshold afferents that convey information about squeeze, pinprick, and pain to the
central nervous system. Even though some methods can be developed to study the
stimulation of one type of afferents by working during the application of pressure
or local anaesthetics to the region, such experiments are technically challenging and
the results are difficult to interpret.
11
Electrical stimuli can also be applied near mixed or muscle nerves in order to
directly activate afferent axons. This technique is most commonly used to activate
primary muscle spindle (Ia) afferents, since these afferents have relatively low
electrical thresholds and make monosynaptic excitatory connections onto motoneu-
rons innervating the same and synergist muscles.
12
Reproducible activation of a given
population of Ia afferents requires careful placement of the stimulating electrodes
and relatively brief (0.5 ms) stimulus pulses.
12
To ensure that a constant proportion
of Ia afferents is activated, the stimulus intensity is generally increased to a level
that will directly activate a small proportion of motoneuron axons, producing an M-
wave. A constant amplitude M-wave is then taken as evidence that the effective
stimulus strength is constant.
12
Stimuli that are suprathreshold for producing an M-
wave will also activate Golgi tendon organ (Ib) afferent fibers in muscle nerves and
low-threshold cutaneous afferents in mixed nerves, complicating the interpretation
of the reflex effects of electrical nerve stimulation.
13
5.3.2 M
ECHANICAL
S
TIMULATION
Mechanical stimulation is more difficult to standardize than electrical stimulation
since its application requires fine control of the duration, the intensity, the shape,
© 2001 by CRC Press LLC
FIGURE 5.1
The effect of the stimulus profile on the masseteric reflex in one subject. The
left column illustrates the force profiles and the right column is the CUSUM of the ipsilateral
masseter muscle SEMG. The effective force applied to the tooth is indicated in Newtons.
Stimuli were delivered at time zero. In all cases, the number of stimuli used was 150; the
push force was about 2.5 N; all had contraction levels of about 10% MVC. Note that the
probability of eliciting an excitatory reflex increases with the increase in the smoothness of
the force delivery. Also note that when the preload is not applied (bottom trace in left column),
even when using the smoothest force profile, the speed of the force delivery increases (not
shown, cf. 14) inducing an inhibitory reflex response.
and the exact location of the stimulus. Furthermore, the profile of the stimulus shape,
including the rate of rise of the stimulus, is difficult to standardize since it changes
with the physical relationship between the stimulating probe and the stimulated area.
If this relationship is not fixed, the stimulus profile and the rate of rise of the stimulus
will also change. It is, therefore, best to physically connect the probe to the area to
be stimulated either by gluing, or by applying some preload to take up the slack and
the space between the probe and the area to be stimulated. The existence of a preload
minimizes the fast component of the force and, hence, is more likely to deliver the
exact stimulus profile that is specified by the wave generating system (see
Fig. 5.1
).
The exact profile of the delivered forceis likely to determine the relative acti-
vation of different types of mechanoreceptors, which in some cases have opposite
reflex effects. An example is given below where an upper incisor tooth of an
individual was stimulated using a probe attached to a vibrator. Various mechanical
force profiles were delivered to the tooth. Some of the profiles had sharp edges (top
two profiles in the left column of
Fig. 5.1
) that preferentially activate periodontal
mechanoreceptors that are particularly sensitive to abrupt changes in force, and
which induce inhibition in jaw closing muscles. However, when the stimulus profile
is smoothed (third waveform from top in the left column in
Fig. 5.1
), the applied
force preferentially activates receptors with excitatory actions on jaw closing mus-
cles. The same force profile, however, induces an inhibitory reflex response when
no preload is applied to take up the slack between the stimulating probe and the
tooth. This is due to the fact that the probe now moves rapidly to take up the slack
and the abrupt change in applied force (not shown here; see Figure 3 in Reference 14)
causes an inhibitory reflex.
© 2001 by CRC Press LLC
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