The Journal of Neurophysiology Vol. 80 No. 4 October 1998, pp.
1839-1851
Copyright ¿1998 by the American Physiological Society
Reticulospinal Systems Mediate Atonia With Short and Long Latencies
Jun Kohyama, Yuan-Yang Lai,
and Jerome M. Siegel
Department of Psychiatry, University of California at Los Angeles School of
Medicine, Neurobiology Research, Sepulveda Veterans Affairs Medical Center,
North Hills, California 91343
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ABSTRACT |
Kohyama, Jun, Yuan-Yang Lai, and Jerome M. Siegel. Reticulospinal
systems mediate atonia with short and long latencies. J. Neurophysiol.
80: 000-000, 1998. The pontomedullary region is responsible
for both the tonic and phasic reduction of muscle activity in rapid-eye-movement
sleep and contributes to the control of muscle tone in waking. This
study focused on determining the time course of activity in the pontomedullary
systems mediating atonia. Short-train stimulations (3 0.2-ms
pulses at 330 Hz) of the pons and medulla suppressed neck and
hindlimb muscle activity in decerebrate cats. We identified two distinct
phases of suppression, early and late. The anatomic sites that produced
each suppression were intermixed. We estimated the dividing value
of the conduction velocity for reticulospinal projections responsible
for early and late phases of hindlimb muscle tone suppression to
be 22.8 m/s. In the medial medulla, 238 reticulospinal units,
which send axons to the L1 level of the spinal cord, were
identified. Pontine stimulation that suppressed hindlimb muscle tone
increased the firing rate of 138 units (type I). Sixteen type
I units showed a delayed response to the pontine stimulation with
a latency of 10 ms or longer (type Id), whereas 122 type
I units exhibited an earlier response (type Ie). Seven type Ie units
had an axonal conduction velocity of <22.8 m/s, whereas the remaining
115 conducted at faster than 22.8 m/s. Early and late hindlimb
muscle tone suppressions were hypothesized to be mediated through
fast and slow conducting type Ie reticulospinal units. The activity
of type Id neurons may contribute to the cessation of the early-phase
suppression as well as to the induction, maintenance, or cessation
of the late-phase suppression.
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INTRODUCTION |
A complete suppression of antigravity muscle tonus occurs in rapid-eye-movement
(REM) sleep (Jouvet 1962). The pontine tegmentum (Hendricks et al. 1982; Henley and Morrison 1974; Jouvet and Delorme 1965; Shouse and Siegel 1992; Webster and Jones 1989) and medial medulla (Holmes and Jones 1994; Schenkel and Siegel 1989) play key roles in maintaining this state-dependent atonia.
In addition to this tonic motor suppression, phasic motor activity
reduction occurs in association with REMs (Gassel et al. 1964) or pontogeniculooccipital (PGO) waves (Glenn and Dement
1982; López-Rodríguez et al. 1992; Morrison
and Bowker 1975; Orem 1980; Pedroarena et al. 1994; Pivik et al. 1982).
Magoun and Rhines (1946) discovered that electrical stimulation of the medial medulla produces
a collapse of decerebrate rigidity. Subsequent work showed that motor
activity in decerebrate cats could be suppressed by stimulating the
midbrain, pontine, and medullary reticular formation both electrically
and chemically (Engberg et al. 1968; Jankowska et al. 1968; Lai et al. 1987; Lai and Siegel 1988, 1990, 1991; Morales et al. 1987; Oka et al. 1993; Takakusaki et al. 1993). Polygraphically defined REM sleep with atonia (Jouvet
1962; Villablanca 1966) and REM-related phasic motor suppression (Seguin et
al. 1973) can occur in the decerebrate animal as well as in human
infants who have no cerebral cortex (Kohyama et al. 1995). The brain stem must contain systems mediating both
tonic and phasic motor activity suppression. Some cells in the medullary
inhibitory region were found to discharge at a high rate in REM sleep
as well as in postural relaxation during waking (Siegel et al. 1979). In both REM sleep and waking, descending systems from
the brain stem may have a role in the suppression of muscle tone.
Kanamori et al. (1980) identified two medullary reticulospinal neurons that were active
during REM sleep with a conduction velocity ranging from 6 to
8 m/s. In contrast, the spike-triggered averaging technique
in decerebrate cats indicated that medullary reticulospinal cells
producing suppression of hindlimb motoneuronal activity conducted
at 80-100 m/s (Takakusaki et al. 1994). Motor activity reduction may be mediated by more than
one reticulospinal system.
In the current study, we stimulated the pons and medulla
by using very short-duration stimulation trains. We found that these trains
produced muscle activity reductions at both short and long latency.
We identified the medullary reticulospinal neurons activated by the
same short stimulation trains that induced atonia. In addition, we
characterized discharge patterns and conduction velocities of these
cells. The time course of discharge in these units was compared with
that of the two distinct phases of muscle tone suppression.
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METHODS |
Surgical procedures
The experiments were performed on 23 adult cats, weighing 1.8-4.8 kg.
Tracheostomy, bilateral ligation of carotid arteries, cannulation
of the left carotid artery for blood pressure monitoring, insertion
of wires around or into the lumbar segment of the spinal cord, and
decerebration at the postmammillary-precollicular level were performed
under halothane-oxygen anesthesia. All animals were allowed to recover
from anesthesia for 3 h before the experiments began. All preparations used
in this study had a mean arterial pressure of >80 mmHg. Core temperature
was maintained between 37 and 38œC by a heating pad.
EMG and unit recording
The electromyogram (EMG) was recorded bilaterally from the occipitoscapularis,
splenius, biventer cervicis, and gastrocnemius-soleus muscles with
bipolar stainless steel electrodes. A stainless steel electrode (0.25-mm-diam
shaft with 8œ tapered tip, AC impedance 5 M; A-M Systems, model 5710) was inserted into the medial medulla
for extracellular recording of medullary reticulospinal units. Only
units with signal-to-noise ratios >4:1, good isolation from other
units, and stable spike amplitudes were studied. For antidromic identification
of reticulospinal cells, the L1 segment of the spinal
cord was stimulated with a pair of wires placed under it (Takakusaki
et al. 1994) or stainless steel wires (50 µm; California Fine
Wire) manually inserted to a depth of 5-6 mm toward the ventrolateral and
ventromedial funiculi (Drew et al. 1986). The criteria for the antidromic identification of reticulospinal
units were constant latency, high-frequency following (200 Hz) (Lipski 1981), and collision.
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FIG. 1.
A: response of muscle activity to brain stem stimulation.
Electrical stimulation [3 0.2-ms cathodal pulses at 330 Hz
(6.3-ms duration), 1.5 T] is delivered to the left pons
every second starting at the dotted line. a: 5 consecutive
rectified electromyogram (EMG) records are taken from the right
splenius muscle. b: average of 10 consecutive EMG recordings
including the 5 above; top horizontal bar, mean baseline value
collected from 50 ms before the stimulation; bottom horizontal
bar, value of the mean minus 2 SDs. The 1st vertical line indicates
the beginning of stimulation; 2nd and 3rd ones indicate the point
where the waveform crosses the value of mean minus 2 SDs, each
of which indicates the onset and offset of muscle tone suppression,
respectively. Arrow, trough of muscle tone suppression. B:
representative examples showing different types of pontine stimulation-induced
EMG activities. Electrical stimulation (a, 1.7 T;
b1, 2.5 T; b2, 1.7 T; c1,
2.1 T; c2, 2.5 T) is delivered at
the dotted line to the left pons. Data are averaged from 30 consecutive
rectified EMG sweeps. a: example of bilateral suppression
of neck and hindlimb muscle tone. These 4 traces were obtained
simultaneously. Hindlimb muscle tone exhibited 2 phases of
suppression (type B suppression). b: 2 types of neck
muscle tone suppression. Two troughs (arrows) are seen in b1,
whereas no trough is determined in b2 (a saucerlike flat
nadir). c: 2 types of hindlimb muscle tone suppression.
c1: early-phase suppression without a subsequent late phase
suppression (type E suppression). c2: late-phase suppression
without a preceding early phase suppression (type L suppression).
OS, occipitoscapularis muscles; GS, gastrocnemius-soleus muscles;
L, left; R, right. |
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EMG signals were amplified by a Grass preamplifier (model
78D), and unit signals were amplified by an A-M Systems differential AC
amplifier (model 1700). They were displayed on a polygraph and an
oscilloscope and were recorded through a CED (1401) computer interface
for later analysis.
Brain stem stimulation
The brain stem was stimulated with a concentric bipolar electrode (Rhodes Medical
Instruments). In most experiments, stimulation consisted of three
0.2-ms cathodal rectangular pulses at 330 Hz (the total duration
of each stimulus train was 6.3 ms). To determine the threshold
(T) for inducing muscle tone suppression, the current intensity
was increased until bilateral muscle activity reduction was visually
identified in sweeps of neck and hindlimb muscles on an oscilloscope
monitor. The sweep was displayed for a 200-ms period including the
50-ms period before the stimulation. The stimulus intensity used
was expressed as a multiple of T. The maximum stimulus intensity
used was 300 µA; stimulation was delivered once every
1-2 s.
Analysis
Rectified, digitized EMG and discriminated unit pulses were collected on a
computer with a binwidth of 1 ms over a 300- to 400-ms
period starting 50 ms before the stimulation and averaged for
30 trials. The 50 ms preceding the stimulus was used to calculate
a baseline level of EMG activity. We measured the latency to onset,
latency to trough, duration or latency to offset, and amplitude at
the minimum trough of the averaged EMG waveform. The onset and offset
of muscle tone suppression were defined as the points where the EMG
first fell 2 SDs of the prestimulus baseline variability below
the baseline level (Fig. 1A).
The minimum amplitude at the trough was expressed as the percentage
of the baseline value (prestimulus baseline level 100%). Thus the
lower the value, the greater the magnitude of stimulation induced
muscle tone suppression.
Histology
Electrolytic lesions (50 µA, DC cathodal current for 20 s)
(Lai et al. 1987) were made at the stimulating point and at the recording
sites. For tracks on which several units were recorded, lesions were
made at the most superficial and the deepest recording sites along
the track. The brain stems were removed and stored in potassium ferrocyanide
with buffered formalin solution. Serial 60-µm sections were
stained with neutral red. The stimulating and recording points were
verified and reconstructed according to the Berman atlas (1968).
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FIG. 2.
Distribution of the latency of 437 identified troughs in pontine-induced
hindlimb muscle tone suppression. The distribution of 217 troughs
on the side ipsilateral to the stimulation is shown in the top
part, whereas that of the contralateral 220 troughs is
shown in the bottom part. Each side has 2 peaks; one
is <40 ms (between 25 and 30 ms) and the other is >40
ms (between 55 and 60 ms). N, number. |
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TABLE 1. Latencies
in different types of hindlimb muscle tone suppression
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Statistical analysis
Student's t-test was used for comparison of waveform parameters and
for assessing the significance of correlation coefficients (r).
An analysis of variance (ANOVA) or a 2 test for independence was used when necessary.
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RESULTS |
EMG analysis
Muscle tone suppression was induced by pontine stimulation in 21 cats
and by medullary stimulation in 9 cats. We found no obvious
difference in the time course of waveforms among occipitoscapularis, splenius,
and biventer cervicis muscles. Therefore we treated suppression of
tone in these muscles together as neck muscle tone suppression. On
each trial, four muscles were monitored: ipsilateral neck, contralateral
neck, ipsilateral hindlimb, and contralateral hindlimb (Fig. 1Ba).
We termed each EMG recording a trace. Thus four traces were gathered
on each trial.
EARLY AND LATE SUPPRESSIONS. By stimulating
the pons and medulla, we identified two phases of suppression, early and late
phases.
PONTINE-INDUCED MUSCLE TONE SUPPRESSION. We
analyzed 148 trials of pontine-induced muscle tone suppression (Fig. 1B).
Neck muscles. In 15 of 296 traces of pontine-induced
neck muscle tone suppression, two troughs were distinguished in a single
trace (Fig. 1Bb1).
In these 15 traces, the mean latency to trough of the earlier
trough was 24.0 ± 6.8 (SD) ms, whereas the mean latency
to trough of the later one was 40.6 ± 7.8 ms. In another
59 traces, discrete troughs were not identified (Fig. 1Bb2).
We described this type of waveform as having a saucerlike flat nadir.
In the other 222 traces of pontine-induced neck muscle tone suppression,
a single trough was identified.
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TABLE 2. Waveform
parameters of pontine-induced muscle tone suppression
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TABLE 3. Waveform
parameters of medullary induced muscle tone suppression
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Hindlimb muscles. In hindlimb muscles, we identified
437 troughs. These troughs (Fig. 1,
Ba, GS, and 1Bc) were divided into two types (Fig.
2),
181 early troughs and 256 late troughs with 40 ms
being the dividing line. Flat nadirs were observed in 21 of 296 traces
of pontine-induced hindlimb muscle tone suppression. Offsets of 4 flat
nadirs were 40 ms of the beginning of stimulation (early nadir), whereas
onsets of the other 17 flat nadirs were >40 ms after stimulation
onset (late nadir). We termed a hindlimb muscle tone suppression
with an early trough or an early nadir an early phase suppression
and that with a late trough or a late nadir a late phase suppression.
Thus among 296 traces of pontine-induced hindlimb muscle tone
suppression, 23 traces had only an early phase (Fig. 1Bc1;
type E suppression), 111 traces had only a late phase (Fig.
1Bc2;
type L suppression), and 162 traces had both early and late
phases (Fig. 1Ba;
type B suppression). In type B suppression, EMG activity did not
always return to a level below 2 SDs from the baseline between
troughs (Fig. 1Ba,
GS R). In these cases, the offset of early-phase suppression and
the onset of late-phase suppression could not be determined.
In pontine-induced hindlimb muscle tone suppression, the
mean latencies to onset and to trough of the early-phase suppression in
type E suppression to the stimulation did not differ significantly from
those in type B suppression (Table 1A).
Also the mean latencies to trough and to offset of the late-phase
suppression in type B suppression showed no significant difference
from those in type L suppression (Table 1A).
Thus we concluded that the early- and late-phase hindlimb muscle
tone suppressions induced by pontine stimulation were independent.
MEDULLARY INDUCED MUSCLE TONE SUPPRESSION.
We analyzed 30 trials of medullary induced muscle tone suppression.
Neck muscles. In 51 of 60 traces, a single
trough was identified. In another four traces, two troughs were distinguished
in a single trace. The mean latency to trough of earlier troughs
was 22.0 ± 8.5 ms, whereas that of later ones was
41.6 ± 10.8 ms. In the other five traces, flat nadirs
were observed.
Hindlimb muscles. Eighty-seven troughs were identified
among 60 traces. No flat nadirs were obtained. Thirty-three traces
were type L suppression, whereas 27 traces were type B suppression.
Among medullary induced hindlimb muscle tone suppression, the mean
latencies to trough and to offset of the late-phase suppression in
type B suppression showed no significant difference from those in
type L suppression (Table 1B).
Therefore as in the case of pontine-induced suppressions, we concluded
that early and late phases of hindlimb muscle tone suppression induced
by medullary stimulation were independent.
Stimulus effects on ipsilateral and contralateral side to the
stimulation
The difference of stimulus effects on waveform parameters obtained from the
side ipsilateral to the stimulation and that from the side contralateral
to the stimulation were analyzed. Except for the duration of the
early-phase suppression of hindlimb muscle tone (type E suppression)
and latency to onset of the late suppression (type L suppression),
data from different types of suppression were pooled. The magnitude
of muscle tone suppression at nadirs was calculated together with
the amplitude at the trough.
PONTINE-INDUCED MUSCLE TONE SUPPRESSION. In
pontine-induced muscle tone suppression (Table 2),
the latency to onset of neck muscle tone suppression was significantly
earlier in the side contralateral to the stimulation. However, in
hindlimb muscle tone suppression, the latencies to onset of both
early and late phases and the latency to trough of the early phase
were significantly earlier in the side ipsilateral to the stimulation.
The other parameters were not statistically different for the two
sides.
MEDULLARY INDUCED MUSCLE TONE SUPPRESSION.
In medullary induced muscle tone suppression (Table 3),
all parameters obtained from both sides had statistically indistinguishable
values.
Effects of stimulus intensity
Correlation coefficients (r) between stimulus intensity and waveform
parameters were assessed.
PONTINE-INDUCED MUSCLE TONE SUPPRESSION. Neck
muscles. In pontine-induced neck muscle tone suppression, latency to onset
showed significant negative correlations with stimulus intensity:
r = -0.22 for the ipsilateral side (|T| =
2.68, P < 0.01, n = 148)
and r = -0.20 for the contralateral side (|T| = 2.51, P < 0.02, n = 148),
respectively. Other parameters (the latency to solitary troughs and
duration and amplitude at trough) showed no significant correlation
with stimulus intensity. In pontine-induced neck muscle tone suppression,
the mean stimulus intensity required to induce two troughs (2.31 T),
to produce a flat nadir (2.06 T), and to elicit a single
trough (2.11 T) showed no significant difference (ANOVA).
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FIG. 3.
Schematic maps of pontine (A) and medullary (B) stimulus
sites on parasagittal planes. Laterality of the pontine stimulation
(n = 27) ranges from 1.4 to 3.8 mm (mean
2.6 ± 0.6), and that of the medullary stimulation
(n = 10) ranges from 0.2 to 2.1 mm (mean
1.1 ± 0.6). All stimulation sites of the pons are
transposed onto a section 2.5-mm lateral (L 2.5) from the midline,
and those of the medulla are transported onto the 1.2-mm plane (L
1.2), respectively. Two pontine sites (P 2.3 mm, H -4.8 mm,
L 2.7 mm and L 3.8 mm) are transposed on the same spot
in A, and there are 26 circles shown in A. In
B, 2 sites (P 12.8 mm, H -8.9 mm, L 1.1 mm
and L 2.1 mm) are transposed on the same spot. Open circles,
5 in the pons and 2 in the medulla, indicate the sites
that did not evoke the early-phase hindlimb muscle tone suppression.
The site with a half-tone circle (P 12.3 mm, H -8.9 mm, L 2.1 mm)
also induced only late-phase suppression. Five pontine stimulus
sites with an arrow (one of them with a star indicates a site P
2.3 mm, H -4.8 mm, L 3.8 mm) were not used for unit recording
studies. V4, 4th ventricle; TB, trapezoid body; 7G, the genu of
the facial nerve; IO, inferior olive. |
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Hindlimb muscles. For the early phase of pontine-induced
hindlimb muscle tone suppression, the latency-to-onset on the contralateral
side had a significant negative correlation with stimulus intensity
[r = -0.22 (|T| = 2.07, P < 0.05),
n = 89], whereas that on the ipsilateral side showed
no significant correlation. Latency to trough of early hindlimb muscle
tone suppression was not affected by stimulus intensity. The magnitude
of the suppression at trough on both sides increased with an increase
of stimulus intensity [ipsi; r = -0.27 (|T| = 2.68, P < 0.01, n = 96),
contra; r = -0.41 (|T| = 4.15, P < 0.001, n = 89)].
For late-phase hindlimb muscle tone suppression, the latency
to trough, latency to offset, amplitude at trough, and latency to
onset in type L suppression were not affected by stimulus intensity.
In pontine-induced hindlimb muscle tone suppression, the
mean stimulus intensity that induced an early-phase suppression (2.28 T,
1.03 SD, n = 185) was significantly higher than that which
evoked late suppression (1.83 T, 0.50 SD, n = 111)
(|T| = 4.30, P < 0.001). However,
an increase of stimulus intensity did not always evoke the early-phase
suppression. Among 28 sets of trials that used more than 3 different
stimulus intensities at the same stimulus site, 10 sets changed
from type L suppression into type B with increasing stimulus intensity,
whereas 15 sets did not change their types of suppression. Results
in the other three sets were inconclusive.
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FIG. 4.
An example of effect of stimulus sites on the early and late phases
of pontine-induced hindlimb muscle tone suppression. In both planes
(P 2.5 and 3.0) in the top part, stimulations (2.6 T)
are delivered to the left pontine reticular formation along 3 tracks
(a, b, c and d, e, f).
In each track, the stimulus points are indicated by closed circles.
Stimulus efficacy of 7 points in each track is shown in the
bottom part of the figure. Stimulus efficacy is assessed by the
amplitude at trough expressed as a percentage of the baseline value
before the stimulation (prestimulus baseline value 100%). Thus the
smaller the percentage, the deeper the trough. filled circles, early
phase of the left side; open circles, early phase of the right side;
filled square, left late phase; open square, right late phase; dotted
line, early phase; solid line, late phase; L, left side; R, right
side, IC, inferior colliculus; CNF, cuneiform nucleus; TRC, central
division of the tegmental reticular nucleus; TB, trapezoid body.
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MEDULLARY INDUCED MUSCLE TONE SUPPRESSION.
Neck muscles. No parameter on medullary induced neck muscle tone suppression
showed a significant correlation with stimulus intensity. No significant
difference was obtained among the mean stimulus intensity to induce
a single trough (1.60 T), to evoke two troughs (1.50 T),
and to elicit a flat nadir (1.76 T) (ANOVA).
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FIG. 5.
Example of effect of stimulus sites on the early and late phases
of medullary induced hindlimb muscle tone suppression. Stimulations
(2.3 T) are delivered to the right medullary reticular
formation (P 11.0) along with 3 tracks (a, b,
c). Stimulus points are expressed by closed circles in each
track. Stimulus efficacy, assessed by the amplitude at trough, of
every 7 points in each track are shown in the bottom part.
filled circle, early phase on the left side; open circle, early
phase on the right side; filled square, left late phase; open square,
right late phase; dotted line, early phase; solid line, late phase,
L, left side; R, right side; IO, inferior olive; 5ST, spinal trigeminal
tract. |
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Hindlimb muscles. In hindlimb muscles, the latency
to trough of the late ipsilateral suppression had a negative correlation
with stimulus intensity (r = -0.39, |T| = 2.25, P < 0.05, n =
30). The other parameters on medullary induced hindlimb muscle tone
suppression showed no significant correlation with stimulus intensity.
As with pontine stimulation, the mean stimulus intensity that produced
type B suppression (1.63 T, 0.56 SD, n = 27)
through medullary stimulation was higher than the mean stimulus intensity
that induced type L suppression (1.59 T, 0.73 SD, n = 33),
although no significant difference was obtained.
Stimulus sites
Of 27 pontine stimulation sites (Fig. 3A)
and 10 medullary stimulation sites (Fig. 3B),
5 sites in the pons and 3 sites in the medulla () elicited only type L suppression. All latencies to
onset and to trough of brain stem-induced muscle tone suppression (Tables
2
and 3)
were shorter in the medullary induced suppressions than in the pontine-induced
suppressions. However, not all of these differences were significant.
Significant differences were obtained in the side ipsilateral to
the stimulation of the neck muscle tone suppression [both latencies
to onset (P < 0.05) and to trough (P < 0.001)]
and the latency to trough of the early-phase hindlimb muscle tone
suppression in the side ipsilateral to the stimulation (P < 0.01).
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FIG. 6.
Action potentials of representative fast (A) and slow (B)
conducting reticulospinal units are shown. A, top trace:
action potentials activated antidromically by double spinal cord
stimulation. Constant latency and the ability to follow high-frequency
stimulation (330 Hz) are verified. On the bottom trace,
the 1st action potentials antidromically activated by the 1st stimulation
of the double spinal cord stimulation collide with action potentials
orthodromically activated by double pontine stimulation. The 2nd
action potential of the unit antidromically activated by the 2nd
stimulation of the double spinal cord stimulation can still be identified.
B: top trace shows the antidromic activation of the
unit by double spinal cord stimulation (250 Hz) with a slow
sweep. The 2nd and the 3rd traces present the same
unit with a faster sweep with the same double spinal cord stimulation.
In the 2nd trace, the constant latency and the ability to
follow high-frequency stimulation can be seen. In the 3rd trace,
the pontine stimulation is combined with double spinal cord stimulation.
Pontine-induced spikes collide with antidromic spikes that are activated
by the 1st spinal cord stimulation. Arrows, spinal cord stimulation
at the L1 level; closed arrowheads, pontine stimulation;
open arrowhead, pontine stimulation. Calibration: 2 (A)
and 5 ms (B), 0.1 mV. |
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In addition to the stimulus sites demonstrated in Fig. 3,
the effective stimulus sites for the occurrence of each phase of hindlimb
muscle tone suppression were systematically investigated in five
cats for the pons (Fig. 4)
and in four cats for the medulla (Fig. 5).
Identical stimulus intensity that was high enough to evoke stable
waveforms (2.00-3.00 T) was used in each cat. Sites that produced
type E, L, and B suppressions were intermixed.
Effects of stimulus parameters on the waveform
After identifying a stimulus site that induced neck and hindlimb muscle tone
suppression bilaterally with three pulses at 330 Hz, the effects
of stimulus parameters (frequency and the number of pulses at 330 Hz)
on the waveform were assessed. Stimulus intensity was adjusted to
be high enough to induce stable waveforms with stimulation of three
pulses at 330 Hz (1.50-2.50 T) and was unchanged in each
cat.
FREQUENCY. For pontine-induced muscle tone
suppression, the effect of stimulation frequency was examined in five cats (8 sets
of trials). Three pulses were delivered over a range of frequencies
(150-1,000 Hz) with a constant intensity (1.50-2.50 T) in
each set. In eight trials (4 at 1,000 Hz, 3 at 750 Hz,
and 1 at 500 Hz), a neck muscle tone facilitation that
was not present at 330 Hz appeared before the suppression in
the side ipsilateral to the stimulation. The magnitude of neck muscle
tone suppression and of both early and late phases of hindlimb muscle
tone suppression showed no significant change with stimulus frequency
ranging from 250 to 1,000 Hz (ANOVA).
For medullary induced muscle tone suppression, we compared
waveforms with 1,000-Hz stimulation with those at 330-Hz stimulation during
the course of the mapping study (Fig. 6)
in two cats (4 tracks). Both early and late phases of hindlimb muscle
tone suppression were obtained at 1,000-Hz stimulation, and no apparent
difference was found in waveform parameters between 330- and
1,000-Hz stimulation.
NUMBER OF PULSES. The effect of number of stimulation
pulses was investigated for pontine-induced suppression in six cats (10 sets
of trials). After adjusting stimulus intensity to be high enough
to elicit stable waveforms with three pulses at 330 Hz (1.50-2.50
T), one to four pulses were delivered at 330 Hz with
a constant intensity in each cat. Stimulation with one pulse never
suppressed muscle activity. Two of 10 trials with two-pulse
stimulation, all 10 trials with three pulses, and 4 of 10 trials
with four-pulse stimulation suppressed neck and hindlimb muscle tone
bilaterally. The other six trials with four pulses elicited neck
muscle tone facilitation in the side ipsilateral to the stimulation.
Therefore current levels that produced muscle tone suppression with
three pulses elicited a mixture of suppression and facilitation when
four pulses were delivered.
Among the four trials in which neck and hindlimb muscle tone
were suppressed bilaterally with 4-pulse stimulation, all 8 neck muscle
tone suppressions and 9 of the 15 hindlimb muscle tone suppressions
(7 early suppressions and 8 late ones) did not show discrete
troughs. Rather they exhibited flat nadirs (4 early nadirs and
5 late ones), although no flat nadir was observed with three-pulse
stimulation of the same sites. Therefore depending on stimulus intensity
used, three-pulse stimulation but not four-pulse stimulation was
suitable for inducing discrete troughs.
Estimation of conduction velocity of atonia systems
The conduction velocity of reticulospinal projections involved in the early-phase
hindlimb muscle tone suppression was assumed to be X m/s and
that of the late phase was presumed to be Y m/s
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(1) |
Brain stem stimulation was postulated to require Tbr ms to activate
reticulospinal projections. The length of the activated reticulospinal
projection was substituted for the distance from the stimulation site
to the motoneuron pool innervating recording muscles (L mm),
which was measured in each cat. Te represented the
latency to trough of the early-phase hindlimb muscle tone suppression,
and Tl stood for that of the late one. Also we assumed
that it took Tperi (peripheral) ms from the arrival of
responsible reticulospinal volleys at the motoneuron to the trough
of EMG changes. Thus the following two formulas were obtained
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(2) |
and
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(3) |
Taking these two formulas together, the following formula was obtained
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(4) |
As shown in the previous section, the latencies to trough for both early and late
phases of hindlimb muscle tone suppression evoked by pontine stimulation
were not affected by stimulus intensity. Then (Tl Te)/L was calculated in all 432 type
B suppressions with 2 troughs (158 traces from the EMG study
and 274 from the following unit study) induced by pontine stimulation.
The formula (Eq. 4)
was found to range from 0.0376 to 0.2513
|
(5) |
Taken together the maximum reported conduction velocity of reticulospinal cells
(160 m/s) (Eccles et al. 1976) with the formula (Eq. 1),
the following formula was obtained
|
(6) |
Taking Eqs. 5 and 6 together, Y was calculated
to be <22.8. Thus we estimated that a reticulospinal projection involved in
the late-phase suppression conducted at <22.8 m/s for hindlimb muscles.
Consequently reticulospinal projections that conduct faster than this
value appeared to mediate the early-phase suppression.
View larger version (27K)
|
FIG. 7.
A: examples of discharge patterns of reticulospinal neurons
that are activated by pontine atonia inducing stimulation (type
I units). They are classified into 3 types. Type Ie-A units
cease firing within 10 ms after the beginning of the stimulation,
type Ie-B units sustain firing even 10 ms after the beginning
of the stimulation, and type Id units begin to increase firing 10 ms
after the beginning of the stimulation. Peak of the firing of this
type Ie-B unit shown is obtained at 13 ms after the beginning
of the stimulation and that of the type Id unit in this figure is
obtained at 23 ms after the beginning of the stimulation, respectively.
B: histogram of response latency of 122 type Ie medullary
reticulospinal units to pontine stimulation. Ninety of 122 units
respond with latency of <2.5 ms to the pontine stimulation. |
|
Reticulospinal units
Discharge characteristics of medullary reticulospinal units that send their
axons to the lumbar segment of the spinal cord (L1) were
determined during pontine stimulation. Hindlimb muscle tone was recorded
simultaneously. In the medullary reticular formation of 19 decerebrate
cats, 238 reticulospinal units were identified. Pontine stimulation
was delivered to 22 sites (Fig. 3A).
Discharge patterns of units were assessed at a stimulus intensity
strong enough to elicit a consistent EMG response. Stimulus intensities
used ranged from 1.50 to 3.75 T with a mean value of
2.26 T (0.56 SD). Action potentials of representative
units are shown (Fig. 6).
Among 238 trials (476 traces), 274 traces belonged to type
B suppression, 150 traces to type L, and the other 52 traces
to type E suppression. According to the 2 test, the proportion of each type of suppression in
the unit recording study showed no significant difference from that
in the EMG study with pontine stimulation.
View larger version (30K)
|
FIG. 8.
Location of type I units (n = 138). They are diffusely
distributed in the medial medulla. Open symbols, fast units (conduction
velocity 22.8 m/s); filled symbols, slow units (conduction velocity
<22.8 m/s); circles, type Ie-A units; diamonds, type Ie-B units;
triangles, type Id. NRGc, nucleus reticularis gigantocellularis;
NRMc, nucleus reticularis magnocellularis; NRPm, nucleus reticularis
paramedianus. |
|
DISCHARGE PATTERNS. The discharge patterns
of 238 units were classified into two types, N and I. Type N units
did not change their discharge pattern after the pontine stimulation
(n = 100, 42.0%), whereas type I units increased
their firing after the stimulation (Fig. 7A).
Among type I units, 122 units showed an earlier response than
the other 16 units. These 122 units that responded to the pontine
stimulation within 10 ms were termed type Ie units. Type Ie-A
units ceased their discharge within 10 ms after the beginning
of the stimulation (n = 59, 24.8%), whereas type
Ie-B units often fired beyond 10 ms after the beginning of the
stimulation (n = 63, 26.5%). The peaks of discharge
of type Ie-B units occurred between 5 and 22 ms after the
beginning of the stimulation with an average value of 11.7 ms.
Most type Ie units (90/122 units) responded to pontine stimulation
with a latency of <2.5 ms (Fig. 7B).
Sixteen units that showed delayed activation were termed type Id
units (n = 16, 6.7%). They began to fire >10 ms after
the beginning of the stimulation. The peaks of their firing occurred
between 13 and 32 ms after the beginning of the stimulation
with a mean value of 24.3 ms. All type I units were diffusely
distributed in the medial medulla from the rostral to caudal areas
(Fig. 8).
SLOW AND FAST CONDUCTING RETICULOSPINAL UNITS.
The conduction velocity of 238 medullary reticulospinal units identified
ranged from 10.1 to 141.2 m/s with an average value of
71.8 ± 28.6 m/s. The average conduction velocity of type
I units (73.5 ± 29.0 m/s) showed no significant
difference from that of type N units (69.4 ± 28.0 m/s).
Among 138 type I units, 9 units had a conduction velocity
of <22.8 m/s (Table 4).
All the trials during which these nine slow conducting type I units
were recorded exhibited late-phase suppressions in bilateral hindlimb
muscle tone (type L or B suppressions). The proportion of slow conducting
units among 122 type Ie units was higher in the nucleus reticularis
magnocellularis (NRMc; 18.2%, 4/22) than in both the gigantocellularis
(NRGc; 3.4%, 2/59) and the paramedianus (NRPm, 2.4%, 1/41) [2 test, P (2 8.32) < 0.02]. The proportion of fast conducting
units was highest in the NRPm (97.6%, 40/41). The conduction velocity
of 16 type Id units ranged from 12.6 to 103.2 m/s
(mean 55.7 ± 30.6 m/s).
View this table: [in
this window]
|
TABLE 4. Discharge
pattern and location of medullary reticulospinal units identified
|
|
|
DISCUSSION |
In the current study, short-train stimulations of the brain stem were found
to suppress neck and hindlimb muscle activity of decerebrate cats
with two distinct phases, early and late. The dividing value of the
conduction velocity for reticulospinal projections responsible for
early and late phases of hindlimb muscle tone suppression was estimated
to be 22.8 m/s. Pontine stimulation that suppressed hindlimb
muscle tone increased the firing rate of 138 of 238 reticulospinal
units identified in the medial medulla.
Early and late phases of brain stem-induced motor suppression
The medullary inhibitory region was discovered by using long-train stimulation
(Magoun and Rhines 1946). Later, long trains also contributed to identifying
the inhibitory regions in the midbrain and pons (Lai and Siegel 1990; Oka et al. 1993). However, long-train stimulations cannot differentiate
the two atonia systems that we demonstrated in this study.
The latency to trough and latency to offset of the late-phase
hindlimb muscle tone suppression induced by both pontine and medullary
stimulation showed no statistical difference between type B and type
L suppressions. The time course of the late-phase suppression was
not affected by the presence of the early suppression. Therefore
despite occurring at latencies of >40 ms, the late-phase suppression
is concluded to be the result of an inactivation of motoneurons by
descending systems rather than the result of a local reflex because
of changes in muscle tone induced by the early-phase suppression.
Also the latency to trough of pontine-induced early-phase suppression
of hindlimb muscles in type E suppression was not significantly different
from that of the early phase in type B suppression. We concluded
that the appearances of the early and late phases of hindlimb muscle
tone suppression were independent. Two troughs could also be identified
in the neck muscle tone suppression induced by stimulating the pons
and medulla. Brain stem stimulation of decerebrate cats suppresses
neck and hindlimb muscle activity with both short and long latencies.
Through intracellular recordings, Peterson et al. (1978) obtained two types of inhibitory postsynaptic potentials (IPSPs)
in neck motoneurons by stimulating the pontomedullary reticular formation:
early IPSPs with short latencies of 1.3 ms and late ones with longer latencies including IPSPs
with a latency of >2.0 ms. They attributed these differences in
the latency of IPSPs to the number of synapses in pathways from the
brain stem to the motoneurons. Corresponding to the long latency
response we see in hindlimb muscles, IPSPs were recorded in lumbar
motoneurons after stimulating the pedunculopontine tegmental nucleus
of the decerebrate cat (Takakusaki et al. 1997) and by stimulating the pontine (Fung et al. 1982) and medullary (Chase et al. 1986) reticular formation during REM sleep. Corresponding
to our early-phase suppression, Drew and Rossignol (1990) reported inhibitory responses of hindlimb muscles in
waking cats (the mean latency to onset 20 ms), and Engberg et
al. (1968) reported a medullary induced inhibitory action on lumbar
motoneurons. Engberg et al. (1968) estimated this inhibitory action to conduct at faster
than 20 m/s. Consistent with this estimation, we determined
the dividing value of the conduction velocity for reticulospinal
projections responsible for early and late phases of hindlimb muscle
tone suppression to be 22.8 m/s.
Consistent with our current observation, both early and late
phases of membrane hyperpolarization were identified simultaneously through
intracellular recordings of lumbar motoneurons by using short trains
delivered to the brain stem. Fung et al. (1982) induced both early (latency 2-15 ms) and late (38-53
ms) phases of synaptic response during REM sleep by stimulating the
pontine reticular formation. Sakamoto et al. (1985) elicited both early (latency 4-6 ms) and late (30-40
ms) membrane responses in decerebrate cats by stimulating the dorsal
part of the mid-pontine tegmental field and reported that earlier
responses were more consistently observed than later ones. In intact
cats, an early hyperpolarizing response without a subsequent late
response was also obtained during waking and non-REM sleep states
by similar pontine stimulation (Fung et al. 1982). An earlier response was more easily elicited than a
later one in these intracellular recording studies, although they
did not describe details of the stimulus intensity. In contrast to
our observation, these studies did not observe peripheral muscle activity
or the time course of brain stem neuronal activation during atonia
eliciting stimulation.
Reticulospinal systems that mediate atonia
More than one-half of medullary reticulospinal units identified (type I units,
138/238) were activated by pontine stimulation that induced atonia.
This unit population appears to serve as the final common path for
motor inhibition. According to our estimate from the EMG study, we
hypothesize that the fast-conducting type Ie units that conduct at
22.8 m/s mediate the early-phase suppression of hindlimb
muscles, whereas the slow-conducting type Ie units that conduct at
<22.8 m/s are involved in the late suppression. Depending on the
conduction velocity, the presumed role of type Id units could extend
from the cessation of the early-phase suppression to the induction,
maintenance, and even the cessation of the late-phase suppression.
We hypothesize that brain stem stimulation evokes muscle tone reduction
and activates these several subpopulations of type I units simultaneously,
resulting in IPSPs in motoneurons (Chase et al. 1986; Fung et al. 1982) and subsequent EMG changes corresponding to these IPSPs.
The delayed activation seen in types Ie-B and Id units could
be caused by sensory inputs elicited by induced EMG changes or by
an interaction between the pons and medulla (Siegel et al. 1986). After transection at the pontomedullary level, stimulation
of the medullary inhibitory region produces little motor suppression
(Siegel et al. 1983). Pontine neurons may recruit medullary neurons mediating
atonia, or reticulospinal cells in the pons (Matsuyama et al. 1997) may directly participate in muscle tone suppression.
Iwakiri et al. (1995) found medullary reticulospinal cells whose activity was suppressed
by pontine stimulation that reduced postural muscle tone. Siegel
et al. (1992) found that muscle tone suppression seen in cataplexy
was correlated with cessation of discharge in the majority of pontine
and medullary neurons. The cessation of activity of noradrenergic
cells in the locus coeruleus (Wu et al. 1996) may also play a role in muscle tone suppression.
Fast conducting neurons (80-100 m/s) that inhibit motoneuronal
excitability were identified in the dorsal medulla (NRGc) (Takakusaki et
al. 1994). We found that the proportion of fast type Ie units was
highest in the caudal medulla (NRPm). Our previous studies implicated
this region in muscle tone suppression (Lai and Siegel 1988; Kodama et al. 1992; Shiromani et al. 1990). Two slow conducting units (6-8 m/s) that fire specifically
during REM sleep were found in the ventral medulla and were hypothesized
to be involved in muscle atonia (Kanamori et al. 1980). Consistent with this report, we found that the proportion
of type Ie slow conducting medullary reticulospinal neurons was highest
in the ventral medulla (NRMc). This is also consistent with the localization
of cataplexy-on units in narcoleptic dogs (Siegel et al. 1991).
The number of slow conducting reticulospinal units we identified
was low in comparison with the amplitude and consistency of the late-phase
hindlimb muscle tone suppressions we obtained. Also we did not see
reticulospinal neurons with conduction velocity of <10 m/s, although
such slow conducting cells do exist (West and Wolstencroft 1983). We could identify more slowly conducting reticulospinal
neurons by adding stimulation of more rostral portions of the spinal
cord for antidromic identification. Under the stimulation conditions
used in the current study, very long latency responses elicited from
caudal spinal stimulation could not easily be discriminated. However,
other possibilities must be kept in mind to explain the low number
of slow conducting reticulospinal neurons identified in the current
study. The late-phase suppression of muscle tone might be mediated
by the delayed activation of fast conducting reticulospinal projections.
Interaction between the pons and medulla (Siegel et al. 1986) could cause this kind of delay. In fact, we found reticulospinal
units that showed delayed activation (types Ie-B and Id) in the medullary
reticular formation. Similar processes causing a delay in muscle
responses might also occur within the spinal cord.
Neuronal mechanisms mediating early and late atonia
Yeomans (1990) proposed that slow conducting fibers reduced response to high-frequency
stimulation compared with fast fibers because of longer absolute
refractory periods in the slow fibers. However, we could not differentiate
the two phases of suppression with 330- and 1,000-Hz stimulation.
In cases of pontine-induced hindlimb muscle tone suppression, the
average stimulus intensity needed to induce early suppression was
higher than that required for evoking late suppression, although
an increase of stimulus intensity at the same stimulus sites where
the late suppression was induced did not always evoke the early-phase
suppression. This indicates that neural elements involved in the
early suppression have a larger current-distance constant than those
responsible in the late one (Tehovnik 1996). According to Hentall et al. (1984), the current-distance constant is negatively correlated
with the conduction velocity. Consequently, although paradoxically,
this would indicate that the neural elements involved in the early-phase
suppression conduct slower than the elements implicated in the late
phase suppression. Although a spatially denser presence of slow fibers
at the stimulus site might explain our results, the appearance of
later responses was found to depend on behavioral states (Fung et
al. 1982). Neuronal mechanisms that cause the state dependency
of neuronal activity remain obscure, and these mechanisms could be
altered in the decerebrate animals we used. The precise mechanisms
that produce the early and late suppressions remain to be determined.
It also remains unclear if atonia systems act directly on
motoneurons or through spinal interneurons. An inhibitory effect on
lumbar motoneurons induced by pontine carbachol injection was proposed
to be mediated via spinal segmental inhibitory interneurons (Takakusaki
et al. 1994), whereas a monosynaptic inhibition on spinal motoneurons
through glycinergic reticulospinal cells was found in the lamprey
(Wannier et al. 1995). In cats, medullary glycinergic neurons are likely to
mediate motor suppression in REM sleep (Rampon et al. 1997), although a role for reticulospinal projections containing
-aminobutyric acid was also suggested (Jones et al.
1991).
Functional implications
The distinct early- and late-phase suppressions we demonstrated may have separate
functional roles. By comparing two papers that described PGO wave-related
IPSPs (López-Rodríguez et al. 1992; Pedroarena et al.
1994), it can be calculated that it took 20-30 ms for volleys
mediating these phasic motor suppressions to conduct from the brain
stem to the lumbar segment of the spinal cord. Taking into account
the distance between these two sites (an average value among our
23 cats was 278 mm), PGO wave-related phasic IPSPs are
likely to be mediated primarily by the slow conducting system. The
fast conducting inhibitory reticulospinal system is proposed to set
the activity of axial and proximal muscles related to postural fixation
(Mori et al. 1995).
We demonstrated two phases of motor activity reduction in
neck and hindlimb muscles elicited bilaterally by short-train stimulation.
Our method may be useful in further studies that analyze and discriminate
between the anatomic and neurochemical substrates of these two atonia
systems. Characterization of the morphology and neurochemistry of
the neurons implicated in each reticulospinal system in the decerebrate
model may clarify the distinct roles of each system in motor control.
|
ACKNOWLEDGEMENTS |
This study was supported by Uehara Memorial Foundation, National
Institutes of Health Grants HL-41370 and NS-14610, and the Medical
Research Service of the Department of Veterans Affairs.
|
FOOTNOTES |
Address for reprint requests: J. M. Siegel, Dept. of Psychiatry,
Neurobiology Research (151A3), UCLA School of Medicine, Sepulveda VAMC, 16111 Plummer
St., North Hills, CA 91343.
Received 7 January 1998; accepted in final form 28 May 1998.
|
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