Progress in Neurobiology Vol. 56, pp.

433 to 506, 1998

# 1998 Elsevier Science Ltd. All rights reserved
Printed in Great Britain
0301-0082/98/$19.00

PII: S0301-0082(98)00046-X

CONTROL OF ABDOMINAL MUSCLES

STEVE ISCOE*
*Department of Physiology, Queen's University, Kingston, Ontario, Canada K7L 3N6
(Received 25 March 1998; accepted in revised form April 1998)
AbstractAbdominal muscles serve many roles; in addition to breathing, especially at higher levels of
chemical drive or at increased end-expiratory lung volumes, they are responsible for, or contribute to,
such protective reexes as cough, sneeze, and vomiting, generate the high intra-abdominal pressures
necessary for defecation and parturition, are active during postural adjustments, and play an essential
role in vocalization in many species. Despite this widespread involvement, however, their control has,
with rare exceptions, received little attention for two major reasons.
First, in most anesthetized or decerebrate preparations, they are relatively inactive at rest, in part
because the position of the preparation (supine or prone with abdomen supported), reduces lung volume
and, therefore, their activity.
Second, unlike phrenic motoneurons innervating the diaphragm, identication of motoneurons to a
particular abdominal muscle is dicult.
At the lumbar level, a given motoneuron may innervate any one of the four abdominal muscles; at the
thoracic level, they are also intermixed with those innervating the intercostals.
The two internal muscles, the internal oblique and the transverse abdominis, respond more to
increases in chemical or volume-related drive than the two external muscles, the rectus abdominis and
external oblique; the basis for this dierential sensitivity is unknown.
Segmental reexes at the thoracic and lumbar levels are sucient to activate abdominal motoneurons
in the absence of descending drive but the basis for these reex eects is also unknown.
Neuroanatomical experiments demonstrate many more inputs to, and outputs from, the nucleus retroambigualis, the brainstem region in which the premotor neurons are located, than can be accounted for
by their respiratory role alone. These other connections likely subserve activities other than respiration.
Studies of the multifunctional roles of the abdominal muscles, on the basis of recent work, hold considerable
promise for improving our understanding of their control. # 1998 Elsevier Science Ltd. All rights reserved

CONTENTS

1. Introduction
2. The muscles
2.1. Anatomy
2.2. Innervation
2.3. Location of motoneurons
2.4. Morphometry
3. Premotor neurons
3.1. Background
3.2. Discharge patterns and spinal projections
3.3. Inputs to cVRG (E neurons)
3.3.1. Electrophysiological studies
3.3.1.1. Medulla
3.3.2. Upper airway
3.3.2.1. Nasal aerents
3.3.2.2. Hypothalamus
3.3.3. Neuroanatomical tracers
3.4. Axonal projections
4. Inputs to abdominal motoneurons
4.1. Neuroanatomical studies
4.1.1. Pathways
4.2. Electrophysiological studies
4.2.1. Expiratory neurons of the caudal ventral respiratory group (cVRG)
4.2.2. Upper cervical inspiratory neurons
4.2.3. Vestibular
4.3. Divergence and convergence
4.3.1. Expiratory bulbospinal (E-BS) neurons
4.3.2. Non-ventral respiratory group (VRG) inputs
4.3.3. Cortical
5. Limitations
5.1. Recording techniques
5.2. Analysis of activity
5.3. Upper airway
5.4. Blood pressure
5.5. Gender
6. State
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434

S. Iscoe

CONTENTS (continued)

6.1. Consciousness and sleep

6.1.1. Motoneurons and muscles
6.2. Anesthesia
6.2.1. Motoneurons and muscles
6.2.2. Premotor neurons
6.3. Local anesthetics
6.4. Development
7. Lung volume and pulmonary slowly adapting receptors
7.1. Shifts in end-expiratory lung volume
7.2. Occlusions (``no-ination tests'')
7.3. Ination in expiration
7.4. Timing
7.5. Neural basis for inhibition/disfacilitation of E-BS neurons
8. Chemical drive
8.1. General considerations
8.2. Carotid chemoreceptors
8.2.1. Abdominal responses
8.2.2. Medullary responses
8.3. Locations of chemosensitive neurons
8.4. Hypoxia
8.4.1. Central hypoxia
8.4.2. Systemic hypoxia (intact peripheral chemoreceptors)
8.4.3. In vitro responses
8.4.4. In vivomedullary recordings
8.5. CO2
8.5.1. Distribution of central and peripheral chemoreceptor drives
8.5.2. Abdominal motoneurons
8.5.3. Medullary premotor neurons
8.5.4. Intracellular recordings
9. Behavioral aspects
9.1. Straining
9.2. Vocalization
10. Segmental control
10.1. Background
10.2. Receptor aerents and projections
10.3. Reex eects
10.4. Abdominal aerents
11. Conclusions
Acknowledgements
References

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ABBREVIATIONS
AUG
BotC
c
C
CPAP
CSF
cVRG
DLH
DRG
E
E-BS
EELV
EMG
EO
EPSP
ETL
DEC
Dial
ECF
ETL
GABA
GTO
HRP
i
I
IO
IPSP
KF
L
MAC
NA

augmenting
Botzinger complex
caudal
cervical
continuous positive airway pressure
cerebrospinal uid
caudal ventral respiratory group
DL-homocysteic acid
dorsal respiratory group
expiratory
expiratory bulbospinal neuron(s)
end-expiratory lung volume
electromyogram, electromyographic
external oblique
excitatory post-synaptic potential
expiratory threshold load
decrementing
diallylbarbituric acid (allobarbital)
extracellular uid
expiratory threshold load
g-amino butyric acid
Golgi tendon organ
horseradish peroxidase
intermediate
inspiratory
internal oblique
inhibitory post-synaptic potential
Kolliker-Fuse nucleus
lumbar
minimal anesthetic concentration
nucleus ambiguus

NAA
NMDA
NPBL
NPBM
NRA
NREM
NTS
P
PAG
PBN
PEEP
Pga
PPB
r
RA
RAR
REM
RFN
RTN
SAR
SLN
STA
T
TA
TI
TE
TS
TTX
vl
VT
VT/TE
WGA-HRP
XCOR

not antidromically activated

N-methyl D-aspartate
nucleus parabrachialis lateralis
nucleus parabrachialis medialis
nucleus retroambigualis
non-rapid eye movement
nucleus of the solitary tract
pump (cells)
periaqueductal gray
parabrachial nuclei
positive end-expiratory pressure
gastric pressure
positive pressure breathing
rostral
rectus abdominis
pulmonary rapidly adapting receptors
rapid eye movement
retrofacial nucleus
retrotrapezoid nucleus
pulmonary slowly adapting receptors
superior laryngeal nerve
spike-triggered averaging
thoracic
transversus abdominis
duration of inspiration
duration of expiration
triangularis sternis
tetrodotoxin
ventrolateral
tidal volume
mean expiratory ow
wheat germ agglutinin conjugated to HRP
cross-correlation.

Control of Abdominal Muscles

1. INTRODUCTION
Abdominal muscles contribute to ventilation when
respiratory drive increases (e.g., exercise, diaphragmatic fatigue), are critical for protective reexes such
as coughing, sneezing, and vomiting, and, depending
on one's viewpoint, contribute to one of humanity's
best or worst attributesspeech. Despite their importance, however, much less is known about their
control compared to that of the intercostal and phrenic motoneurons. We know virtually nothing about
the inputs to their medullary premotor neurons and
the organization, at the spinal level, of the connections between their aerents, interneurons, and
motoneurons within and between segments and this
is reected in the limited attention they receive in
most recent reviews (Feldman, 1986; Shannon, 1986;
Dun et al., 1995; Berger and Bellingham, 1995;
Bianchi et al., 1995; Hilaire and Monteau, (1997),
including one related to birds (Gleeson and Molony,
1989). Four exceptions are those of Monteau and
Hilaire (1991) and Hilaire and Monteau (1997), a
recent, but brief (84 references) review by Bishop
(1997), an update of an earlier one (Bishop, 1963) by
her, and that by Leevers and Road (1995a) on reex
inuences on muscles of the chest wall. In contrast,
just four of 603 references by Bianchi et al. (1995)
refer explicitly to abdominal muscles although
another 54 are indirectly related, primarily because
of results related to pre-motor neurons. In one
review, only the locations of their motoneurons
(Berger and Bellingham, 1995) are described; in
another, only the drives to phrenic and intercostal,
but not abdominal, motoneurons (Monteau and
Hilaire, 1991). The neglect of abdominal motor control is typied by a recent review of respiratory
rhythmogenesis; a schematic of the ``main groups of
respiratory neurons in mammalian brainstem and
spinal cord'' omits abdominal motoneurons (Dun
et al., 1995). Research on proprioceptive inputs from
respiratory muscles emphasizes those from the diaphragm and intercostals (e.g. Duron et al., 1978;
Duron, 1981; Jammes et al., 1983a; Jammes and
Speck, 1995; Hussain and Roussos, 1995; Revelette
and Davenport, 1995; Jammes, 1995). Shannon,
who, with his colleagues, has done much of the work
on abdominal aerents (Shannon, 1980; Shannon
and Freeman, 1981; Shannon and Lindsey, 1983;
Hernandez et al., 1989), devotes eleven pages to thoracic, but only one to abdominal, receptors in his
review (Shannon, 1986). A recent review of the respiratory responses to loads concentrates on the diaphragm (Bazzy and Feldman, 1991).
Contraction of the abdominal muscles contributes
to inspiration by lengthening the diaphragm (or
reducing or preventing its shortening at increased
lung volumes, whether caused by loads, changes in
posture, or airway obstruction), thereby maintaining
the diaphragm closer to its optimal length for tension generation (contractility). Abdominal tone also
reduces the compliance of the abdominal compartment (Goldman et al., 1986a), enabling the region in
contact with rib cage (the area of apposition) to act
as a fulcrum for expansion of the lower rib cage
during inspiration. These considerations account for
the use of abdominal muscle binders in quadriple-

435

gics (e.g. Goldman et al., 1986b). Finally, by forcing

lung volume below the passive end-expiratory position, the onset of the next inspiration is passive,
resulting from the outward recoil of the respiratory
system when abdominal muscles relax. Dogs (De
Troyer et al., 1989) and horses (Koterba et al.,
1988) use this breathing pattern at rest; man (Henke
et al., 1988) and dogs (Ainsworth et al., 1989a), but
not ponies (Gutting et al., 1991), use it during exercise. The net eect is to distribute the work of
breathing between the two sets of muscles or, in the
case of human subjects whose use of abdominal
muscles at rest is minimal, to share it at higher ventilatory levels. All these points are made by many, if
not most, researchers studying this aspect of respiratory function, are covered in a recent paper by
Aliverti et al. (1997) and recent reviews describing
the complexity of their action (De Troyer and
Loring, 1986; Grassino and Goldman, 1986; De
Troyer and Loring, 1995; De Troyer, 1997;
Decramer, 1997), and are not presented in more
detail here.
Abdominal activity, either measured directly from
electromyographic (EMG) recordings or deduced
from either the pressures (which are related to discharge rate and recruitment of abdominal motor
units during voluntary increases in abdominal pressure; Sant'Ambrogio et al., 1967) or conguration of
the abdomen (Grimby et al., 1976; see also Aliverti
et al., 1997 for references to related works), is present under conditions unrelated to such specic
behaviors as coughing, sneezing, vomiting and
straining, and vocalization. Patients with airway
obstruction (or chronic obstructive pulmonary disease) typically have active abdominal muscles
(Martin et al., 1980, 1983; Dodd et al., 1984; Lopata
et al., 1985b; Vergeret et al., 1987; Ninane et al.,
1992; Breslin, 1992), their use depending on the
degree of obstruction (Martinez et al., 1990). In
such patients, they are recruited during exercise
(Dodd et al., 1984) or application of continuous
positive airway pressure (CPAP) (Petrof et al., 1990)
when their activity may oset the benets (reduced
dyspnea) resulting from CPAP. Activity is also present in patients with cystic brosis (Cerny et al.,
1992), generalized muscle weakness of diverse origins (Grinman and Whitelaw, 1983; Passerini et al.,
1985; Rimmer and Whitelaw, 1993), under conditions of impaired diaphragmatic function (including diaphragmatic fatigue) (Yan et al., 1993a,b;
Katagiri et al., 1994; Sliwinski et al., 1996), and
after maximal voluntary ventilation (Kyroussis et
al., 1996) and thoracic surgery (Simonneau et al.,
1983; Duggan and Drummond, 1987, 1989; Couture
et al., 1994; Clergue et al., 1995). Despite their clinical signicance, isolated examples of which are provided in several recent reviews (Slack and Shucart,
1994; Brown, 1994; Teitelbaum and Borel, 1994;
Carter and Noseworthy, 1994; Zulueta and
Fanburg, 1994; Kaplan and Hollander, 1994; Lynn
et al., 1994), these will not be discussed further
because they provide little information about the
underlying neurophysiological control mechanisms
at the central or spinal level.
Some studies document remarkably little eect of
their absence on ventilation, probably because other

436

S. Iscoe

respiratory muscles, including the pectorals, compensate (Ainsworth et al., 1992a,b). For example,
quadriplegics defend ventilation as well as control
subjects against an expiratory load (O'Donnell et
al., 1993). Subjects lacking abdominal muscles
(prune belly syndrome) have only modest impairments of ventilatory performance and exercise capacity (080% of predicted) (Ewig et al., 1996).
Anesthetized supine dogs with paralyzed abdominal
muscles still can generate satisfactory tidal volumes
(VT) (Warner et al., 1991; Brichant et al., 1993; but
see Schroeder et al., 1991; Farkas and Schroeder,
1993); sudden loss of expiratory muscle activity, perhaps because of subtle changes in posture, has no
eect on VT, inspiratory ow, or end-tidal CO2 in
awake dogs (Saupe et al., 1992). In healthy men,
blockade of intercostal nerves T612 with local anesthetic has little eect on peak expiratory ow and
none at all on the ventilatory response to CO2 or
exercise (Hecker et al., 1989), possibly because lumbar innervation (see below) was not blocked or
because accessory expiratory muscles such as triangularis sternis (TS) were recruited. Nevertheless, the
signicance of the contribution of abdominal
muscles is illustrated by the respiratory diculties
encountered by patients with spinal cord injuries
(Slack and Shucart, 1994), degenerative diseases
(Grinman and Whitelaw, 1983; Rimmer and
Whitelaw, 1993; Teitelbaum and Borel, 1994; Carter
and Noseworthy, 1994; Zulueta and Fanburg, 1994;
Kaplan and Hollander, 1994; Lynn et al., 1994), or
after upper abdominal surgery (see Ford et al., 1993
for review). Physiotherapy of abdominal muscles
improves exercise capacity and maximal expiratory
pressure generation in patients with chronic obstructive pulmonary disease (Vergeret et al., 1987).
Recently, magnetic stimulation has been used to
activate abdominal muscles, the resulting pressures
and ows being similar to those observed in natural
cough (Kyroussis et al., 1997; Lin et al., 1998); such
a procedure has an obvious application to individuals with disrupted control of expiratory motoneurons (e.g. spinal cord injury).
The three preceding paragraphs testify to the
many conditions when abdominal muscles are used
but, as indicated earlier, the control mechanisms
operating under these conditions are unknown. In
this review, I concentrate on the abdominal muscles
and their innervation, the locations and characteristics of their motoneurons, the medullary pre-motor
neurons (discharge patterns, projections, inputs), the
responses of both premotor neurons and motoneurons to various inputs which aect their discharge
patterns during eupnea, their responses to changes
in lung volume and respiratory drive (hypercapnia
and hypoxia), and their roles in such specic activities as straining and vocalization. Puckree et al.
(1998) have recently described task-specicity of individual abdominal motor units in upright humans;
units recruited during a respiratory manoeuvre (an
increase in end-expiratory lung volume) are not
recruited during a postural one (leg lift). Readers
interested in details about their roles in postural
control are directed to the literature on this topic
(e.g. Carman et al., 1972; Grillner et al., 1978;
de Sousa and Furlani, 1982; De Troyer, 1983;

Thorstensson et al., 1985; Goldman et al., 1987;

Oddsson and Thorstensson, 1987, 1990; Cresswell et
al., 1994; Hodges et al., 1997) and recent reviews of
the role of the vestibular system in the control of
expiratory premotor neurons (Shiba et al., 1996a)
and respiratory muscles (e.g. Huang et al., 1991;
Yates et al., 1993; Rossiter et al., 1996) by Yates
and Miller (1996, 1997). In addition, the reader is
referred to recent brief reviews of such protective
respiratory reexes as cough and sneezing by
Shannon and colleagues (1996 and 1997) and an earlier and exhaustive review by Korpas and Tomori
(1979). Vomiting has been the subject of several
recent reviews (Grelot and Miller, 1994, 1997;
Miller, 1995; Miller and Grelot, 1996).

2. THE MUSCLES
2.1. Anatomy
The respiratory abdominal muscles comprise two
outer (external oblique, EO, and rectus abdominis,
RA) and two inner (internal oblique, IO, and transversus abdominis, TA) muscles. A generic description of their anatomical arrangements is provided
by Monteau and Hilaire (1991) but the anatomy
varies considerably between species (Rizk, 1980); in
some species of bats, for example, the EO is poorly
developed (Lancaster and Henson, 1995a). A complete description (architecture, ber type, and innervation) of rat RA is available (Hijikata et al., 1992)
as is a description of the ber types of all four
muscles in man (Haggmark and Thorstensson, 1979;
Caix et al., 1984), the contractile properties of
canine RA and EO (Farkas and Rochester, 1988),
and rat EO during development (Watchko et al.,
1992). Two studies, both in man (Sant'Ambrogio et
al., 1967; Puckree et al., 1998), indicate that the
peak ring frequencies of abdominal motor units
are less than 20 s1 even during expulsive manoeuvres, suggesting that recruitment accounts for
much of the increment in force generation.
Limited data exist concerning ber type. In man
(Caix et al., 1984), most bers in all four muscles
are slow oxidative, fatigue resistant (type I), somewhat fewer are type IIa (fast, fatigue resistant),
whereas relatively few are type IIb (fast, fatiguable);
RA has the highest percentage of type I bers (69%
based on the presence of ATPase) and the lowest
percentage of type IIa bers (31%). These percentages dier from those reported earlier for RA by
Johnson et al. (1973) who classied 46% as type I
and 54% as type II (IIa + IIb). According to
Polgar et al. (1973), RA type I bers average 43 mm
in diameter, signicantly smaller than type II bers
(56 mm). In contrast, canine TA contains equal percentages of only type I and IIa bers (based on
myobrillar ATPase), the diameters averaging approximately 35 and 44 mm, respectively (Reid et al.,
1987).
2.2. Innervation
Anatomical texts indicate that, in man, all four
muscles receive branches from the lower six inter-

Control of Abdominal Muscles

costal nerves, the internal muscles also receiving a

branch from L1; none mentions innervation from
more rostral segments. In cat, all four muscles are
innervated by branches from the ventral rami of internal intercostal nerves of thoracic segments T412
and, caudally, by branches from the rostral and cranial iliohypogastric and ilioinguinal nerves (L13).
Miller (1987) and Holstege et al. (1987b) both used
intramuscular injections of horseradish peroxidase
(HRP) to label feline motoneurons, the latter also
applying HRP to the central end of nerves to various abdominal muscles. Miller found motoneurons
of all four muscles as caudal as L3 but their rostral
extents dier between muscles: RA to T4, EO to T6,
TA to T9, and IO to T13. Holstege et al. (1987b)
also observed HRP-labeled motoneurons of all four
muscles in L3 but, in their study, motoneurons were
found more rostral (RA and EO in C7, and IO and
TA in C8). They acknowledged that the labeled cells
in the cervical spinal cord could represent false positives resulting from leakage of HRP, a possibility
supported by Miller's observations (1987) that (1)
microstimulation in the ventral horn of C7 and C8
does not elicit contractions of abdominal muscles,
(2) section of the phrenic nerve ipsilateral to the site
of HRP injection into RA eliminates labeling of
motoneurons in the cervical spinal cord (consistent
with interdigitation of RA and diaphragmatic
bers), and (3) twitches elicited in dierent muscles
by electrical microstimulation of the ventral horn
correspond to the distribution of labeled motoneurons in dierent segments. Recently, Tami et al.
(1994) used injections of cholera toxin subunit B
bound to latex beads (which limits spread) to label
motoneurons innervating feline trunk muscles; the
distribution of labeled cells resembles that found by
Miller (EO, T6 to L2; IO T11 to L2; RA T4 to L2).
A schematic representation of the arrangement of
nerves from L1, L2, and L3 in cat is provided in
Fig. 1. In my experience and that of others (Grelot
and Fregosi, personal communications), phasic
expiratory activity is recorded typically from the
caudal branches of these nerves, the cranial
branches rarely displaying phasic activity even in
decerebrate cats breathing at elevated end-expiratory lung volumes. Because of the overlap in innervation of dierent muscles by motor axons in a
given nerve (Fig. 2; Fregosi et al., 1992) and variations between dierent muscles in levels of activities, particularly as a result of changes in posture
(Section 7.1) or chemical drive (Section 8), a better
description of the innervation of abdominal muscles
is needed.
In rat, RA is innervated by branches originating
from T313 (Hijikata et al., 1992). However, injections of a dye into RA and EO labels motoneurons
in the cervical spinal cord; EO motoneurons are
found in the extreme ventrolateral tips of C67 but
no labeled RA motoneurons are found in the cervical spinal cord or in T12 (Charlton et al., 1988).
Although these workers claimed to have prevented
spread of the dye to other muscles, it is unclear if
the presence of EO motoneurons in C67 represents
false positives (due to spread of the dye to the overlying cutaneous maximus) or if the distribution of

437

Fig. 1. Schematic representation of lumbar abdominal

nerves in cat. Phasic expiratory activity is typically
observed in caudal branches. Heavy arrow indicates site of
stimulation and recording of activity from TA and IO
motor axons described by Fregosi et al. 1992 (see Fig. 2).

abdominal motoneurons in the spinal cord really is

dierent in cats and rats.
In many studies of thoracic expiratory motoneurons, there is an implicit assumption that they are
intercostal motoneurons. Although expiratory (abdominal) activity is preferentially suppressed in
anesthetized preparations (Merrill, 1974), this
assumption may be invalid if both abdominal and
internal (typically, but not always, expiratory) intercostal motoneurons are suppressed similarly by
anesthetics. Experimental conditions which enhance
expiratory activity (higher levels of respiratory drive
and lung volumes are common interventions in studies of respiratory control) may elicit increased activity in both pools of motoneurons. However,
because the relative sensitivities of abdominal and
expiratory intercostal (including TS) motoneuronal
pools to anesthetic agents, changes in lung volume,
and respiratory drive (hypoxia or hypercapnia) are

Fig. 2. Response of IO and TA of a spontaneously breathing, chloralose-anesthetized cat to positive end-expiratory

pressure (PEEP) and electrical stimulation of the transverse
(caudal) branch of L1 (arrow in Fig. 1). PEEP elicited activity of TA and IO, verifying intact innervation of the
muscles. Low intensity stimulation (2.5 to 3 times the
motor threshold for TA) always elicited tonic activity in
TA and usually IO but not EO and RA (not shown), indicating that the site of stimulation (arrow in Fig. 1) includes
axons innervating TA and, to a lesser degree, IO but not
EO and RA. Modied with permission from Fregosi et al.
1992.

438

S. Iscoe

unknown, one cannot assume that expiratory intercostal, but not abdominal, motoneurons are activated.
For
example,
internal
(expiratory)
intercostals and abdominal muscles may be
``uncoupled'' during particular behaviors (e.g.
vomiting; Iscoe and Grelot, 1992). Finally, identication of motoneurons as ``intercostal'' is often
based on their antidromic activation following
stimulation of the internal intercostal nerve. But if
the nerve is stimulated central to the origin of
branches to the abdominal muscles, both abdominal
and internal intercostal motoneurons will be activated. Similar arguments apply to neuroanatomical
studies of labeling in the thoracic ventral horns
(Feldman et al., 1985), electrophysiological studies
of the connections between medullary expiratory
neurons and internal intercostal motoneurons using
cross-correlation (XCOR) (Cohen et al., 1985;
Merrill and Lipski, 1987) (see Section 3.3.1), spiketriggered averaging (STA) of membrane potentials
or extracellular eld potentials (Merrill and Lipski,
1987; Kirkwood, 1995) (see Section 3.3.1), and antidromic activation of medullary pre-motor neurons
by spinal cord stimulation (Merrill and Lipski,
1987).
2.3. Location of Motoneurons
Abdominal motoneurons innervating dierent
muscles are located in specic regions of the ventral
horn with varying degrees of overlap. In cat, RA
motoneurons occur centrally, EO motoneurons ventrolateral to them (Rikard-Bell et al., 1985a; Tani et
al., 1994), overlapping IO motoneurons which
extend to the lateral edge of the horn (Tani et al.,
1994). Holstege et al. (1987b) reported RA motoneurons as being more lateral in the rostral thoracic
cord, assuming a medial position by T8; TA motoneurons are located in the lateral part of the ventral
horn. Miller (1987) also observed RA motoneurons
in the central part, the motoneurons of the other abdominal muscles overlapping in the ventrolateral
horns of T6 to L3, a result similar to that of RikardBell et al. (1985a). The results of Holstege and his
colleagues (1987b) suggest that internal intercostal
motoneurons do not overlap with those of IO, the
former extending to T10, the latter starting at T11.
Motoneurons innervating EO occupy the same segments as those innervating expiratory internal intercostals but are located more medially in the ventral
horn.
The locations of expiratory motoneurons in rat
are similar. EO motoneurons occupy a similar location to those of cat (Smith and Hollyday, 1983),
expiratory (internal intercostal and EO) motoneurons of T67 occupying the medial and the ventrolateral part of the ventral horn (Saji and Miura, 1990).
In monkey, abdominal motoneurons are distributed like those in cat; retrogradely labeled RA and
EO motoneurons are found as far rostrally as T23,
TA and IO to T67, all extending caudally to about
L3 (Schriever and Jurgens, 1989). However, the distributions of motoneurons within dierent spinal
segments are, except for RA, variable; most TA
motoneurons occur between T12 and L2 with a secondary peak between T79, the numbers of IO moto-

neurons increase gradually from T7, peaking

between T13L2; EO peaks at L12, T10, and T68.
This variation, similar to that found in the results of
Miller (1987) and Holstege et al. (1987b), does not
appear to be an artifact due to uneven distribution
of intramuscularly injected HRP. Motoneurons of
all four muscles are distributed in the ventral horn
of the appropriate segments with a tendency for RA
to be central, IO and EO lateral, and TA more
evenly distributed. However, in the most caudal
thoracic segments, many motoneurons are located
in the lateral part of the ventral horn, a region also
containing internal intercostal motoneurons.
Locations of motoneurons, including those innervating the respiratory muscles, in the cat are summarized by Holstege (1996). Given the overlap
between many motoneuronal pools, identication of
a motoneuron as innervating a particular muscle on
the basis of its coordinates, stereotaxic or histologic,
is unjustied.
2.4. Morphometry
Miller (1987) briey described abdominal motoneurons as having somal diameters ranging between
12 and 41 mm with an average diameter of 025 mm.
Additional details, such as information about any
dierences between motoneurons based on either
the muscle it innervated or the segment in which it
was located, are unavailable. Information about the
morphometry of thoracic expiratory motoneurons is
limited to one study of four HRP-injected rostral
(T4) expiratory motoneurons in cat antidromically
activated by stimulation of the internal intercostal
nerve just distal to its branching from the external
intercostal nerve (Lipski and Martin-Body, 1987).
Therefore, they could be either internal intercostal,
RA, or TS motoneurons. The somata were oriented
longitudinally, with diameters of 068 and 45 mm in
the sagittal and transverse planes, respectively. They
had extensive dendritic arbors, primarily along the
medial and lateral borders of the ventral horn.
Because only four motoneurons were reconstructed,
it is impossible to generalize from this sample about
the properties of expiratory motoneurons, not just
because their projections were not identied but also
because motoneurons in dierent segments may not
have the same morphometry even if they innervate
the same muscle. Although the locations of motoneuronal somata may be related to the arrangement
of the respective muscles (Tani et al., 1994), the
extent of dendritic arborizations and distributions of
synaptic inputs may be more important to motoneuronal, and hence motor unit, function than the
location of the soma.

3. PREMOTOR NEURONS
3.1. Background
Of recent reviews of respiratory control and
rhythmogenesis (Euler, 1986; Feldman, 1986; Ezure,
1990; Monteau and Hilaire, 1991; Berger and
Bellingham, 1995; Dick et al., 1995; Bianchi et al.,
1995; Ramirez and Richter, 1996; Bianchi and

Control of Abdominal Muscles

Pasaro, 1997; Harper, 1997; Denavit-Saubie and

Foutz, 1997; Rekling and Feldman, 1998), Long
and Dun (1986) provide the most detailed review
of E neurons of the caudal ventral respiratory group
(cVRG) and the reader is referred to it for most material more than a decade old. They concluded,
based on the evidence then available, all of it from
cats, that: (1) expiratory bulbospinal (EBS) neurons of the cVRG usually start ring after post-I
(also called early expiratory) cells stop discharging,
indicating the presence of inhibitory post-synaptic
potentials (IPSPs) during the initial part of expiration when residual inspiratory (phrenic) activity is
present (stage 1 expiration); (2) they have augmenting (AUG) discharge patterns due to excitatory
post-synaptic potentials (EPSPs) and not decreasing
inhibitory inputs (i.e. disinhibition); (3) during early
I, they are maximally hyperpolarized by IPSPs, the
intensity of which diminishes during I; (4) they have
little or no synaptic interactions with neighboring
neurons based on the absence of peaks or troughs in
the XCOR between them; (5) they receive inhibitory
medullary inputs from early I neurons of the rostral
nucleus retroambigualis (rNRA, part of the VRG)
(with uncertainty about the dominance of ipsi- versus contralateral projections), post-I neurons of the
contralateral rNRA (although tracers indicate a
stronger ipsilateral projection than that indicated by
antidromic mapping), late I neurons of the rNRA,
and perhaps late I neurons of the ventrolateral
nucleus tractus solitarius (vlNTS). The axonal
arborizations of the latter two populations, however, are not very extensive in the cVRG and
Merrill (1979), on the basis of prolonged XCOR of
the activities of late I and cVRG E-BS neurons (taking advantage of the slight temporal overlap of their
discharges), concluded that the connections are
either non-existent or too weak to be revealed by
this technique; (6) they are driven by inputs from
late E neurons of the ipsi- and contralateral retrofacial nucleus (also called the Botzinger (BotC) complex or nucleus), despite the absence of supporting
evidence from XCOR between the two neuronal
populations; (7) they may receive inputs from other
brainstem areas such as the pons (nuclei parabrachialis medialis (NPBM) and lateralis (NPBL),
Kolliker-Fuse (KF), and locus coeruleus) and
medulla (paragigantocellularis dorsalis and lateralis,
reticularis pontis oralis, and reticular formation
between NTS and nucleus ambiguus (NA); in many
studies, however, the identities of the neurons (e.g.
whether or not they are respiratory) are unknown or
the connections are rare and/or weak; (8) they
receive indirect inputs from pulmonary slowly
(SAR) and rapidly (RAR) adapting receptors;
inputs from the peripheral chemoreceptors elicit
diverse responses in dierent cVRG E neurons
whereas central chemoreceptor activation (hypercapnia) uniformly excites all E neurons; they may be
less responsive than I neurons to changes in chemical drive; and (9) they project almost exclusively to
the contralateral thoracic and upper lumbar spinal
cord with no collaterals at the cervical level despite
the presence of anterograde label in the cervical and
upper thoracic cord (Feldman et al., 1985). Since

439

that review, new data (described below) have

appeared.
3.2. Discharge Patterns and Spinal Projections
The cat was the preferred experimental model at
the time of Long and Dun's 1986 review and most
work since then conrms that, in this species, E-BS
neurons of the cVRG have AUG discharge patterns
in which the neurons start to re at variable intervals after the start of the E phase, reaching a peak
in late expiration (Cohen et al., 1985; Miller et al.,
1985; Ballantyne and Richter, 1986; Miller et al.,
1987; Arita et al., 1987; Jodkowski and Berger,
1988; Ballantyne et al., 1988; Hernandez et al., 1989;
Anders et al., 1991; Takeda and Haji, 1991;
Feldman et al., 1992; Klages et al., 1993; Richter et
al., 1993; Oku et al., 1994; Sasaki et al., 1994; Lalley
et al., 1994; Kirkwood, 1995). This is particularly
true of cVRG neurons with conrmed projections to
the lumbar cord as established by antidromic activation (Miller et al., 1985; Jodkowski and Berger,
1988; Ballantyne et al., 1988; Hernandez et al., 1989;
Feldman et al., 1992). Indeed, Richter (personal
communication) states that this discharge pattern is
so characteristic of cVRG E-BS neurons that he and
his colleagues discontinued testing for axonal projections.
The rat has become a more popular experimental
model but the presence of the equivalent population
has not been fully established. Neurons are present
in the appropriate location (Saether et al., 1987;
Ezure et al., 1988; Zheng et al., 1991, 1992b) with
the anticipated discharge patterns (Schwarzacher et
al., 1991; Zheng et al., 1991) or membrane potential
trajectories (Zheng et al., 1991, 1992b) but either the
axonal projections were not tested (Ezure et al.,
1988), the discharge patterns of the E-BS neurons
not determined (Saether et al., 1987), or they did
not have the expected spinal projections (Zheng et
al., 1991, 1992b). Schwarzacher et al. (1991)
recorded extracellularly from E-AUG discharge patterns rostral to the obex and with axons in the
spinal cord but all E neurons from which they later
recorded intracellularly at the same level had DEC
discharge patterns. Since intracellular recordings are
more successful from large cells, smaller neurons
with dierent discharge patterns may have dierent
projections (and functions), but insucient data are
available to conrm or refute this hypothesis.
E-AUG neurons are found in the brainstemspinal cord preparation of the neonatal rat but represent only 2% of all respiratory neurons (Smith et
al., 1990b). Discharge patterns may, however, reect
conditions specic to this in vitro preparation. Paton
(1996a) has shown that perfusion of the heart-brainstem preparation of the mouse results in a normal
AUG discharge pattern of the phrenic nerve, unlike
the DEC pattern typically observed in the superfused brainstem-spinal cord preparation of the neonatal rat. However, the discharge pattern in the
mouse can be converted from AUG to DEC by a
low perfusion pressure (Paton, 1996a) or hypoxia
(Paton, 1996b). If hypoperfusion results in a low tissue Po2, as occurs more than 300 mm from the surface in the superfused neonatal rat brainstem

440

S. Iscoe

(Okada et al., 1993a), the discharge patterns may be

abnormal. The situation is complicated by the presence or absence of pulmonary (SAR) feedback
which has marked eects on respiratory activity in
neonatal rats (Fedorko et al., 1988) and the degree
of maturation of the animal since discharge patterns
display developmental changes (Paton and Richter,
1995).
In the working heart-brainstem preparation of the
mouse, (late) expiratory neurons with AUG discharge patterns are relatively common (16 of 96
neurons from which extracellular recordings were
made; Paton, 1996b) but their projections down the
spinal cord were not tested. Paton (personal communication) indicates that these expiratory neurons,
which are seldom if ever reported in the brainstemspinal cord preparation of the neonatal rat, were
recorded from the cVRG.
In dog, E-BS neurons are slightly more caudal
(about 1 mm) and about 0.5 mm more lateral, relative to the obex, than those in the cat (Zuperku and
Hopp, 1987; Bajic et al., 1992). Almost all recorded
neurons are bulbospinal; most have a discharge pattern in which peak frequency is reached before midexpiration, then either plateau or decline, usually
stopping before the onset of the next inspiration
- ogas et al., 1995).
(Bajic et al., 1992, 1994; D
However, neurons with AUG discharge patterns are
also present; these start ring during expiration,
reach their peak discharge frequencies before midexpiration, and then maintain their ring at this
level until the onset of the next inspiration. It is
unclear if this pattern is due to a dierence in sensitivity to SAR input (Tonkovic-Capin et al., 1992;
see below). I refer to these neurons as plateau neurons to distinguish them from `traditional' AUG
neurons which reach peak discharge frequencies at
the end of the discharge phase; Ezure (1990) refers
to them as CON (constant) neurons. However, the
plateau discharge pattern does not seem to be due
to the experimental preparation (paralyzed and ventilated) since E neurons with similar discharge patterns have been recorded in spontaneously breathing
dog (Adams et al., 1987); although their projections
were not determined, because many were caudal to
the obex, they were likely bulbospinal.
The DEC pattern of some E neurons corresponds
to that of the integrated discharge of L1 reported by
Fregosi et al. (1987) and Fregosi and Bartlett (1988)
using a ``standard'' preparation, the decerebrate,
paralyzed and ventilated cat with bilateral vagotomy
and pneumothorax. This pattern is also observed in
spontaneously breathing pentobarbital-anesthetized
dogs with intact vagi (Van Lunteren et al., 1988b).
It diers, however, from the AUG-plateau pattern
of L1 or the integrated EMGs of IO or TA in
chloralose- and pentobarbital-anesthetized, spontaneously breathing dogs (Ledlie et al., 1983; Farkas
and De Troyer, 1989; Farkas and Schroeder, 1990;
Schroeder et al., 1991), of L1 activity in decerebrate
servo-ventilated cats (Fregosi et al., 1990), of EO
motor units in spontaneously breathing anesthetized
cats (Mateika et al., 1996), and the AUG pattern in
lightly anesthetized dogs (Estenne et al., 1990a) and
conscious ponies (Brice et al., 1991), all with intact
vagi. Caution should, however, be used in evaluat-

ing these discharge patterns because they often

exhibit considerable inter-breath variations. For
example, the discharge pattern of TA varied breathby-breath between plateau and DEC in pentobarbital-anesthetized spontaneously breathing dogs with
intact vagi (Van Lunteren et al., 1988a); in one dog,
TA discharged only for the rst 15% of expiration,
an extreme example of a DEC discharge pattern. In
another paper from the same group, using the same
preparation, the plateau discharge pattern of TA
during eupnea converted to a DEC pattern during
CO2 rebreathing (Arnold et al., 1988). Motor axons
to TA and IO in decerebrate, paralyzed, ventilated
and vagotomized cats typically have DEC discharge
patterns (Fig. 3; Fregosi et al., 1992) but AUG discharge patterns are present in decerebrate, paralyzed
and ventilated cats with intact vagi (e.g. Oku et al.,
1994; see Fig. 12). The reasons for these dierences
may be related not just to the presence or absence of
SAR feedback but to such other experimental conditions as levels of respiratory drive, anesthetic (if
any) level, posture, feedback from the lung (including the upper airway) and chest wall, and the actual
site of recording because the abdominal muscles and
the other expiratory muscles of the rib cage (TS,
rostral, mid-thoracic, and caudal internal intercostals) constitute a heterogeneous group with dierent
mechanical actions requiring dierent discharge pat-

Fig. 3. Eect of hypercapnia on discharge of an abdominal

(TA or IO) motoneuron in a decerebrate, vagotomized,
and ventilated cat. Traces from top down: integrated phrenic activity (fPhr), activity of whole L1, and activity of an
abdominal motor axon from contralateral L1. Hypercapnia
increased the peak discharge frequency at the onset of the
discharge phase. Note decrementing discharge pattern in
this vagotomized preparation, compared with the augmenting pattern characteristic of preparations with intact vagi
(Fig. 12). Reproduced with permission from Fregosi et al.
1992.

Control of Abdominal Muscles

terns. Variations in the relative strengths of IPSPs

and EPSPs under dierent experimental conditions
likely contribute to the dierent discharge patterns
(e.g. AUG versus DEC) of E-BS neurons
(Ballantyne and Richter, 1986) and motoneurons
reported by various investigators. The reasons for
the diverse discharge patterns displayed by ostensibly similar preparations are unknown.
The organization of the respiratory centers in rabbit appears similar to that of cat (Jiang and Shen,
1991); all three cVRG E neurons with AUG discharge patterns had axons in the spinal cord but the
small sample size precludes generalizations about
the projections and laterality of their axons. E-AUG
neurons in the rVRG also project to the spinal cord
but these may belong to the population of BotC EAUG neurons which inhibit phrenic motoneurons
(Merrill and Fedorko, 1984). In an earlier study by
Schmid et al. (1985), six of 43 E neurons had their
axons in the spinal cord but the locations of their
somata were not provided.
One study is available on respiratory neurons of
the cVRG in adult guinea pig (Richerson and
Getting, 1992). The organization is similar to that in
the cat. However, recordings were made between 0
and 2.5 mm rostral to the obex, corresponding to
the intermediate VRG (iVRG) which, as in cat, contains I and E neurons. Thus, denitive studies on EBS neurons in the cVRG are still needed.
The piglet (Lawson et al., 1989b) possesses respiratory neurons with discharge patterns identical to
those in the cat but the E-AUG neurons were not
apparently tested for projections to the spinal cord.
Later studies from the same laboratory (CzyzykKrzeska and Lawson, 1991; Lawson et al., 1991)
veried that most of these were bulbospinal, having
ramp depolarizations starting immediately upon cessation of the phrenic burst.
3.3. Inputs to CVRG (E Neurons)
The neurons driving cVRG E-BS neurons are still
not identied. Comparisons of the discharge patterns of dierent neuronal populations indicate
possible candidates. For example, Merrill (1974)
suggested that the early-burst I neurons inhibit E
neurons, silencing the latter at the end of the E
phase. Cohen et al. (1985) suggested that early E
neurons of the nucleus of the solitary tract (NTS)
(Feldman and Cohen, 1978) with DEC discharge
patterns inhibit E neurons of the cVRG with AUG
discharge patterns (see Section 7.5). Many reviews
(e.g. Cohen, 1979; Euler, 1986; Richter et al., 1986;
Orem and Trotter, 1994; Dun et al., 1995; Bianchi
et al., 1995; Bianchi and Pasaro, 1997) provide pictorial representations of either the discharge patterns or membrane potential trajectories of dierent
neuronal populations.
3.3.1. Electrophysiological Studies
More direct evidence of the presence and properties of connections between putative pre-motor
neurons and abdominal motoneurons is obtained
using XCOR, STA, and antidromic stimulation/
mapping. XCOR uses extracellularly recorded ac-

441

tivities whereas STA uses the cell's membrane potential or, less often, the terminal or focal synaptic
potentials; these techniques, and their limitations,
have been reviewed (Kirkwood, 1979; Berger and
Bellingham, 1995). XCOR describes the probability
of discharge of a neuron B (or pool of neurons) following a trigger (reference) event (e.g. an action potential of neuron A). The presence of signicant
peaks (or troughs) in the XCOR (Sears and Stagg,
1976; Graham and Dun, 1981; Dun and Iscoe,
1996), indicated by the ratio of the peak (or trough)
to the mean bin count away from the region of
interest (the k ratio; Sears and Stagg, 1976), indicates if A and B are connected or share a common
input. A peak (or trough) with a rapid rise- (or fall-)
time and a narrow width indicates a monosynaptic
projection. STA allows one to extract post-synaptic
potentials (PSP) from neuron B following a reference event (e.g., action potential of neuron A) from
the synaptic ``noise'' associated with other, presumably random, events. The strength of the putative
connection is given by the amplitude of the PSP. As
is the case in XCOR, a rapid change in the averaged
potential indicates a monosynaptic projection.
Antidromic mapping involves stimulating discrete
regions in the spinal cord containing a putative projection (stem axon or terminal) to elicit an antidromic spike and then plotting the intensity of
stimulation as a function of space; this provides information about the trajectory of the axon and the
distribution of axonal terminals (e.g. Merrill, 1970;
1974; Merrill and Lipski, 1987; Dun and Lipski,
1987; Hoskin et al., 1988; Jiang and Lipski, 1990;
Kirkwood, 1995).
3.3.1.1. Medulla
Models of respiratory rhythmogenesis (Richter et
al., 1986; Botros and Bruce, 1990; Ogilvie et al.,
1992; Rybak et al., 1997a,b) typically indicate that
respiratory, particularly E, neurons receive tonic excitatory input from the reticular activating system
and chemoreceptors. This is consistent with the
tonic discharge of E neurons during hypocapnic
apnea (see below) but we know much less about
these excitatory inputs compared to the inhibitory
ones to cVRG E-BS neurons (for reviews, see Euler,
1986; Feldman, 1986; Ezure, 1990; Richter et al.,
1992; Dun et al., 1995; Bianchi et al., 1995).
Bianchi et al. (1995), for example, list ve neuronal
populations supplying inhibitory inputs: pre-I, early
I, I-AUG, post-I neurons, and, surprisingly considering the similarity of their discharge patterns, EAUG of the BotC. The models of Rybak et al.
(1997b) show inhibitory synaptic connections but
also indicate a tonic excitatory input from other,
undened, neurons. Ezure (1990) indicates an excitatory connection to the cVRG from I neurons with
plateau discharge patterns in the rVRG (Otake et
al., 1990). Aside from an obvious problemthe
neurons re in opposite phasesSTA between these
neurons and cVRG E-BS neurons reveals only
monosynaptic IPSPs (Ezure et al., 1990). Both EAUG and E-DEC of BotC inhibit cVRG E neurons
but two of 49 cVRG E-BS neurons received monosynaptic EPSPs from BotC E-AUG neurons (Jiang

442

S. Iscoe

and Lipski, 1990). Interestingly, many BotC E-DEC

neurons are excited, but E-AUG neurons suppressed, by lung ination (Manabe and Ezure,
1988), a response relevant to the responses of E-BS
neurons to changes in lung volume (see Section 7).
The putative excitatory projection(s) responsible
for the AUG discharging patterns of cVRG E-BS
neurons have not been discovered despite assertions
to the contrary (Euler, 1983, 1986). The idea that
BotC E-AUG drive cVRG E-BS neurons is based
not just on the similarity of their discharge patterns
but the presence of axonal projections from the former to the ipsilateral and, to a lesser degree, the
contralateral cVRG (Bystrzycka, 1980; Bianchi and
Barillot, 1982; Fedorko and Merrill, 1984; Jiang and
Lipski, 1990). Although BotC E-AUG neurons can
be antidromically activated by shocks to the ipsiand contralateral cVRG (Fedorko and Merrill,
1984), I know of no studies reporting peaks in the
XCOR, consistent with monosynaptic projections
(or common excitation) or EPSPs, between the two
populations; indeed, XCOR between eight pairs of
BotC E and E-BS neurons were all at (Hilaire et
al., 1984). Jiang and Lipski (1990), using STA,
observed 12 IPSPs but only two EPSPs in 58 pairs
of BotC E-AUG and cVRG E-BS neurons. Lindsey
and colleagues (1987) found evidence only of inhibitory interactions between four of 11 pairs of EAUG (and not antidomically activated (NAA) E)
neurons in caudal medulla. Although antidromic
microstimulation and STA indicates that BotC EDEC project to the contralateral VRG, none of the
VRG neurons was bulbospinal (Ezure and Manabe,
1988); monosynaptic IPSPs were, however, obtained
in I-BS, I-NAA, and vagal motoneurons. Moreover,
XCOR between 22 pairs of cVRG E neurons (separation 250 to 350 mm) were all at (Graham and
Dun, 1981); similar results were obtained in a
study of 31 pairs (separation 100 to 1000 mm)
(Merrill, 1978). Both results are consistent with an
absence of shared inputs and, in accord with the
absence of axonal collaterals (Arita et al., 1987), no
or very weak recurrent excitation (Bianchi et al.,
1995), at least over these inter-electrode distances.
Although other workers have reported a high incidence of peaks in the XCOR between neurons
recorded from the same electrode (Feldman et al.,
1980), a result consistent with recurrent excitation
(or shared inputs), XCOR derived from a single
electrode are susceptible to false positives (Graham
and Dun, 1981). While excitatory connections
may have been missed for technical reasons (e.g.
inputs to inactive neurons or small active neurons
from which recordings are dicult), the source(s) of
excitation to E-BS neurons of the cVRG remain
speculative, including those from chemoreceptors
and the reticular activating system. Finally, E-AUG
of BotC of conscious cats do not discharge during
sneeze when abdominal muscles are active (Orem
and Brooks, 1986), suggesting they are not driving
cVRG E-BS neurons. This result is consistent with
other studies by Orem (1988, 1989, 1990, 1994b) indicating that medullary respiratory neurons are subjected to control by neurons not involved in the
control of respiratory timing and amplitude

observed in the typical anesthetized or decerebrate

preparation.
The only known interaction of an identied
cVRG E-BS AUG neuron with another medullary
neurons is an apparent inhibition of two NAA
rVRG E neurons (Lindsey et al., 1987), a result contrary to Merrill's and Ezure's claims that E-BS neurons of the cVRG project only to the spinal cord.
Until, however, the results of Lindsey and colleagues (1987) are substantiated by analysis from
more E-BS neurons, the belief that they project only
to the spinal cord (Merrill, 1974; Ezure, 1990)
should be retained (e.g. for modeling).
Despite the absence of evidence based on XCOR
and STA of projections from other medullary neurons to cVRG E-BS neurons, other evidence, in addition to that provided by antidromic activation
(Fedorko and Merrill, 1984), suggests that BotC
neurons project to E-BS neurons. Unilateral cooling
of BotC (and the para-ambigual region, the DRG,
and the rostral ventrolateral medulla at a site where
cooling causes apnea) can increase both I (phrenic
and external intercostal) and E (abdominal) activity
(Budzinska et al., 1985a); these increases can be
both tonic and phasic, the tonic activity being unaffected by CO2 (Budzinska et al., 1985b). Although
cooling aects both neurons and axons of passage,
these results suggest that various brainstem structures suppress E activity, either by blocking excitatory input or by inhibiting `intrinsically' active
neurons. However, electrical stimulation in a region
of BotC containing E-AUG neurons causes apnea
(bilateral suppression of phrenic and external intercostal activity) and elicits tonic bilateral activity of
abdominal muscles (Bongianni et al., 1988b).
Microinjection of DL-homocysteic acid (DLH), an
excitatory amino acid, elicits the same responses, indicating that the eects are due to activation of
neurons and not axons of passage. Bongianni et al.
(1990) later showed that the same stimuli applied to
the region of BotC containing E-AUG neurons activates cVRG E neurons (not tested for projections to
the spinal cord but their discharge patterns and location are consistent with them being bulbospinal);
single shocks activated E neurons bilaterally, even
during hypocapnic apnea, at latencies of 3.0 to 8.4
ms (similar to the latencies of IPSPs determined by
STA between I neurons of the retrofacial nucleus
(RFN; close to E neurons of BotC) and cVRG EBS neurons (Anders et al., 1991), and many neurons
could follow stimulus frequencies exceeding 40 s1.
Injection of DLH caused inspiratory apnea and
tonic activation of the same neurons; moreover,
injections of DLH more than 0.5 mm from the original injection site were without eect, indicating that
the eect was not due to stimulation of structures
distant from the site of injection (Lipski et al.,
1988). During ctive cough and swallowing induced
by stimulation of the superior laryngeal nerve (SLN)
in decerebrate ventilated cats, abdominal (L1) motor
nerve, cVRG E-BS and BotC E-AUG neurons discharge similarly (Shannon et al., 1997; Grelot and
Bianchi, 1997), indicating excitatory projections
from BotC E-AUG neurons to cVRG E-BS neurons. A recent study by Bongianni et al. (1998) of the
responses of Botzinger E-AUG neurons reveals a

Control of Abdominal Muscles

linear relation between their peak neuronal discharge frequencies and peak integrated EMG activity of EO (Fig. 4). In decerebrate, ventilated cats,
systemic administration of codeine blocks completely the development of fos-like immunoreactivity in
multiple brainstem regions, including the NRA and
RFN, during ctive coughing elicited by stimulation
of the SLN (Gestreau et al., 1997). It would be of
interest to determine the eects of microinjections of
codeine into selected regions, including BotC, on the
activation of E-BS neurons in NRA. Taken
together, these results indicate that, despite the
absence of supporting evidence from XCOR or
STA, some neurons in BotC excite cVRG E-BS
neurons. However, conicting resultssilence of
BotC E-AUG neurons during active expiration in
conscious cats (Orem and Brooks, 1986) and inhibition of BotC E-AUG neurons following single
shocks or short tetani to SLN that evoke excitatory
responses in cVRG E-BS neurons (Bongianni et al.,
1988a)indicate that these connections need more
detailed examination.

443

Dierent responses to stimulation of BotC are

obtained from rabbits. Microinjection of DLH in
the region of BotC containing E-AUG neurons
depresses both phrenic and abdominal motor activity whereas electrical stimulation suppresses phrenic activity but increases abdominal activity, even
when none is present (Bongianni et al., 1997b).
While these latter eects may have been due to
stimulation of axons of passage, the reasons for the
dierent responses of cats and rabbits to injection of
DLH are unknown. Injection of procaine into the
medial RFN, close to BotC, causes apnea and
cVRG E neurons (projections unknown) become
tonically active but at a lower frequency than when
phasically active (Zhang et al., 1991). As the authors
point out, the spread of procaine into a relatively
large area, including ones which, when cooled, result
in apnea in cats (Budzinska et al., 1985a), is consistent with block of central chemoreceptor input to
brainstem respiratory neurons.
In cats (and, presumably other species), vestibular
nerve stimulation elicits a variety of responses, some
excitatory, others inhibitory or mixed, on cVRG
E-BS neurons (Shiba et al., 1996a). Because the
latencies of these responses are typically longer than
those of the abdominal nerves, vestibular inputs to
abdominal motoneurons appear to bypass, at least
in part, medullary premotor neurons. The longer
latencies of the latter may result from vestibular
inputs rst projecting to BotC, many neurons of
which respond to vestibular nerve stimulation
(Nakazawa et al., 1997).
In rabbit, many E neurons, perhaps in cVRG, are
excited by shocks to pontine nuclei (NPBM or locus
coeruleus) at latencies (up to 11.8 ms) suggesting
multisynaptic pathways (Schmid et al., 1985).
Although the results were interpreted in terms of
phase-switching, they may also relate to behavioral
aspects such as vocalization, mediated via the periaqueductal gray (PAG) (see Section 9.2).
Study of the interactions between mid-line (raphe)
respiratory-related neurons in cats indicates few
mono- or paucisynaptic connections to cVRG E
neurons (110 of 2310 pairs; Lindsey et al., 1994), of
which only three included a neuron with a spinal
projection. Only four of 83 pairs involving a cVRG
E-AUG neuron displayed any short-time scale interactions; two had positive time lags, one negative,
and one was centered at time zero. These results are
consistent with cVRG E-BS neurons having few if
any interactions with respiratory (or even non-respiratory) neurons other than those of the BotC.
3.3.2. Upper Airway

Fig. 4. Responses of BotC E-AUG neurons and abdominal

EMG to mechanical stimulation of tracheobronchial tree
in a pentobarbitone-anesthetized cat. (A) Traces from top
down: phrenic neurogram (Phr), instantaneous discharge
frequency of a BotC E-AUG neuron, raw activity of the
BotC E-AUG neuron, and integrated abdominal (probably
EO) EMG activity (fAbd). (B) Relation between fAbd
(expressed as a per cent of maximum fAbd) and peak instantaneous discharge frequency (expressed as a per cent of
maximum) in 12 BotC E-AUG neurons during coughing
(n = 101). Modied with permission from Bongianni et al.
(1998).

As expected from the involvement of abdominal

muscles in vocalization (Section 9.2), aerents from
the upper airway, principally those carried in the
SLN, aect E-BS neurons. Responses, however,
cannot be monosynaptic because SLN aerents project only to the NTS (Lucier et al., 1986; for review,
see Kubin and Davies, 1995). Trains of stimuli to
SLN, at intensities no greater than twice that of a
single shock which elicits a transient reduction in
phrenic activity, suppress phrenic and external intercostal activity but elicit tonic abdominal (IO or

444

S. Iscoe

EO), cVRG E-BS, and BotC E-AUG neuronal activity (Bongianni et al., 1988a). The level of tonic E
activity, whether muscle or neuronal, increases with
PACO2, consistent with disinhibition at the medullary and spinal levels. Single shocks or brief tetani
at low intensity (1.42 times threshold), however,
evoked no responses in E muscles while cVRG E-BS
neurons were either unaected (n = 20), inhibited
(n = 8) or excited (n = 2); all 10 BotC E-AUG
neurons were inhibited. At 36 times threshold, the
E muscles and 18 of 23 cVRG E-BS were excited
(perhaps an expression of the `expiratory reex'; see
Korpas and Tomori, 1979) although the responses
were not elicited in I (possibly because of the pentobarbital anesthesia), but BotC E-AUG neurons were
still inhibited. This last result suggests that SLN
inputs to cVRG E-BS neurons are not mediated by
this population of BotC E-AUG neurons. All responses were unaected by changes in PACO2, indicating that SLN inputs have relatively direct access
to medullary E neurons.
In similar experiments, Jodkowski and Berger
(1988) obtained very dierent results. Electrical
stimulation of the SLN, sucient to suppress phrenic activity, activated internal intercostal activity
while simultaneously reducing or silencing cVRG EBS neurons. Their results are consistent with disinhibition of E neurons and motoneurons during the
SLN-induced apnea (see preceding paragraph)
which would then, especially under the conditions of
slight hypercapnia employed in their study, become
active. This explanation is also consistent with internal intercostal activity decreasing only when
phrenic activity reappeared seconds after termination of SLN stimulation or when brief and small
bursts of phrenic activity occurred during SLN
stimulation. The dierences in responses of E-BS
neurons to electrical stimulation from those reported
by Bongianni et al. (1988a) may be due to dierent
stimulus intensities, since Jodkowski and Berger
used ones which elicited ``maximal inhibition of
phrenic activity.'' During instillation of water into
the larynx (which may have activated additional
upper airway aerents), eight of 56 E-BS neurons
were activated, suggesting that electrical and `natural' activation of SLN aerents are not equivalent.
The receptor properties of the aerents responsible
for these dierent responses are unknown.
Stimulation during E of the SLN in decerebrate
cats suppressed the ring of 12 of 14 cVRG E-BS
neurons at latencies ranging between 4.8 and 7.0 ms
(Oku et al., 1994). These latencies exceeded those of
the suppression of E-AUG neurons (3.8 to 5.0 ms)
elicited by the same stimulation, indicating that
SLN inputs to both neuronal populations are probably indirect. In a survey of the responses of dierent medullary neurons to SLN stimulation, Jiang
and Lipski (1992) observed IPSPs in 13 of 16 E-BS
neurons of the cVRG; the latencies (mean 04.2 ms)
and rise-times and half-widths of the IPSPs indicate
that they are not monosynaptic. However, the mean
latency of IPSPs in E-AUG neurons of BotC was
05.4 ms, indicating that the latter do not mediate
the response of E-BS neurons (i.e. by disfacilitation
or withdrawal of synaptic input). Injection of water
into the larynx of anesthetized cats hyperpolarizes

E-BS neurons and delays their onset of discharge

(Ballantyne and Richter, 1986). Similar results, but
with electrical stimulation, were obtained in piglets
(Czyzyk-Krzeska and Lawson, 1991); their reversal
by Cl or negative current injections indicates the
responses were due to Cl-mediated post-synaptic
inhibition. The much shorter latencies (03 ms) compared to those reported by Oku et al. (1994) and
Jiang and Lipski (1992) could be due to species but
it is nevertheless surprising as the marginally smaller
size of the piglets (47 d, 1.12.6 kg) compared to
adult cats would presumably be oset by lower conduction velocities of the aerents in the former.
3.3.2.1. Nasal aerents
Stimulation of nasal receptors evokes sneeze; electrical stimulation of their aerents in branches (anterior ethmoidal, posterior nasal, and infraorbital)
of the trigeminal nerve also elicits sneezing (see
review by Shannon et al., 1997). These aerents project not to brainstem regions containing respiratory
neurons but to the trigeminal nucleus; electrical
stimulation of its ventromedial region and adjacent
reticular formation evokes sneezes (Nonaka et al.,
1990). In sneezing cats, fos-like immunoreactivity, a
marker of increased cell activity, is distributed not
just to areas to which nasal aerents project but
also to the NTS, cVRG, the pontine NPBM-KF as
well as the lateral part of the parvicellular reticular
formation (Wallois et al., 1995). Electrical stimulation of the anterior ethmoidal and/or posterior
nasal nerve excited 11 of 14 E-BS neurons, probably
in the cVRG (Wallois et al., 1992). Latencies were
less during expiration than inspiration, but excitation in inspiration was possible only in ketamine-,
not pentobarbital-, anesthetized cats, clearly indicating a multisynaptic pathway, in accord with the
latencies (013 and 018 ms in expiration and inspiration (including data from non-BS neurons), respectively). Inhibitory responses had shorter
latencies, mean 6.3 and 7.3 ms for ethmoidal and
posterior nasal, respectively. Developmental aspects
inuence the eectiveness of sneezing; kittens, unlike
adult cats, lack the preparatory inspiratory eort,
and thus generate weaker expiratory eorts (Wallois
et al., 1993). The authors attribute the dierence to
immaturity of the connections to dierent populations of respiratory neurons but the weaker preparatory inspiration could, by reducing the amount
of inhibition of E neurons, also reduce post-inhibitory rebound (depolarization) of E neurons (see
Section 6.2.2).
3.3.2.2. Hypothalamus
Short trains of pulses to the perifornical region of
the hypothalamus evoked EPSPs followed by Clmediated IPSPs in cVRG E and E-BS neurons at
latencies between 412 ms and 835 ms, respectively
(Ballantyne et al., 1988). The amplitudes of the
EPSPs were phase-dependent, being greatest during
I when the neurons were hyperpolarized. It is
unclear if the EPSPs were mono- or polysynaptic.
Because longer trains of stimuli evoked tachypnea,
increases in blood pressure, and pupillary dilation,
the responses may represent a component of the

Control of Abdominal Muscles

`defense reaction' and even contribute to vocalization (Section 9.2).

3.3.3. Neuroanatomical Tracers
Tracers provide information about connections
between neurons. When injected extracellularly into
the cVRG, the cell bodies of neurons projecting to
the cVRG are stained due to transport of the dye
after its uptake by their axon terminals (retrograde
tracing); the sites to which cVRG neurons project
can be identied due to the presence of dye in their
axonal terminals (anterograde tracing). Although
one cannot assume that neurons that have taken up
the tracer necessarily project to the specic neuronal
population of interest (in this case, E-BS neurons),
the results do indicate where to record to conrm
projections; this is necessary because some tracers
(e.g. HRP) can be taken up by damaged axons of
passage, resulting in false positives. Intracellular
injection allows one to trace the cell's axon and any
collaterals. This technique has the advantage that
the cell's function(s) can often be determined from
its discharge pattern and projection site by antidromic stimulation but the process is laborious and
biased to larger cells (somata and, occasionally,
axons) which are easier to penetrate and hold.
Projections from the VRG to abdominal (and
other respiratory) motoneurons develop early, at
least in marsupials. Farber (1985) indicates that abdominal activity is present as early as 30 d in
Didelphis virginiana. In Monodelphis domestica,
which is born 1415 d post-conception, injections of
fast blue into the lumbar and cervical spinal cord
even at this early age retrogradely label neurons in
multiple brainstem sites, including the NRA (Wang
et al., 1992); functional identication of the projecting and receiving neurons is not available, nor have
the muscles used for breathing been identied.
Injection of HRP into the VRG labels neurons in
the pons (locus coeruleus and subcoeruleus, and the
lateral and medial parabrachial and the KF nuclei)
and medullary nuclei (reticularispontis oralis, retrofacial, paragigantocellularis lateralis, and the ventrolateral NTS) (Bystrzycka, 1980) but the size of the
injection site (NA and NRA) makes it impossible to
specify which sites project only to the cVRG.
Similar results were obtained by Takeuchi et al.
(1980) who observed dense labeling in the ipsilateral
parabrachial nuclei (PBN) after injections of HRP
into NA. Injection of wheat germ agglutinin (WGA)
conjugated to HRP (WGA-HRP) into the cVRG
retrogradely and anterogradely labels neurons in
many regions of the brainstem (J.C. Smith et al.,
1989) although electrophysiological mapping indicates that feline cVRG E-AUG neurons project only
to the spinal cord (see Long and Dun, 1986 and
Ezure, 1990 for reviews). In rat, however, one of
seven cVRG E neurons had extensive local axonal
collaterals (Sun et al., 1996) and some E-BS neurons
had medullary axon collaterals (Zheng et al.,
1992a). Therefore, either the cVRG includes other
(inactive) neurons projecting to these dierent
regions or the injected label spread beyond the borders of the cVRG. The former explanation is plausible, but disparate ndings in two cats following

445

injection of the label into ostensibly the same region

suggest caution: in one cat, anterograde labeling was
present in both the ipsi- and contralateral magnocellular tegmental elds and the postpyramidal nucleus
of the raphe whereas in the other cat no labeling
appeared in these regions (Smith et al., 1989b).
Gerrits and Holstege (1996) have recently
reported, also in cat, the sites of uptake of WGAHRP injected into the cVRG (determined from
stereotaxic coordinates and not the presence of E activity). Label is detected in the PAG (bilateral), the
ventrolateral PBN and KF (primarily ipsilateral),
the retrotrapezoid nucleus (RTN) (ipsilateral), ventrolateral to the facial (BotC and pre-BotC), the
peri-ambigual region (bilateral), the lateral tegmental eld (including BotC) and NTS (bilateral), and
two groups in the medial tegmental eld (one at the
level of the facial and another just rostral to the
hypoglossal nuclei) (ipsilateral). Injection of an anterograde tracer, tritiated leucine, conrms these projections but not the nding of Smith et al. (1989b)
of an input from nuclei raphe pallidus and magnus.
Gerrits and Holstege (1996) emphasized the role of
the PAG, critical in vocalization (Section 9.2), as the
most rostral structure with inputs to the VRG, and
that of the two discrete regions of the ventromedial
medullary medial tegmental eld as a possible relay
from rostral limbic structures. Earlier, Holstege
(1989) had interpreted the connections to and from
the cVRG (NRA) determined from retrograde
transport of HRP and anterograde transport of tritiated leucine in terms of the structures involved in
vocalization. Thus, VRG neurons receive input bilaterally from the lateral part of the caudal PAG
from which vocalizations can be elicited by electrical
stimulation (Section 9.2) and in the tegmentum just
lateral to this region. cVRG neurons not only project down the spinal cord, where he noted considerable re-crossing of terminal bers to ipsilateral
motoneurons, but also to neurons innervating
muscles of the upper airway and mouth, all of
which are involved in vocalization. Thus, the extensive projections of cVRG neurons to other regions
in the medulla (J.C. Smith et al., 1989; NunezAbades et al., 1993; Gaytan et al., 1997) make sense
if interpreted in terms of behaviors other than
breathing. However, this means that the cVRG
must contain (pre-motor)neurons dedicated to behavioral rather than just the metabolic aspects of respiration.
More recent studies in rat using tracers like uororuby, diamino yellow, and fast blue conrm the
extensive connections of the cVRG with other brainstem sites (Nunez-Abades et al., 1993; Morillo et al.,
1995; Gaytan et al., 1997); they receive inputs from
rVRG and from BotC (which projects to both
rVRG and cVRG; Morillo et al., 1995), many subdivisions of the NTS, the area postrema, the PBN and
KF, and the nucleus lateral paragigantocellularis
(Nunez-Abades et al., 1993; Morillo et al., 1995).
The cVRG projects bilaterally, in the medulla, to
NA, the periambigual area, the lateral nucleus paragigantoceullularis, and the dorsal part of the lateral
reticular nucleus; in the pons, to the caudal part of
the PBN and KF (Gaytan et al., 1997). One cannot
tell, however, if there is a projection from BotC to

446

S. Iscoe

cVRG. Even though the injected region contains E

neurons, interpretation must still be cautious as the
injected regions undoubtedly contain neurons whose
primary function(s) are non-respiratory.
These studies illustrate some of the diculties
involved in interpreting results using tracers.
Although many sites of retrograde and anterograde
labeling are similar, others are not; it is unclear if
this reects spread of the label, small dierences in
the site of injection (particularly in the absence of
recordings from the desired neurons), or just the
`normal' biological variation between animals. The
problem is accentuated by injections of tracers into
larger regions containing dierent neuronal populations. For example, injections of HRP into both
the NA and NRA (Bystrzycka, 1980) cause extensive labeling of cells in contralateral vlNTS and in
bilateral RFN and nucleus paragigantocellularis
lateralis, and the pons (locus coeruleus, PBN, and
KF). Given the diverse neuronal populations in the
VRG (e.g. cranial motoneurons and spinal premotor neurons, along with propriobulbar neurons),
interpretation is dicult. This point is made particularly well by Yajima and Larson (1993); many neurons around NA in awake vocalizing monkeys
discharge only in association with vocalization or
swallowing or respiration. Disparities between electrophysiological and neuroanatomical results
emphasize the importance of a conservative interpretation of the results of experiments using tracers until conrmatory electrophysiological data are
available.
In cat, injection of HRP into NA also labels the
pontine regions described above as well as neurons
in the mid-brain (central gray, reticular formation,
deep tectum and red nucleus) and diencephalon (lateral and peri- and paraventricular hypothalamic)
(Rose, 1981). Since many of these latter regions
include estrogen-containing neurons, Rose postulated that these neurons may be involved in the
vocalization associated with estrous behaviors
(Section 9.2).
In rat, intracellular labeling of BotC E neurons
reveals three major synaptic targets (based on boutons): near the cell bodies, neurons of rVRG, and
neurons of cVRG (Bryant et al., 1993). These results
agree with those in cat using antidromic stimulation
(Bianchi and Barillot, 1982; Fedorko and Merrill,
1984) and STA (Jiang and Lipski, 1990); however,
no neuroanatomical data (axonal terminals or boutons) in cat yet conrm the electrophysiological evidence because eorts to trace the axons as far as the
cVRG have either been unsuccessful (Otake et al.,
1987) or restricted to more rostral portions of the
VRG (Ezure and Manabe, 1988; Otake et al., 1988).
These anatomical and electrophysiological results
raise an important question: why do cVRG E-BS
neurons re? Even if their AUG discharge results
from gradually increasing disinhibition during E
(Ballantyne and Richter, 1986), this does not answer
the question. They must receive excitatory inputs
because transverse lesions just rostral to the border
of the cVRG, at about the level of the obex, abolish
their activity (Merrill, 1979). The source could be
supra-medullary because Kalia (1981) reported
labeling of neurons in the ipsilateral NPBM and KF

nuclei following HRP injections into a region of the

cVRG containing E neurons; additional details
beyond those presented in her review are unavailable. Electrical stimulation of the NPBM in anesthetized rabbits excites or inhibits E neurons (Schmid
et al., 1985) but one cannot determine, from the information provided, the responses of cVRG E-BS
neurons. However, E-BS neurons of decerebrate
cats made apneustic by bilateral cold block of the
pneumotaxic region continue to discharge rhythmically, albeit with an altered discharge pattern (St.
John and Bianchi, 1983); thus, input from the
NPBM and KF is not mandatory. Moreover, Speck
and Beck (1989) reported that bilateral lesions
restricted to the rVRG abolish cVRG E activity.
Thus, either neurons of the rVRG excite cVRG E
neurons or inputs from some other source (e.g. chemoreceptors) pass through the rVRG, with or without synapsing on intermediary neurons. This last
result, however, indicates that cVRG E neurons cannot be intrinsically chemosensitive; otherwise, their
discharge would have persisted. However, the longer
dendrites of some feline cVRG E-BS neurons extend
towards the ventral surface of the medulla (Arita et
al., 1987), where they could sense changes in the
chemical environment. Pilowsky et al. (1990) (rat)
and Grelot et al. (1988) (cat) report that some respiratory neurons in the rVRG also have dendrites
within 100200 mm of the ventral surface of the
medulla. However, proximity to the central surface
may not be a prerequisite for chemosensitivity. King
(1980a, b) has described respiratory neurons
arranged in sheets corresponding to the locations of
blood vessels in the brainstem and Pilowsky et al.
(1990) indicate that some neurons have dendritic
arbors close to blood vessels. The functional consequences of such arrangements, however, remain to
be established.
In summary, although neuroanatomical (labeling)
evidence indicates diverse sources of input to cVRG,
electrophysiological evidence is less compelling, perhaps because these inputs are related to non-respiratory behaviors.
3.4. Axonal Projections
In cat (Merrill, 1970) and rat (Saether et al.,
1987), axons of cVRG E neurons cross the medulla
at approximately the level of their cell bodies (see
Monteau and Hilaire, 1991 for review) between C1
and the obex (Nakayama and von Baumgarten,
1964; Merrill, 1974; Miller et al., 1987, 1989; Arita
et al., 1987) and descend in the ventral column of
the lateral spinal cord (Nakayama and von
Baumgarten, 1964; Merrill, 1970, 1974; Richter et
al., 1975; Merrill and Lipski, 1987; Jiang and
Lipski, 1990; Kirkwood, 1995); spinal projections of
cVRG E neurons in rat appear to be rare (only 5/
139, Saether et al., 1987; 0/10 for E-AUG, Zheng et
al., 1992b).
cVRG E neurons are, compared to other medullary respiratory neurons, unusual in that they do
not have collaterals to other respiratory neurons in
the medulla (Merrill, 1974; Arita et al., 1987) and
are thus `pure' pre-motor neurons to internal intercostal and abdominal motoneurons. Even slightly

Control of Abdominal Muscles

more rostral (obex 2 1 mm) E-BS AUG neurons

rarely interact with other neurons. For example,
Lindsey et al. (1989), using XCOR, obtained evidence for synaptic interactions in only ve of 63 EAUG ipsilateral pairs and 1/13 ipsilateral trios. Of
the former, only two of 10 neurons were bulbospinal; of the latter, none of the neurons displaying
concurrent inhibitory interactions was bulbospinal
(two did not have axons in the spinal cord or vagus
and one was not tested). An earlier study (Lindsey
et al., 1987) of VRG E-AUG neurons yielded similar results. Antidromic activation of cVRG E-BS
neurons has no eect on rVRG I neurons, indicating
the absence of axon collaterals to the latter. That
cVRG E-BS neurons have no role in respiratory
rhythmogenesis is substantiated by the negligible
eects of transverse sections of the medulla just rostral to them; the discharge patterns of I neurons
above the lesion are unaected (Merrill, 1979) while
transections of the medulla 2 mm caudal to or at the
level of the obex have almost no eect on the respiratory-related discharge of the facial or mylohyoid
nerves (Huang and St. John, 1988). Finally, injection of local anesthetic into the cVRG has no eect
on respiratory rhythmicity (Zhang et al., 1991).
Thus, axons of cVRG E-BS neurons appear to be
restricted to the spinal cord.
Merrill (1970) tested for projections of E neurons
of the caudal NRA; the vast majority (81 of 83) had
descending projections only to the contralateral
spinal cord as determined by antidromic activation
at C3, ndings later conrmed (Merrill, 1974;
Merrill and Lipski, 1987). In cats, injections of HRP
into the lumbar spinal cord label cVRG neurons bilaterally (Miller et al., 1989); mid-sagittal lesions
between C1 and obex prevent labeling of contralateral cVRG neurons but no mention is made of
HRP-labeled neurons ipsilateral to the site of injection. Because the injected HRP did not spread to
the other side of the cord, labeling of brainstem
neurons ipsilateral to the injection site was due to
pickup of the HRP by descending axons with terminals recrossing the spinal cord (Holstege, 1989;
Kirkwood, 1995). Thus, identication of an E neuron as bulbospinal and contralateral based on the
presence of its axon in the cervical or upper thoracic
spinal cord (e.g. Merrill, 1970; Bianchi, 1971;
Merrill, 1974; Arita et al., 1987; Zheng et al., 1992b)
does not necessarily mean that its axon terminals
are restricted to the contralateral side.
In contrast to the results of Merrill (preceding
paragraph), none of the 10 cVRG E-AUG (based
on the trajectory of the membrane depolarization)
neurons in decerebrate rats studied by Zheng et al.
(1992b) was bulbospinal, a nding they attributed to
the failure of the antidromic action potential to
invade a non-spiking soma (28 of 37 neurons were
not spiking at the time of penetration); however,
one of the E-all neurons with an axon in the spinal
cord was inactive. Thus, the failure to detect spinal
cord projections of E-AUG neurons likely represents a ``false negative'' (see Ezure, 1990).
Dierences in the type of neurons recorded by extracellular and intracellular microelectrodes may
explain the discrepancy between these results and
those of Merrill (1970, 1974). The combination of

447

extracellular recording and barbiturate anesthesia

would restrict recordings to active E-BS neurons; in
contrast, inactive (presumably larger) E-AUG neurons with non-bulbospinal (propriobulbar?) projections
would
be
missed
when
recording
extracellularly but preferentially recorded intracellularly. No data, however, indicate if soma size and
function (projection) are related.
Although the axons of E-BS neurons form a relatively discrete bundle in the ventrolateral quadrant
of C3, the axons disperse by T1; Merrill (1974), and
later Merrill and Lipski (1987), noted extensive axonal arborizations of a given axon, often extending
over as many thoracic segments as were exposed.
Similar results have recently been reported for axonal projections in the lumbar and sacral spinal cord
of cat (Sasaki et al., 1994). In many studies, the site
of antidromic stimulation (often C3) makes it
impossible to determine the precise target(s) of the
bulbospinal neurons: motoneurons of dierent
abdominal muscles, TS, and internal intercostals, or
some combination. In the absence of identication
of either the motoneurons (by antidromic activation
from a particular motor nerve) or recordings from
motor nerves to identied muscles, one cannot
assume that these projections are distributed uniformly to all motoneurons in a given segment(s).
Indeed, during ctive vomiting (Miller et al., 1987),
some VRG E-BS neurons discharge during the interval between simultaneous bursts of abdominal and
phrenic activity, when some internal intercostals are
active (Iscoe and Grelot, 1992); thus, at least during
this particular behavior, the discharges of motoneurons with ostensibly similar roles can be uncoupled.
Such uncoupling could also result from activation of
dierent medullary pre-motor neurons.
Ezure (1990) concluded that E-BS neurons of the
cVRG act only as pre-motor neurons to E motoneurons; the axonal morphology of cVRG E (probably bulbospinal) neurons conrms this assessment
because none of the seven stained neurons had
medullary axon collaterals (Arita et al., 1987).
However, Bongianni and colleagues (1994) observed
that microinjections of DLH into the cVRG of cat,
at sites containing E-AUG activity, activated contralateral E-AUG neurons and abdominal nerve activities while simultaneously suppressing medullary
(rVRG I) and phrenic nerve activity. They argued
that these eects on respiratory timing were
mediated by axon collaterals of cVRG E neurons
rather than, as they acknowledge, other neurons.
Anterograde tracing indicates projections of cVRG
neurons to other brainstem sites (J.C. Smith et al.,
1989) despite the absence, in cat, of medullary axon
collaterals (Merrill, 1974; Arita et al., 1987).
Because interpretation of the morphology and functions of cVRG are biased by recordings from spontaneously active cVRG neurons, these ndings
(projections to other brainstem sites, eects on respiratory pattern) may result from activation of
quiescent E neurons with dierent properties or
from other neuronal types within the cVRG. As
Bongianni et al. (1994) point out, injection of DLH
activates all neurons, including those recruited only
during forceful contractions of the abdominal
muscles or speech. Such recruited neurons may have

448

S. Iscoe

properties dierent from those used in `normal' respiration.

Recently, Shiba et al. (1997b) reported that EDEC or plateau neurons of the cVRG both project
to the contralateral NA and receive inputs from the
PAG; furthermore, electrical stimulation of the NA
elicits spikes of constant latency in silent cells in the
cVRG (suggesting an antidromic projection).
Stimulation of the PAG also elicits orthodromic
spikes in silent cells in the cVRG. In contrast, stimulation of NA never elicits antidromic spikes in
cVRG bulbospinal E-AUG neurons. Thus, the
cVRG appears to be made up of at least two populations of E neurons: bulbospinal E-AUG neurons
providing drive to expiratory motoneurons and EDEC and plateau neurons involved in vocalization
(see Section 9.2) and, perhaps, other motor activities
requiring co-ordination of muscles of the upper airway with expiratory muscles of the trunk.
Finally, Vanderhorst and Holstege (1995) report
extensive projections of cVRG neurons to the lumbosacral cord in cat; these are probably involved in
lordosis (Section 9.2) which requires activation of
muscles of the hindlimbs and trunk. Consequently,
projections to the cVRG need not be related to respiration.

4. INPUTS TO ABDOMINAL MOTONEURONS

In the lumbar spinal cord, all motoneurons with
respiratory-related discharges are abdominal motoneurons; in the mid- to lower thoracic cord, abdominal
motoneurons
co-exist
with
intercostal
motoneurons, the discharges of which vary as a
function of rostral-caudal location and laterality (Le
Bars and Duron, 1984). Thus, to identify a motoneuron unambiguously, one has to antidromically
activate the motoneuron from a branch of the nerve
at its entrance to an identied muscle.
4.1. Neuroanatomical Studies
Retrograde tracers injected into the ventral horn
of the spinal cord label neurons in the brainstem
and more rostral sites. Such studies cannot prove a
particular functional projection, only that neurons at
site A project to (moto)neurons at site B. Since
injected tracers can spread to regions containing
non-respiratory neurons, nding labeled cells in
regions not associated with E activity is expected.
Moreover, some tracers (e.g. HRP) can be taken up
by injured axons and not just by axonal terminals,
so the presence of labeled neurons does not necessarily prove that these neurons project to the site of
axon terminals. Dierent studies, using dierent tracers, provide evidence for projections by various
neuronal populations to the lumbar spinal cord. All
studies reveal labeled cells in the contralateral
cVRG containing E premotor neurons. Section of
the descending axons by a mid-sagittal lesion
between C1 and the obex prevents uptake of HRP
by neurons in the cVRG (Miller et al., 1989).
Dierent studies, however, also reveal uptake of the
label (typically HRP) by other nuclei.

In cat, Miller et al. (1989) injected HRP into sites

containing abdominal motoneurons in the ventral
horn of L12 and observed labeled cells in the
ventromedial reticular formation (containing premotor neurons to muscles of the back, the motoneurons of which are located in the upper lumbar
cord). The contributions of reticulospinal and vestibulospinal neurons, both involved in postural control, to the control of abdominal motoneurons have,
to my knowledge, been investigated only by Miller,
Yates and their colleagues (Miller et al., 1995b;
Miller and Yates, 1996; Yates and Miller, 1996;
Siniaia and Miller, 1996). In another study (Portillo
et al., 1986), injection of fast blue into the ventrolateral horn of L13 retrogradely labeled cells in the
contralateral cVRG but also, and much more intensely, in the ipsilateral NPBM-KF. Labeled neurons
were also detected in the contralateral NPBM-KF
and NA, and the ipsilateral BotC. The reasons for
the more extensive labeling in this study, compared
to the results reported by Miller et al. (1989), are
unclear but may be related to the dierent tracers or
spread of tracers outside the ventral horn. The labeling in areas other than the cVRG is consistent with
spinal projections, at least to the cervical spinal cord
(Fedorko and Merrill, 1984), of some neurons of
BotC and the role of the NPBM-KF in straining
and possibly vocalization (Section 9.2).
Injection of HRP into T89 at a site containing E
motoneurons retrogradely labels neurons primarily
in the contralateral VRG and, to a lesser degree,
DRG and the ipsilateral PBN (Rikard-Bell et al.,
1985a). The presence of labeled VRG neurons ipsilateral to the injection site can be explained by
crossing over of the terminal axons (see Kirkwood,
1995) and of labeled cells in the DRG by spread of
the injectate into regions containing I motoneurons.
Injections of HRP into C2, T1 and S1 cause much
more labeling in the contralateral than ipsilateral
VRG (Holstege, 1989); nevertheless, many cells in
the contralateral VRG are not labeled, a result consistent with the widespread connections between
neurons in the cVRG and other brainstem regions,
including those in the pons (J.C. Smith et al., 1989),
and the role of these pontine structures in straining
and vocalization (Section 9). HRP injected into the
thoracic spinal cord labels cells in various brainstem
nuclei, most prominently those of the NPBL, KF
and the vestibular nuclei; injections into the lumbar
cord label multiple cell groups in the brainstem,
including the medial reticular formation, raphe, lateral vestibular nucleus, pontine cell groups near the
rubrospinal tract, the locus coeruleus and subcoeruleus (Tohyama et al., 1979). Following HRP injections in the cervical, thoracic and, to a lesser degree,
lumbar cord, labeled cells are found in the medulla
(vestibular nucleus and raphe) and pons (ipsilateral
locus coeruleus and subcoeruleus, the contralateral
ventrolateral pons adjoining the rubrospinal tract,
and contralateral red nucleus) as well as the mesencephalic central gray and dorsal hypothalamus
(Kuypers and Maisky, 1975).
The putative roles of most of these labeled cells
(other than the cVRG) are unknown; some, as indicated above, can be explained, e.g. the labeling of
cells in the vestibular nuclei is consistent with a pos-

Control of Abdominal Muscles

tural role of the abdominal muscles. For others, the

roles(s) still need elucidation, assuming that the
labeling is not due to uptake by, for example,
damaged axons.
In rat, injection of HRP into the thoracic (T56)
spinal cord at the site of the maximum antidromic
eld potential elicited by shocks to the internal
intercostal nerve retrogradely labels cells primarily
in the VRG, with a slight tendency for a stronger
contralateral projection (Saji and Miura, 1990).
4.1.1. Pathways
The pathways subserving abdominal activity have
been studied by lesions in cats. Abdominal activity
associated with cough is markedly reduced or eliminated by lesions immediately ventral to the ventral
horn; they also reduce abdominal activity, either
spontaneous or induced by an expiratory threshold
load (ETL) (Newsom Davis and Plum, 1972).
However, lesions of the ventral cord do not abolish
the abdominal discharge during defecation
(Newsom Davis and Plum, 1972), indicating that a
dierent pathway subserves this function. Amino
and Sears (1971) had earlier demonstrated that the
excitatory response of internal intercostal motor
axons to cortical (sensorimotor cortex) stimulation
persists after lesions of the ventrolateral spinal cord
which abolish spontaneous activity related to respiration. Thus, excitatory input to abdominal motoneurons is mediated by dierent pathways.
Descending spinal pathways have been reviewed by
Holstege and Kuypers (1982).
4.2. Electrophysiological Studies
4.2.1. Expiratory Neurons of the Caudal Ventral
Respiratory Group (CVRG)
Miller and colleagues (1985) tested the projections
of VRG E neurons between the RFN and the rostral border of C1. Only neurons of the cVRG (70 of
121) had projections to the contralateral L1; of
these, only two of 27 tested had, on the basis of
XCOR with contralateral L1 and L2 motor activity,
monosynaptic projections and these were only to
one, not both, segments despite extensive arborizations within the lumbar cord as determined by antidromic stimulation. Fourteen of 41 neurons with
projections to L1 also projected as far caudally as
L45; there was some evidence for a topographical
organization as neurons in the most caudal VRG
had a higher incidence of projections to L45. The
low incidence of monosynaptic projections indicates
either weak connections (and hence dicult to
extract using XCOR) or ones directed to high
threshold motoneurons inactive under the experimental conditions; alternatively, most connections
could be mediated via oligo- or multisynaptic pathways. Almost all cVRG neurons had AUG discharge patterns.
In thoracic spinal cord, monosynaptic connections
between cVRG neurons and E motoneurons are
found but the incidence diers. Cohen et al. (1985)
observed short latency peaks with rapid rise times in
17 of 42 XCOR between cVRG E neurons and activity in the T8 internal intercostal nerve. In con-

449

trast, using STA, Merrill and Lipski (1987) found

evidence for monosynaptic connections in only two
of 57 pairings of cVRG E-BS neurons and T8 E
motoneurons.
Of 30 E-BS neurons tested by Cohen et al. (1985)
against both ipsi- and contralateral T8 nerves, 11
had peaks (6 contralateral, 3 ipsilateral, and 2 bilateral). The presence of ipsilateral peaks suggests
either bilateral axonal arborizations (because the
axons of E-BS neurons decussate in the medulla;
Merrill, 1974; Miller et al., 1987; Arita et al., 1987)
or limited ipsilateral projections (because injection
of an anterograde label into the cVRG results in bilateral labeling in the cervical spinal cord; Feldman
et al., 1985). Moreover, XCOR between the left and
right T8 internal intercostal nerves in four of six cats
revealed a broad (2535 ms) peak centered at time
zero, indicative of synchronized bilateral drive
(Cohen et al., 1985). Davies et al. (1985) have
shown that some I-BS neurons project monosynaptically to motoneurons in multiple segments; comparable data for E-BS neurons are unavailable but EBS neurons, based on the presence of terminal or
focal synaptic potentials, distribute axon terminals
to multiple adjacent segments (T79) (Kirkwood,
1995). Road and Kirkwood, in a preliminary report
(1993), indicate that a given E-BS neuron projects
not only to dierent segments (T8 and L1) but also
to dierent muscles (internal intercostal, TA and
IO).
Fifteen of the 17 neurons with monosynaptic projections studied by Cohen et al. (1985) had ramp, as
opposed to step-ramp, discharge patterns. We do
not know, however, if the discharge pattern (step or
step-ramp) of bulbospinal neurons determines the
discharge patterns of individual motoneurons; such
a result would imply projections to specic (abdominal versus intercostal?) motoneuronal pools. The
step-ramp discharge pattern may be peculiar to animals ventilated with a pump triggered by phrenic activity since such discharge patterns are not found in
other studies (e.g. Bajic et al., 1992; Tonkovic-Capin
et al., 1992; Kirkwood, 1995). Ramp-step neurons
may receive inputs, albeit indirect ones, from SAR
with high dynamic sensitivity or even RAR.
Kirkwood (1995) tested the projections of 27 EBS neurons to contralateral and, occasionally, ipsilateral internal intercostal nerves of T79 of anesthetized cats. Short-latency narrow peaks indicative of
monosynaptic contralateral connections were
obtained in 58% and evidence of some connection
in 89% of all XCOR; monosynaptic connections
were also detected in 29% of XCOR to ipsilateral
nerves, indicating substantial cross-over of terminal
axonal arbors. (Projections also originated from
neurons with discharge properties reminiscent of
pump neurons, or P cells, which re in response to
lung inationSection 7.5.) The incidence of monosynaptic projections to contralateral nerves is similar
to that found by Cohen et al. (1985) but much
greater than that found by Merrill and Lipski
(1987). The reasons for the low incidence obtained
by Merrill and Lipski are not known but could be
related to the site within the segment in which
recordings were made; axonal projections, as determined by STA to detect terminal potentials and

450

S. Iscoe

focal synaptic potentials, are more concentrated in

the rostral part of the segment (Kirkwood, 1995). In
addition, Kirkwood recorded from whole internal
intercostal nerves (including axons to abdominal
muscles). In contrast, Merrill and Lipski (1987)
recorded intracellularly, most (29 of 52) neurons
having small (<1 mV) respiratory-related changes
in membrane potential. Although they describe the
neurons from which they recorded as having ``substantial'' central respiratory drive potentials, they
may have recorded from larger somata which either
receive no direct projections (i.e. connections are
primarily via interneurons; Kirkwood et al., 1988;
Schmid et al., 1993; Kirkwood et al., 1993) or ones
too weak to be revealed by STA even using a minimum of 5000 sweeps. XCOR to spontaneously
active motor axons is biased towards motoneurons
with the lowest thresholds and, possibly, the most
direct connections. As argued by Kirkwood (1995;
and cited references), other (inactive) motoneurons
may depend much more on interneuron-mediated
transmission of descending drive.
Kirkwood (1995) did not distinguish between internal intercostal and abdominal motoneurons. In a
recent preliminary report, he and Road (1995)
found a high incidence of peaks (12 of 15) in the
XCOR between cVRG E-BS neurons and EO
motor nerves (T8). These peaks were characterized
not just by high k values (average 1.170 versus 1.113
for phrenic; Davies et al., 1985) but by fast rise
times and short half-widths, features indicative of
monosynaptic projections. It is unclear if this high
incidence of monosynaptic projections is due to
their recording from a nerve to a specic abdominal
muscle rather than the entire internal intercostal
nerve. We do not know if motoneurons innervating
abdominal muscles receive a more direct projection
from cVRG E-BS premotor neurons than those
innervating intercostal muscles. Another preliminary
report from Road and Kirkwood (1993) describes
not just monosynaptic projections from E-BS neurons to EO motoneurons of T8 and to TA, IO and
EO motoneurons of L1 but also projections of some
E-BS neurons to both intercostal and abdominal
motoneurons. These latter results are consistent
with multi-segmental distribution of bulbospinal
axonal arbors (Merrill, 1974; Merrill and Lipski,
1987; Sasaki et al., 1991, 1994; Kirkwood, 1995)
(Section 4.3).
In rabbit (Jiang and Shen, 1991), the axons of
cVRG E neurons at T1 are in the ventral funiculus,
like those in cat (Newsom Davis and Plum, 1972).
Projections are distributed equally to the ipsi- and
contralateral cord but only 10 cVRG E neurons
were tested; all three AUG and four DEC neurons
and three of four neurons with plateau or tonic discharges had axons in the spinal cord (Jiang and
Shen, 1991). Projections beyond T1 were not studied
so we do not know if dierent discharge patterns
are specic to dierent expiratory muscles. In addition, because recordings were made from cVRG
no more than 1 mm caudal to the obex, many, perhaps most, E-BS neurons would have been missed if
their distribution is similar to that in cat.
The nature (monosynaptic versus paucisynaptic,
perhaps via interneurons) of the projection to the

thoracic (as opposed to lumbar) motoneuronal

pools from the cVRG remains unresolved, in part
because the situation is compounded by the failure
until recently (Kirkwood and Road, 1994, 1995) to
identify motoneurons as abdominal when recording
from proximal internal intercostal
nerves.
Kirkwood, Sears, Davies and colleagues (see
Kirkwood, 1995 for references) have argued, based
on comparisons of the amplitudes of observed
EPSPs and calculations of the number of EPSPs
required to drive motoneurons to threshold and
then re at observed rates, that approximately 90%
of the input to intercostal motoneurons is mediated
via interneurons. This agrees with the low incidence
of monosynaptic projections detected by Merrill and
Lipski (1987) (see above); Sears, Kirkwood, and
their colleagues suggested that interneurons mediate
most of the descending excitatory drive to thoracic
respiratory motoneurons not just because of the
scarcity of monosynaptic EPSPs but because they
observed E-phased discharges close to the motoneurons, which they attributed to interneurons.
Even if they did not identify the motoneurons as internal (expiratory) intercostals or abdominal motoneurons, the low incidence of monosynaptic
projections suggests that direct connections, at least
at the thoracic level, are rare, a conclusion similar to
that of Miller et al. (1985) for abdominal motoneurons and Davies et al. (1985) for inspiratory intercostal motoneurons. The higher incidence of
monosynaptic projections to abdominal motoneurons (Kirkwood, 1995; Kirkwood and Road, 1995),
however, suggests that interneurons mediate less of
the drive to abdominal motoneurons.
4.2.2. Upper Cervical Inspiratory Neurons
Thoracic and presumably lumbar E motoneurons
are inhibited during I (e.g. Sears, 1964c; Merrill,
1974), possibly from local inhibitory interneurons
(Amino and Sears, 1971). The role of upper cervical inspiratory neurons was evaluated by Hoskin et
al. (1988). Most (66 of 70) upper cervical (C1 and
rostral half of C2) I neurons have axonal projections
to T9, but the number of neurons projecting caudally decreases progressively (e.g. of 21 neurons, 13
projected to T12 but only seven to L1 and one to
L3). However, STA revealed no PSPs in any of the
111 E motoneurons in T910. The deep surgical level
of barbiturate anesthesia and the consequent depression of interneuronal activity (Davies et al.,
1985) may have contributed to these results.
In rat, a few (3%) neurons in C38 have axon collaterals extending both to C1 or above and as far
caudally as L23 (Verburgh and Kuypers, 1987). Of
neurons at C58 with a collateral to T2 or below,
13% also have a collateral to C24; of those with a
collateral to T2 or below, 29% also have a collateral
to C1 or above. The function of the branching neurons with projections up and down the spinal cord is
unknown.
4.2.3. Vestibular
As indicated earlier, vestibular nerve stimulation
elicits a variety of responses, excitatory, inhibitory,
and mixed, in the abdominal nerves of decerebrate

Control of Abdominal Muscles

cats (Shiba et al., 1996a). However, these responses

are reduced by only approximately 30% after cutting the axons of cVRG E-BS neurons (sagittal section of the medulla between C1 and the obex),
indicating that vestibular inputs project to abdominal motoneurons, probably via the vestibulo- or reticulospinal tracts, and bypass medullary premotor
neurons (Shiba et al., 1996a). Similarly, after injections of kainic acid into the cVRG, a procedure
which abolishes or reduces expiratory activity in the
abdominal nerves, electrical stimulation of the vestibular nerve still elicits a short latency (018 ms) excitation of contralateral L1 (Umezaki et al., 1997).
4.3. Divergence and Convergence
4.3.1. Expiratory Bulbospinal (E-BS) Neurons
The degree of divergence and convergence to
thoracic E motoneurons of the projections of two
(of 57) E pre-motor neurons with conrmed (STA)
monosynaptic connections was examined by Merrill
and Lipski (1987). A monosynaptic EPSP between a
premotor E-BS neuron and an E motoneuron was
not duplicated when the trigger neuron was shifted
to a neighboring E-BS neuron; in the other case, the
EPSP was not duplicated when the trigger neuron
was retained and the intracellular recording shifted
to two neighboring motoneurons. Moreover, even
when a short-latency peak in the XCOR was
obtained between a premotor neuron and the external (I) intercostal nerve, no evidence for monosynaptic projections was obtained from STA of six I
motoneurons in the same segment. These results, in
pentobarbital-anesthetized cats, indicate limited
divergence of projections despite extensive axonal
arbors. Because barbiturates depress interneuronal
activity, it would be instructive to repeat these experiments in decerebrate animals and test the eects
of anesthetics on neuronal connectivity.
The narrow(est) peaks in XCOR are due to divergence (branching of pre-motor axons to dierent
motoneurons, even if via interneurons) (Carr et al.,
1994). Peaks in XCOR are also due to synchronization of premotor neurons (presynaptic synchronization) but widening of the peaks can be expected due
to even slight dierences in the conduction velocities
of axons of dierent neurons (see Kirkwood, 1995).
But how much divergence, based on XCOR, exists?
Miller et al. (1985) found no evidence for projections to both L1 and L2. In contrast, in the thoracic
spinal cord, Kirkwood (1995) showed that 24 of 38
XCOR between the activities of E-BS neurons and
contralateral internal intercostal nerves (T79)
(based on mean counts r1082) had narrow width
peaks, indicating extensive monosynaptic projections; lower incidences (6 of 19) of narrow peaks in
the ipsilateral XCOR were also observed, indicating
signicant re-crossing of the terminal axonal arbors.
Moreover, 12 of 19 E-BS neurons tested for projections to two or three segments had narrow-width
peaks (mean counts >121) in the XCOR
(Kirkwood, personal communication). Since lower
mean counts likely underestimate the number of signicant narrow-width peaks, monosynaptic projections appear to be the rule rather than the

451

exception, at least for spontaneously active E-BS

neurons. There thus appears to be a discrepancy
between the extent of divergence of E-BS projections
in the thoracic and lumbar cords but more study of
the projections to the latter is needed.
A preliminary report by Kirkwood and Road
(1994) indicates more synchronization (higher k
ratio) between activities of motor nerves originating
from a given segment than from distant segments;
more importantly, the k ratios of XCOR between
activities of abdominal motor nerves of segments T8
and L1 were greater than those between motor activities of internal intercostal nerve of T8 (innervating the internal intercostal muscle) and IO of L1.
These results suggest that abdominal muscles even
of distant segments share more common drive than
motoneurons to dierent (abdominal versus internal
intercostal) muscles in the same segment.
4.3.2. Non-Ventral Respiratory Group (VRG) Inputs
The volitional control of abdominal muscles illustrates that neurons other than those of the cVRG
can drive abdominal motoneurons. But are such
inputs mediated by cVRG E-BS neurons or do they
use another pathway? Cohen et al. (1992) observed
near zero coherences between phrenic and abdominal motoneuron discharges during ctive vomiting,
a result suggesting that these motoneuronal pools
are driven by dierent pre-motor neurons despite
their synchronous discharge during this behavior.
4.3.3. Cortical
The presence of a direct projection from the cortex (Plassman and Gandevia, 1989) is consistent
with the ability of magnetic stimulation of the
motor cortex in human subjects to evoke potentials
in RA (Carr et al., 1994). Moreover, the XCOR
between the activities of the left and right RA (elicited by raising the legs) has a strong central peak,
indicative of a common drive to the motoneuronal
pools (Carr et al., 1994). In contrast, Cohen et al.
(1992) observed no coherence between activities in
adjacent (but not bilateral) abdominal nerves during
ctive vomiting in cats. Thus, assuming dierences
in species are not responsible, the projections or organization of inputs to abdominal motoneurons
appear to dier depending on function; volitional
contractions via corticospinal pathways involve synchronized inputs to abdominal motoneurons but
those in vomiting using bulbospinal pathways do
not. The peak in the XCOR during raising of the
legs could reect synchronization of premotor neurons in the motor cortex (presynaptic synchronization), more uniform conduction velocities of
corticospinal axons, fewer interneurons between premotor neurons and motoneurons, or some combination of these properties; the absence of a peak in
the XCOR during resting `breathing' or ctive
vomiting suggests weak or asynchronous activation
of medullary premotor neurons. It may also reect
mediation of descending medullary drive by interposed interneurons; Davies et al. (1985) have
suggested that less than 10% of projections to thoracic respiratory motoneurons are monosynaptic, a
value lower than that calculated for phrenic moto-

452

S. Iscoe

neurons. According to Kirkwood (1995), the incidence of monosynaptic projections to abdominal

motoneurons (41 of 65) is much greater than that
for external intercostals (50 of 295) and marginally
greater than for phrenic (13 of 27). He calculated
that the input from E-BS neurons provides about
two-thirds of the depolarization needed to bring abdominal motoneurons to threshold, a value greater
than that required for external intercostal and even
phrenic motoneurons. In abdominal nerves, shortterm synchronization is usually present, the k values
between abdominal nerves of dierent segments (e.g.
T8 and L1) being greater than those between abdominal and intercostal nerves in the same segment
(Kirkwood and Road, 1994). All these results
suggest the coupling between E-BS neurons and abdominal motoneurons is `tighter' than that between
other populations of respiratory premotor neurons
and motoneurons.
In accordance with the voluntary activation of abdominal muscles, stimulation of the motor cortex in
anesthetized cats elicits a dominant excitatory response in the internal intercostal nerves with a
latency as fast as 8 ms (Amino and Sears, 1971;
Bassal and Bianchi, 1981a). Similar responses can be
elicited by stimulation of diencephalic and mesencephalic structures (but not PBN) (Bassal and
Bianchi, 1981b). Because E-BS neurons are not activated quickly enough to account for the shortlatency activation of the internal intercostals, Bassal
et al. (1981) argued that the connection is direct
(corticospinalpyramidal and extrapyramidal). The
presence of retrogradely transported HRP in the
motor cortex of cats following its injection into the
T89 spinal cord at a site containing active E motoneurons proves that the corticospinal connection is
a direct one (Rikard-Bell et al., 1985b).
Recent work in human subjects using percutaneous electrical (Plassman and Gandevia, 1989) or
magnetic (Carr et al., 1994; Lissens et al., 1995)
stimulation of motor cortex conrms the contralateral projection. Low threshold stimulation of the
motor cortex activates only the contralateral RA
and EO muscles (Plassman and Gandevia, 1989) but
RA responses to stimulation just lateral to the midline are bilateral, with equal latencies and similar
amplitudes (Carr et al., 1994). The bilateral responses are not, according to the authors, due to
stimulus spread to the left and right motor cortices
because stimulation at a more lateral site still evokes
bilateral responses. The discrepancy between these
two results (Plassman and Gandevia, 1989; Carr et
al., 1994) is likely due to dierences in stimulation
technique (percutaneous electric versus magnetic)
because both groups recorded from RA.
Stimulation of the motor cortex is eective even
during imposed respiratory and postural tasks
(Plassman and Gandevia, 1989), suggesting that cortical inputs use a separate descending pathway; such
a result is consistent with other studies indicating
that specic tasks are mediated through descending
pathways other than those subserving respiration.
Lesions of the ventrolateral columns abolish rhythmic respiratory activity of internal intercostal motoneurons without blocking their excitatory response
to stimulation of the sensorimotor cortex (Amino

and Sears, 1971). Because the discharge characteristics and central conduction times for activation of
EO and RA are comparable to those for other limb
muscles known to receive a direct cortical projection,
Plassman and Gandevia (1989) concluded that the responses are not mediated by brainstem respiratory
neurons. During voluntary respiratory eorts, however, premotor negative potentials are recorded from
the cortex approximately 1.2 s before EMG activity,
representing the time required for organizing activation of multiple muscles (Maceeld and Gandevia,
1991); these potentials are absent during quiet breathing, indicating that the cortex does not contribute to
respiration in this state. This does not mean that the
cortex must bypass the brainstem respiratory centers;
Orem and Netick (1986) and Orem and Brooks
(1986) have elegantly demonstrated that the discharge
patterns of brainstem neurons of cats are modied by
conditioned behaviors, indicating that these two systems can interact. Moreover, human subjects can, if
requested, suppress EMG responses of EO, IO, and
TA to imposition of positive pressure loads (Lansing
and Meyerink, 1981), evidence favoring the presence
of cortical inputs to abdominal motoneurons.
Finally, abdominal muscles, unlike the diaphragm,
are not maximally activated during expulsive voluntary maneuvers and trunk exion because cortical
stimulation elicits additional increases in gastric
pressure (Pga) whereas bilateral phrenic nerve stimulation does not (Gandevia et al., 1990). Postural
changes (trunk exion) elicit larger increases in abdominal activity than those observed during expulsive
eorts, implying that some motoneurons are not
accessible to the respiratory controller.

5. LIMITATIONS
Dierences in experimental procedures and conditions limit our ability to compare and interpret the
eects of various interventions on abdominal activities from dierent laboratories. These include:
uncontrolled or unknown central respiratory
drive(s), recording techniques, quantication and expression of EMG or neural activities, end-expiratory
lung volume and posture (including segmental proprioceptive eects; Section 10), and status of the
upper airway (intact or bypassed), blood pressure,
and gender.
5.1. Recording Techniques
In studies on animals other than man, recordings
of EMG activity are made using electrodes inserted
directly into a particular muscle. This, however,
does not necessarily prevent contamination of the
signal by activity from adjacent muscles (e.g.
Gilmartin et al., 1987), particularly when recording
from thinner muscles of smaller species. Surface
electrodes, although still used (e.g. Barrett et al.,
1994; Hodges et al., 1997), can be relatively insensitive (e.g. de Sousa and Furlani, 1974; Druz and
Sharp, 1981) and may account for the failure to
record increased phasic abdominal activity during
shifts in posture because the internal abdominal
muscles are more sensitive to posture-induced

Control of Abdominal Muscles

changes in resting length (De Troyer, 1983).

Although the advent of EO activity during rebreathing appears simultaneously on surface and needle
electrodes (Hill et al., 1985), such results are only
possible when recording from supercial abdominal
muscles (RA and EO) which are less sensitive than
the internal muscles to increases in lung volume
(Gilmartin et al., 1987; De Troyer et al., 1989;
Leevers and Road, 1989, 1993a) or CO2 (Gilmartin
et al., 1987; Farkas and De Troyer, 1989; Leevers
and Road, 1994; Abe et al., 1996) (Fig. 5). Surface
electrodes can also pick up activity unrelated to that
made simultaneously from intramuscular needle
electrodes (Strohl et al., 1981; Hill et al., 1985).
Surface electrodes have been replaced in many studies in humans by needle electrodes inserted into
specic muscles using computed tomography
(Goldman et al., 1987) or ultrasound (Strohl et al.,
1981; Ninane et al., 1992; Cresswell et al., 1992;
Hodges et al., 1997; Puckree et al., 1998), but they
sample only proximate motor units, not the activity
of the whole muscle. Although the placement of
electrodes based on distances determined by tomography has been criticized (Wakai et al., 1992), the
procedures and recordings made by Goldman et al.
(1987) indicate that correct placement using tomography is feasible despite the lack of direct visualization. Misuri et al. (1997) have recently reported
that increases in muscle thickness visualized with
ultrasound may be useful in evaluating the contributions of individual abdominal muscles to specic
respiratory manoeuvres: in seated men, TA, IO, and
RA increased their thickness more during maximal
expirations than EO which thickened more during
trunk rotation.
The high thresholds for recruitment of abdominal
muscles during increased ventilation in some studies
(Campbell, 1952; Campbell and Green, 1955; Strohl
et al., 1981) using surface electrodes compared to
recent ones using needle electrodes (De Troyer et

453

al., 1990; Wakai et al., 1992) are probably not due

to the type of electrode but rather to the hypocapnia
induced by voluntary hyperventilation. Campbell
and Green (1955) reported little activity of abdominal muscles until ventilations exceeded 70 L/min in
erect human subjects whether rebreathing from a
sprirometer or voluntarily hyperventilating (with
consequent hypocapnia), suggesting that the high
threshold for recruitment resulted from the use of
insensitive surface electrodes, although hypoxia
during rebreathing may have suppressed abdominal
activity (Fregosi et al., 1987).
5.2. Analysis of Activity
Abdominal discharges often have a step-ramp discharge pattern characterized by a rapid rise to an
early peak followed either by a plateau or a fall
until the onset of the next inspiration. In addition,
activity may be absent for part of expiration, a situation more likely when recording from individual
motor units with dierent thresholds of recruitment.
In contrast, phrenic activity is usually ramp-like and
lasts for the duration of inspiration (TI). Indeed, the
duration of the phrenic burst, from onset to start of
rapid decline, denes TI whereas abdominal activity
does not dene the duration of expiration, TE.
Thus, although one can use peak activity or the rate
of rise of phrenic (or diaphragmatic EMG) activity
as an index of drive if inspiratory duration changes,
this is usually not possible with abdominal activity.
To quantify abdominal activity, Ledlie et al.
(1983) calculated the mean electrical activity during
its discharge phase. Others (Praud et al., 1993) used
the product of the peak amplitude of the integrated
EMG activity and the instantaneous frequency of
the breath; this assumes no relative changes in TI
and TE. Some use peak activity even though TE
changes in hypoxia or hypercapnia (e.g. Bellemare
et al., 1991; Yasuma et al., 1993), particularly in ani-

Fig. 5. Internal (TA and IO) abdominal muscles respond more to increases in CO2 and lung volume. (A)
Progressive hypercapnia in an upright human subject. Moving time average of EMG activity expressed
as per cent dierence between minimum and maximum values during the breath when activity rst
appeared. The two internal muscles, TA and IO, are the most responsive, in terms of both threshold of
activation and sensitivity to CO2. Reproduced with permission from Abe et al., 1996. (B) Lung ination
in anesthetized dogs. Change in peak integrated EMG amplitude expressed as per cent of value when activity rst appeared. Reproduced with permission from Leevers and Road (1989).

454

S. Iscoe

mals with intact vagi, or after vagotomy (e.g. De

Troyer et al., 1989). The signicance of these dierent techniques is debatable; Arnold et al. (1988)
observed a linear relation between peak integrated
EMG and shortening of TA muscle bers during
CO2 rebreathing despite changes in TE and shape of
the integrated EMG. Fregosi et al. (1990) reported
that peak integrated activity yields results similar to
those obtained using mean electrical activity; they
also reported that the discharge pattern (rate and
duration of rise to peak) varied both within and
between cats. The best method of analyzing the
more complex (compared to phrenic) waveforms of
abdominal EMG activity remains uncertain.
Analysis of medullary neuronal discharges entails
similar diculties. Many workers express activity,
however analyzed, as a fraction control eupneic or
``normocapnic'' values or of maximal values
obtained during rebreathing or inhalation of a
hypercapnic gas mixture (e.g. at a xed value of
PaCO2 or PETCO2) or during positive pressure
breathing (e.g. De Troyer et al., 1989; Farkas and
De Troyer, 1989; Farkas and Schroeder, 1990).
The problem of unknown or uncontrolled changes
in input (central respiratory drive) can be circumvented by normalizing the data to an output of the
respiratory controller, e.g. ventilation. Many interventions such as expiratory loads change ventilation.
What variable should be used to normalize individual measurements of abdominal muscle activity (e.g.
EMG, changes in length)? Some individuals have
used VT, others ventilation, but there is no consensus about which index is best nor even that an index
is needed. An ideal index should be restricted as
much as possible to expiratory-related activity, e.g.
mean expiratory ow (VT/TE), rather than VT or
ventilation (see Yasuma et al., 1993), both of which
incorporate inspiratory contributions. (However, in
dogs, horses and ponies, expiratory muscles contribute to the generation of inspiratory ow and VT
both by driving lung volume below the passive resting position, thereby allowing the onset of the next
inspiration to be passive, and by increasing the precontractile length of the diaphragm.) VT may be
suitable under steady-state conditions when the
inspired and expired volumes are equal but this may
not be true during transients (e.g. the onset of loading). However, even VT/TE is imperfect since it, like
VT, can include passive contributions such as
increased recoil at elevated end-expiratory lung
volumes (EELV). Since PACO2 (PETCO2) depends
on alveolar ventilation, at a given V CO2, one could
use PETCO2 as an index; however, as explained in
Section 8.1, PETCO2 does not always accurately indicate brain PCO2. Thus, like the analysis of EMG
or neuronal discharges, there is no consensus about
how best to express changes in abdominal muscle
activity to enable comparisons of abdominal activity
within or between studies.
5.3. Upper Airway
Decreases in upper airway resistance unload the
abdominal muscles, reexly decreasing their activity
(Remmers and Bartlett, 1977). Therefore, results
may vary depending on whether or not breathing is

through an intact upper airway, a feature seldom

considered when relating experimental ndings to
normal physiological function. In both awake and
sleeping dogs, tracheal breathing abolishes tonic,
and reduces the amplitude of phasic, abdominal activity present during nasal breathing (Plowman et
al., 1990). Farkas and Schroeder (1990) studied
anesthetized intubated dogs in the supine and prone
postures. When supine, expiration was rapid, TE
consisting primarily of an expiratory pause with no
ow; when prone, with abdomen pendant, expiratory ow was initially rapid (to about half of VT)
and then decreased linearly with time until 12 s
before the onset of the next inspiration. The initial
rapid expiration was likely due to elastic recoil of
the lung and the slower part, in the prone position,
to activation of the expiratory (including abdominal) muscles as EELV was driven below the passive
value and not to the braking action of the muscles
of the upper airway which are sensitive to posture
(see Iscoe, 1988 for review). These results dier from
those expected due to activation of SAR which inhibit and excite E-BS neurons at high and low transpulmonary pressures, respectively (see Section 7.3).
The role of segmental reexes in this response is
unknown. Moreover, the status of the upper airway
is complicated by the higher PaCO2 (03 mmHg) in
the prone position. Although static and oscillatory
changes in upper airway pressure cause immediate
(rst 23 breaths) and sustained decreases in TA activity in sleeping dogs (Plowman et al., 1991), I am
aware of no studies which deal with the contributions of upper airway as opposed to SAR aerents on abdominal responses to sudden changes in
loads.
Preterm infants with respiratory distress, unlike
healthy preterm infants, display phasic EO activity
accompanying `grunt' caused by expiratory ow
through an adducted larynx; intubation does not
abolish EO activity if the infants are maintained on
CPAP (South et al., 1987). Removal of CPAP
reduces or abolishes EO activity and the infants
breathe rapidly, presumably to prevent decreases in
EELV. These results suggest that SAR, not upper
airway receptors, are responsible for EO recruitment.

5.4. Blood Pressure

Interpretation of studies in which interventions
aect blood pressure is complicated by the state of
the animal. Conscious dogs, unlike their anesthetized counterparts, increase ventilation substantially,
possibly via a neurohormonal pathway, in response
to even small decreases in blood pressure (Jennings
et al., 1995). Many interventions (e.g. positive pressure breathing, PPB) which elicit abdominal activity
also lower blood pressure. Such changes are seldom
considered in the interpretation of responses. Blood
pressure, depending on the degree of autoregulatory
control available, may also aect cerebral blood
ow (Section 8.1) accounting for attempts to x
blood pressure in some preparations (e.g. England
et al., 1995).

Control of Abdominal Muscles

5.5. Gender
During halothane anesthesia (see Section 6.2), supine women had active parasternals, supine men
active TA (Warner et al., 1996); during CO2
rebreathing, men did not recruit the parasternals but
women recruited TA. An earlier study by Kaul et al.
(1973) mentions only one gender-related nding:
two of 10 men anesthetized with N2O/O2 after induction with thiopentone failed to develop expiratory muscle EMG activity whereas all 12 female
patients did. The reason(s) for these dierences,
which need to be conrmed, are unknown.

6. STATE
State refers to the level of arousal of the organism; it includes variations associated with attention,
sleep state, and type and level of anesthesia, all of
which aect interpretation of the responses of
expiratory muscles. In assessing the eects of
changes in state, one must determine if they are
direct, i.e. due to altered synaptic inputs from CNS
neurons whose activities change with alterations of
state, or indirect, i.e. due to changes in feedback due
to state-induced changes in other structures (e.g. the
upper airway; see Iscoe, 1988 for review). A confounding factor in any study of the responses to
interventions used to recruit abdominal activity is
the availability of other options to maintain expiration without necessarily recruiting abdominal
muscles: decreased laryngeal braking, increased
EELV to increase passive recoil, and increases in the
fraction of the respiratory cycle devoted to expiration (e.g. Hill et al., 1985).
This section is restricted to a review of the `peripheral' eects of changes of state on abdominal
muscles and their antecedent (moto)neurons. Most
work in this eld concentrates on the inspiratory
components of ventilation (e.g. the diaphragm
(Sieck et al., 1984) or intercostals (Dick et al.,
1982)). Readers are referred to recent reviews for
details on contributions of supra-pontine structures
and state to ventilatory control (Orem, 1988;
Harper, 1991; Harper et al., 1996; Harper, 1997).
Orem and his colleagues have emphasized the variable responses of neurons with weak but detectable
respiratory-related discharge patterns; these, they
contend, are responsible for the changes in respiratory pattern because they, unlike `pure' respiratory
neurons, are susceptible to state-related inputs. In
addition, the responses of neurons to which functions are attributed on the basis of their discharge
patterns or connections in anesthetized or decerebrate preparations can be very dierent when
awake; for example, BotC E-AUG neurons, which
may drive E-BS neurons of the cVRG (Bongianni et
al., 1988b; 1990), are silent during conditioned
apneas in awake cats (Orem and Brooks, 1986).
6.1. Consciousness and Sleep
6.1.1. Motoneurons and Muscles
The level of activity, and its distribution between
various muscles in man, is aected primarily by pos-

455

ture (Section 7.1). However, recruitment of quiescent muscles is also aected by state. For example,
hyperination does not recruit abdominal muscles
during non-rapid eye movement (NREM) sleep
(Begle and Skatrud, 1990; Wakai et al., 1992) unless
CO2 increases. This agrees with a number of studies
(Skatrud et al., 1988; Henke et al., 1991) suggesting
that recruitment of abdominal muscles occurs only
because of hypoventilation-induced CO2 retention.
Increased EELV decreases the threshold for activation of abdominal muscles by CO2 (Wakai et al.,
1992) such that even slight hypoventilation may be
sucient to recruit abdominal muscles. Indeed, peripheral chemoreceptor and SAR inputs interact
additively at the level of various respiratory neurons, including cVRG E-BS neurons, in dogs (Bajic
et al., 1994). The response may also depend on load.
Sustained, but not acute, inspiratory resistive loads,
which mimic snoring, recruit abdominal muscles
during NREM sleep, presumably because of the
load-induced hypoventilation (010% drop in ventilation) despite no measurable changes in PETCO2
(Badr et al., 1990). Abdominal activity could persist
despite apparent isocapnia due to increased segmental input resulting from the load and a consequent
reduction in threshold to descending supraspinal
inputs.
In awake standing goats, injection of clonidine,
an a2-adrenoreceptor agonist which produces sedation, preferentially decreased TA and TS, but not
diaphragmatic, activity despite a decrease in PaO2
and increase in PaCO2 due to hypoventilation
(Hedrick et al., 1998); the mechanism is unknown
but does indicate that inspiratory and expiratory
motoneurons exhibit dierential sensitivity to this
agent even when they respond equally to stimulation
of the central and peripheral chemoreceptors
(NaCN, hypoxia, hypercapnia; see Section 8).
Although abdominal muscles are typically inactive
in supine humans at rest, they become active when
the level of arousal is decreased by sleep, sedation,
or anesthesia. Administration of a sedative, midazolam, increased abdominal activity in 7 of 9 subjects
(as indicated either by needle electrodes (EO), or
changes in Pga); total pulmonary resistance, due to
reduced genioglossus activity, also increased but diaphragmatic activity (indicated by a smaller gastric to
pleural pressure ratio, Pga/Ppl) and ventilation
decreased (Molliex et al., 1993). Flumazenil, a
benzodiazepine antagonist, reversed these eects.
Although the authors suggest that the hypoventilation-induced increase in PCO2, estimated at 010%
and presumably due to the increased resistance, was
not sucient to recruit abdominal muscles, other
work (see below) suggests this is a plausible explanation.
On the basis of the slow onset of increases in Pga
and decreases in abdominal cross-sectional area
during the occlusive phase of NREM sleep, Onal
and Lopata (1986) concluded that changes in chemical drive rather than proprioceptive reexes during
occlusion recruit abdominal muscles. Skatrud and
Dempsey (1985) found that three of four snorers
recruited abdominal muscles (increased Pga during
expiration) because of hypoventilation-induced
increases in CO2 due to increased inspiratory resist-

456

S. Iscoe

ance (a narrowed upper airway) during sleep. Thus,

`state', excluding volitional changes, aects abdominal muscles indirectly; resistance of the upper airway
increases (Orem et al., 1977) because reduced levels
of arousal depress airway dilator motoneurons (see
Iscoe, 1988 for review), leading to CO2 retention
which in turn increases abdominal activity. Similar
mechanisms probably account for the increased abdominal activity observed in dogs when breathing
through a tracheostomy rather than the intact upper
airway (nasal breathing) and during slow wave sleep
compared to wakefulness, regardless of the route of
breathing (Plowman et al., 1990).
Direct recordings of abdominal activity support
this interpretation. In healthy human subjects who
snored occasionally during sleep, abdominal, probably EO, activity was present in three of 17 subjects
(one with needle and two with surface electrodes)
while awake (Skatrud et al., 1988) but in nine of 17
(5 needle, 4 surface) during NREM sleep. The
authors contend that recruitment of expiratory
muscles in sleep was due to CO2 retention secondary
to increased airway resistance because decreasing
airway resistance with a He-O2 mixture during
NREM sleep lowered CO2 and decreased EO activity compared to responses while awake and
breathing room air. Even in healthy non-snorers,
abdominal (likely EO) activity was inconsistently
present in ve awake subjects but present in eight of
11 subjects in NREM sleep, probably because of the
higher PETCO2 (mean 41.2 versus 36.9 mmHg)
(Badr et al., 1990). Acute (3 breaths) inspiratory
resistive loading (IRL) caused no recruitment of EO
in awake or sleeping supine subjects (see also
Martin and De Troyer, 1982), suggesting that proprioceptors were not activated. Sustained (3 min)
IRL elicited no change in diaphragmatic activity but
variable increases in EO activity between subjects
(mean +51%, range 18 to +300%). (The unanalyzed ``erratic and highly variable'' responses of
awake subjects (Dempsey, personal communication)
probably were cortical in origin, illustrating the diculties of studying awake subjects.) Despite no
change in PETCO2 from control during the sustained
load, they attributed the increase in EO activity
during NREM sleep to increased upper airway resistance and CO2 retention, suggesting that
``measurement[s] of PETCO2 may not accurately
reect chemoreceptor stimuli'' (see Section 8.1). In
contrast, Martin and De Troyer (1982) observed responses to inspiratory resistive and elastic loads
only in RA and not EO in seated subjects, despite
an apparent hypoventilation.
In semi-recumbent subjects with generalized
muscle weakness or diaphragmatic paresis, EO is
active, RA less so, both when awake and during
NREM sleep (White et al., 1995); in two subjects,
EO activity was much greater during NREM sleep
but for no apparent reason (including postural
changes). Although phasic REM sleep reduces, compared to NREM sleep, respiratory (including EO)
activity, with considerable inter-patient variability, it
is impossible to attribute such changes to state in
the absence of measurements of CO2. The authors
emphasize that in patients with respiratory muscle
weakness, obstructive apneas may be mistaken for

central (non-obstructive) apneas because such

patients cannot generate the pressures characteristic
of obstruction, even at higher PCO2s.
In children, phasic abdominal (EO, possibly IO
and TA) activity was present during >50% of sleep
time in 10/20 patients with obstructive sleep apneas
(OSA) versus only one of 12 patients without OSA
(Jeries et al., 1984). The former all had PETCO2s
>46 mmHg, suggesting increased airway resistance
during sleep. In another study of sleeping prepubertal snorers, abdominal (likely EO) activity also
increased progressively during OSA during NREM
sleep, indicating the role of increased chemical drive
(Praud et al., 1989); during REM sleep, abdominal
activity was absent even during snoring and obstructive apnea. In sleeping premature infants studied at
term (040 wk), CO2 rebreathing recruited and
increased abdominal activity but only during
NREM sleep (Praud et al., 1991). The response to
CO2 can, therefore, apparently be blocked by sleep
state.
In dog, slow wave (NREM) sleep, compared to
the awake state, increases abdominal activity; phasic
REM sleep, however, abolishes abdominal activity
(Plowman et al., 1990). The NREM sleep-induced
increase in abdominal activity occurred whether or
not the dogs breathed through an intact upper airway (nasal breathing) or through an endotracheal
tube inserted into a chronic tracheal stoma (tracheal
breathing). During nasal breathing, abdominal activity increased despite an average `fall' in PETCO2
of 0.6 mmHg (range 1.3 to +0.6 mmHg); during
tracheal breathing, activity increased despite a `fall'
of 0.3 mmHg (range 0.6 to +0.4 mmHg).
Although the absolute levels of abdominal activity
during tracheal breathing were only 025% of those
during tracheal breathing, the percent increases
during slow wave (NREM) sleep were similar (55
and 62% during nasal and tracheal breathing, respectively). If the reduced levels of abdominal activity during tracheal breathing are attributed to a
lower airway resistance and associated fall in
PETCO2, this implies great sensitivity of the premotor neurons to CO2: while awake, the switch to
tracheal breathing `lowered' PETCO2 by an average
1.0 mmHg; during sleep, the fall averaged 1.35
mmHg. If one accepts end-tidal CO2 as an accurate
representation of chemical drive, two conclusions
follow: (1) NREM sleep induces an increase in abdominal activity unrelated to changes in CO2
because abdominal activity increased despite a `fall'
in PETCO2; and (2) abdominal pre-motor neurons
are driven by neurons which are very sensitive to
even small changes in CO2 because a fall of only 1
mmHg due to tracheal breathing reduced abdominal
activity. The central mechanisms are unknown.
In cat, instillation of 50 ml of saline into the trachea elicits coughing in awake cats 80% of the time
but never in sleeping (REM) cats, although weaker
expiratory eorts may be present in NREM sleep
(Anderson et al., 1996). This suppression is not due
to atonia in REM sleep because it also occurs in
NREM sleep. Thus, state blocks the eects of upper
airway inputs. However, it is unclear where this
eect occurs: the level of second order aerents,
interneurons, or E-BS neurons. In addition, this

Control of Abdominal Muscles

block is directed specically at the network generating cough since saline causes arousal/apnea.
The activity of expiratory intercostals in cats
increases during the transition from wakefulness to
NREM sleep, but is reduced or abolished when
REM sleep starts (Dick et al., 1982). The progressive increase in activity may be a direct result of a
sleep-related process or secondary to a sleep-induced
decrease in, for example, ventilation and a consequent increase in CO2. I am aware of no other studies indicating similar changes in other respiratory
muscles.
Although several groups have examined the eect
of state on neuronal discharge patterns (Orem,
1980, 1994a; Orem and Netick, 1982; Orem et al.,
1985; Orem and Trotter, 1992; Chang, 1992), I
know of no studies which include identied E-BS
neurons. Limited data suggest that many, if not
most, respiratory neurons discharge less, to the
point of silence, during NREM sleep (Orem et al.,
1974, 1985) but more during phasic REM sleep
(Orem, 1980); tonic REM sleep has variable eects
on dierent respiratory neurons, those in the VRG
being inactivated (Orem, 1980). The source of these
changes is unknown but may be related to the discharge of neurons in the gigantocellular and lateral
tegmental eld of the medulla which are active only
in REM sleep (Netick et al., 1977).

6.2. Anesthesia
6.2.1. Motoneurons and Muscles
In supine awake human subjects, abdominal (EO,
IO, RA) activity is often absent (Campbell and
Green, 1953; Freund et al., 1964; Kaul et al., 1973;
de Sousa and Furlani, 1974; Druz and Sharp, 1981;
Goldman et al., 1987; Takasaki et al., 1989; Barrett
et al., 1994; Warner et al., 1996; Puckree et al.,
1998; but see Warner et al., 1995a; Abe et al., 1996)
but appears or increases during halothane or N2O
anesthesia (Freund et al., 1964; Kaul et al., 1973;
Warner et al., 1995a). Activity occasionally appears
after induction of anesthesia with thiopentone/thiopental (Freund et al., 1964; Kaul et al., 1973); this is
apparently not an eect of changes in ventilation
during induction of anesthesia. In one study
(Freund et al., 1964), neither ventilation, PETCO2,
nor pulmonary resistance changed in the transition
from wakefulness to anesthesia. Limited data in
another study, however, indicate an almost 40%
average drop in alveolar ventilation during
halothane anesthesia (Warner et al., 1995a) and,
according to the companion paper (Warner and
Warner, 1995), a rise in resting PaCO2 from 41 to
51 mmHg, suggesting that CO2 contributed to the
response. Halothane may also aect the abdominal
response to loads but results are equivocal. Whereas
Freund et al. (1964) observed a rst-breath decrease
in abdominal activity during expiratory obstruction,
Kaul et al. (1973) observed the opposite (equivalent
to the BreuerHering expiratory promoting reex);
the latter group noted, but did not comment on, the
dierence. In halothane-anesthetized subjects, addition of N2O increases mean TA activity despite no

457

change in duration of discharge; this could reect a

higher PaCO2 (+4.5 mmHg) (Warner et al., 1998).
The increase in abdominal activity cannot be
attributed to an anesthetic-induced increase in
EELV because FRC fell in all subjects studied by
Warner et al. (1995a). Stimulation of the upper airways (by passage of an oropharyngeal airway) or
application of local anesthesia had no eect on abdominal activity (Kaul et al., 1973). Because vocal
arousal of subjects suppressed abdominal activity,
Freund et al. (1964) concluded that the increase in
abdominal activity during halothane anesthesia is
due to abolition of descending inhibition from
suprapontine structures, a suggestion similar to that
of Tenney and Ou (1977) who observed that decortication of cats causes tachypnea which is eliminated
by decerebration. In other words, cortical inuences
suppress excitatory inputs from the mid-brain;
decortication (1anesthesia) therefore disinhibits
breathing, evident as an increase in abdominal activity and respiratory frequency. The halothaneinduced increase in respiratory frequency in human
subjects may also be due to sensitization of pulmonary slowly adapting receptor (SAR) by halothane
(Coleridge et al., 1968); at the concentrations used
in these studies, increased SAR activity could
reexly increase respiratory frequency.
In contrast to the eects of halothane, human
subjects anesthetized with methoxyurane, do not,
unlike their conscious counterparts, recruit abdominal muscles during PPB since increases in EELV
were identical before and after paralysis (Derenne et
al., 1986). Thus, methoxyurane acts much like
NREM sleep in depressing abdominal responses to
increased EELV, in this case, by PPB.
In cats, some anesthetics profoundly depress the
activity of E neurons or motoneurons. Fregosi et al.
(1987) were unable to obtain any abdominal (L1) activity in chloralose/urethane- and pentobarbitalanesthetized cats even during hypercapnia, whereas
four of seven ketamine-anesthetized cats had phasic
activity (PCO2 not given); in contrast, phasic activity
was present in 10 of 13 decerebrate cats at a PaCO2
of 38 mmHg, and brief anoxia converted the tonic
activity in the other three to a stable phasic discharge. Intravenous injections of small doses of
pentobarbital to a decerebrate cat suppressed abdominal activity without aecting phrenic activity.
Increasing anesthetic depth with additional doses of
pentobarbital reduces or abolishes EO/RA responses
to ETL (DiMarco et al., 1984; Fregosi et al., 1987).
These eects are similar to those reported by
Fregosi and Bartlett (1989) in laments to expiratory intercostals. They dier somewhat, however,
from results in chloralose-anesthetized, supine cats
with intact vagi and breathing a hyperoxic gas mixture (Fregosi, 1994b); IO, EO, and TA remained
active, albeit at low levels. Thus, chloralose does not
necessarily suppress abdominal activity, even under
conditions when peripheral chemoreceptor inputs
are reduced or absent due to hyperoxia (Davies et
al., 1982; Fitzgerald and Dehghani, 1982; Mokashi
and Lahiri, 1991). The presence of abdominal activity in this preparation may reect higher than
normal PaCO2s (average 42.6 versus 24.9 mmHg in

458

S. Iscoe

decerebrate spontaneously breathing cats; Iscoe and

Fisher, 1995).
In dogs, volatile anesthetics (halothane, isourane) depress or abolish abdominal activity in dogs
(unlike humans) whether one records activity of the
muscles (Warner et al., 1994; 1995b) or monitors
their shortening (Leevers and Road, 1995c).
Moreover, addition of 1 MAC (minimal anesthetic
concentration) halothane abolishes TA and EO activity present under `light' pentobarbital anesthesia
which does not suppress abdominal activity (Warner
et al., 1994). Increasing isourane concentration,
however, from MAC 1 to MAC 2 restored TA and
EO activity, albeit to low levels; in contrast, inspiratory (parasternal and diaphragmatic) activity was
unaected. Importantly, the halothane-induced
abolition of abdominal activity was independent of
changes in blood gases; the PaCO2 at MAC 2 was
less than the PaCO2 with `deep' pentobarbital and
similar to that at MAC 2 isourane. Thus,
halothane specically suppresses abdominal activity.
Moreover, in response to positive end-expiratory
pressure (PEEP), halothane was the only anesthetic
to depress the responses of EO and TA; nevertheless, PEEP recruited TA, EO and IO, illustrating the
importance of maintaining eective diaphragmatic
contraction by controlling EELV. Despite changes
in abdominal activity, there was little dierence in
the rib cage and abdominal contributions to VT
except at MAC 2 halothane. In a later study,
Warner et al. (1995b) conrmed that TA and EO activity in dogs is suppressed by halothane (MAC 2)
not only at rest but during rebreathing up to a PCO2
of 76 mmHg. Thus, halothane appears to block the
chemoreceptor drive to abdominal muscles.
Interpretation of these results is complicated by
halothane's suppression of carotid body chemoreception (Mitchell and Selby, 1988; Davies et al.,
1982) and its sensitization of SAR (Kelsen, 1984).
The net eect of halothane-induced suppression of
abdominal activity is that the dog is less able to prevent increases in EELV in response to loads, thereby
compromising inspiratory (diaphragmatic) muscle
function. In contrast, addition of N2O to pentobarbital-anesthetized dogs signicantly increases mean
TA and EO activity despite no change in the duration of discharge (Warner et al., 1998). The eects
on expiratory muscle EMG activity appear, therefore, to depend on the particular anesthetic.
The presence of TA, occasionally EO and even
less often RA, activity in conscious sitting, standing,
and recumbent dogs (De Troyer et al., 1989) is not
greatly aected by light pentobarbital anesthesia. In
eight supine dogs lightly anesthetized with pentobarbital, phasic TA activity was present in ve, phasic
activity of EO in two (but tonic activity in ve), and
RA was inactive; surprisingly, supplemental anesthesia depressed TA but had little eect on EO.
Dierences in incidence of activity are as likely to be
due to changes in posture and, therefore of EELV
(Section 7.1), as anesthesia. Oliven and Kelsen
(1989b) observed activity in all four abdominal
muscles in about half of their supine pentobarbitalanesthetized dogs breathing 100% O2. However,
both thoracic expiratory muscles (internal intercostal IC9 and TS IC34) were active in all dogs. The

reasons for this dierence are unclear; we do not

know if this reects their posture or an eect of the
anesthetic at the spinal or supraspinal levels. This
observation is, however, important in terms of the
dierential control of abdominal muscles; i.e. not all
expiratory muscles are the same. Indeed, the combined eects of hypercapnia and PEEP were greater
in abdominal muscles than in thoracic expiratory
muscles.
A review of the literature reveals no study of the
interaction of anesthetic and posture on activity of
various abdominal muscles, nor of their eects on
regional activity within a given muscle. One would
predict that motor units in the most dependent
regions, subjected to the greatest stretch, would be
less aected.
In piglets, abdominal muscles are relatively insensitive to halothane. TA activity was present in 11 of
12 halothane-anesthetized piglets (Watchko et al.,
1990), all of which responded to increases in CO2
with increased activity.
In ferrets, halothane abolished the emetic response of ferrets and depressed control levels of
tongue (genioglossal), abdominal (unidentied), and
diaphragmatic activity (Zunini et al., 1990). The
authors attribute the depression to inhibition of second order vagal aerents.
6.2.2. Premotor Neurons
In studies of the eects of anesthetics, one has to
separate the eects of the agent itself from any eect
it exerts due to hypoventilation-induced increases in
PCO2. Ideally, one should maintain isocapnia. If
recording in vivo, one can paralyze and ventilate the
animal; isocapnic conditions can be easily maintained in in vitro preparations.
When interpreting the results of various anesthetic
agents on membrane potential, changes in timing
must also be considered. Halothane, for example,
typically decreases TI and TE (Kaul et al., 1973;
Takeda et al., 1990; Takeda and Haji, 1992; Warner
et al., 1994, 1995a; Warner and Warner, 1995;
Warner et al., 1996; but see Grelot and Bianchi,
1987; Stuth et al., 1992, 1994). Isourane shortens
TI and TE in vagotomized cats (Takeda and Haji,
1993). Therefore, for a ramp (AUG)-type neuron,
the maximum depolarization will be less. This
applies even to DEC neurons if their discharges are
aected by the intensity of any post-inhibitory
rebound; reduced depolarization during the preceding phase will result in a reduced discharge of the
neuron at the onset of its active phase. The eects
of changes in phase duration have not always been
considered when comparing membrane potentials
and discharge intensities; compensating for changes
in phase duration is possible for AUG neurons but
not DEC neurons if post-inhibitory rebound contributes to the initial peak. The changes in timing
induced by halothane imply that it acts on the circuitry controlling phase durations and that eects
on amplitude (e.g. membrane potential, peak discharge frequency) are secondary.
Halothane (13%) excites feline and canine SAR
activity; at higher concentrations (520%), it initially sensitizes and then depresses SAR activity

Control of Abdominal Muscles

(Coleridge et al., 1968). At low concentrations,

therefore, increases in SAR activity would depress
E-BS neurons (see Section 7.3), and therefore reduce
abdominal activity, which is what is observed at
0MAC 1 (Warner et al., 1994; Leevers and Road,
1995c). Although Younes and Youssef (1978) contend that the data of Coleridge et al. (1968) show
that halothane converts tonic activity to phasic activity and elevates the threshold for activation, those
responses were obtained at higher concentrations of
halothane (420%) than those used by Younes and
Youssef (2%). At lower concentrations, the initial
increase in peak discharge frequency was sustained
(Coleridge et al., 1968). However, because some
SAR displayed a gradual increase in threshold
(Coleridge et al., 1968) during exposure to
halothane, the suggestion of Younes and Youssef
(1978) that the reduced eectiveness of phasic vagal
activity on respiratory control is due to prolonged
exposure to halothane needs to be tested. Because
halothane excites abdominal activity in humans
(Freund et al., 1964; Kaul et al., 1973; Warner et al.,
1995a; Warner and Warner, 1995), unlike its eect
in dogs, either SAR in humans respond, if they do
respond, very dierently to halothane or SAR exerts
dierent central eects on E-BS activity. These possibilities have not, to my knowledge, been tested.
In cats, Merrill (1974) stated that only three types
of respiratory neurons (E, early I, and late I) are
active in cats deeply anesthetized with pentobarbital.
Sears (1964a) noted that increasing the depth of
anesthesia preferentially reduced a- but not g-motoneuron activity in laments to the internal intercostal muscle. Thus, E-BS neurons of the cVRG
remain active under anesthetic conditions which
silence respiratory muscles other than the diaphragm, implying that anesthesia also aects neurotransmission in the spinal cord, possibly at the level
of intervening interneurons. Administration of pentobarbital to decerebrate cats abolishes the responses of expiratory intercostal motor axons to
medullary stimulation (Merrill, 1974).
Inhalation anesthetics have been used to test the
eects of anesthetics on neuronal discharge because
their eects are rapidly reversible, enabling comparisons of activity and/or membrane potentials before
and after their administration. Because only limited
data about the responses of E-BS neurons are available, I will review the responses of all neuronal
types. Centrally, the results of their administration
are unpredictable.
In decerebrate vagotomized and paralyzed ventilated cats, isourane depolarized ve and hyperpolarized seven E neurons (Takeda and Haji, 1993);
according to Takeda (personal communication),
three E-BS neurons were depolarized and three
hyperpolarized. Regardless of the shift in membrane
potential, swings in membrane potential between
respiratory phases were reduced, as was synaptic
noise, indicating that isourane suppressed both
EPSPs and IPSPs. A residual depolarization in late
expiration remained after administration of tetrodotoxin (TTX), probably due to distant synaptic
inputs; moreover, after TTX, isourane no longer
aected the membrane potential, indicating that its
eects are exerted on the fast Na+ channel. Takeda

459

and Haji (1993) attributed the idiosyncratic eects

of isourane not to experimental conditions but to
the properties of the individual neuron, the response
(depolarization or hyperpolarization) reecting the
relative strengths of tonic excitatory and inhibitory
inputs to the cell from neurons whose activities must
also have been aected by the anesthetic.
In a similar preparation, variable eects of
halothane on dierent types of medullary respiratory neurons, none in the cVRG, were also obtained
(Takeda et al., 1990; Takeda and Haji, 1992); the
cats of the rst study (Takeda et al., 1990) were also
peripherally chemodenervated. Most neurons
decreased their discharge frequencies whether depolarized or hyperpolarized during brief (90 s) inhalation of halothane (Takeda and Haji, 1992). In
contrast to the variable eects of inhaled anesthetics, thiopental depolarized all neurons tested
(Takeda et al., 1990). The individual responses to
anesthetics (Takeda et al., 1990; Takeda and Haji,
1992; Takeda and Haji, 1993) and ethanol (Takeda
and Haji, 1990) of neurons belonging to ostensibly
the same population (e.g. E-BS), although reproducible, may be due to slight dierences in initial conditions rather than to some intrinsic dierence
between neurons (Takeda, personal communication). Interpretation of such diverse results is impossible at this time.
In decerebrate cats, Grelot and Bianchi (1987)
observed a small but signicant halothane-induced
reduction of peak, but not mean, discharge frequencies of 9 BotC E neurons, two of which had projections to the spinal cord, presumably inhibiting
phrenic motoneurons. These neurons belong to the
pool of neurons which probably drive some E-BS
neurons (Bongianni et al., 1988b, 1990; Jiang and
Lipski, 1990). The suppression of E activity, however, was less than that of BotC I neurons and
could explain why, in dogs, higher isourane levels
abolish phrenic activity but E activity persists, albeit
at low tonic levels (Stuth et al., 1992). This observation resembles those reported by other workers
(Cohen, 1968; Bainton and Kirkwood, 1979; Sears
et al., 1982), that at low levels of respiratory drive
(normo- or hyperoxic hypocapnia), tonic E activity
persists and I activity is abolished. Merrill (1974)
reported that the antidromic latencies of E neurons
were minimal under conditions of hyperventilatory
apnea whereas those of I neurons exceeded the
minima (i.e. E neurons were depolarized and I neurons hyperpolarized). These results suggest that low
respiratory drive and some anesthetics aect the circuitry generating respiratory rhythm through similar
mechanisms. However, pentobarbital abolishes abdominal activity without aecting phrenic activity in
decerebrate vagotomized cats (Fregosi et al., 1987).
Thus, the mechanisms by which anesthesia depresses
various populations of respiratory neurons and
motoneurons are still unresolved, in part because of
the diversity of responses.
In dogs, the excitatory eects of central CO2 drive
on canine E-BS neurons are reduced by both
halothane (Stuth et al., 1994) and isourane (Stuth
et al., 1992) but phrenic activity is suppressed, indicating E-BS neurons are less sensitive. At a PaCO2
of 27.5 mmHg, phrenic activity was absent but E-BS

460

S. Iscoe

activity was tonic and unaected by increases in isourane. At PaCO2s of 46 and 68 mmHg, increasing
isourane concentrations depressed peak discharge
frequencies of phasically active E-BS neurons.
However, as indicated above and in Section 5.2, the
use of peak discharge frequency as an index of sensitivity depends on the discharge pattern (AUG or
DEC) and changes in phase duration; DEC neurons
are less susceptible to the eects of changes in phase
duration because their peak frequencies occur at the
onset of the phase. In both studies, frequency was
measured as spike counts in 100 ms intervals, which
becomes progressively less accurate as discharge frequency falls.
Although these results suggest that expiratory
muscles of dogs should be more resistant to anesthetics than the diaphragm, this is not the case. In
dogs, Warner et al. (1994) observed greater reductions of abdominal than inspiratory muscle activity during anesthesia with halothane and
isourane than with pentobarbital. They suggested
that the ndings of Stuth et al. (1994), that E-BS
neurons are relatively insensitive to halothane, are
consistent with a non-medullary (vagal?) origin of
the depression but its source remains unknown.
The eects of anesthetics are complicated by one
other nding. Pentobarbital abolishes TA and EO
activity in dogs (Warner et al., 1992); over time
(4 h), however, and at constant PaCO2 (4649
mmHg) and plasma barbiturate levels, expiratory
muscle activity returns. In contrast, diaphragmatic
and parasternal activity remain constant. These
results indicate the greater instability, for unknown
reasons, of expiratory/abdominal activity compared
to that of the phrenic/diaphragm and intercostals.
6.3. Local Anesthetics
Cortical or neocortical, including hippocampal,
neurons are more easily depressed by hypoxia than
brainstem neurons (Manaker and Zucchi, 1993).
Although local anesthetics promote faster recovery
of hippocampal neurons from hypoxic exposure
(Lucas et al., 1989), I am aware of no studies in
which the eects of local anesthetics on medullary
respiratory neurons, either in vivo or in vitro, have
been tested.
6.4. Development
Farber (1983, 1985) indicates that immature
(<20 d) suckling opossums do not generate expiratory activity in response to loads (CPAP, PPB) or
asphyxia, whether anesthetized or unanesthetized.
As the animals mature, abdominal responses appear
(Farber, 1986); this could reect maturation of the
SAR, central processing of SAR input, the motor
system (including segmental reexes), or some combination. In younger opossums, PPB can suppress
the abdominal response but not that of the dilators
of the upper airway (Farber, 1985). Maturation of
the abdominal responses is faster than that of the
intercostals (Farber, 1986). More rostral muscles are
seldom recruited so the dierence may also be functional rather than just developmental, especially
because forelimb development in young (20100 d)

opossums is relatively advanced. The applicability

of results from suckling opossums, a marsupial, to
placental mammals is uncertain in that it is ``born''
prematurely and develops in the mother's pouch.
However, many workers study neonates; in the presence of rapid development, changes of only a few
days could be critical.
In chloralose-urethane anesthetized piglets (<6 d
or 1421 d) hypercapnia is equally eective in stimulating abdominal activity in both age groups but the
biphasic responses of TA, the diaphragm, and TS to
hypoxia are weaker in the older group (Litmanovitz
et al., 1993). Bilateral vagotomy increases activity of
all muscles, implying an inhibitory eect of vagal
aerents, but does not aect their relative responses
to CO2 and hypoxia.

7. LUNG VOLUME AND PULMONARY

SLOWLY ADAPTING RECEPTORS
7.1. Shifts in End-Expiratory Lung Volume
Abdominal expiratory muscles are activated by
increases in EELV whether evoked by ination
(Russell and Bishop, 1976) or various types of positive pressure breathing (CPAP, PPB, PEEP) or ETL
(Bishop, 1964; Bishop, 1967; Bishop and Bachofen,
1972a; Urbscheit et al., 1973; Mortola and
Sant'Ambrogio, 1973; Kelsen et al., 1977; Baker et
al., 1979; Davies et al., 1980; Farber, 1982; Jammes
et al., 1983a,b; DiMarco et al., 1984; Finkler and
Iscoe, 1984; Farber, 1986; South et al., 1987; Farkas
and De Troyer, 1989; Oliven and Kelsen, 1989b;
Road and Leevers, 1990; Begle and Skatrud, 1990;
Road et al., 1991; Bellemare et al., 1991; Wakai et
al., 1992; Leevers and Road, 1993a; Warner et al.,
1994; Barrett et al., 1994; Leevers and Road, 1995b;
Mateika et al., 1996), or negative body surface
pressure (Begle and Skatrud, 1990; Brice et al.,
1991; Erickson et al., 1994). In most supine awake
and all sleeping (NREM) subjects, CPAP of up to
15 cmH2O does not recruit abdominal muscles
(Wakai et al., 1992). The response may therefore
depend in part on the technique used to increase
EELV; negative body pressure recruited EO in six
of six but PEEP in only three of six sleeping
(NREM) subjects (Begle and Skatrud, 1990). The
role of expiratory muscle activity in limiting
increases in EELV, thereby protecting diaphragmatic function, is described in many of the cited
papers and has recently been reviewed by De Troyer
and Loring (1995), Younes (1995), De Troyer
(1997), Decramer (1997), Epstein (1994) and, in relation to neuromuscular diseases, by Rochester and
Esau (1994).
Posture aects abdominal muscles indirectly by
inuencing EELV, ventilation/perfusion distribution, and upper airway geometry (possibly dead
space), the rst aecting SAR and segmental
reexes, the latter two aecting PaCO2 and therefore drive to respiratory muscles. It may however
have a direct component since stretching the
muscles, particularly the internal TA and IO, probably reexly increases, via spindle aerents, the ex-

Control of Abdominal Muscles

citability of their motoneurons, perhaps driving

them above threshold.
Changes in posture from the supine to the upright
or standing position, which allows gravity to distend
the abdomen, increasing EELV, recruit abdominal
activity regardless of species (Mortola and
Sant'Ambrogio, 1973; Davies et al., 1980; Strohl et
al., 1981; De Troyer, 1983; Lopata et al., 1985a;
Goldman et al., 1987; De Troyer and Ninane, 1987;
Baer et al., 1987; Gilmartin et al., 1987; Hoit et al.,
1988; Farkas et al., 1988; De Troyer et al., 1989;
Farkas and De Troyer, 1989; Farkas and Schroeder,
1990; Bellemare et al., 1991; Gorini and Estenne,
1991; Barrett et al., 1994; Abe et al., 1996) although
RA, in one study, was silent in all postures (de
Sousa and Furlani, 1974). Two exceptions to this
`rule' merit attention. All abdominal muscles in the
upright naive subjects of Hodges et al. (1997) were
silent and when activity did appear, it could be suppressed by instructing the subjects to relax. Puckree
et al. (1998) have recently reported that in one
upright subject only one of 55 motor units in IO
and none of 24 in TA were phasically active during
quiet breathing. Abdominal motor units in the other
two subjects displayed similar discharge characteristics. (The high task specicity demonstrated by abdominal motor unitsonly two units red during
quiet breathing, leg lift, and breathing against an
ETLcontrasts with that of phrenic motoneurons,
most of which re during quiet breathing, coughing
and vomiting (Milano et al., 1992).) In general,
these results conrm those obtained based on thoracoabdominal conguration; when supine, conscious
subjects return to the passive end-expiratory position, indicating that expiratory muscles are silent
(see also Aliverti et al., 1997); when sitting, however,
they breathe such that the antero-posterior dimension of the abdomen is less at end-expiration, indicating use of expiratory (probably abdominal)
muscles (Loring and Mead, 1982; Lopata et al.,
1985a) although considerable variation is observed
both within and between subjects. Mortola and
Sant'Ambrogio (1973) concluded that postural
changes are more eective than loads in stimulating
abdominal activity, even with identical increases in
EELV, because tilting to the upright posture elicits
a segmental (proprioceptive) contribution due to
greater stretch of the abdominal muscles. This reex
should be greater in the dependent (lower) regions
because of the greater hydraulic load, resulting in
more activity, and this is indeed observed (Strohl et
al., 1981; Martin and De Troyer, 1982; De Troyer,
1983; Hoit et al., 1988); the load required to evoke
phasic abdominal activity is less when subjects are
upright (Barrett et al., 1994). In addition, the preferential recruitment of internal abdominal muscles
during postural changes suggests that they are
stretched more (Gilmartin et al., 1987; De Troyer et
al., 1989; Leevers and Road, 1993b; Abe et al.,
1996). On the other hand, Misuri et al. (1997)
recently reported that EO in seated human subjects
thickens (contracts ) more than the other abdominal
muscles during trunk rotation.
In awake subjects, inspiratory elastic and resistive
loads evoke abdominal (RA and EO) activity only
when upright (Martin and De Troyer, 1982),

461

suggesting the importance of proprioceptive reexes.

In anesthetized cats, dorsal rhizotomy (T8L3)
abolishes abdominal responses to loads (Bishop,
1964); tilting to the upright position, but not CPAP,
still elicits abdominal activity in vagotomized
anesthetized dogs (Bellemare et al., 1991). Extension
of the forelimbs of anesthetized dogs increases both
EO and TA (and TS) activity (Schroeder et al.,
1991); this eect, however, is absent if the change in
lung volume is small (Schroeder et al., 1991). While
most researchers indicate the position of the experimental animals, they seldom indicate forelimb
position. When an animal is prone, even in a stereotaxic frame, few indicate if the abdomen was supported; spindle and possibly tendon organ, aerent
activity will dier from that of an animal whose
abdomen is pendant. Paralysis of the prone animal
in a stereotaxic frame will, by abolishing muscle
tone and causing greater stretch of the pendant
abdomen (Da Silva et al., 1977), increase spindle
and possibly tendon organ activity. Moreover,
motor activity varies within an abdominal muscle
depending on its placement in the gravitational eld;
dependent parts of the muscle will be more active
(e.g. De Troyer, 1983; Hoit et al., 1988). Variable responses of abdominal muscles from dierent laboratories may therefore reect not just dierences in
EELV due to the animal's posture and limb position
but also whether or not the abdomen was pendant.
The eects of posture on regional activities are illustrated by the results of one study in conscious
dogs (De Troyer et al., 1989). While sitting, all eight
dogs had phasic TA, four had phasic EO, and one
phasic RA; results were similar in other postures
although, in six of seven dogs, there was more TA
activity sitting than standing and in seven of seven,
more TA activity sitting than prone. The dierences,
discounting any changes in CO2 levels in the dierent postures, may be due to increased hydraulic
loads in the sitting compared to the standing and
prone postures, leading to more proprioceptive feedback and reex enhancement of abdominal activity.
Such feedback, if present, appears to have been directed at TA rather than EO/IO and completely
absent in RA. The absence in dogs of tonic activity,
observed in upright humans, is surprising but may
reect the smaller hydraulic loads or recording sites
in non-dependent regions. TA activity and the eect
of posture on TA activity persisted after bilateral
vagotomy in four dogs. However, interpretation of
the responses to changes in posture is complicated
by the prolonged TE post-vagotomy; since TA activity had an AUG discharge pattern, measurements
of peak integrated activity could overestimate the
retention of abdominal activity, particularly if postural changes also aect TE (see below). Nevertheless, these data suggest that non-pulmonary input(s),
possibly proprioceptive, inuence abdominal motor
activity. Considerable caution should therefore be
used in interpreting the eects of vagotomy on abdominal responses in anesthetized animals.
Abdominal activity increases or decreases immediately (rst breath) upon application or removal of a
load (e.g. Bishop, 1964, 1967; Bishop and Bachofen,
1972a; Mortola and Sant'Ambrogio, 1973; Finkler
and Iscoe, 1984), indicating the response, which is

462

S. Iscoe

abolished by vagotomy (e.g. Bishop and Bachofen,

1972a; Russell and Bishop, 1976), to be neural, not
humoral, in origin. The powerful eect of SAR
input is illustrated by its ability to elicit abdominal
activity even in dogs anesthetized with halothane,
despite this anesthetic's suppression of expiratory
activity in this species (Warner et al., 1994) (Section
6.2). Load-induced increases in abdominal activity
after vagotomy, if they occur at all, are smaller
regardless of species or state (awake or anesthetized)
(De Troyer and Ninane, 1987; Gilmartin et al.,
1987; Farkas et al., 1988; Bellemare et al., 1991;
Brice et al., 1991; Gorini and Estenne, 1991; Road
et al., 1991; Leevers and Road, 1995b). Postvagotomy responses to loads are delayed, indicating
a humoral origin (Bishop, 1964). Proprioceptive
reexes, due to stretching of the muscles, particularly the IO and TA, also contribute. Bishop (1964)
has demonstrated that dorsal rhizotomy (T8L3)
eliminates the abdominal response to PPB in
anesthetized cats with intact vagi. The importance,
perhaps necessity, of proprioceptive input to recruitment of abdominal muscles when EELV increases is
illustrated by the observation in apneic anesthetized
cats that expiratory internal intercostal activity elicited by lung ination is abolished by thoracic dorsal rhizotomy of the same segment (Sears, 1964d).
The failure of awake dogs to recruit TA or EO
during hypoxia or hypercapnia when the vagi are
blocked (Yasuma et al., 1993), a result unlike that
of others (Ledlie et al., 1983; Fregosi et al., 1987; De
Troyer et al., 1989;), has been attributed to the
recumbent posture of the dogs because even small
shifts in posture, with a probable eect on proprioceptive reexes, resulted in the appearance of activity. This nding emphasizes how easily the
responses of abdominal muscles may be aected by
factors which are dicult to control and which may
account for the considerable variation of responses,
both within and between animals observed in many
studies. Moreover, it suggests that segmental
reexes, set by the resting length of the muscles, inuence the sensitivity of abdominal motoneurons to
descending drive.
Interpretation of the response which persists after
vagotomy is complicated not just by proprioceptive
inputs but also by changes in PCO2. For example,
in supine anesthetized dogs tilted to the head-up
position, TA activity still increases after vagotomy,
albeit less than pre-vagotomy (Gorini and Estenne,
1991). Because, however, PETCO2 in the upright
posture was less than the pre-vagotomy value, the
response probably underestimates that present
under isocapnic conditions. The relative contributions of segmental reexes and CO2-related drive
to postural changes and loads have yet to be determined.
State also inuences the abdominal response to
changes in EELV. In Dial-urethane anesthetized
cats, PPB does not elicit abdominal activity after
lower cervical or upper thoracic cordotomy despite
intact vagi (Bishop, 1964), even when CO2 levels
increase due to hypoventilation (Bishop and
Bachofen, 1972a; 1972b), possibly because spinal
reexes were suppressed by the anesthetic. In contrast, abdominal responses to loads that increase

EELV persist even after vagotomy in awake dogs

(De Troyer et al., 1989; Leevers and Road, 1995b),
although the response was less despite similar
PaCO2s (Leevers and Road, 1995b).
In the absence of EMG recordings, increased abdominal activity can be inferred from changes in
Pga during expiration or displacements away from
the relaxed pressurevolume relation of the abdominal compartment (see Grimby et al., 1976; Loring
and Mead, 1982; Lopata et al., 1985a; Aliverti et al.,
1997). Activation of abdominal muscles increases
during exercise (Henke et al., 1988; Aliverti et al.,
1997) or breathing against an ETL (Wolfson et al.,
1983) in healthy subjects, during CO2 rebreathing
(Lopata et al., 1985a; b) or breathing against CPAP
in patients with chronic obstructive lung disease
(Petrof et al., 1990), or in response to histamineinduced bronchoconstriction in asthmatics (Martin
et al., 1980, 1983). These responses were measured
under steady-state conditions when interpretation of
the responses is complicated by changes in blood
gases, proprioceptive feedback, adaptation of the
receptors, and habituation of the centrally-mediated
response.
7.2. Occlusions (``No-Ination Tests'')
Occlusions have been used to test the response of
putative premotor neurons, motoneurons, and
motor units during a single respiratory cycle.
Because responses occur before changes in blood
gases, they can be attributed to neural reexes.
Cohen et al. (1985) observed that withholding lung
ination (the `no-ination test') from decerebrate
cats ventilated in phase with phrenic activity delays
the onset but increases the duration, and therefore,
peak amplitude, of the internal intercostal (T8)
nerve and cVRG E unit activity (Fig. 6A); the rates
of rise of their activities either decrease (ramp and
some step-ramp units) or do not change consistently
(step-ramp units) during the expiratory phase of the
no-ination test. These results suggest that reduced
SAR feedback during the no-ination test (Iscoe
and Gordon, 1992) increases E unit activity by
prolonging TE. Similar results were obtained by
Bajic et al. (1992) in anesthetized dogs (Fig. 6B).
Fregosi et al. (1990), also studying decerebrate
cats, obtained dierent results in their study of the
responses of L1 to no-ination tests but reached a
similar conclusion. TE is prolonged and peak integrated abdominal activity increases (Fig. 7A). This
increase in activity is not, however, due to prolongation of TE because peak activity occurs at the
onset of the burst and results from an increase in
slope at the onset of L1 activity. Phasic SAR feedback, they concluded, inhibits abdominal activity
because, in its absence, L1 activity increases. They
proposed two explanations: (1) prolongation of TE
and (2) delayed inhibition of E-BS neurons by phasic SAR feedback. The ``delay'' occurs because the
inhibitory eects of SAR activity during inspiration
do not appear until the expiratory phase. The rst
explanation is untenable because the greater peak
integrated L1 activity occurred at the start of expiration. The second requires that the eect of SAR
input on the discharge of E neurons be delayed;

Control of Abdominal Muscles

463

Fig. 6. Responses of expiratory neurons and/or expiratory EMG to withholding of lung ination for one
respiratory cycle in a paralyzed, ventilated decerebrate cat. (A) Traces from top down: binned integrated
phrenic activity (Phr), tracheal pressure (Ptr), T8 internal intercostal nerve (IntIC), and activity of a
ramp expiratory neuron of the nucleus retroambigualis (Unit). Withholding lung ination delayed onset
of internal intercostal and unit activity, did not aect rate of increase in activity, but increased peak activity because of phase prolongation. Modied with permission from Cohen et al. 1985. (B) Averaged
control and no-ination responses of four E-BS DEC (a) and four E-BS plateau (AUG) (b) neurons
from thiopental-anesthetized paralyzed dogs. Heavy lines, control discharges; thin lines, no-ination responses; horizontal lines, 1 s. Down arrow indicates onset of expiration, rst and second up arrows indicate onset of inspiration (phrenic activity) during control and no-ination cycles, respectively. Responses
to no-ination varied between neurons; rates of increase in discharge frequency of neurons in top panels
were unaected during no-ination cycle whereas those of neurons in lower panels increased. DEC neuron in lower left panel discharged only during control (ination in inspiratory phase) cycles. Plateau neurons had higher discharge frequencies than DEC neurons but only DEC neurons increased their peak
discharge frequencies during no-ination cycles. Modied with permission from Bajic et al. 1992.

during no-ination respiratory cycles, delays of as

much as several hundreds of milliseconds occur
(Cohen et al., 1985). Modeling of the eects of electrical stimulation of SAR aerents on TE indicates
that central (brainstem) `integration' of SAR input
can involve mechanisms (temporal summation) with
time constants of 00.8 s and 018 s (Zuperku et al.,

1982) but the underlying mechanism(s) remain

unknown.
Rebound excitation following the termination of
inspiration could account for the increased rate of
rise of integrated L1 activity during the no-ination
test (Fig. 7A; Fregosi et al., 1990). The rebound
would be greater because increased I activity during

464

S. Iscoe

Fig. 7. Rebound excitation of expiratory neuron or abdominal motor units following termination of ination or
prolongation of inspiration. (A) Eect of withholding lung
ination for one respiratory cycle in a paralyzed, servoventilated decerebrate cat with open chest wall. Traces
from top down: integrated abdominal (TA) activity
(fAbd), integrated phrenic activity (fPhr), and tracheal
pressure (PTR). Rate of rise of abdominal activity was
greatly augmented during occluded cycle. Reproduced with
permission from Fregosi et al. 1990. (B) Eect of a ramp
ination during expiration on discharge of an E-BS DEC
neuron in an anesthetized dog. Traces from top down:
binned discharge frequency of the neuron and tracheal
pressure (PTR). Heavy solid lines, control discharge and
PTR; lighter lines, test cycle. Horizontal bar indicates control inspiratory phase. PTR >4 mmHg decrease discharge
frequency. Sudden withdrawal of ination results in
rebound excitation of the neuron. Modied with permission from Bajic et al. 1992.

the no-ination test would cause greater inhibition

of E neurons during the inspiratory phase; this may
apply to the results of Fregosi et al. (1990) because
L1 activity started immediately at the onset of the
expiratory phase. In contrast, the onset of E activities in the study of Cohen et al. (1985) was delayed.
Rebound excitations of E-BS neurons do, however,
occur when inations in expiration terminate
(Fig. 7B) (Bajic et al., 1992; Tonkovic-Capin et al.,
1992), indicating that SAR inputs generate inhibitory inputs to many E-BS neurons. In pentobarbital-anesthetized spontaneously breathing dogs,
however, occluded inspirations do not result in
increased TA activity during the expiratory phase
following the occlusion (Arnold et al., 1988). The
reasons for this discrepancy are unclear. Although
the preparations are very dierentthe cats had bilateral pneumothoraces and were paralyzed and ventilated (positive pressure) whereas the dogs breathed

spontaneously (sub-atmospheric pressures)this

does not cause major changes in SAR discharge patterns. During no-ination tests in paralyzed ventilated preparations, phasic SAR input is abolished;
in spontaneously breathing animals, however, SAR
input persists during occlusions, albeit at a reduced
levels, because of distortion of the airways (Iscoe
and Gordon, 1992). Moreover, proprioceptive feedback from the abdominal and rib cage muscles in
paralyzed ventilated animals depends only on the
degree of passive stretch of the muscles but will
change, presumably increase, during occluded
inspiratory eorts in its spontaneously breathing
counterpart. Thus, interpretations of the eects of
no-ination tests in paralyzed ventilated animals are
less complicated than those of occlusions in spontaneously breathing animals because of the absence
of feedback from other parts of the respiratory system (e.g. chest wall proprioceptors; Shannon, 1980).
However, we know little about the eects of such
feedback, both segmental and supraspinal, on abdominal activity.
The importance of post-inhibitory rebound to EBS discharge pattern is, however, still debatable.
Zuperku and colleagues (personal communication)
indicate that marked changes in both the duration
and intensity of phrenic discharge induced by inhalation of isourane had no eect on the peak discharge frequency of E-BS neurons in pentobarbitalor halothane-anesthetized dogs. Moreover, in the
same preparation, picoinjections of picrotoxin, a
GABAA receptor channel blocker at the site of
recording from an E-BS neuron results in the neuron starting to re during inspiration but its peak
discharge frequency at the onset of expiration is
unaected. Because nothing is known of the eects
of anesthetics on post-inhibitory rebound, it would
be of interest to determine if similar ndings can
also be obtained in decerebrate preparations and if
the peripherally (SAR)-mediated post-inhibitory
rebound described by Fregosi et al. (1990) is aected
by anesthetics.
The ionic basis for post-inhibitory rebound, by
which events in one phase (e.g. increased activity of
I neurons) aect the discharge patterns of E neurons
during the accompanying expiratory phase (e.g.
increased discharge frequency of discharge at the
onset of expiration) has been tentatively explained
by Richter and colleagues (1993): recovery from inactivation (``deinactivation'') of low voltage Ca2+
channels requires hyperpolarization; the greater the
hyperpolarization of E neurons by I neurons (e.g.
during the increased I activity of the no-ination
test), the greater the discharge of E neurons during
their active phase, and vice versa. This, however,
cannot be the complete explanation because no-ination tests delay, not advance, the onset of discharge of E neurons despite greater I activity
(Cohen et al., 1985).
7.3. Ination in Expiration
Merrill (1968) originally reported that inations
in expiration depress E-BS activity (Fig. 8) and subsequent work conrms his nding. Maintained inations (transpulmonary pressure 07 cmH2O) in

Control of Abdominal Muscles

465

Fig. 8. Eects of inations in expiration on E-BS activities. (A) Instantaneous discharge frequency (top
trace) of an E-BS neuron of a spontaneously breathing anesthetized cat during control (no-ination)
expiratory cycle (left panel), and expirations with superimposed modest (center panel), and high (right
panel) inations (indicated by increase in chest circumference). Modied with permission from Merrill,
1968). (B) Eects of a maintained ination during expiration in a paralyzed, ventilated decerebrate cat.
Traces from top down: average binned integrated phrenic activity (Phr), tracheal pressure (Ptr), T8 internal intercostal nerve (Int IC), and activity of an expiratory neuron of the nucleus retroambigualis
(same neuron as in Fig. 6A). Maintained ination did not delay onset of internal intercostal or unit activity but reduced rate of rise of activity in both. Peak activity increased because of prolongation of
expiration. Modied with permission from Cohen et al. 1985. (C) Averaged discharge frequencies (Freq)
of an E-BS plateau (AUG) neuron in a thiopental-anesthetized paralyzed dog during control cycles
(heavy lines) and expiratory cycles with maintained inations at low (3 mmHg) and high (9 mmHg) tracheal pressures (Ptr). Ptr of 9 mmHg reduced the discharge of the neuron. Phases indicated by phrenic
activity (fPhr, top trace). Modied with permission from Bajic et al. 1992.

expiration reduced the rate of increase in activity of

most E neurons (16 of 21 ramp and ve of 12 stepramp neurons) (Fig. 8B; Cohen et al., 1985) whereas
more moderate inations (<4 cmH2O) caused
greater E neuronal activity. Thus, SAR feedback
exerts dierent eects on E neurons depending on
transpulmonary pressure and, therefore, the level of
SAR feedback.
This was later conrmed by detailed studies by a
Wisconsin group of the responses of E-BS neurons
to SAR input in anesthetized paralyzed and ventilated dogs (Fig. 8C) (Bajic et al., 1992; TonkovicCapin et al., 1992; Bajic et al., 1994). E-DEC neurons are excited at low (1.4 to 06.3 cmH2O) but
`inhibited' at higher (06.3 to 016 cmH2O) transpulmonary pressures; in contrast, E-plateau (their EAUG) neurons are inhibited only by inations at a
transpulmonary pressure >4.5 cmH2O (Bajic et al.,
1992). The eects of a ramp ination show this
eect clearly; the neuron's discharge increased at
low but was suppressed at high tracheal pressures

(Fig. 7B). Similar, but less detailed, results had been

reported earlier for unidentied E neurons in
anesthetized dogs by Koepchen et al. (1973). The inhibitory eect of SAR input (electrical stimulation)
on both E-DEC and E-plateau neurons is mediated
via the ipsilateral vagus whereas the longer latency
excitation of E-DEC neurons is bilateral (TonkovicCapin et al., 1992). They proposed that excitation at
low and inhibition at high transpulmonary pressures
was due either to SAR with dierent responses
to transpulmonary pressure (Miserocchi and
Sant'Ambrogio, 1974) or to dierent central processing of SAR inputs. They also suggested that SAR
input, represented by transpulmonary pressure, controls E-BS discharge; at high transpulmonary pressures, E-BS neurons are inhibited or disfacilitated
because E activity is not needed when passive recoil
of the lung can generate expiratory ow. As expiration proceeds and transpulmonary pressure falls, the
inhibition or disfacilitation decreases and is replaced
by excitation.

466

S. Iscoe

In anesthetized cats, E neurons, some of which

were probably bulbospinal, had discharge proles
during expiratory resistive loading (Baker et al.,
1979) consistent with this proposal. At the onset of
expiration against the load at high transpulmonary
pressures, there was little dierence in discharge frequency between loaded and control cycles; however,
as expiration proceeded and transpulmonary pressure fell, the discharge frequency at a given time
remained high or even increased despite the lower
lung volume.
Other results support the contention that SAR
feedback inhibits E-BS activity. In halothaneanesthetized human subjects, maintained ination
during expiration reduces the intensity of abdominal
activity (Freund et al., 1964). In rats, electrical
stimulation of the vagus at an intensity which presumably stimulates only SAR aerents depolarizes
E-DEC neurons but hyperpolarizes all others
(Hayashi et al., 1996); none was an E-BS neuron.
7.4. Timing
Compensation for changes in timing (TE) when
evaluating the eects of SAR input on abdominal
activity is important. In newborn (<21 d) anesthetized piglets, vagotomy during 7% CO2 inhalation
increased peak TA activity. Because, however, the
discharge patterns appear to have been AUG, a
49% increase in TE due to vagotomy would have
increased peak integrated TA activity. Variations in
the eects of vagotomy on TE in dierent experimental preparations could account for the reported
disparities of the eects of vagal feedback on abdominal activity discussed by Litmanovitz et al.
(1993).
7.5. Neural Basis for Inhibition/Disfacilitation of EBS Neurons
The nature of the stimulus (maintained inations
in E) eliciting reex changes in E-BS activity indicates that it is due to activation of SAR, not RAR
(Long and Dun, 1986). What neurons mediate the
SAR-induced suppression of E-BS neurons? The
eect is not direct (i.e. to inhibitory interneurons in
the cVRG) because SAR aerents terminate in various subnuclei of the NTS (for review, see Kubin
and Davies, 1995). Nor can it be mediated by Ib
neurons, second-order aerents found primarily in
the ventrolateral NTS (part of the DRG), which
also receive central inspiratory drive, because they
are silent during expiration. The only other populations that could be responsible are P (pump) cells
(the other second order aerents), BotC neurons
which have known inhibitory connections to cVRG
E neurons (Section 3.3.1), or early E (DEC) neurons
in the NTS.
P cells were rst described in cat by Euler et al.
(1973) as neurons responding only to lung ination
and having no central inspiratory drive. They have
since been studied more intensively by Berger (1977)
and others (Sessle et al., 1978; Shannon, 1980;
Cohen and Feldman, 1984; Pantaleo and Corda,
1986; Davies et al., 1987; Ezure and Tanaka, 1996;
Ezure et al., 1997), particularly for their role in

the termination of inspiration (Bonham and

McCrimmon, 1990; McCrimmon et al., 1993;
Bonham et al., 1993); they occur ventrolateral,
ventromedial and dorsal to the NTS (for review, see
Kubin and Davies, 1995). The rst detailed study of
their projections (Davies et al., 1987), using antidromic mapping, tested only for projections to the contralateral NTS. Ezure and Tanaka (1996) have
conrmed this projection and others to the ipsilateral BotC, facial nucleus, NA, and, importantly for
this review, axonal arborizations of some P cells in
the ipsilateral cVRG. This pathway could account
for the ipsilateral depression of E-BS activity by
either lung ination or stimulation of SAR (Bajic et
al., 1992; Tonkovic-Capin et al., 1992); the contralateral projection could account for the delayed excitation (Tonkovic-Capin et al., 1992). A recent study
from the same laboratory indicates projections of P
cells to the pontine respiratory group and limited
projections within the medulla of decerebrate cat
(Ezure et al., 1998).
Kirkwood (1995) described three neurons in the
cVRG which discharged only during expiration and
in bursts synchronized to lung ination; because
SAR do not project to this region (see below), these
neurons are likely second order aerents but the
source of their inputs is unknown. One had a monosynaptic projection, as determined by XCOR, to
motoneurons in a mid-thoracic internal intercostal
nerve; another, based on STA of focal synaptic potentials, also projected to the thoracic spinal cord
(Kirkwood, personal communication). These cells
may be identical to the E neurons reported by
Cohen et al. (1985) to be excited by lung ination.
In addition, Bainton and Kirkwood (1979) had previously described E-BS neurons of the cVRG and
expiratory intercostal motor axons with discharges
modulated by lung ination; because their cats had
intact chest walls and vagi, the source of excitation
could not be determined. The rapid ventilator frequency of 90 min1 (cycle duration = 0.67 s, ination duration = 0.33 s at a duty cycle of 0.5)
makes it dicult to determine the phase relation
between ination and medullary neuronal discharge
although Bainton and Kirkwood (1979) reported
that E-BS discharge lagged that of the intercostal
motoneurons by ``about 908'' and that the latter was
``approximately in phase with tracheal pressure''.
More work is therefore needed to determine both
the origin of the ination-mediated modulation of
E-BS discharge and their temporal relations.
Another possible source of SAR-initiated inhibition of E-BS neurons is, as suggested by Cohen et
al. (1985), early E (DEC) neurons of the rostral
NTS. They have three properties which suggest their
involvement: (1) they are excited by ination, (2)
they are located in the region to which SAR project
(see Kubin and Davies, 1995 for review), and (3)
they have DEC discharge patterns, the inverse of
the AUG pattern of the E-BS neurons in cat
(Feldman and Cohen, 1978). Although not abundant (only six of 229 neurons from which recordings
were made; Feldman and Cohen, 1978), their numbers could be underestimated if they have small
somata; moreover, they may act in concert with P

Control of Abdominal Muscles

cells, also found in the NTS. There are no data conrming their projections to E-BS neurons.
Neurons of BotC, which excite or inhibit cVRG
neurons (Bongianni et al., 1988b; 1990; Jiang and
Lipski, 1990), may also mediate the response of EBS neurons to SAR input. P cells projecting to the
ipsilateral BotC (Ezure and Tanaka, 1996) could
mediate the excitation of E-DEC neurons induced
by lung ination (Manabe and Ezure, 1988;
Kanjhan et al., 1995). Although many of these EDEC neurons inhibit various neuronal types in the
contralateral VRG, including vagal E motoneurons,
none of the neurons tested was caudal enough to
have been in the cVRG (Ezure and Manabe, 1988).
Because the axons of these BotC E-DEC neurons
continue caudal to the obex towards the cVRG,
they may be responsible for or contribute to the inhibition of E-BS neurons by lung ination. The reciprocal nature of their discharges (as E-DEC
discharge falls, E-AUG discharge increases), is consistent with this role. However, we still have no
direct evidence for inhibitory connections between
them. Lindsey et al. (1987) describe inhibitory interactions between E-DEC and E-AUG neurons in the
VRG; however, the incidence of inhibition was low
(typically <5% of recorded pairs) and no recordings were made from E neurons more than 1 mm
caudal to the obex. Therefore, data about inhibitory
projections to E-BS premotor neurons are still unavailable.
Two observations complicate the proposal that EDEC neurons of BotC mediate at least part of the
inhibition of E-BS neurons. First, E-AUG neurons
of the BotC, some of which generate monosynaptic
IPSPs in E neurons of the cVRG (Jiang and Lipski,
1990), are suppressed by lung ination (Manabe and
Ezure, 1988); similar results have been obtained in
rat in which maintained lung ination reduces the
activity of most BotC neurons (Kanjhan et al.,
1995). Consequently, E-BS activity should be facilitated (disinhibited) by lung ination. Second, excitation of neurons in the BotC using DLH or
electrical shocks stimulates, not inhibits, E activity
in the cVRG and abdominal (EO) muscles of cat
(Bongianni et al., 1988b; 1990). In rabbits, however,
microinjection of DLH into BotC reduces both I
and E activity (Bongianni et al., 1997b), suggesting
a very dierent neuronal organization in this species
or a dierent functional response to lung ination.
Adult rabbits have stronger BreuerHering reexes
than other species (Widdicombe, 1961; Gaultier and
Mortola, 1981).
Comparison of results from dierent species, particularly ones of dierent sizes, is risky. Mead stated
in 1976 (Mead, 1976) that guinea pigs, because of
their small size, ``never get up''. In other words, a
change in posture from the prone to the upright
position does not generate the large hydraulic loads
and, therefore, the shifts in EELV characteristic of
larger animals. As a result, the guinea pig does not
defend EELV as do conscious, naive human subjects. It, and other small animals, can aord to have
stronger BreuerHering reexes because they do not
experience large posture-induced changes in lung
volume. Therefore, considerable caution should be
used in extrapolating ndings from rats, increasingly

467

used as an experimental model for respiratory control, to larger ones when studying respiratory (and
abdominal muscle) control in response to shifts in
EELV, whether caused by loads or postural shifts.
Interpretation of such results is further complicated
because anesthesia strengthens the BreuerHering
reexes (e.g. Sant'Ambrogio and Widdicombe, 1965;
Finkler and Iscoe, 1984).
In summary, two opposing eects operate when
EELV increases. Evidence from dierent laboratories and preparations uniformly indicate that
increases in EELV and expiratory loads) recruit
and/or increase the discharge frequency of abdominal motoneurons. Yet evidence also clearly establishes that SAR inputs depress the discharge of EBS neurons and expiratory (intercostal and abdominal) motoneurons at high transpulmonary pressures
or during larger inations. This apparent contradiction is resolved as follows: although E activity is
both delayed and suppressed (increases more slowly)
when SAR input increases, this is more than oset
by the prolonged TE which allows peak E activity to
reach greater values. The reduction in E activity at
the onset of expiration at increased lung volumes
does not compromise expiration because the higher
transpulmonary pressure provides the necessary
driving pressure for expiratory ow. The neural
pathway responsible is unknown. The applicability
of these results, obtained primarily from animals, especially dogs, which use abdominal muscles at rest
to drive EELV below the passive position at endexpiration, to man in whom expiration is typically
passive, is also unknown.

8. CHEMICAL DRIVE
In this section, I review the control of abdominal
motoneurons and muscles and E premotor neurons
by central and peripheral chemoreceptors; literature
which focuses on inspiratory (phrenic or diaphragmatic, occasionally intercostal) activity is therefore
excluded. The roles of hypoxia and hypercapnia in
respiratory control are detailed in recent reviews
(Haddad and Rosen, 1991; Bisgard and Neubauer,
1995; Nattie, 1995).
8.1. General Considerations
To demonstrate that hypercapnia or hypoxia
alone increases abdominal activity, other inputs
must be either controlled or eliminated. These
include SAR feedback (due to ination and/or shifts
in EELV; eliminated by blocking their aerents,
typically by vagotomy or by ventilating at xed tidal
volume, VT, and frequency, f), proprioceptive feedback from the chest wall (by pneumothorax in
paralyzed ventilated preparations and/or xation of
posture), input from peripheral chemoreceptors
when testing the eects of central chemoreceptor activation (blocked by hyperoxia or peripheral chemoreceptor denervation), input from central
chemoreceptors when testing the eects of peripheral chemoreceptor activation (by using discrete peripheral stimuli with responses too rapid to be due to
activation of central chemoreceptors; e.g. Eldridge,

468

S. Iscoe

1976; Marek and Prabhakar, 1985; Fregosi et al.,

1987; C. A. Smith et al., 1990; Fregosi, 1994b),
maintaining isocapnia, by cooling of (Haxhiu et al.,
1985; Chonan et al., 1991), or application of local
anesthetic to (Schwanghart et al., 1974), the ventral
medullary surface, the putative site of central chemoreceptors), and blood pressure (by preventing
changes with a pressure reservoir added to the arterial circuit (Melton et al., 1992; England et al., 1995)
or by in vitro experiments).
The chemical environment of the brainstem (the
central chemoreceptors, neurons which drive the EBS neurons, and the E-BS neurons themselves), is
particularly dicult to control for three major
reasons. First, hypoxia and hypercapnia both
increase cerebral blood ow (Borgstrom et al., 1975;
Johannsson and Siesjo, 1975; Nolan and Davies,
1982a,b; Nolan et al., 1982; Neubauer et al., 1985;
Davies et al., 1986; Fortune et al., 1992), washing
out CO2 in open (non-rebreathing) circuits; hypoxia
is particularly eective in increasing blood ow to
the caudal brainstem in awake cats (Nolan et al.,
1982; Neubauer and Edelman, 1984). The increase
in cerebral blood ow due to hypoxia is, however,
limited by the hypocapnia resulting from the
increase in ventilation during hypoxia (Shapiro et
al., 1970; Davies et al., 1986); the decrease in central
(CO2) respiratory drive accounts for the depression
of ventilation in dogs with central hypoxia and normoxic carotid bodies (Lee and Milhorn, 1975).
Second, hypoxia decreases tissue PCO2 due to the
Haldane shift. And third, both hypocapnia and hypoxia aect metabolism, increasing lactate production (Granholm and Siesjo, 1969; Musch et al.,
1983; LaManna et al., 1996; see Haddad and Rosen,
1991 and Haddad and Jiang, 1993 for review) which
acidies brain extracellular uid (ECF) during
hypoxic exposure (Davies et al., 1986). Hyperventilation and the resulting alkalosis oset to an
unknown degree any tissue acidication resulting
from increased lactate production. The increase in
cerebral blood ow is due to hypoxia, not tissue
acidosis, because increases in blood ow precede
any build-up in lactate (Borgstrom et al., 1975).
Interestingly, hypoxia potentiates the responses of
neurons of the rostral ventrolateral medulla (the rostral chemosensitive area) to increases in [H+]
(Jarolimek et al., 1990). The relative contributions
of these factors may account for variable results
between studies.
If E-BS neurons are sensitive to CO2 or CO2-related input (which depends on state/anesthetic
level), then even small local changes in CO2 could
account for dierent results between studies.
Hypoxia-induced increases in cerebral blood ow
occur even in peripherally denervated cats in which
ventilation decreases, the initial decrease in [H+] at
the ventral medullary surface being consistent with
increased perfusion (Nolan et al., 1982; Neubauer et
al., 1985). As hypoxia becomes more severe, ventilation continues to fall even though [H+] increases
above control values, presumably because of anaerobic metabolism (see Musch et al., 1983). Why
ventilation fails to increase is still unclear but may
be related to a hypoxia-induced hyperpolarization
of central chemoreceptors, i.e. a decreased [H+] gra-

dient across the cell membrane due to increased intracellular production of lactic acid (Severinghaus,
1995); the ventilatory response to CO2, which is not
impaired by hypoxia (Kiwull-Schone and Kiwull,
1983), is thus explained by restoration of this gradient by increased PaCO2 (Severinghaus, 1995).
Correcting for changes in cerebral blood ow is
dicult. Addition of CO2, for example, to the inspirate of subjects hyperventilating in response to hypoxia does not guarantee brain isocapnia because
neither PETCO2 nor PaCO2, used as indicators of
isocapnia, accurately represent brain PCO2 in open
circuits, especially because cerebral blood ow is
only a fraction of total systemic ow. Although ventilation decreases in peripherally chemodenervated,
anesthetized, spontaneously breathing cats during
`isocapnic' hypoxemia in the absence of changes in
PCO2 and [H+] of medullary extracellular uid
(Javaheri and Teppema, 1987), gradients in PCO2
and especially [H+] between the extracellular uid
and the tissue may persist. In experiments in which
O2 and/or CO2 levels are changed, the resulting
alterations in cerebral blood ow and metabolism
make it dicult, if not impossible, to attribute
changes in activity of medullary respiratory neurons,
spinal motoneurons, and motor units to changes in
O2 or CO2 levels in arterial blood or alveolar gas.
Thus, claims of isocapnia in many experiments
should be viewed with caution, if not scepticism.
Recent work in anesthetized dogs also shows that
a low PCO2 of the blood perfusing the carotid bodies
reduces the ventilatory response to concurrent hypoxic stimulation of the carotid body (C.A. Smith et
al., 1997). Thus, interpretation of responses to hypoxia depends not just on brainstem but carotid
body PCO2. Since the carotid body has a high blood
ow, its PCO2 is likely independent of local metabolism, reecting only the degree of hyperventilation.
In other words, hyperventilation in response to hypoxia is limited not just by central alkalosis but by
carotid body hypocapnia.
In vitro studies, although they have their own
technical demands, `merely' involve changing the
concentration of the gases with which the superfusate is equilibrated and that of the gas above the
slice. I know of only one study of the eects of
changes in gas concentration in either the superfusate or the gas to which the slice is exposed on
metabolism (e.g. lactate production) and the acidbase status of the slice; increasing the acidity (with
CO2 or xed acid) of the superfusate of isolated
brainstem spinal cord of the neonatal rat increases
tissue [H+] (Okada et al., 1993a). The situation is
complicated even when recordings are made from
medullary neurons in vivo. Exposure of the medulla
to air results in loss of CO2 from the tissue (Navari
et al., 1978); the resulting constriction of surface
blood vessels reduces perfusion, causing local acidemia just below the surface (Arita et al., 1989), an
eect which can counter any hypoxia-induced
increase in perfusion (Nolan and Davies, 1982b).
Depending on the extent of exposure, the responses
of putative chemoreceptors near the ventral medullary surface can be aected.
Changes in the chemical environment of the
brainstem due to, for example, inhalation of hypoxic

Control of Abdominal Muscles

gas mixtures complicates interpretation of the responses of medullary respiratory neurons to activation of the peripheral chemoreceptors. The
resulting brain hypocapnia would lead to decreased
central respiratory drive, reducing neuronal discharge, leading to an underestimate of the eects of
peripheral chemoreceptor activation. Attempts to
maintain arterial or alveolar `isocapnia' by adding
CO2 to the inspired gas do not necessarily result in
brain isocapnia; thus, responses of medullary respiratory neurons will be aected, to an unknown
degree, by their acid-base environment and that of
the central chemoreceptors. Aside from any direct
neuronal eects of O2 and CO2, the eects of
changes in perfusion should be considered when
evaluating claims that peripheral and central chemoreceptors project primarily to I and E neurons,
respectively (see below).
The eects of descending inuences (e.g. from
forebrain in conscious animals) are dicult to control and even harder to interpret; decerebration
eliminates variations in anesthetic depth but some
mesencephalic structures, now free from inhibition
from ablated rostral ones, can inuence brainstem
respiratory function. Hypoxia, by depressing forebrain structures, acts somewhat like decortication
and decerebration (see Bisgard and Neubauer,
1995). The ventilatory response to hypoxia in the
absence of peripheral chemoreceptors depends on
the state of the animal; hypoxia depresses ventilation in anesthetized animals but stimulates it in
conscious ones (see below). The results in conscious
animals may reect the loss of cortically-induced
suppression of the excitatory eects from the diencephalon on the brainstem respiratory centers, i.e. disinhibition (Tenney and Ou, 1977).
In experiments designed to assess the role of central chemoreceptors in the regulation of expiratory
activity, hyperoxia is often used under the assumption that peripheral chemoreceptor input is abolished. However, their discharge persists in cats,
albeit at low levels, even at PO2s approximating 400
mmHg (Lahiri et al., 1981; Davies et al., 1982;
Fitzgerald and Dehghani, 1982; Mokashi and
Lahiri, 1991); carotid body chemoreceptor responses
to CO2 are blunted but not abolished by hyperoxia
(Lahiri and DeLaney, 1975). It is unclear if this
applies to other species.
Developmental status (maturation) aects the responses to chemical stimuli and their interpretation.
Neonates, for example, do not sustain the ventilatory response to hypoxia, perhaps because of
dierences in brainstem neuronal responses to hypoxia (see below), but also because of dierences in
their metabolic response to hypoxia (see Mortola
and Gautier, 1995; Gautier, 1996; Mortola, 1996 for
review). A newborn's O2 consumption is not limited
by O2 availability because, at a given level of hypoxia, it can still increase its O2 consumption
(Rohlicek et al., 1998). Thus, some unknown mechanism, possibly operating via the hypothalamus
which includes neurons sensitive to hypoxia (Dillon
and Waldrop, 1992, 1993; Ryan and Waldrop,
1995), is responsible for the newborn's `decision' to
lower its metabolism; this, naturally, has consequences for respiratory regulation.

469

8.2. Carotid Chemoreceptors

Carotid body chemoreceptor aerents terminate
almost exclusively in subnuclei of the NTS in both
rat and cat (Lipski et al., 1977a,b; Berger, 1979;
Panneton and Loewy, 1980; Davies and Kalia, 1981;
Claps and Torrealba, 1988; Housley and Sinclair,
1988; Finley and Katz, 1992; Sapru, 1996). Kainic
acid-induced lesions of the sites to which these aerents project in the rat greatly reduce, and almost
abolish, the ventilatory response to hypoxia
(Housley and Sinclair, 1988). However, in cats,
Davies and Edwards (1973) observed short-latency
responses to shocks to the carotid sinus nerve in
both the NTS and the NA at the level of the obex
and Davies and Kalia (1981) reported the presence
of labeled bers and some labeled cells in the NA
following injection of HRP into a carotid sinus
nerve. Finley and Katz (1992) reported, in rat, a
heavy projection to the NTS and a substantial projection to the NRA following microinjection of
WGA-HRP into the vascularly isolated carotid
body; they attributed the labeling in the NRA to
higher concentrations of the label in the isolated carotid body and longer survival times (4 d vs typically
2 d in other studies). It may therefore be premature,
at least in rats, to discount a projection of carotid
chemoreceptors to the VRG, but more studies are
needed.
Discrete stimulation of the peripheral, almost
invariably carotid, chemoreceptors provides information about their projections to medullary neurons
and respiratory motoneurons when latencies of the
responses, to either electrical shocks or more `natural' activation of the carotid chemoreceptors, are
suciently short to exclude activation of the central
chemoreceptors. These procedures eliminate or
reduce many of the diculties associated with
steady-state stimulation of the central and peripheral chemoreceptors by inhalation of gas mixtures.
8.2.1. Abdominal Responses
Electrical (Eldridge, 1976; Marek and Prabhakar,
1985; Fregosi et al., 1987; Fregosi, 1994b) or chemical (NaCN; (e.g. Hedrick et al., 1998); hypoxia (several breaths of N2; C.A. Smith et al., 1990; Praud et
al., 1993); almitrine (Fregosi et al., 1987; Saupe et
al., 1992)) stimulation of carotid sinus aerents activates abdominal motor unit or nerve activity. (Some
cats, however, also display inhibitory responses to
stimulation of carotid chemoreceptors by close
arterial injections of NaCN (Fregosi et al., 1987).)
The long (>75 ms) latency of the response following electrical stimulation of the carotid sinus nerve
in expiration suggests a polysynaptic and unknown
pathway (Eldridge, 1976). Brief electrical shocks to
the carotid sinus nerve (and the aortic sinus nerve
and ventral medullary surface) aect expiratory
intercostals and abdominal muscles only when delivered in expiration (Marek and Prabhakar, 1985).
Although the phase-dependence of responses is not
criticalexcitatory inputs may be ineective while a
motoneuron is being inhibited, i.e. gatedthese
results show that peripheral chemoreceptors can
excite E neurons. Marek and Prabhakar (1985) had
no explanation for the longer latencies of excitation

470

S. Iscoe

of E than I activities (80120 ms during stimulation

in expiration versus 1525 ms for the latter when
stimuli were delivered in inspiration). These transient responses can dier markedly from the steadystate eects of hypoxia, which reduce abdominal (or
internal intercostal) activity in some studies
(Bouverot and Fitzgerald, 1969; Sears et al., 1982;
Fregosi et al., 1987; Fregosi and Bartlett, 1989).
Smith et al. (1990a), unlike Fregosi and Bartlett
(1988), observed no link between I activity and E responses; increased TA activity could occur with or
without changes in diaphragmatic activity, implying
that the amplitude of the preceding inspiratory
eort did not necessarily aect that of the subsequent expiratory burst. Because both I and E
motor activities are excited by stimuli delivered
during their respective active phases, peripheral chemoreceptor inputs to I and E premotor neurons
may be direct or mediated via neurons, including
non-respiratory ones, which are not inhibited during
part of the respiratory cycle (see below).
In chloralose-anesthetized spontaneously breathing cats, electrical stimulation is more eective than
isocapnic hypoxia in increasing EO and IO, but not
TA, activity when data are compared at the same
ventilatory levels; systemic hypercapnia is more
eective than hypoxia in increasing EO and IO
activity but only at ventilations greater than 2.5 L
min1 (Fregosi, 1994b). These results imply central
hypoxic depression of peripheral chemoreceptorinduced stimulation of respiratory activity.
Vagotomy abolishes the abdominal responses to
stimulation of carotid chemoreceptors by hypoxia
or almitrine and reduces the responses to hypercapnia. This suppression, which is not observed in conscious animals (e.g. Saupe et al., 1992; Praud et al.,
1993; Leevers and Road, 1995b), may reect the
eects of anesthesia and/or posture (see Yasuma et
al., 1993) and suggests that the dependence, in cats,
of abdominal activity on SAR feedback (Russell
and Bishop, 1976) may be an artifact of anesthesia.
At similar levels of hyperpnea elicited by stimulation of carotid (almitrine) and central (CO2 inhalation) chemoreceptors in awake dogs (Saupe et al.,
1992), expiratory (abdominal) and inspiratory (diaphragm and parasternal) muscles are activated
equally, indicating no preferential distribution of
peripheral and central chemoreceptor inputs to I
and E neurons, respectively. Similar results have
been obtained both in awake goats (Engwall et al.,
1994; Hedrick et al., 1998) responding to hypoxia,
systemic hypercapnia and NaCN, even after termination of the stimulus when the excitatory response
persists (Engwall et al., 1994), and in awake dogs in
whom reduction or inhibition of carotid body chemoreceptor feedback by hyperoxia or infusion of
dopamine reduces both inspiratory and expiratory
(TS and TA) activities (C.A. Smith et al., 1990).
Saupe et al. (1992) argued that other results indicating a preferential eect of peripheral chemoreceptors
on I neurons during hypoxia should be attributed
instead, at least in awake animals, to disfacilitation
of E neurons due to hypocapnia or to direct depression of E neurons by hypoxia. Evidence from
anesthetized animals indicates the explanation is
probably more complicated. Sears et al. (1982) had

earlier shown in anesthetized cats that normocapnic

hypoxia (PO2 031 mmHg) increases phrenic but
decreases expiratory intercostal activity, so the suppression could, instead, result from greater reciprocal inhibition of E neurons and/or motoneurons by
I neurons at the medullary/spinal levels instead
of the eects of hypocapnia. Interestingly, the
increased phrenic activity during hypoxia, indicating
preferential peripheral chemoreceptor input to I
neurons, was not accompanied by more expiratory
activity due to post-inhibitory rebound.
8.2.2. Medullary Responses
Limited data are available about the eects of
carotid chemoreceptor stimulation on E-BS neurons.
Injections of boluses of CO2-saturated saline into
the carotid arteries of thiopental-anesthetized dogs
during late I increase the discharges of cVRG EAUG and E-DEC neurons, the vast majority of
which were bulbospinal, during the subsequent E
phase (Bajic et al., 1994). Responses did not depend
on changes in activity of the preceding I phase
which was, in any case, unaected. The excitatory
response to the bolus increased as expiration progressed (Fig. 9), even in the presence of lung inations that inhibit E-BS activity (Figs. 7 and 8).
Therefore, the eects on E neurons are `direct' in
the sense that they are not mediated by I neurons.
They are also mediated by NMDA receptors
because microinjection of an NMDA receptor antagonist in the vicinity of the neurons blocks the responses to injection of CO2-saturated boli in the
- ogas et al., 1995). Injection of
same preparation (D
non-CO2 equilibrated solutions (PO2 not stated) in
two studies (Lipski et al., 1984; Bajic et al., 1994)
had no eect on unit activity. Moreover, boli with
low PO2 elicit, but at much longer latencies, responses of both chemoreceptor aerents and medullary neurons (Lipski, personal communication).
Thus, carotid chemoreceptor aerents activate E-BS
activity. The neurons mediating this response are
unknown but cannot be I neurons because the
eects occur in the same phase as activation of the
carotid chemoreceptor aerents. Activation of peripheral chemoreceptors by lobeline in chloraloseanesthetized dogs activates E but not I neurons
(probably in the VRG) during apnea (Koepchen et
al., 1973); thus, in this case, peripheral chemoreceptor inputs were directed primarily to E, not I, neurons although the responses of I neurons could have
been blocked if they were hyperpolarized during
apnea.
In chloralose-urethane anesthetized cats, close bilateral intra-arterial (thyroid) injections of CO2equilibrated saline during expiration excited most
(17 of 25) cVRG E neurons at latencies (180440
ms) consistent with excitation of peripheral chemoreceptors (Lipski et al., 1984); units also responded
to systemic hypoxia (20 s inhalation of N2) with
increased discharge but only very slowly, if at all, to
hypoxic boli (Lipski, personal communication).
Some (4 of 9) BotC E neurons were also excited by
injections but it is unclear if their responses were
earlier than those of the cVRG E neurons and,
therefore, if they mediated excitation of the latter.

Control of Abdominal Muscles

471

Fig. 9. Interaction of carotid chemoreceptor stimulation (bolus of CO2-saturated saline) and lung ination on discharge of E-BS neurons in thiopental-anesthetized ventilated dogs. Left panel, traces from
top down: integrated phrenic activity (Phr); binned discharge frequency of an E-BS AUG neuron during
no-ination (NIL) respiratory cycles with (B) and without (NB) bolus injection (second panel) and respiratory cycles with lung ination (IL) (third panel); tracheal pressure (Pt). Boli activated the neuron
despite the inhibitory eect of lung ination (compare corresponding ination and no-ination traces
from second and third panels). Panel on right shows the average responses of four E-plateau (AUG)
neurons. Periods 1, 2 and 3 refer to the rst, middle, and last third of the expiratory phase. Inations
reduced discharge frequencies in the middle and last third of expiration; boli increased discharge frequencies during all phases of expiration. Modied with permission from Bajic et al. 1994.

In Dial-urethane anesthetized cats, E-AUG and

E-DEC neurons in the NA and cVRG displayed
varied responses (four increased, four decreased, ve
no change) to injections of CO2-saturated saline into
the carotid artery close to the carotid sinus (Morris
et al., 1996). BotC E neurons in paralyzed ventilated
rats are also excited by hypoxia (10 s inhalation of
N2) (Kanjhan et al., 1995).
The eects of chemoreceptor activation may be
mediated via non-respiratory neurons. In decerebrate, spontaneously breathing cats, Arita et al.
(1988a) studied the responses of medullary non-respiratory neurons to injections of boli of CO2-saturated saline into the vertebral and carotid arteries to
activate the central or peripheral chemoreceptors,
respectively. Most neurons, just over half of which
responded to injections of CO2-equilibrated saline
into both arteries, were scattered around or ventral
to the rVRG, near the RFN or the ventral medullary surface; no receptive neurons were found in the
cVRG. All chemosensitive neurons located near the
ventral medullary surface responded only to boli
injected into the vertebral artery, as did some neurons at the level of the rVRG just ventral to the solitary tract. Many were in or close to the RTN,
lesions of which block phrenic activity and the respiratory response to CO2 in cats and rats (Nattie et
al., 1991; Nattie and Li, 1994). The responses of E
neurons and motoneurons to hypercapnia following

such lesions have not, to my knowledge, been studied. Although these data do not prove these nonrespiratory modulated neurons are chemosensitive
or are driven by chemoreceptors, they could mediate
the CO2-induced excitation of E-BS neurons.
Lawson et al. (1989a) had suggested that carotid
sinus inputs are mediated via respiratory neurons
because averaging of membrane potentials in I and
post-I neurons following shocks to the carotid sinus
nerve revealed no short latency postsynaptic potentials.
Earlier work by St. John and Wang (1977), however, indicates that the discharges of non-respiratory
modulated neurons in the DRG and VRG of
decerebrate, vagotomized, paralyzed and paralyzed
cats are relatively unaected by steady-state hypercapnia and hypoxia. Instead, isocapnic hypoxia
increased the discharge of most, but not all, E neurons; after bilateral section of the carotid sinus
nerves, hypoxia depressed neuronal activity.
However, all E neurons studied were at or rostral to
the NA, and therefore unlikely to have been bulbospinal. They suggested that central chemoreceptors uniformly excite I and E neurons but that
peripheral chemoreceptors do not. Moreover, the
neuronal response to hypoxia, they claimed, represented the net eect of the excitatory eects of
peripheral chemoreceptor inputs and the depressive
central eects of hypoxia. In an identical prep-

472

S. Iscoe

aration, St. John (1981) observed that stimulation of

the carotid chemoreceptors by intracarotid infusions
of NaCN or nicotine was less eective than hypercapnia in activating E neurons of the VRG (projections not identied but some could have been
bulbospinal); indeed, some units displayed reduced
activity even though phrenic activity increased.
These results were again interpreted as indicating
dissimilar distributions of peripheral and central
chemoreceptor inputs. The dierent results of the
studies of St. John and Wang (1977) and Arita et al.
(1988a), both in decerebrate cats, may reect recordings from dierent populations or dierent techniques (steady-state responses to inhalation of
dierent gas mixtures vs transient responses to interarterial injections of CO2-equilibrated saline).
8.3. Locations of Chemosensitive Neurons
Nattie (1995) has recently reviewed the responses
of medullary neurons to CO2/H+. Cited studies indicate that putative chemoreceptors are widely dispersed throughout the medulla, most being close to
the ventral surface, others just ventrolateral to the
NTS. Many neurons were in regions which became
more acidic immediately following injection of CO2saturated saline into the vertebral artery (Arita et
al., 1989); others were located further from the
medullary surface. These regions may contain carbonic anhydrase which would accelerate the hydration of CO2 and the formation of H+
(Ridderstrale and Hanson, 1985). In rats, small (1
nl) injections of acetazolamide into many sites
within the VRG cause localized acidosis and
increased phrenic activity (Nattie and Li, 1996);
however, the lack of temporal correspondence
between local [H+] and phrenic responses in some
cases suggests that H+ alone is not responsible for
the increased phrenic activity. What is also not clear
is if these chemosensitive regions coincide with the
`sheets' of blood vessels described by King and
Knox (1984). I am aware of no studies in which the
responses of abdominal nerves or muscles to such
interventions have been monitored.
Although almost all expiratory neurons responding to increased CO2 in the superfusate of the neonatal rat brainstem-spinal cord preparation had
dendrites to within 50 mm of the ventral medullary
surface (Kawai et al., 1996; Ballantyne, personal
communication), none of the E neurons in this
study (none of which was likely bulbospinal) nor the
E-BS neurons in decerebrate cats (Arita et al., 1987)
had dendritic trees extending towards the ventral
medullary surface; they are thus unlikely to have
been directly aected by the composition of ventricular cerebrospinal uid (CSF). Emphasis on the
ventral medullary surface as the sole source of central chemoreceptor inputs (e.g. Pilowsky et al., 1993)
may, however, be misplaced. If neurons with intrinsic chemosensitivity are indeed widely distributed
(Nattie, 1995), the association of medullary respiratory neurons with capillaries (King and Knox, 1984)
means that many could just as easily detect changes
in PCO2 of the blood, extracellular uid, and tissue.
Preliminary reports indicate that, in rat, some
medullary raphe neurons intrinsically sensitive to

CO2 project to phrenic motoneurons (Richerson and

Wang, 1996; Wang and Richerson, 1996), results
extending earlier studies revealing that phrenic
motoneurons in rat (Dobbins and Feldman, 1994)
and cat (Holtman et al., 1984) receive projections
from raphe neurons. Some raphe neurons in cat project not only to phrenic but also to abdominal
motor nuclei (Portillo et al., 1994), suggesting at
least one pathway by which abdominal motoneurons can be driven by CO2. These results, in turn,
extend previous ones indicating substantial projections of medullary raphe neurons to the thoracic,
lumbar and sacral segments of the spinal cord
(Holstege and Tan, 1987a; Kausz, 1991; Wang et
al., 1992; Li et al., 1993; see Holstege and Kuypers,
1987 for review) and other brainstem regions (Sim
and Joseph, 1992; Li et al., 1993).
Immunocytochemistry has been used to localize
expression of c-fos, a marker of neuronal activity,
and
indicates
that
CO2-sensitive
neurons
(FICO2=0.10, 0.13 and 0.15) in rats are concentrated just below the ventral medullary surface and,
to a lesser degree, near the NTS (Sato et al., 1992).
Longer exposures cause more widespread labeling,
including neurons in several subnuclei of the NTS
and, in the ventral medulla, in two columns, one
extending from the pyramidal decussation to the
nucleus paragigantocellularis, just ventral to the
NA, and the other from the inferior olive to the retrotrapezoid body (Sato et al., 1992), results similar
to those of another study (Teppema et al., 1995). Cfos labeled neurons are also found in the parapyramidal rostroventromedial medulla; kainate-induced
lesions in this region block the ventilatory response
to inhalation of 15% CO2 (Miura et al., 1996). In
spontaneously breathing, anesthetized cats, inhalation of 10% CO2 results in the production of foslike protein in cells located almost exclusively in the
RTN (Teppema et al., 1994); in both cat (Nattie et
al., 1991) and rat (Nattie and Li, 1994), lesions of
the RTN reduce or block the ventilatory response to
hypercapnia. However, in a recent study by Larnicol
et al. (1994), inhalation of 5% CO2 in spontaneously
breathing cats induced c-fos in the PBM and some
subnuclei of the NTS but not, for reasons that are
unclear, in the RTN; moreover, the distribution of
c-fos diered from that found after exposure to hypoxia (see next paragraph). Why the distributions in
these two studies diered so much is unknown, especially because feedback resulting from increased
ventilation, and not just hypercapnia, would be
expected to result in more widespread distribution
of c-fos; this also complicates comparisons with
other studies in which the animals were paralyzed
and ventilated. Another factor to consider is that
high concentrations of CO2 (>10%) are often used
to elicit fos production, raising the issue of relevance
to `normal' physiology.
Stimulation of the peripheral chemoreceptors
(electrical stimulation of the carotid sinus nerves in
anesthetized rats or hypoxic exposure in awake rats)
results in the production of fos-like protein within
NTS (the site of termination of carotid chemoreceptor aerents), the ventrolateral medulla, area postrema, raphe pallidus, along the ventral medullary
surface (Erickson and Millhorn, 1991), and, in a

Control of Abdominal Muscles

more recent study (Erickson and Millhorn, 1994), in

more rostral structures, including the PBN, KF and
the central gray. A common nding of all these studies is an absence of CO2 sensitive neurons in the
cVRG. Like hypercapnia, hypoxia also induces expression of fos-like immunoreactive protein.
Exposure to hypoxia, with unknown levels of ventilation and hypocapnia, of awake spontaneously
breathing rats (Erickson and Millhorn, 1994; Kanter
et al., 1996) or stimulation of the carotid sinus nerve
in paralyzed ventilated rats (Erickson and Millhorn,
1991, 1994) results in expression, to varying degrees,
of fos in neurons in various regions of the dorsal
medulla (commisural nucleus, area postrema, raphe
pallidus, dorsal motor nucleus of the vagus, and the
NTS) and ventrolateral medulla (between the NA
and the lateral reticular nucleus). Because hypocapnia likely co-existed with the hypoxia in these spontaneously breathing rats, the similarity of results is
impressive. Comparable results were obtained by
Haxhiu et al. (1995) who also found labeled cells in
PBN and KF. No labeled neurons are found in the
cVRG but more labeled cells are found, after exposure to hypoxia, in the ventrolateral medulla of
rats aged 314 d but not older than 28 d (White et
al., 1994). In spontaneously breathing cats, hypoxia
(FIO2=0.11) induces c-fos in the NPBM, the RTN,
and the dorsal subnuclei of the NTS (Larnicol et al.,
1994), the distribution diering in some respects
from that observed following exposure to hypercapnia (see preceding paragraph); these results are complicated by an unknown degree of brainstem
hypocapnia. However, location does not dene
function; neuroanatomical studies indicate many
more connections between the cVRG and other
regions than exist for E-BS neurons (Section 3.3.2).
Thus, the presence of fos-positive neurons in regions
known to include E-BS neurons does not mean that
E-BS neurons receive inputs from peripheral chemoreceptors.
MK-801, an NMDA receptor antagonist, blocks
the expression of the fos-like protein during systemic
hypoxia in conscious rats (Haxhiu et al., 1995).
These authors limited their analysis to the NTS,
which they considered to contain second order aerents, although many other areas of the brainstem,
including the ventrolateral medulla, contained neurons expressing fos. In rat, carotid sinus aerents
also appear to project to the NRA (Finley and
Katz, 1992; see above); second order aerents may
not, therefore, be restricted to the NTS.
8.4. Hypoxia
The initial increase in ventilation in response to
hypoxia is attributed to stimulation of the carotid
chemoreceptors; ventilation then slowly declines (the
``ventilatory roll-o '') due, according to conventional theory, to the resulting hypocapnia. This decline,
however, may also be due to the central eects of
hypoxia. As reviewed by Haddad and Jiang (1993)
(see also Neubauer et al., 1990; Haddad and Rosen,
1991; Richter et al., 1991; Katsura et al., 1992;
Somjen et al., 1993; Johnston, 1993), hypoxia depolarizes brainstem neurons and may, depending on
the degree of depolarization, prevent cell discharge

473

(depolarization blockade). The response to hypoxia

is age-dependent; brainstem neurons from newborns, compared to those of adults, exhibit less depolarization, smaller increases in membrane
resistance and discharge frequency, and no depolarizing block. This may contribute to the newborn's
inability to sustain the ventilatory response to hypoxia. Although ventilation may decrease below
control levels in newborns, this does not represent
hypoventilation because, unlike adults, they reduce
their O2 consumption during hypoxia (for reviews,
see Mortola and Gautier, 1995; Gautier, 1996;
Mortola, 1996). Caution is advised, however, in
interpreting results, whether in vivo or in vitro; we
do not yet know if the responses in altricial (immature) newborns such as the rat (the animal of choice
for most in vitro studies) are similar to those of precocial newborns (e.g. guinea pigs).
Hypoxemia elicits profound cardiorespiratory responses which conserve or even increase the availability of O2 for essential tissues. This response
involves immediate and transient increases in sympathetic activity due to hypoxia-mediated activation
of medullary vasomotor neurons (see Sun and Reis,
1994a and Sun, 1995 for reviews). Sun and Reis
(1994c) have shown in peripherally chemodenervated rats that the excitatory response to systemic
hypoxia is restricted to bulbospinal vasomotor neurons (see also Nolan and Waldrop, 1993, below);
most adjacent respiratory neurons are inhibited.
Because vasomotor neurons respond only weakly to
H+, HCO
3 and lactate, they attributed the response
to hypoxia and not metabolites. However, systemic
(brain) hypoxia acutely increases ventilation in peripherally chemodenervated dogs (Davenport et al.,
1947), goats (Daristotle et al., 1991; Weizhen et al.,
1992), and rats (Olson et al., 1988), so respiratory
neurons must be activated. However, denervation of
the peripheral chemoreceptors prevents hypoxiainduced increases in ventilation in ponies (Forster et
al., 1976) or causes alveolar hypoventilation in cats
due to a pronounced tachypnea (Miller and Tenney,
1975). The reasons for this discrepancy are
unknown.
The net eect of hypoxia on ventilatory outcome
may, in addition to any metabolic changes in tissues,
reect the balance between levels of excitatory and
inhibitory amino acids at central chemoreceptors.
Kazemi et al. (1996) measured changes in the concentrations of glutamate, g-amino butyric acid
(GABA), and glycine near the ventral medullary
surface of paralyzed ventilated rats during hypoxia.
Not all `changes' were signicant and the fall in
blood pressure (from 105 to 63 mmHg) during hypoxia raises questions about blood ow despite the
presence of arterial isocapnia.
8.4.1. Central Hypoxia
Traditionally, hypoxia is thought to depress neuronal activity. However, considerable evidence
suggests that brain(stem) hypoxia excites expiratory
activity. In anesthetized cats with intact peripheral
chemoreceptors, hypoxic hypocapnia causes low
levels of tonic activity of both the internal intercostal and phrenic nerves (Sears et al., 1982). After

474

S. Iscoe

stopping the ventilator at a PaO2 of 29 mmHg and

a PaCO2 of 15 mmHg, PaO2 fell more rapidly than
PaCO2 increased (because of buering of CO2) and
was accompanied by a gradual increase in phrenic
activity and a reciprocal decrease in internal intercostal activity, a result consistent with preferential
distribution of peripheral chemoreceptor inputs to I
neurons (see also St. John and Wang, 1977; St. John
and Bianchi, 1985) which then reciprocally inhibit E
neurons. After peripheral denervation, however, the
same protocol activated E activity (at a PaCO2 of
020 mmHg) before the onset of phrenic activity,
suggesting that central hypoxia, and not ``the central
action of CO2'' (Sears et al., 1982), excited E neurons. The earlier activation of E activity in denervated cats is important because, in the absence of I
activity, one cannot attribute this response to
greater post-inhibitory rebound.
Thus, the assumption that central hypoxia
depresses respiratory neurons appears invalid. As
reviewed by Neubauer et al. (1990), animals still
respond `normally' to CO2 or carotid sinus nerve
stimulation when hypoxic. Moreover, hypoxia often
elicits transient depolarization and increased activity
of E-BS neurons (Richter et al., 1991), not
depresses, respiratory activity (see below). In the hypoxic chemodenervated barbiturate-anesthetized
cats of Sears et al. (1982), phrenic activity reappeared at a PaCO2 of 024 mmHg. However, during
rebreathing starting from hyperoxic (i.e. suppressed
peripheral chemoreceptor activity) hypocapnia, it reappears at a PaCO2 of 034 mmHg in decerebrate
cats (Iscoe et al., 1998). Thus, I premotor neurons
were activated at a lower PaCO2 during hypoxia
(despite the anesthesia), suggesting that, in the
absence of peripheral chemoreceptor input, brainstem hypoxia, not CO2, activates E premotor neurons. This hypothesis must be qualied by any direct
eects of hypoxia and hypocapnia on the motoneurons. I am aware of no in vitro studies of the eects
of hypoxia on identied E neurons.
In awake goats, systemic (brain) hypoxia (040
mmHg) combined with independent perfusion of the
carotid bodies with normoxic blood, increases TA
but not diaphragmatic, parasternal or TS activity
(Smith et al., 1993). The true stimulatory eect of
hypoxia may have been underestimated due to any
brain hypocapnia caused by hypoxia-induced
increases in cerebral blood ow. The absence of
increases in inspiratory muscle activity could indicate a greater sensitivity of their premotor neurons
to hypocapnia (withdrawal of CO2-related drive).
Similar results are obtained when the brain is normoxic and the carotid bodies hypoxic, or when both
the brain and carotid bodies are hypoxic. Thus,
brain hypoxia stimulates ventilation and does not
prevent stimulation of ventilation when the carotid
bodies are hypoxic. Either the levels of hypoxia used
in these studies had no eect on brainstem respiratory function or any supra-pontine hypoxia-induced
depression was oset by hypoxia-induced excitation
of brainstem respiratory neurons. This latter idea is
consistent with the eects of hypoxia on brainstem
versus cortical neurons (see Haddad and Jiang, 1993
for review). The roles of segmental reexes and
SAR feedback (due to changes, if any, in EELV) in

recruitment of TA are, however, unclear. Finally,

the similarity of inspiratory and expiratory muscle
responses to any combination of brain and carotid
body hypoxia to those elicited by whole-body hyperoxic hypercapnia suggests no preferential distribution of central and peripheral chemoreceptor
drives to I and E neurons in awake goats.
In awake ponies, however, with or without carotid chemoreceptor or SAR feedback, hypoxia
decreases TA activity, in part due to decreases in TE
(Brice et al., 1990). Ventilation increases in carotid
body denervated ponies during `isocapnic' hypoxia
(PaO2 037 mmHg; PaCO2 fell by 02 mmHg) but all
indices of TA activity (peak, slope, time to peak,
duration, total and mean activity) decrease signicantly. Although TA activity decreases similarly in
both carotid body intact and denervated ponies, interpretation is complicated because, when intact, the
ponies are hypocapnic during hypoxia (PaCO2 028
mmHg; PaO2 46 mmHg) but hypercapnic when
denervated (PaCO2 048 mmHg; PaO2 37 mmHg).
The authors acknowledge that PaCO2 and [H+]a
may not accurately represent brain PCO2 and [H+],
both of which, in addition to hypoxia, aect the discharges of pH-sensitive neurons in vitro (Jarolimek
et al., 1990).
8.4.2. Systemic Hypoxia (Intact Peripheral
Chemoreceptors)
When the peripheral chemoreceptors are intact,
the responses to hypoxia reect its combined central
and peripheral eects. To my knowledge, no one
has yet evaluated the direct eects of hypoxia on abdominal motoneurons, independent of descending
drive. A critical issue in the studies described below
is whether or not true isocapnia was present.
Isocapnic hypoxia, a non-physiological condition, is
dicult to achieve because changes in cerebral
blood ow and cerebral metabolism result in
unknown changes in the intracellular environment.
Moreover, increases in abdominal activity may be
not just a cause but also a result of increased ventilation. Increases in VT would cause greater SAR
feedback which, at low transpulmonary pressures
activates E-BS neurons (Section 7.2 and 7.3). We do
not know if increases in ventilation, even modest
ones, activate segmental reexes and, if so, if these
reexes aect the sensitivity of the motoneurons to
supra-spinal inputs. After section of the axons of EBS premotor neurons, segmental reexes are powerful enough to account for the persistence of abdominal activity during vomiting (Miller and Nonaka,
1990).
In various preparations in which isocapnia is
claimed (awake humans (Takasaki et al., 1989),
dogs (C.A. Smith et al., 1989; Yasuma et al., 1993)
and lambs (Praud et al., 1993) with intact vagi;
decerebrate, vagotomized, paralyzed and ventilated
cats (Fregosi et al., 1990); chloralose-anesthetized
spontaneously breathing dogs (Kelsen et al., 1977)
or cats (Mateika et al., 1996) with intact vagi; chloralose-anesthetized paralyzed and ventilated dogs
(Ledlie et al., 1983); halothane-anesthetized spontaneously breathing piglets (Watchko et al., 1990)),
hypoxia increases abdominal activity although the

Control of Abdominal Muscles

responses dier in degree between studies. For

example, in awake dogs (C.A. Smith et al., 1989),
isocapnic and hypocapnic hypoxia are equally eective, perhaps because of the considerable interanimal variability, reecting dierences in CO2
washout, chemosensitivity of the peripheral chemoreceptors, and sensitivities of brainstem neurons to
peripheral chemoreceptor input. The initial increase
in TA activity to hypocapnic hypoxia is not sustained, a result consistent with washout of CO2
from the brain. The authors also suggest that TA
activity may have increased because their animals
were awake and had intact vagi. In contrast, hypoxia increases EO motor unit activity more during
isocapnic than hypocapnic hypoxia in lambs (Praud
et al., 1993) and only during isocapnic hypoxia in
cats (Mateika et al., 1996), indicating a loss of CO2related excitation. In the cats (Mateika et al., 1996),
11 of 29 EO motor units stopped ring at the transition from isocapnic to hypocapnic hypoxia and
ve did not re at all during hypocapnia. In conscious man, hypoxia (saturation 070%) recruited
EO in only six of 15 trials in ve subjects (Takasaki
et al., 1989); this low incidence of recruitment may
reect the subjects' supine posture (Section 7.1), an
inadequate stimulus (although PaO2 would have
been 040 mmHg at this saturation), or recording
from a muscle (EO) with a higher threshold than IO
or TA for recruitment (Section 7.1).
In awake lambs, inhalation of 100% O2 for ve
breaths to test the contribution of peripheral chemoreceptors to ventilatory drive (Dejours test)
during hypocapnic hypoxia causes a transient drop
in both ventilation and EO activity, the latter occasionally disappearing and not returning for 100 s
(Praud et al., 1993); these responses are weaker
during isocapnic hypoxia, indicating that peripheral
chemoreceptors drive ventilation and EO activity
during hypocapnic hypoxia. Vagotomy does not
aect the responses to the Dejours test, indicating
that the loss of pulmonary or other vagallymediated feedback resulting from the fall in ventilation is not responsible for the decrease in EO activity. Similarly, increases in abdominal activity
during hypoxia in spontaneously breathing animals
(e.g. Kelsen et al., 1977) are not due to greater proprioceptive feedback resulting from increased ventilation because this increase is observed even in
paralyzed ventilated chloralose-anesthetized dogs
during progressive isocapnic hypoxia, the eect
being most pronounced below a PaO2 of 40 mmHg
(Ledlie et al., 1983); excitatory responses are also
observed in paralyzed, ventilated cats (Fregosi et al.,
1990).
In piglets, the hypoxia-induced increase in TA
(and diaphragmatic) activity is transient, the response returning to control (eupneic) values
(Watchko et al., 1990) probably because of CO2
washout since peripheral chemoreceptors do not
adapt (Blanco et al., 1984). The return of TA activity to control levels despite hypoxemia suggests
that any central depressive eects are oset by the
excitatory eects of peripheral chemoreceptor
inputs.
In many studies, however, hypoxia suppresses abdominal activity. In Dial-urethane anesthetized

475

spontaneously breathing cats, steady-state inhalation of 12.4% O2, with only a modest drop in
PETCO2, fails to elicit EO activity (Bishop and
Bachofen, 1972b) but increases in EELV do,
suggesting that the reex pathway activated by
increases in SAR feedback is less susceptible to suppression by anesthetics than that activated by the
peripheral chemoreceptors. In decerebrate, vagotomized, paralyzed and ventilated cats with bilateral
pneumothoraces, isocapnic hypoxia (PETO2=71
mmHg) increased phrenic activity but depressed abdominal nerve activity in most, but not all, cats
(Fregosi et al., 1987); peripheral chemodenervation
exacerbated the abdominal responses in two of three
cats tested and depressed phrenic nerve activity.
Thus, with or without peripheral chemoreceptor
input, hypoxia usually depresses, not excites, abdominal activity, although considerable inter-animal
dierences are present. A later study (Fregosi and
Bartlett, 1989) of expiratory intercostals yielded
similar results, i.e. hypoxia depressed expiratory
intercostal activity in some cats, stimulated it in
others. It is unclear if this variability is typical of
expiratory muscles or is more marked in expiratory
muscles of the rib cage. Sears et al. (1982) and
Bouverot and Fitzgerald (1969) had previously
reported hypoxic suppression of internal intercostal
activity in anesthetized cats and rabbits, respectively.
The study of Fregosi et al. (1987) has been criticized
(Brice et al., 1990) on the grounds that carotid body
denervation caused hypotension, which activates abdominal muscles (Fregosi, 1994a), in four of 7 cats
and that the eects on abdominal activity of hypoxia in the other three were equivocal. Moreover,
hypoxia was modest and O2 delivery to tissues
would not have been compromised.
As indicated above, Sears et al. (1982) showed
that hypoxic hypocapnia caused low levels of tonic
activity of both the internal intercostal and phrenic
nerves. Increasing the severity of hypoxia gradually
increased phrenic activity with a reciprocal decrease
in internal intercostal activity, indicating preferential
distribution of peripheral chemoreceptor inputs to I
neurons (see also St. John and Wang, 1977; St. John
and Bianchi, 1985). A similar conclusion was
reached by Huang et al. (1989) but using a dierent
approach. In decerebrate cats with intact peripheral
chemoreceptors, tonic internal intercostal activity
and absence of phrenic activity during hyperoxic
hypocapnia is replaced by phasic alternating bursts
of phrenic and internal intercostal activity when the
cats are switched to hypoxic hypocapnia. Although
Huang et al. did not dierentiate between inhibition
of E motoneurons resulting from hypoxia per se and
reciprocal inhibition originating from active I neurons, their results, like those of Sears et al. (1982),
are consistent with distribution of peripheral chemoreceptor inputs to I neurons which then reciprocally inhibit E neurons. Moreover, hypoxia does not
appear to have driven E premotor neurons because,
during the transition from hyperoxic to hypoxic
hypocapnia, internal intercostal activity increased
only after the reappearance of phrenic activity.
Comparison of this study with that of Sears et al.
(1982) is complicated by the dierent levels of O2:
Huang et al. (1989) started from hyperoxia with PO2

476

S. Iscoe

remaining above 40 mmHg whereas Sears et al.

(1982) started from hypoxia (PO2=29 mmHg) which
fell to 015 mmHg.
Yasuma and colleagues (1993), studying conscious
dogs, also provided evidence that peripheral chemoreceptor inputs are distributed preferentially to I
neurons. At a given VT, TA and EO activities are
similar during hyperpneas produced by isocapnic
hypoxia and hyperoxic hypercapnia but hypoxia elicits greater diaphragmatic activity than hypercapnia.
Moreover, at a given VT, TE is less during hypoxia
than during hypercapnia (raising the problem of
how best to compare data; see Section 5.2), indicating that hypoxia promotes the onset of inspiration,
a result also indicative of preferential input to I
neurons. However, for a given ventilation, hypercapnia produces a greater VT than hypoxia.
Hypocapnic hypoxia, although physiological, has
limited utility in determining the mechanisms underlying the respiratory responses to hypoxia because
its eects on blood ow are oset to an unknown
degree by that due to hypocapnia; as with `isocapnic' hypoxia, the brainstem intracellular environment is undetermined. Thus, although there are
many studies of the abdominal responses during
hypocapnic hypoxia, some of which are indicated
above, they will not be described because they provide no basis for understanding the underlying control mechanisms.
8.4.3. In Vitro Responses
Because E-BS neurons cannot be identied in
slices and have not been identied in brainstemspinal cord preparations, there are no studies in
these preparations of their responses to hypoxia.
Although their membrane properties may be similar
to those of other respiratory, and possibly non-respiratory, medullary neurons, this assumption needs
to be veried. The eects of hypoxia on neurons
have been thoroughly reviewed recently by Haddad
and Jiang (1993).
Brief (60 s) exposures to moderate hypoxia (PO2
in gas above the slice 070 mmHg) excites ventrolateral medullary neurons; severe (09 mmHg) hypoxia
is even more eective (Nolan and Waldrop, 1993).
Because excitation persists after synaptic blockade
(low [Ca2+]-high [Mg2+]), hypoxia exerts its eects
directly on the cell, possibly by modifying the conductance of one or more ion channels. One feature
that has yet to be examined is whether brainstem
respiratory neurons have O2-sensitive K+ and Ca2+
ion channels similar to those in glomus cells of the
carotid body (see Lopez-Barneo, 1996 for review).
Hypoxia depolarizes hypoglossal neurons, even
during synaptic blockade, indicating it to be an inherent property, and neuronal activity increases
unless depolarization block occurs; these eects are
less pronounced in neurons from neonates (Haddad
and Donnelly, 1990; see also Nolan and Waldrop,
1996) and opposite to those in cortical (hippocampal) neurons in which neuronal excitability
decreases. Hypoxia depolarizes brainstem hypoglossal neurons of both newborn and adult rats; those
of adults, however, depolarize, re more, and
increase membrane resistance, about half eventually

displaying depolarization block (Haddad and

Donnelly, 1990). In contrast, neonatal neurons tolerate hypoxia better in that they do become blocked,
possibly because of reduced eux of K+, thereby
maintaining their excitability. In hypoglossal and
neocortical neurons in slices from adult rats, anoxia
causes more rapid and greater depolarization than
hypoxia, and these eects are greater in hypoglossal
neurons; however, hypoglossal neurons fail to
recover when re-oxygenated after prolonged anoxia
(O'Reilly et al., 1995). It is unclear if these dierences reect maturation and if they apply to other
medullary respiratory neurons. Locus coeruleus
neurons in pontine slices from young rats hyperpolarize when exposed to a hypoxic medium but depolarize if initially hyperpolarized (Nieber et al.,
1995). These directionally-sensitive changes are
reminiscent of those obtained in neurons of the dorsal motor nucleus of the vagus of young (3545 d)
rats; neurons with intracellular pH <7.2 hyperpolarize in response to hypoxia whereas those with intracellular pH >7.3 depolarize (Cowan and Martin,
1995). Indeed, Donnelly et al. (1992) also showed
that hypoxia depolarizes brainstem (dorsal motor
nucleus of the vagus and hypoglossal) more than
cortical (hippocampal) neurons and that the former
are more excitable before the onset of depolarization
blockade. Dierences in the duration and severity of
hypoxia, as well as the initial conditions (intra- and
extracellular pH), may be responsible for the variations in neuronal responses between studies.
Hypoxia-induced increases in discharge and depolarization also occur in pacemaker neurons of the
rostral ventrolateral nucleus of medullary slices of
young rats, even during synaptic blockade (Sun and
Reis, 1994b). Because reductions of [Ca2+]e reduce,
and CoCl2 and NiCl2 abolish, the inward currents
elicited by hypoxia or cyanide, Sun and Reis
(1994b) concluded that hypoxia activates a Ca2+dependent inward current, due either to the channel
being O2-sensitive or to activation of second messengers. In peripherally chemodenervated rats, the same
authors also indicate (Sun and Reis, 1994d) that inhibition of protein kinase C does not prevent the excitation of these neurons by systemic hypoxia. I am
aware of no similar studies on medullary respiratory
neurons. Depletion of O2 by adding sodium hydrosulte to the bathing solution increased the discharge frequency of isolated cultured neurons from
fetal rats (Rigatto et al., 1992).
Because hypoxia causes metabolic changes, such
as production of lactate (see above), the resulting
acidication of the tissue (Cowan and Martin, 1995)
will activate H+-sensitive neurons near the ventral
surface of slices of rat medulla (Jarolimek et al.,
1990); these, in turn, may drive respiratory, including E-BS, neurons. Because their discharges are
potentiated by hypoxia (Jarolimek et al., 1990), it
becomes increasingly dicult to attribute responses
to a particular input. The eect of hypoxia would be
expected to be even greater in regions distant from
the surface, particularly in larger slices from adults
(Jiang et al., 1991).

Control of Abdominal Muscles

8.4.4. In VivoMedullary Recordings

Neurons supposedly belonging to a single population display considerable variability in the relative
eects of central hypoxia and excitatory inputs from
peripheral chemoreceptors. St. John and Wang
(1977) observed that isocapnic hypoxia elicits such
variable eects on VRG E and other respiratory
neurons in paralyzed, ventilated vagotomized
decerebrate cats that one can only conclude that, at
the mild levels of hypoxia employed (061 mmHg),
the strengths of peripheral chemoreceptor inputs
and the eects of brainstem hypoxia vary between
neurons. In the same preparation, isocapnic hypoxia
(FIO2 00.080.10) increased neither mean nor maximum discharge frequencies of VRG E-BS neurons,
but considerable variation was present (40% to
240% of control; four of 12 neurons decreased and
four of 12 increased mean frequency; St. John and
Bianchi, 1985); in contrast, eight had unambiguous
increases during hypercapnia eliciting an equivalent
increase in phrenic activity. In both studies, true isocapnia may not have been present; even small reductions in brain PCO2 could have oset the eects
of a decrease in FIO2. Another reason for this variability could be that not all E-BS neurons are aected
similarly by hypoxia; some may even be excited
(Haddad and Jiang, 1993). St. John had previously
shown (1981) that stimulation of the carotid chemoreceptors with intracarotid infusions of cyanide
or nicotine resulted in less augmentation of activity
than systemic hyperoxic hypercapnia. However, in
that study, one of 13 VRG E neurons decreased and
9/13 increased their mean discharge frequencies
during carotid body stimulation. The applicability
of these results to control of abdominal motoneurons is tenuous because only ve neurons were in the
cVRG and their projections were not identied.
In pentobarbital-anesthetized cats, acute hypoxia
reduced and abolished activity of ve BotC E-AUG
neurons. Although expiratory motor activity was
not monitored, these limited data suggest that the
continuous activity of E motoneurons of some preparations during hypocapnic hypoxia (Sears et al.,
1982) is not the result of input from BotC E-AUG
neurons despite excitatory projections from them to
E-BS neurons of the cVRG in cat (Bongianni et al.,
1988b, 1990, 1994).
In peripherally chemodenervated decerebrate cats,
hypoxia or asphyxia sucient to drop arterial and
local PO2 to <30 and 00 mmHg, respectively, cause
an initial depolarization, and enhanced ring, of EBS neurons followed by a secondary depression and
then, after 02 min, cessation of discharge due to depolarization blockade before phrenic activity stops;
with intact chemoreceptors, the initial excitation is
followed by the depression but respiratory activity
persists (Richter et al., 1991). Because ischemia
causes similar responses, depolarization cannot have
been due to brain hypocapnia secondary to hypoxia-induced increases in perfusion. The cessation
of discharge in denervated cats is not the result of a
lack of excitability due to depletion of energy
reserves because they can still be antidromically activated, at least until the late stages of hypoxia when
they no longer re. The most pronounced synaptic

477

eect is a decrease in inhibitory inputs, evident as

less hyperpolarization, during I, the membrane potential assuming a level characteristic of that during
E. This should decrease the maximum antidromic
latency, indicating increased excitability, but Bianchi
and St. John (1985) had previously shown that the
antidromic latencies of E-BS neurons increase
during inspiration. Richter et al. (1991) suggested
that peripheral chemoreceptors maintain, through
an unknown, possibly neurohumoral, mechanism,
the neurons' ability to re, a proposal consistent
with studies indicating that selective stimulation of
the carotid bodies increases abdominal activity (e.g.
Saupe et al., 1992). Bisgard and Neubauer (1995)
interpreted the results of Richter et al. (1991) as indicating that both IPSPs and EPSPs are suppressed
by CNS hypoxia.
The hypoxia-induced failure of neuronal activity
after 02 min diers from the sustained abdominal
motor activity described by Fregosi et al. (1987) in
decerebrate hypoxic cats; the most likely explanation
is that these cats were subjected to mild hypoxia
(PETO2 71 mmHg) compared to the more severe hypoxia imposed by Richter et al. (1991). However,
even this milder hypoxia severely compromised the
cats; only three of the seven could maintain acceptable arterial pressures during hypoxia after chemodenervation and of the three that did, hypoxia reduced
abdominal activity in two.
The results of Richter et al. (1991), in which systemic hypoxia in decerebrate ventilated cats stopped
E neuronal discharge before that of the phrenic, do
not necessarily support the hypothesis of hypoxiainduced suppression because even in ventilated cats,
hypoxia could still cause CNS hypocapnia (Section
8.1). Richter et al. reported an apneic threshold (cessation of phrenic discharge) at PaCO2s between 27
and 47 mmHg. In decerebrate cats, the central chemoreex threshold to CO2 (reappearance of phrenic
activity during hyperoxic CO2 rebreathing) is 035
mmHg (Iscoe et al., 1998); since brain (mixed
venous) PCO2 is about 68 mmHg greater than
PaCO2 (i.e. >41 mmHg), most cats studied by
Richter et al. probably had brain PCO2s exceeding
the central chemoreex threshold. Therefore, apnea
was likely due to hypoxia rather than central hypocapnia.
In chloralose-urethane anesthetized rats, most
neurons of the ventrolateral medulla respond to
transient (60 s) hypoxia by increasing their discharge
frequency, even after peripheral baro- and chemodenervation (Nolan and Waldrop, 1993). Some had
discharges related to respiration but the phase was
not identied and none was caudal enough to have
been in the cVRG. Hypocapnic hypoxia increased
the discharges of most (080%) neurons of the ventrolateral medulla, many of which had cardiac- or
respiratory-related, or both, discharges. Specically,
of the 35 neurons excited, four were respiratory and
17 cardiac-respiratory; of the 10 neurons depressed
by hypoxia, two were respiratory and ve cardiacrespiratory. Their responses, despite unknown functional identities, suggest they are involved in the
central ischemic response (see Sun, 1995) in which
ventilation and blood pressure increase.

478

S. Iscoe

To summarize, hypoxia decreases ventilation in

peripherally denervated preparations despite excitatory responses of brainstem, possibly respiratory,
neurons; the ventilatory depression reects a combination of decreased synaptic drive from neuronal
populations which generate rhythmic respiratory activity and depressed excitability of pre-motor neurons, perhaps due to depolarization block. (I know
of no studies of the eects of hypoxia on these putative generators in pre-BotC (Smith et al., 1991b) or
even of the eects of hypoxia on central chemoreceptors.) The eects may also be due to the eects,
if any, of hypoxia-induced depression on nonmedullary neurons inuencing ventilation. For
example, many caudal hypothalamic neurons are
activated by hypoxia and hypercapnia, both in vitro,
even after synaptic blockade (Dillon and Waldrop,
1992), and in vivo (Dillon and Waldrop, 1993; Ryan
and Waldrop, 1995), even after peripheral chemoand barodenervation (Dillon and Waldrop, 1993).
These eects are complicated by release of neuromodulators and washout of CO2 with resulting
changes in the acid-base status of the tissues.
8.5. CO2
8.5.1. Distribution of Central and Peripheral
Chemoreceptor Drives
During hypocapnic apnea, I neurons are silent
and E neurons and motoneurons discharge tonically
(Cohen, 1968; Sears, 1977; Bainton et al., 1978;
Bainton and Kirkwood, 1979; Huang et al., 1989;
Bongianni et al., 1990; Stuth et al., 1992); as CO2
increases, tonic E activity becomes phasic when I activity resumes (Cohen, 1968; Sears, 1977; Bainton et
al., 1978; Bainton and Kirkwood, 1979; Sears et al.,
1982; Bongianni et al., 1990). As Merrill (1974)
observed, ``expiratory neurons are normally biased
near their ring thresholds by continuous synaptic
bombardment [from central chemoreceptors?] and
stop ring only when synaptically inhibited by early
I neurons''. Hypocapnia due to hyperventilation
indeed causes E-BS neurons to depolarize to a level
characteristic of that during the expiratory phase
(Richter et al., 1993). These results imply a fairly
direct connection from central chemoreceptors to E
neurons.
Details have been elaborated by Bainton,
Kirkwood, Sears, Berger and Phillipson (Sears,
1977; Bainton et al., 1978; Bainton and Kirkwood,
1979; Sears et al., 1982). In decerebrate cats (and
one human subject), normoxic or hyperoxic hypocapnia caused tonic I or E motor activity; increases
in CO2 produced graded increases in I or E activity,
depending on the initial state, until a level of CO2
was reached at which rhythmic activity resumed
(Bainton et al., 1978). Section of the axons of descending I-BS neurons converted E motoneuron discharge from phasic to tonic and extended the range
of PACO2 over which CO2 elicited graded increases
in discharge frequency to 60 mmHg, indicating that
inhibition of E motoneurons also occurs at the
spinal level (Bainton et al., 1978); these eects were
essentially duplicated when recordings were made
from E-BS neurons (Bainton and Kirkwood, 1979).

Bainton et al. (1978) proposed that inputs from peripheral and central chemoreceptors, along with proprioceptive reexes, determine the discharge of
respiratory motoneurons but concluded that ``nothing is known of the mechanism which transforms
such a [CO2-dependent] drive into the normal augmenting patterns of inspiratory (and expiratory) bulbospinal discharge.''
In decerebrate spontaneously breathing cats,
injections of CO2-equilibrated saline into the vertebral arteries rst excites expiratory (internal intercostal) activity (Arita et al., 1988b). These results
are consistent with a preferential distribution of peripheral chemoreceptor inputs to I premotor neurons,
at least in inspiratory-biased preparations. Although
Sears et al. (1982) concluded that CO2, acting via
the central chemoreceptors, preferentially activated
E premotor neurons, recent data (see above) suggest
that central hypoxia is responsible for the excitation
of brainstem E neurons.
8.5.2. Abdominal Motoneurons
In preparations in which feedback is blocked
(paralysis, mechanical ventilation, and vagotomy),
CO2 consistently increases abdominal (Ledlie et al.,
1983; Fregosi et al., 1987, 1992; Fregosi and
Bartlett, 1988) or internal (albeit inspiratory) intercostal (Fregosi and Mitchell, 1994) activity. In
decerebrate vagotomized and paralyzed ventilated
cats, hypercapnia increases the discharge frequencies
of active TA and IO motor axons but does not
recruit inactive ones (Fregosi et al., 1992); moreover,
CO2 enhances DEC discharge patterns (see Fig. 3),
perhaps due to increased post-inhibitory rebound
following greater inspiratory activity (see Richter et
al., 1993), suggesting that the membrane potential
trajectories, and therefore the discharge patterns, of
premotor neurons shift to a more DEC pattern.
The ventral medullary surface, putative site of the
central chemoreceptors, is important to the discharge of abdominal and other motoneurons.
Bilateral cooling of the intermediate area of the ventral surface in anesthetized dogs reduces activity of
EO, IO and TA but has less eect on expiratory
muscles of the rib cage (Chonan et al., 1991).
Cooling also reduces EO activity more than that of
the diaphragm in anesthetized cats (Haxhiu et al.,
1985). Application of cyanide to the same region in
anesthetized hyperoxic cats reduces TA activity
more than that of inspiratory muscles (Haxhiu et
al., 1993).
CO2 increases abdominal muscle activity in
diverse preparations with various intact feedback
loops, including the vagi: spontaneously breathing
unanesthetized suckling opossums (Farber, 1983),
chloralose- (Kelsen et al., 1977; Oliven et al., 1985)
or barbiturate- (Gilmartin et al., 1987; Ninane et al.,
1988; Ameredes and Clanton, 1989; Oliven and
Kelsen, 1989b; Estenne et al., 1990a; Bellemare et
al., 1991) anesthetized dogs, chloralose- (Fregosi,
1994b) or barbiturate- (Bishop and Bachofen,
1972b) anesthetized cats, halothane-anesthetized
newborn piglets (Watchko et al., 1990), sleeping rats
(Sherrey et al., 1988), standing C. A. Smith et al.,
1989; Ainsworth et al., 1989b, 1992b) or recumbent

Control of Abdominal Muscles

(Yasuma et al., 1993; Leevers and Road, 1994)

awake dogs, awake standing goats (Smith et al.,
1993b) and horses (Ainsworth et al., 1995; but see
Gutting et al., 1991) and upright awake (Lopata et
al., 1985a; De Troyer et al., 1990; Saupe et al., 1992)
or supine awake and/or sleeping (NREM) (Lopata
et al., 1985a; Takasaki et al., 1989; Henke et al.,
1991; Wakai et al., 1992; Warner and Warner, 1995;
Warner et al., 1996; Abe et al., 1996) or anesthetized
(Warner and Warner, 1995; Warner et al., 1996)
human subjects, including sleeping (NREM) infants
(Praud et al., 1991). The response may be diminished by sleep (Wakai et al., 1992), anesthesia
(Bishop and Bachofen, 1972b; Oliven et al., 1985),
and reduced (Farber, 1983; Oliven et al., 1985) or
even abolished (Bishop and Bachofen, 1972b) after
vagotomy in anesthetized preparations or vagal
cooling in conscious dogs (Yasuma et al., 1993).
However,
in
halothane-anesthetized
piglets
(Watchko et al., 1990), vagotomy does not abolish
CO2-induced increases in abdominal activity. This
dierence may reect the inuence of species,
anesthesia (Section 6.2), contribution of vagal aerents, developmental stage, or some combination of
these factors but not the muscle since recordings
were made from TA in both piglet (Watchko et al.,
1990) and dog (Yasuma et al., 1993).
CO2-related inputs are not distributed uniformly
to the abdominal muscles. In conscious man, the internal muscles increase their activity much more
than those of the external muscles (Fig. 5; Abe et
al., 1996). Similar results have been obtained in
dogs (Gilmartin et al., 1987; Leevers and Road,
1994); indeed, TA retains its response to progressive
hypercapnia but EO does not (Gilmartin et al.,
1987).
Abdominal motoneurons are probably not
directly excited by CO2. Although data for them are
unavailable, CO2 decreases the excitability (amplitude of antidromic eld potential, latency and
amplitude of orthodromic responses of the motor
nerves to microstimulation of the motor nuclei) of
phrenic and internal intercostal motoneurons in spinalized cats (Jodkowski and Lipski, 1986); moreover, increases in PaCO2 in these preparations
hyperpolarized phrenic motoneurons.
8.5.3. Medullary Premotor Neurons
CO2 may aect E-BS neurons directly, indirectly,
or both. ``Direct'' means that CO2 aects the membrane potential even when synaptic transmission via
fast channels is blocked, e.g. with tetrodotoxin
(TTX) or low [Ca2+]-high [Mg2+]. ``Indirect'' eects
are mediated by synaptic inputs either from chemoreceptors or from other (respiratory) neurons with
synaptic inputs from chemoreceptors. Attribution of
eects to central chemoreceptors requires either peripheral chemodenervation or xed peripheral drive;
attribution to peripheral chemoreceptors requires
xed central drive, a condition dicult to achieve
for reasons elucidated above. Proprioceptive (e.g.
SAR) inputs are usually not a concern because
stable extra- and intracellular recordings often
involve vagotomy or, when the vagi are intact, controlled ventilation (e.g. no-ination tests or con-

479

trolled inations in paralyzed preparations). In vitro

preparations are of limited utility because one cannot identify E-BS neurons; moreover, as indicated
elsewhere, merely recording from the cVRG is not
denitive because it contains neurons involved in
non-respiratory behaviors using abdominal muscles.
Systemic hypercapnia increases the discharges of
E neurons (St. John and Wang, 1977; St. John,
1981; St. John and Bianchi, 1985; but see Folgering
and Smolders, 1979), a response unaected by carotid body denervation (St. John and Wang, 1977), indicating that peripheral chemoreceptors are not
required. Although comparisons have limited value
because of the dierences in stimuli, responses to
central chemoreceptor stimulation are greater than
those to peripheral chemoreceptor stimulation
(NaCN or nicotine; St. John, 1981 or hypoxia; St.
John and Bianchi, 1985), implying that central chemoreceptors are more inuential than peripheral
chemoreceptors in determining the discharge of E
neurons.
Reductions in drive, regardless of origin, elicit a
common response: tonic activity of E neurons or
motoneurons or motor units. Hypocapnia in vagotomized anesthetized or decerebrate cats silences I
neurons but elicits tonic activity in many E, including E-BS, neurons (Cohen, 1968; Merrill, 1974;
Bainton and Kirkwood, 1979) and motor nerves
(Bainton et al., 1978; Bainton and Kirkwood, 1979);
E-BS neurons are depolarized (Richter et al., 1993).
Cooling the ventral medullary surface of chloraloseanesthetized cats to 25 C reduces phasic abdominal
activity much more than diaphragmatic activity; at
10 C, however, abdominal activity increases and
includes a substantial tonic component (Haxhiu et
al., 1985). Similar eects, i.e. tonic discharge of E
neurons and motoneurons, are elicited by application of local anesthetic to the ventral medullary
surface of vagotomized, carotid body denervated,
paralyzed and ventilated chloralose-anesthetized
dogs (Schwanghart et al., 1974) and, in anesthetized
cats, during the apnea induced by stimulation of the
SLN (Bongianni et al., 1988a). In fact, the level of
tonic expiratory (cVRG E-BS and BotC E-AUG)
activity during SLN-induced apnea depends on the
PACO2; BotC E-AUG neurons, in a limited sample,
were more sensitive to CO2 than cVRG E-BS neurons (Bongianni et al., 1988a). CO2 thus appears to
exert a direct (i.e. not mediated by I neurons) excitatory eect on E premotor neurons.
Indirect evidence suggests that increased central
chemoreceptor drive does not increase neuronal activity by eliciting more depolarization. Merrill
(1974) observed in cats hyperventilated to hypocapnic apnea that the antidromic latencies, a measure
of cell excitability, of tonically-active VRG E, probably bulbospinal, neurons assume minimal values
identical to those during expiration when breathing.
Bianchi and St. John (1985) obtained similar results;
hypoxia and hypercapnia do not decrease antidromic latencies during the active phase but increase
maximum latencies during the inactive phase. Thus,
increased chemoreceptor drive provides more inhibition but not more excitation. In other words,
increased neuronal activity results from more intense

480

S. Iscoe

post-inhibitory rebound, commensurate with greater

swings in membrane potential.
8.5.4. Intracellular Recordings
The eects of CO2 on the membrane potentials of
respiratory neurons were rst studied by Mitchell
and Herbert (1974); most cVRG E-AUG neurons
tested were bulbospinal (Mitchell, 1977) and discharged continuously during hypocapnia. As CO2
increased, hyperpolarization during inspiration
increased but depolarization during expiration did
not; i.e. the greater swing in membrane potential
between respiratory phases was due solely to more
hyperpolarization during the inactive phase, a result
in agreement with those obtained by measurements
of antidromic latencies (preceding paragraph).
Mitchell (1977) attributed the increased discharge
during E to faster depolarization, implying, since
the cell depolarized to the same potential, that TE
must have decreased. Because hypercapnia hyperpolarized, not depolarized, all neurons, they concluded that these cells are not themselves
chemosensitive but instead receive input from chemoreceptors. To date, the pathway between chemosensitive cells and E-BS neurons has not been
elucidated.
In glomectomized anesthetized cats, hypocapnia
depolarizes E-BS neurons to a potential similar to
that during the neurons' active phase (Richter et al.,
1993), indicating that the changes in membrane potential associated with the respiratory phases arise
primarily from inhibitory inputs originating from I
and post-I neurons. Hypercapnia in decerebrate,
vagotomized, and glomectomized cats produces
both greater depolarization during expiration and
hyperpolarization during inspiration in all VRG,
including a few E-BS, neurons (Takeda and Haji,
1991). The greater depolarization during expiration
contrasts with earlier results showing that the average latency of antidromic activation does not
decrease (Bianchi and St. John, 1985), implying no
hypercapnia-induced increase in excitability. The
waveform associated with depolarization (the degree
of post-inhibitory rebound) is aected by the level
of hyperpolarization, probably via low voltage activated Ca2+ channels; the resulting increase in intracellular [Ca2+] then activates K+ channels and the
resulting eux of K+ repolarizes the membrane
(Richter et al., 1993).
If a cell is not intrinsically chemosensitive, blockade of synaptic inputs should prevent its response to
CO2. Limited data indicate that the responses to
CO2 are not intrinsic, results consistent with the
absence of c-fos in the cVRG following inhalation
of CO2 (see Section 8.3). In ventilated, decerebrate,
vagotomized, and glomectomized cats, intracellular
injection of Cl reverses CO2-induced hyperpolarization, and block of Na+ channels by application of
TTX to various VRG, including three E-BS, neurons prevents the larger swings in membrane potential (greater depolarization and hyperpolarization)
elicited by hypercapnia (Takeda and Haji, 1991). E
neurons stop ring, a response similar to some E
neurons of NA studied by Mitchell and Herbert
(1974). These results dier from those in the isolated

brainstem-spinal cord of the neonatal rat in which I

and tonically active neurons depolarize and E and
post-I (or early E) neurons hyperpolarize when CO2
in the superfusate is increased (Kawai et al., 1996).
In four E neurons, this hyperpolarization was
reduced but not eliminated when the composition of
the superfusate was switched to low [Ca2+]-high
[Mg2+] to block synaptic transmission; in one E
neuron, TTX did not aect the response to
increased CO2. Chemosensitive E neurons were,
however, all located rostral to the obex and, therefore, unlikely to have been bulbospinal.
Many pre-I neurons in the rostral ventrolateral
medulla of the neonatal rat behave similarly when
exposed to increased CO2 levels; they continue to
re phasically even after exposure to a low [Ca2+]high [Mg2+] superfusate which abolishes rhythmic
phrenic activity (Onimaru et al., 1989). Isolated cultured neurons from the NA and NTS of fetal rats
respond to pulses of CO2 and H+ with increased
discharge frequency and a slight depolarization
(Rigatto et al. 1992). Approximately 30% of ventrolateral medullary (central chemoreceptors?) and
midline raphe neurons in 100 mm brainstem slices, a
thickness which would eliminate most synaptic
inputs, from young rats respond to increased CO2 in
the superfusate, half increasing, the other half
decreasing, their discharge (Richerson, 1995).
Almost half (136 of 316) the neurons in slices of the
rostral ventrolateral medulla (the rostral chemosensitive area) of rat transiently increase their ring
after increases in [H+] (decreases in [HCO
3 ]) of the
superfusate (Jarolimek et al., 1990); these responses
persist after reduction or abolition of synaptic transmission, are stronger when elicited by increases in
PCO2 rather than decreases in [HCO
3 ], and are
potentiated by decreases in PO2.
Reasons for these dierences between adult cat
and neonatal rat may be related to development;
researchers hypothesize that a pacemaker component responsible for breathing in newborn animals is gradually replaced by a network component
as the animal matures (Smith et al., 1991b; Hayashi
and Lipski, 1992; Richter et al., 1992). Maturation,
however, may not be the entire explanation since approximately a third of neurons in the NTS in slices
of adult rat brainstem respond to increases in CO2
with more depolarization and/or increases in ring
and most of these respond similarly after synaptic
blockade (Dean et al., 1990). However, the responses of other brainstem neurons may not apply
to E and E-BS neurons. In the neonatal rat brainstem-spinal cord preparation, nine of 10 medullary
E neurons were either inhibited or unaected by
increasing the PCO2 of the superfusate; only one was
excited (Okada et al., 1993b). Of the 89 non-respiratory units, only one was converted to an E unit by
hypercapnia. Even allowing for the diversity of
neurons from which recordings were made, these
results indicate that CO2 does not exert a marked
excitatory eect on E neurons in this preparation. It
would be interesting to monitor the neuronal responses to CO2 in a more mature, in vitro preparation such as that recently introduced by Paton
(1996a).

Control of Abdominal Muscles

Evidence of intrinsic chemosensitivity of neurons

not just in the traditional chemosensitive areas on
or just below the ventral medullary surface is accumulating and convincing; several regions contain
neurons excited by hypercapnia or H+ (Dean et al.,
1989, 1990; Neubauer et al., 1991; Dillon and
Waldrop, 1992; Rigatto et al., 1992; Coates et al.,
1993; Morin-Surun et al., 1994; Rigatto et al., 1994;
Teppema et al., 1994; Richerson, 1995; Teppema et
al., 1995; Bernard et al., 1996; Kawai et al., 1996;
Nattie and Li, 1996) even when synaptic transmission is blocked (Onimaru et al., 1989; Dean et
al., 1990; Rigatto et al., 1992; Richerson, 1995). The
mechanism by which CO2 aects the membrane potential is unknown but may be related to a reduced
conductance of inward rectier K+ channels due to
decreased intracellular [H+], as proposed by Pineda
and Aghajanian (1997) for neurons of the locus
coeruleus.

9. BEHAVIORAL ASPECTS
9.1. Straining
Straining involves prolonged co-contraction of
the abdominal (and often expiratory muscles of the
rib cage) and the diaphragm against a closed glottis
in order to increase abdominal pressure. This
increased pressure causes, depending on the circumstances (contents of the gut, bladder, or uterus, and
degree of contraction or relaxation of various
sphincters), defecation, vomiting, micturition, or
parturition. In contrast, transport of esophageal
contents into the stomach requires an increased esophageal-gastric pressure gradient; accordingly, esophageal distension abolishes abdominal (but
increases rib cage expiratory) activity in pentobarbital-anesthetized dogs, even under conditions (hypercapnia, elevated EELV) which augment abdominal
activity (Van Lunteren et al., 1988a; Oliven et al.,
1989).
Distension of the rectum, vagina or bladder or
stimulation of pelvic aerents in decerebrate dogs
elicits a posture typical of defecation accompanied
by activation of the muscles that close the glottis
and increased and rhythmic discharges of the diaphragm and RA (or phrenic and L1) (Fukuda and
Fukai, 1986a,b). Similar results are obtained in
anesthetized rats (Cueva-Rolon et al., 1995). The
increases in RA activity are due to increased activity
of E-BS neurons (Fukuda and Fukai, 1988).
Transections of the rostral pons and 05 mm caudal
to the obex, respectively, abolish the slow rhythmic
increases and the maintained increases in abdominal
muscle activity elicited by stimulation of the pelvic
nerves. Thus, the rhythmic component is mediated
via a rostral pontine structure, likely the KF
(Fukuda and Fukai, 1986b) which is responsible for
the co-ordinated activities of many dierent muscle
groups; this may account for the widespread distribution of outputs from this region (Tohyama et al.,
1979; Rose, 1981; Stevens et al., 1982; Fulwiler and
Saper, 1984; Gang et al., 1990, 1991, 1993, 1995;
Bingmann et al., 1995; Gerrits and Holstege, 1996);
an analogous structure seems to exist in the pigeon

481

(Wild et al., 1990). Stimulation of the posterior sigmoid gyrus of the motor cortex in anesthetized dogs
can also generate straining behavior but only when
conditioned by pelvic nerve stimulation (Fukuda
and Koga, 1991).
Despite evidence (see preceding paragraph) that
the PBN and KF nuclei are responsible for rhythmic
straining eorts, electrophysiological evidence of
connections between the pons and cVRG E neurons
is lacking. Segers et al. (1985) investigated connections between neurons of the rostrolateral pons and
the medulla, but no XCOR was between a pontine
neuron and a cVRG expiratory neuron. Bianchi and
St. John (1982) had earlier established the presence
of ponto-medullary (VRG) connections using antidromic activation but they did not stimulate the
cVRG. Considerable neuroanatomical evidence
(Section 3.3.2) is consistent, however, with connections between the rostrolateral pons (PBN and KF)
and the cVRG.
Simulation of vaginal aerents in pregnant rats
elicits similar responses of the respiratory muscles,
leading to expulsion of the fetus (Higuchi et al.,
1987); bilateral section of the pelvic nerves not only
prevents these reex responses, leading to delayed
and prolonged delivery of the pups, but also prevents micturition.
The activities of various muscles during vomiting
and its underlying mechanisms have been recently
reviewed (Miller, 1990; Grelot and Miller, 1994,
1997). As with straining, there is concurrent contraction of the diaphragm, some intercostals, and the
abdominal muscles, combined with closure of the
glottis, to raise abdominal pressure. Contractions
are rhythmic during the retching phase; during the
following expulsion phase, the gastroesophageal
sphincter relaxes during co-contraction of the
muscles of the chest wall. Similar behavior is exhibited by infants during regurgitation (Menon et al.,
1985). The circuitry responsible for vomiting resides
in the brainstem because it can be elicited in decerebrate cats but appears to be diusely organized.
Although many E-BS neurons of the cVRG discharge in phase with, and drive, abdominal and internal intercostal motoneurons during retching and
vomiting, most do not (Miller et al., 1987); they
likely drive intercostal motoneurons ring out of
phase with phrenic and abdominal motoneurons
(e.g. Iscoe and Grelot, 1992). Although abdominal
muscle activity during vomiting persists even after a
mid-sagittal section between C1 and the obex (Miller
et al., 1987) which severs the axons of E-BS neurons, this does not indicate a dierent supraspinal
input because paralysis, which eliminates feedback
from the contracting muscles, abolishes activity in
the nerves to the same muscles; the residual activity
after section of the axons of E-BS neurons must
therefore be of segmental origin (Miller and
Nonaka, 1990) (see Section 10).
Increases in abdominal pressure during straining
are associated with changes in activity to the gastroesophageal, anal, and urethral sphincters. During
the bursts of RA activity evoked by stimulation of
pelvic aerents in dogs, anal sphincter activity is
inhibited but that of the urethral sphincter increased
to prevent voiding (Fukuda and Fukai, 1986a). In

482

S. Iscoe

humans, rapid increases in abdominal pressure, as

occurs during cough, increase activity of the anal
sphincter, thereby preventing incontinence, whereas
slow increases, as occurs in defecation, do not or
even abolish activity (Floyd and Walls, 1953;
Shak, 1991). During vomiting, the gastroesophageal sphincter opens only during the expulsion
phase. E-BS neurons of the cVRG with projections
to S1 (Kuzuhara et al., 1980; Holstege and Tan,
1987a; Sasaki et al., 1994; Sasaki and Uchino,
1995), the site of motoneurons (nucleus of Onuf)
innervating the urethral and anal sphincters (see
Kuzuhara et al., 1980; Ueyama et al., 1984;
Holstege and Tan, 1987a), maintain bladder and
bowel continence during the retching and expulsive
phases of vomiting; their discharges increase synchronously with that of abdominal motoneurons
and are abolished (Miller et al., 1995a) by the same
lesion, mid-sagittal between C1 and the obex, that
cuts the axons of E-BS neurons of the cVRG.
Neuroanatomical evidence supports these results:
injection of tritiated leucine into brainstem and midbrain regions containing neurons labeled by HRP
injections into the sacral spinal cord reveals neurons
in the dorsolateral pontine reticular formation (PBN
and KF) and the cVRG projecting to the nucleus of
Onuf (Holstege and Tan, 1987a). As Miller and colleagues point out (1995a), E-BS premotor neurons
do more than just drive expiratory motoneurons.
Neurons of the PBN and KF also project to the
medullary raphe nuclei (Holstege, 1988; Gang et al.,
1990, 1991, 1993); some raphe neurons also project
to the nucleus of Onuf (Holstege and Tan, 1987a).
During intromission, nociceptive responses are suppressed (Rose and Flynn, 1993; Cueva-Rolon et al.,
1995), a role in which the raphe is implicated (Gray
and Dostrovsky, 1983; Katayama et al., 1986).
Aside from descending projections to the spinal
cord, the raphe has extensive connections with more
rostral structures, including the PAG and PBN (Sim
and Joseph, 1992), both of which have a prominent
role in vocalization (next section).
9.2. Vocalization
Vocalization requires highly co-ordinated contraction not just of expiratory muscles which produce
airow but also muscles of the upper airway (larynx,
pharynx, and oral cavity), including the tongue (for
review, see Sakamoto et al., 1997). Poor co-ordination can result in the unstable sub-glottal pressures
characteristic of stuttering speech (Zocchi et al.,
1990); it is unclear if this is also responsible for
vocal tremor characterized by oscillations in expiratory ow (Hachinski et al., 1975) coupled to rhythmic discharges in various muscles, including RA
(Tomoda et al., 1987). Abdominal muscles have a
prominent role in speech production, their levels of
activity being dependent on amplitude (loudness),
lung volume, and body posture (Hoit et al., 1988;
Estenne et al., 1990b). Because the premotor neurons and motoneurons innervating all of these structures are located in the brainstem, it is not
surprising that many neuroanatomical studies
(Smith et al., 1989; Nunez-Abades et al., 1993;
Morillo et al., 1995; Gaytan et al., 1997) indicate

extensive interconnections to multiple regions within

the brain(stem), even in animals with a limited range
of vocalization; these connections should be even
more extensive in species with more complex vocal
abilities.
Vocalization does not necessarily require structures rostral to the midbrain; anencephalic newborns, for example, vocalize (Schenk et al., 1968);
anesthetized human subjects also vocalize when
stimulated appropriately (Perec, 1971). The role of
midbrain and brainstem neurons in vocalization has
been recently reviewed by Davis et al. (1996) and
Sakamoto et al. (1997). A major focus of the work
of Davies and her collaborators, and others, is the
role of the midbrain periaqueductal gray (PAG).
Injection of DLH into the caudolateral part of the
feline PAG evokes both ``voiced'' (howl, mew, and
growl) and ``unvoiced'' (hissing) sounds characterized by distinct patterns of recruitment of respiratory pump, including abdominal, and airway
muscles; these cannot be distinguished from `natural' vocalizations (Zhang et al., 1994). Electrical
stimulation in the same site also elicits vocalization
(Katada et al., 1996; Shiba et al., 1996b, 1997) as
does stimulation of the adjacent ventrolateral pons
near the medial lemniscus (de Lanerolle, 1990;
Sakamoto et al., 1993), along the pathway between
suprapontine and brainstem regions (Kanai and
Wang, 1962), resulting in co-ordinated activities of
the posterior cricoarytenoid, thyroarytenoid, and
diaphragm (Sakamoto et al., 1993). Vocalizations
are just part of the spectrum of behavioral and cardiovascular reactions associated with defensive reactions (immobilization, ight, threat) in the cat, the
nature and intensity of which varies with the site of
stimulation within the PAG (Carrive et al., 1987,
1988, 1989; Bandler and Carrive, 1988; Zhang et al.,
1990; Bandler et al., 1991).
Although dierent patterns of vocalization can be
elicited from dierent sites in the PAG, stimulation
always evokes co-ordinated eorts (e.g. Katada et
al., 1996; Shiba et al., 1997) rather than activity in
discrete muscles, as occurs with injections of DLH
in VRG (Zhang et al., 1995). However, PAG outputs are not distributed directly to expiratory and
laryngeal motoneurons but via neurons in the
cVRG (Holstege, 1989; Shiba et al., 1997) because
transections caudal to the obex progressively eliminate activity in muscles with motoneurons rostral to
the transection (Zhang et al., 1995) and because
destruction of neurons in the cVRG with kainic acid
neither aects activity in the recurrent laryngeal
nerve to muscles of the upper airway during respiration, swallowing, and vomiting nor blocks their responses to SLN stimulation (Umezaki et al., 1997).
Transections do, however, block the expiratory
components (abdominal activity and laryngeal
adduction) of vocalization (Shiba et al., 1997).
Shiba et al. (1997) conrmed that PAG projections
to laryngeal motoneurons are relayed via the cVRG.
Indeed, they recorded from ve cVRG neurons,
with DEC and plateau but not AUG discharge patterns, that received an input from PAG and projected to the contralateral NA in which laryngeal
motoneurons are located. Attempts to antidromically activate E-AUG neurons from the contralat-

Control of Abdominal Muscles

eral NA failed, but did elicit action potentials, as

did PAG stimulation, from silent neurons,
suggesting that E-AUG and E-DEC neurons have
dierent functional roles. This may, however, may
not be true of all species; E-BS neurons in anesthetized dog usually have DEC or plateau (rather than
true AUG) discharge patterns (Bajic et al., 1992).
Unlike laryngeal motoneurons, orofacial motoneurons are not driven by cVRG neurons (Zhang et al.,
1995); instead, because of their role in articulation
of specic sounds, they are driven directly from the
motor cortex. Neurons of the parabrachial region of
the pons, which display varied discharge patterns
during vocalizations in conscious cats (Farley et al.,
1992), may also have a role.
Our ability to adduct the larynx only during
expiration suggests inputs to laryngeal motoneurons
are gated by E neurons, a hypothesis supported by
the recent ndings of Shiba et al. (1997) (see above).
Although stimulation of the cortex (subdivision of
Brodmann's area 6) elicits contraction of the thyroarytenoid (vocal cord adduction), it is unclear if
the responses to stimuli delivered ``during the interval between inspiration and expiration'', occurred
only during expiratory ow (Hast and Milojevic,
1966).
Katada et al. (1996) have recently and elegantly
demonstrated the PAG-cVRG pathway in the
decerebrate cat; stimulation of the PAG increased
the discharges of 24 of 31 E neurons of the cVRG
and abdominal motor activity; 19 of the 24 neurons
had projections to the contralateral lumbar cord,
and six of these 19 were orthodromically activated
from the PAG. Complementary results have recently
been reported by Shiba et al. (1997); kainic acid
induced lesions of the cVRG no longer aected
vocal cord adduction and abolished phasic modulation of abdominal activity during PAG stimulation. Neurons of the cVRG thus represent the
``nal common pathway'' for vocalization
(VanderHorst and Holstege, 1996), a conclusion
consistent with their extensive projections to multiple sites in the brainstem (J.C. Smith et al., 1989),
especially NA which contains the motoneurons of
upper airway muscles (for reviews, see Bartlett,
1986; Iscoe, 1988).
Davis et al. (1996) have reviewed evidence favoring the PAG as a site through which higher centers
produce vocalization: cortical and forebrain structures have extensive projections to the PAG.
Lesions of PAG in experimental animals eliminate
both spontaneous and evoked vocalizations; humans
with lesions of the midbrain including the PAG cannot speak (see Jurgens and Ploog, 1970 for references). It is unclear, however, if the PAG mediates
the eects of peripheral feedback on vocalizations.
Increases in airway pressure, for example, prolong
the duration of the vocalization indenitely, an
eect blocked by cooling of the vagus nerves, and
vocalization is modulated by input from upper airway, probably laryngeal, receptors. Although the
PAG-evoked discharge patterns of various nerves
(phrenic, L1, recurrent laryngeal, and SLN) active in
vocalization in cats are unchanged after paralysis
(Shiba et al., 1996b), indicating that the responses
are programmed centrally, blockade of SLN aer-

483

ents in monkey distorts vocalizations of particular

sounds, especially at frequencies above 4 kHz
(Thoms and Jurgens, 1981). Blockade of superior
laryngeal nerve aerents in cats causes vocal distortions (Shiba et al., 1995). West and Larson (1993)
have suggested that SLN feedback is responsible for
modulating expiratory airow, although a role for
SAR aerents, based on changes in durations of laryngeal and diaphragmatic bursts during vocalizations when the trachea is bypassed, cannot be
excluded (Sakamoto et al., 1993). Paralyzed animals
provide information about central discharge patterns in the absence of feedback but are incomplete
models of vocalization.
In monkey, Saimiri sciureus, all four abdominal
muscles (particularly IO) and the internal and external intercostals are involved in vocalization (Jurgens
and Schriever, 1991). Although dierent vocal patterns can be elicited by electrical stimulation at
many sites in the brain, the PAG is common to
most and elicits vocalizations at the shortest
latencies (Jurgens and Ploog, 1970). Lesions involving the PAG and the lateral pons (PBN) abolish
vocalizations (as is true in other species; see Jurgens
and Pratt, 1979 for references) elicited by stimulation of rostral structures; vocalizations elicited by
stimulation of caudal structures, e.g. the ventrolateral medulla, are unnatural (Jurgens and Pratt,
1979). An anterograde tracer injected into the PAG
at a site eliciting vocalization reveals bers terminating in PBN and the lateral pontine reticular formation; in the medulla, many bers terminate
around the trigeminal and facial nuclei and, especially, the NA (Jurgens and Pratt, 1979) but no
mention is made of regions caudal to NA. Despite
apparently conclusive results about the role of PAG,
the neuroanatomical basis for vocalization is likely
more complex; HRP injected into the ambigual,
hypoglossal, facial and trigeminal nuclei retrogradely labels cells in many more regions, including
PAG and PBN, than have direct connections to
these four nuclei, as indicated by anterograde labeling following injection of tritiated leucine into these
retrogradely labeled regions (Thoms and Jurgens,
1987). Because vocalizations serving dierent behavioral roles arise from dierent regions of the brain
(Jurgens and Ploog, 1970; Ploog, 1981) and expiratory muscles are involved in multiple functions, it is
not surprising that labeling indicates many more
connections than can be accounted for by respiration.
In bats, only the roles of the laryngeal motoneurons, not the abdominal muscles, in vocalization
have been studied (Rubsamen and Schuller, 1981;
Yajima and Hayashi, 1983; Rubsamen and Betz,
1986; Rubsamen and Schweizer, 1986; Schuller and
Radtke-Schuller, 1990), reecting interest in the
complex ultrasonic `chirps' used for echolocation of
prey and avoidance of obstacles. In microchiroptera,
the abdominal wall consists of highly developed IO
and EO which, through the aponeuroses, seem
designed to generate intra-abdominal pressures
rather than postural adjustments (Lancaster and
Henson, 1995a). Bats, either at rest or in ight, generate the subglottic pressures required for ultrasonic

484

S. Iscoe

vocalization by brief (2025 ms) bursts of activity in

IO and TA (Lancaster et al., 1995b).
In copulating female cats, the ``estrous cry'' is elicited by intromission (Rose, 1981); this response is
facilitated by estrogens (Rose and Sutin, 1973b).
Both pontine and medullary (including laryngeal
motoneurons) neurons respond to vaginal stimulation (Rose and Sutin, 1973a; Rose, 1975) and the
responses appear to be estrogen-sensitive (Rose,
1973, 1975); similar results have been obtained in
monkeys (Rose and Michael, 1978; Rose, 1979).
This hormonal inuence extends to the spinal cord.
Estrous cats or ovariectomized cats administered estrogen have a much more intense projection (more
terminals and increased numbers of axonal arbors)
from cVRG to motoneurons of the lumbosacral
spinal cord (VanderHorst and Holstege, 1996,
1997c); such changes are not observed in the
rubrospinal pathway (VanderHorst and Holstege,
1997c). One can only speculate about the projections
in male sopranos (castrati) (Melicow and Pulrang,
1974).
Mating behavior is associated with a posture (lordosis) characterized by increased concavity of the
lower spinal cord due to activation of muscles of the
lower back, abdomen, and hindlimbs; many of the
motoneurons are located in the lumbosacral cord.
Lordosis can be induced in chronically decerebrate
rats by stimulation of the anks of the animal and is
potentiated by cervical stimulation (Rose and
Flynn, 1993). The association between the mating
posture and vocalization accounts for Holstege's
recent suggestion (VanderHorst and Holstege, 1996)
that these two behaviors share common neuronal
pathways, specically from PAG to cVRG to abdominal and other spinal motoneurons. Both social
and mating behaviour have been implicated in vocalization elicited by stimulation of discrete regions of
the PAG in guinea pigs (Kyuhou and Gemba,
1998). The connections between neurons of the
cVRG and motoneurons, including abdominal
motoneurons, in the lumbosacral spinal cord of cats
have recently been elucidated using WGA-HRP
(VanderHorst and Holstege, 1995, 1997b); when
coupled with injections of cholera toxin into hindlimb muscles, electronmicroscopy reveals monosynaptic connections (VanderHorst and Holstege,
1997d). Motoneurons of the feline hindlimb, pelvic
oor and lower back in these spinal segments, the
organization of which has just been described
(VanderHorst and Holstege, 1997a), all receive projections from the same region as that containing EBS neurons. Lordosis thus accounts, in part, for the
diversity of inputs to and projections from the
`cVRG' (see Section 3).
The eects of sex steroids on ventilatory control
has been the subject of a number of studies (see
(Bayliss and Millhorn, 1992) for a partial review)
but the increased ventilation or ventilatory response
to hypoxia during pregnancy (Hannhart et al., 1989)
or following administration of progesterone (Bayliss
et al., 1987, 1990; Hannhart et al., 1990) in cats and
the increased ventilatory drive in pregnant women
(Contreras et al., 1991) have been interpreted almost
exclusively in terms of central mechanisms (although
increased carotid body sensitivity may also play a

role; Glogowska and Richardson, 1973). The ndings of VanderHorst and Holstege (1996, 1997c),
cited in the preceding paragraph, suggest that
increased strengths of projections to respiratory
motoneurons could contribute to an increased response; for a given drive (output from premotor
neurons), motoneuronal output would be greater.
However, it is unclear if projections to the motoneurons are actually strengthened and, if so, if all respiratory motoneurons are aected. Studies of the
eects of hormones on ventilatory control typically
involve measurements of ventilation (e.g. Takano,
1984; Regensteiner et al., 1989; Tatsumi et al.,
1991), less often occlusion pressure (Contreras et al.,
1991) or phrenic activity (e.g. Bayliss et al., 1990)
but ignore the expiratory muscles. Only one study,
to my knowledge, has examined the eects of pregnancy on expiratory muscle strength; maximal
expiratory pressures did not increase (Contreras et
al., 1991) despite increased (>2000 fold) estrogen
levels in pregnancy. However, interpretation of such
results is confounded by the changes in muscle geometry during pregnancy.
Other than many primates, only songbirds have a
complex vocal repertoire dependent on airow
through the airway. The neural control of birdsong
(for reviews, see Brackenbury, 1989; Wild, 1997a,b)
is remarkably similar to that of vocalization in
mammals. Birds possess abdominal muscles with innervation and discharge patterns during normal
breathing similar to those of mammals (Kadono et
al., 1963; DeWet et al., 1967; Fedde et al., 1969;
Peek et al., 1975; see Fedde, 1987 for review).
Abdominal motoneurons are controlled by retroambigual E-BS neurons (Wild, 1993b, 1997a) which
receive inputs from the dorsomedial nucleus of the
intercollicular complex in the midbrain, the analog
of the PAG in other vertebrates (Wild and Vicario,
personal communications). The dorsomedial intercollicular complex, in turn, receives input from the
nucleus robustus archistriatalis, a structure that has
no analog in mammals; robustus also projects to
syringeal motoneurons in the hypoglossal nucleus
(Vicario, 1991; Wild, 1993a), in much the same way
that cortical speech areas project directly to orofacial, including hypoglossal, motoneurons. Neurons
in RA also respond to auditory inputs, the strongest
responses being to the bird's own song (Vicario and
Yohay, 1993). The forebrain includes a higher vocal
center, the analog of which, at least in humans, may
be Broca's and Wiernicke's areas. Stimulation of
RA and this higher vocal center evokes complex
songs specic to individual birds (Vicario and
Simpson, 1995).
During vocalization in canaries, abdominal activity may occur in bursts lasting less than 25 ms
(Hartley, 1990); similar short bursts are also
observed in an adult rooster (Peek et al., 1975). In
man, rapid repeated glottal closure results in similarly brief bursts of abdominal activity (Mead and
Reid, 1988) so body size does not explain the rapidity of the abdominal bursts. Moreover, abdominal
muscle activity compensates ``almost instantaneously'' for changes in syringeal resistance
(Suthers et al., 1994), thereby maintaining sound
production. While the force-velocity relation may

Control of Abdominal Muscles

help stabilize abdominal force generation in the face

of changing loads, a segmental reex probably
accounts for the rapid changes in abdominal activity. Remmers and Bartlett (1977) observed a
short latency (01520 ms) decrease in abdominal activity when the upper airway was suddenly bypassed
in chronically instrumented awake cats. Unloading,
they suggested, reduces abdominal spindle aerent
activity which in turn suppresses or disfacilitates abdominal discharge (see Section 10.1). A recent
review of muscle spindles in birds (Maier, 1992) indicates only one study of spindles in abdominal
muscles; the TA of chicken, a bird of undistinguished vocal ability, has few spindles (DeWet et al.,
1971). There are no studies comparing spindle densities in abdominal muscles of birds that sing with
those that do not, nor of abdominal muscle activity
during normal respiration and singing, nor of gender dierences (since males usually sing but females
do not).
Song production is hormone sensitive: administration of estrogen or estradiol at birth to female
chicks masculinizes the neural structures involved in
vocalization; the volumes of the nuclei increase and
connections between the higher vocal center and the
RA and area X of the lobus paraolfactorius develop
(Simpson and Vicario, 1991b). This converts the
vocal behavior to one characteristic of males, the
eects being less if hormone treatment is started
later in development (Simpson and Vicario, 1991a).
Intercollicular estrogen implants in ovariectomized
doves restores cooing behavior associated with nesting, conrming hormonal eects on vocalization
(Cohen and Cheng, 1981) but it is not known if
neuronal connections to abdominal muscles are
aected. Although song production serves the same
purposes as vocalizations in other animals (territorial claims, attracting a mate, warning competitors),
it is unclear if the hormonal eects described here
correspond to those described above for the eects
of estrogen on the pathways involved in lordosis in
cats.

10. SEGMENTAL CONTROL

10.1. Background
The presence of abdominal segmental reexes is
suggested by several ndings. First, the abdominal
response to PPB is abolished by dorsal rhizotomy
(T8 to L3) in anesthetized cats (Bishop, 1964); second, after cervical spinal transection in anesthetized
dogs, increases in EELV still elicit abdominal activity, albeit at lower levels and in phase with
inspiratory muscles (Reinoso et al., 1996); and third,
abdominal activity during vomiting persists even
after transection of the spinal cord at T2 (Fig. 10).
The reduced delay between the onsets of phrenic
and abdominal nerve activities after a midsagittal
lesion of the axons of E-BS neurons (Fig. 11) or
upper thoracic cordotomy is consistent with stretch
reexes originating from the abdominal wall (Miller
and Nonaka, 1990). As discussed in Section 7.1,
tonic activity is more common in the more dependent abdominal muscles; when the animal is upright,

485

the dependent muscles are subjected to greater

hydraulic loads and therefore greater stretch. As a
result, for identical increases in EELV, abdominal
activity is more easily elicited by shifts in posture
than loads. In awake dogs, postural adjustments
which stretch the abdominal muscles restore abdominal activity abolished by vagal cooling during
progressive hypercapnia and hypoxia (Yasuma et
al., 1993). In human subjects, the threshold for eliciting phasic abdominal activity is less in the upright
compared to the supine position, an observation
consistent with increased excitability of abdominal
motoneurons (Barrett et al., 1994). Lower abdominal muscles are more tonically active than upper
ones in upright humans (Martin and De Troyer,
1982; De Troyer, 1983; Hoit et al., 1988), implying
either greater segmental inputs due to more stretch
of dependent regions or, less likely, increased drive
from supraspinal inputs to more caudal motoneurons (i.e. a topographic distribution of inputs). On
the other hand, phasic activity, when present, is
greater in the upper portions which also respond
more to imposition of inspiratory loads (Martin and
De Troyer, 1982). Similar results are obtained in response to ETL in awake dogs; based on changes in
muscle lengths, Leevers and Road (1993a) found
evidence for tonic activation (decrease in baseline
length from length at rest) of IO during loadinduced increases in EELV, results consistent with
increased g eerent discharge in abdominal eerents
during PPB in cats (Russell et al., 1987). Because
muscle lengths are increased passively by stretch of
the muscles at increased EELV, the absence of a
change in resting length of TA suggests compensatory tonic activity in this muscle. More stretching of
the abdominal muscles during inspiration, superimposed on that due to the load, should activate the
spindles and the motoneurons, depending on their
excitability, and result in abdominal muscle activity.
This prediction diers from the results obtained by
Kondo et al. (1986) in human subjects in whom they
observed stronger abdominal stretch reexes, elicited
by tapping the abdomen, at residual volume than at
total lung capacity. They suggested that some input
other than that from spindles or premotor neurons
is responsible for the increased excitability of abdominal motoneurons.
The contribution of SAR aerents to abdominal
a and g motoneuronal discharge in response to
loads was investigated by Russell et al. (1987); bilateral vagotomy abolished respiratory modulation of
both types of co-activated motoneurons. Thus, abdominal muscles possess feedback systems capable
of load-compensation and the descending drive
necessary for their co-activation is aected by SAR
feedback. Jammes et al. (1983b) also found that
blockade of vagal aerents in anesthetized dogs on
ETL prevented not just the increase in abdominal
activity but also the proprioceptor-mediated increase
in abdominal pressure. However, how reduced SAR
feedback, as occurs at low lung volumes, aects the
abdominal stretch reex (Kondo et al., 1986) and
the role of SAR feedback in modulating abdominal
motoneuron reex excitability are both unknown.
The vagally mediated contribution may, however,
depend on state. In awake dogs, IO and TA, and to

486

S. Iscoe

Fig. 10. Eect of spinal cord transection (T2) on diaphragmatic and EO EMG activity during vomiting
in a decerebrate cat. Spinal reexes account for persistence of synchronous EO activity, although at
reduced amplitude (note change in gain from A to B), after cordotomy. Reproduced with permission
from Miller and Nonaka, 1990.

a lesser degree EO, still actively shorten in response

to ETL and CO2 after vagal blockade (Leevers and
Road, 1995b). These results are similar to those
obtained in response to hypercapnia (Leevers and
Road, 1994); although vagal aerents are not activated by CO2, internal (IO and TA) muscles were
more strongly recruited. The authors attributed the
responses of IO and TA to abdominal proprioceptors.
Activation of abdominal muscle aerents with
brief (1 ms) mechanical deections (12 mm) of the

Fig. 11. Eect of a mid-sagittal lesion from obex to C1 on

timing of phrenic and abdominal (L1) bursts during ctive
vomiting in a decerebrate cat. Delay between onsets of
phrenic and L1 activities decreased from an average 110 to
25 ms following the lesion (20 ms following cord section at
T2), indicating that abdominal motoneurons are normally
inhibited in intact cats at the start of each burst.
Reproduced with permission from Miller and Nonaka,
1990.

muscle evokes a reex excitation of the muscle; the

average latency of the ipsilateral reex was 13.7 ms
and that of the smaller contralateral reex 19.1 ms,
implying peripheral conduction velocities between
54 and 59 m . s1 (Maceeld and Gandevia, 1992).
Vibration of the linea alba elicits activity in TA
(Jammes et al., 1983a).
Reexes can also be evoked from cutaneous abdominal aerents. Stimulation of the central end of
a cutaneous branch of T13 to L4 in anesthetized or
decerebrate cats or rabbits elicits reex contractions
of the abdominal muscles with latencies of 1015 ms
(Chennells and Floyd, 1952). The response depends
on the depth of anesthesia and the intensity of
stimulation. In more lightly anesthetized animals or
as stimulus intensity increases, the reex spreads
from the ipsilateral IO and EO to the contralateral
muscles and adjacent segments. In decerebrate but
not anesthetized animals, the response to continued
stimulation is maintained. When expiratory activity
is present, responses are maximal in expiration.
Because expiratory activity was not usually present,
it is unclear if cutaneous aerents inhibit expiratory
activity. Cutaneous mechanical or electrical stimulation or electrical stimulation of the intercostal
nerves in human subjects does, however, inhibit EO
and RA activity (Kugelberg and Hagbarth, 1958);
this inhibition often precedes and follows the excitatory response, all of which are, on the basis of their
latencies, segmental in origin.
Among the three major respiratory motoneuronal
pools (phrenic, intercostal, and abdominal), most
work has been done on the intercostals by Sears,
Kirkwood, and their colleagues who have elucidated
many of the features determining their discharge
patterns (for references, see Kirkwood and Sears,

Control of Abdominal Muscles

1991; Kirkwood, 1995). These include the

distribution of supraspinal inputs, eects of spindle
aerent inputs, synchronization of discharges of
intercostal motoneurons, and, recently, characterization of thoracic respiratory interneurons
(Kirkwood et al., 1988; Schmid et al., 1993;
Kirkwood et al., 1993). Although Kirkwood et al.
(1988) estimated that interneurons are ten times
more numerous than motoneurons, few (18 of 310)
neurons (presumably interneurons) had pumpmodulated discharge patterns in cats with intact
chest walls; of the eight expiratory-phased neurons,
ve were excited by ination, one by deation and
two were ambiguous. Because most (32 of 54) interneurons had contralateral axons (as later conrmed
by Schmid et al., 1993), they suggested that interneurons serve three roles: (1) mediation of descending respiratory drive to motoneurons; (2) mediation
of inhibition of motoneurons during their silent
phase (e.g. inhibition of expiratory neurons during
inspiration); and (3) coordination of bilateral contractions of muscles for either respiration or postural changes (Kirkwood et al., 1988). However, as
they point out, interneurons are not activated by
stimulation of aerents at intensities less than ve
times the threshold for the motor axons, indicating
that proprioceptor-mediated coordination is unlikely. Comparable data for abdominal motor control are unavailable.
Although most work on thoracic spindle aerents
has been done on those of the intercostal muscles,
limited evidence indicates that abdominal muscles
are also inuenced by spindle aerent feedback.
Segmental reexes are likely responsible for the sudden decrease in abdominal activity in awake cats
when expiratory ow is diverted from the upper airway through a tracheostomy (Remmers and
Bartlett, 1977). The latency of the response, 01520
ms, is too short to be due to a reex originating in
the upper airway, transmitted via the SLN to the
medulla, and then to the lumbar cord and muscles.
The sudden decrease in load on the muscles would
result in a disproportionately greater shortening of
extrafusal compared to intrafusal bers, unload the
spindles, and remove excitatory spindle aerent
feedback. Similar mechanisms may operate in the
control of subsyringeal pressures in birds during
singing (Section 9.2). In intercostal muscles, similar
responses occur in response to loading and unloading of the muscles (e.g. Critchlow and Euler, 1963;
Corda et al., 1965; Andersen and Sears, 1970;
Newsom Davis and Sears, 1970; De Troyer, 1996;
see Sant'Ambrogio and Remmers, 1985; Shannon,
1986; Leevers and Road, 1995a for reviews).
However, there are several reasons to be cautious
about concluding that abdominal reexes operate
similarly to those of the intercostals or that reexes
initiated in intercostal muscles must also aect abdominal muscles with motoneurons in the same segment. First, unlike abdominal muscles, the
intercostals are restricted to individual segments and
are subjected to dierent regional stresses depending
on both rostral-caudal location and laterality.
Second, the internal abdominal muscles (IO and
TA) are more responsive than the external ones to
such interventions as increases in respiratory drive

487

and EELV, perhaps because of dierences in

strengths of supraspinal inputs, which could also
reect dierences in the involvement of interneurons. Third, there is evidence for a topographical
segregation of the motoneurons in the ventral horn
(Section 2.3); the locations of intercostal and abdominal motoneurons display little overlap (Tani et
al., 1994). Although basic information about the responses of abdominal muscles to proprioceptive
inputs is available (see below), we have no information about the control of feedback from spindles
of abdominal muscles, as is available for the intercostals (Greer and Stein, 1990), nor about the spinal
organization of abdominal aerents, interneurons,
and motoneurons.
10.2. Receptor Aerents and Projections
Activation of abdominal muscle spindle aerents
elicits a monosynaptic stretch reex (Garcia Ramos
and Lopez Mendoza, 1959; Bishop, 1964; Jammes et
al., 1983a; Kondo et al., 1986; Kondo and Bishop,
1987). In thoracic expiratory motoneurons, some of
which were probably abdominal motoneurons, activation of Golgi tendon organ (GTO) aerents elicits
IPSPs which reduce the amplitude of spindle aerent-induced EPSPs (Sears, 1964b). Opening the
chest of ventilated chloralose-urethane anesthetized
supine cats abolishes the excitatory response of RA
to stimulation of the carotid sinus nerve but combined pneumothorax and bilateral vagotomy does
not (Eldridge, 1976), an eect consistent with activation of GTO aerents. Spindle, and possibly
GTO, aerents project to motoneurons in other segments because their stimulation in one branch innervating EO elicits activity in parts of EO innervated
by nerves originating in other spinal segments
(Kondo and Bishop, 1987). The synaptic organization underlying these responses is unknown.
Evidence, however, indicates that spindle and possibly GTO aerents from one muscle are not distributed to all abdominal motoneurons. Continuous
electrical stimulation of TA aerents at 2.53 times
the threshold for the motor bers, which would presumably activate spindle and possibly some GTO
aerents, elicits tonic activity in TA (as expected)
and IO but not EO and RA (Fregosi et al., 1992). In
decerebrate cat, XCOR of activity of a spindle aerent in left L2 with eerent activity in left L1 and
right L1 and L2 revealed no eect on the probability
of discharge of these eerents (Fig. 12) even though
stimulation of aerents at an intensity sucient to
activate all aerents elicited marked excitatory and/
or inhibitory responses in these same eerents
(Fig. 13). The reason(s) for the absence of eects of
spindle aerent discharge on the probability of discharge of the eerents are unknown but could
include any or all of the following: (1) the eects of
activation of this particular spindle could be
restricted to ipsilateral motoneurons of the same
segment, (2) insucient counts may have been accumulated to reveal any weak eects; (3) the motoneurons aected by this particular aerent may have
been inactive; and (4) the eects may be mediated
via a pauci- or multisynaptic pathway, particularly
to motoneurons in other segments or contralateral

Fig. 12. Absence of eect of abdominal muscle spindle discharge on eerent abdominal activity in a decerebrate, ventilated cat with intact chest wall. Left panel, traces from
top down: raw phrenic activity (Phr), integrated phrenic activity (fPhr), eerent activity of the caudal branch of left L1 (L1L), unit discharge of the spindle aerent from a lament of left L2 (L2L), eerent activities of the caudal branches of right L1 (L1R) and L2 (L2R), and tracheal pressure (PTR). Note increased discharge of the aerent during
lung ination. Right panel, traces from top down: autocorrelogram of the aerent at control (expiratory threshold load of 0 cmH2O, ETL = 0) and increased (ETL = 5
cmH2O) end-expiratory lung volume, and XCOR of spindle activity to eerent activity in L1L, L1R, and L2R. The small increase in aerent activity during lung ination at
ETL = 0 (left panel) is apparent as a small inection (arrow) in the autocorrelogram; at increased end-expiratory lung volume, the discharge of the aerent is accentuated and
is apparent as a separate, earlier peak in the autocorrelogram. However, the discharge of this aerent had no eect on the probability of discharge of the eerents in ipsilateral
L1 or contralateral (right) L1 and L2.

488
S. Iscoe

Control of Abdominal Muscles

489

Fig. 13. Eects of high intensity shocks (>60 times threshold for a-motoneurons) to caudal branch of
left L2 on eerent activity in ipsilateral L1 and contralateral L1 and L2. Decerebrate, ventilated cat. For
discussion, see text.

motoneurons in the same segment, and therefore

too temporally dispersed to be apparent.
The responses to single high-intensity shocks activating all axons, aerent and eerent, are depicted in
Fig. 13. Stimulation elicited a short-latency (3.75 ms)
narrow (half width 0.5 ms) excitation followed by an
almost complete and prolonged (025 ms) suppression of activity in ipsilateral L1. These eects, especially the short-latency excitation, were much
weaker in contralateral L1. Within the same segment,
but contralateral, shocks elicited a longer latency
(5.25 ms), weaker, and wider (half-width 1.5 ms) excitation followed by a profound and prolonged (030
ms) suppression of eerent activity. The short
latency responses are consistent with activation of
large myelinated aerents with conduction velocities
of 050 m
s1. However, the weakness of the contralateral excitation at the same segmental level compared to the strong ipsilateral response in the rostral

segment indicates that the projections of these aerents and the interneurons to which they project are
stronger ipsilaterally. Suppression of activity was
almost complete in ipsilateral L1 whereas that in contralateral L2 was not, suggesting that the aerents responsible for the suppression are also distributed
primarily ipsilateral. However, the suppression could
result from several factors, the contributions of
which are unknown: (1) presynaptic inhibition from
unknown aerents, (2) disynaptic inhibition from
myelinated aerents (GTO, maybe spindles?); (3)
temporal dispersion of long latency inhibitory eects
of slowly conducting unmyelinated aerents; (4)
motoneuronal refractoriness; (5) loss of excitatory
input due to inhibition of medullary premotor neurons (Hernandez et al., 1989); and (6) recurrent inhibition (likely only within the same segment).

490

S. Iscoe

10.3. Reex Eects

10.4. Abdominal Aerents

The stretch reex activated by abdominal spindle

aerents enhances abdominal muscle contraction
when, for example, the muscles are loaded (e.g.
Russell et al., 1987). In awake dogs, proprioceptive
reexes probably contribute to the recruitment of TA
and IO during hypercapnia and load-induced
increases in EELV (De Troyer et al., 1989; Leevers
and Road, 1994, 1995b); a similar eect may be present in awake humans (Wakai et al., 1992). During
hypercapnia-induced increases in tidal volume
(Leevers and Road, 1994), for example, increases in
tonic activity would slow inspiration, placing the
inspiratory muscles on a more advantageous part of
the force-velocity relation. Greater stretch of TA and
IO, and increased activation of their spindles, could
account for their greater reex increase in activity
(Leevers and Road, 1989) during changes in posture.
Responses to activation of GTO, on the other hand,
are less well understood but would presumably
involve inhibition of homonymous motoneurons
(Sears, 1964b). Although the equivalent of a tendon
jerk reex can be activated by forceful stretching of
the abdominal wall (Kugelberg and Hagbarth, 1958),
imposition of sudden loads activates EMG activity of
dierent abdominal muscles with latencies (74, 79,
and 95 ms for IO, EO and RA, respectively) too long
to be due to reex (spinal) activation of GTO
(Lansing and Meyerink, 1981); indeed, these responses to sudden changes in positive pressure loads can
be volitionally suppressed (Lansing and Meyerink,
1981), an observation also inconsistent with the presence of a reex originating in the muscles.
Individual expiratory muscles of the rib cage and
abdomen can dier greatly in their responses to
changes in chemical drive (C.A. Smith et al., 1989;
Abe et al., 1996); these dierences are medullary in
origin but changes in activity secondary to proprioceptive feedback cannot be excluded. After upper
abdominal surgery, TA no longer responds to
increases in EELV and chemical drive whereas TS
and EO activities are unaected or even increase
(Farkas and De Troyer, 1989). A midline laparotomy prevents activation of TA, but not TS and EO,
during cough induced by mechanical stimuli to the
upper airway (Farkas et al., 1989); the aerents/
pathways responsible for this preferential suppression, visceral or somatic, and the level (spinal,
supraspinal) at which they act, are unknown. This
inhibition of TA activity, similar to that of the diaphragm after upper abdominal surgery (Simonneau
et al., 1983; Ford et al., 1983; Road et al., 1984;
Dureuil et al., 1986), and attributed to activation of
visceral aerents (Simonneau et al., 1983; Ford et
al., 1988), would shift breathing from the diaphragm/abdomen to the rib cage. After upper abdominal surgery, the threshold (concentration of
inhaled nebulized capsaicin or citric acid) for coughing increases, a change which cannot be explained
by post-surgical medication (Dilworth et al., 1990).
Abdominal nociceptive aerents, believed to be responsible for inhibition of diaphragmatic contraction after upper abdominal surgery (see Leevers and
Road, 1995a for review), may be involved; their site
of action could be spinal, supraspinal, or both.

Shannon, in his 1986 review, cited four studies of

the segmental eects of stimulation of abdominal
aerents, only one describing the responses of
medullary neurons to their activation. A more
recent review by Leevers and Road (1995a) describes
the eects of activation of aerents from the abdominal viscera but not the muscles. The little new
work since these reviews conrms the projection of
abdominal aerents to the brainstem on the basis of
changes in respiratory timing (Jammes et al., 1983a)
or the responses of some DRG inspiratory neurons
(Iscoe et al., 1990). Abdominal aerents also evoke,
in human subjects, cortical potentials with a latency
of 025 ms (Maceeld and Gandevia, 1992). Of particular importance is the demonstration by
Hernandez et al. (1989) that the discharges of most
E-BS neurons of the cVRG are suppressed by electrical stimulation of both internal intercostal and
abdominal (L12) nerves, responses which they attribute to activation of GTO rather than spindle aerents. The functional signicance of these responses
is unknown.
Jankowska and Odutola (1980) probably included
abdominal motoneurons in their study of the responses of motoneurons (of back muscles) in T13L2
to electrical stimulation of the dorsal and ventral
rami. Activation of low threshold ipsilateral aerents elicited monosynaptic EPSPs while activation
of higher threshold ipsi- and contralateral aerents
elicited polysynaptic EPSPs, IPSPs, or both, and
ipsilateral recurrent inhibition. They did not observe
contralateral disynaptic inhibition from group I
aerents or contralateral recurrent inhibition, ndings consistent with coactivation of back and
abdominal muscles, unlike the asymmetrical contractions of exors and extensors in hindlimb
muscles. Because none of the motoneurons was
identied as abdominal, this work needs to be
extended to abdominal motoneurons.
Nakata and colleagues (1994a, b) studied the responses of EO and RA motoneurons to stimulation
of aerents from the cutaneous branch of the nerve
to cutaneous maximus in chloralose or decerebratespinalized (T4) ventilated cats. No mono- or disynaptic EPSPs or IPSPs were observed, responses
being limited to ipsi- and contralateral polysynaptic
EPSPs and, less frequently, IPSPs, especially in RA.
The results were interpreted in terms of stabilization
of the trunk during locomotion. The authors do not
mention any central respiratory drive potentials in
the motoneurons from which they recorded; at a
FETCO2 level of 00.04, the animals may have been
apneic. Because the reexes originated from cutaneous maximus, a non-respiratory muscle, they
may have little or no applicability to respiratory
control.

11. CONCLUSIONS
Our expectations of the properties and connections of expiratory premotor neurons and abdominal muscles are based in large measure on their
behavior(s) under conditions which eliminate much

Control of Abdominal Muscles

if not most of what they do. Deep barbiturate

anesthesia, decerebration less so, reduces respiratory
neuronal discharge patterns to those essential for
respiration; this facilitates our understanding of the
processes underlying breathing but necessarily eliminates the non-respiratory functions in which they
participate. Neuroanatomical studies prove that the
cNRA has extensive interconnections with many
other brainstem structures, a nding in apparent
conict with evidence that, in this region, the only
neurons active under most experimental conditions,
E-BS neurons, are strictly bulbospinal. The cNRA
therefore contains a reserve of inactive neurons,
some undoubtedly premotor, which are not involved
in ``normal'' respiration. The diverse functions
(straining, vocalization, lordosis) described in this
review suggest that the term VRG, despite its utility,
should be replaced with the less restrictive and more
anatomically precise one, nucleus retroambigualis,
NRA.
A responsibility of any reviewer is to indicate prospective areas of research. My task is particularly
easy because, as should now be evident, so little
work has been done on control of abdominal motoneurons; this is also true, but less so, of their premotor neurons. Answers to the following and other
questions should do much to enhance our understanding of the diverse roles played by these versatile muscles. Major problems include the following:
What are the sources of excitatory synaptic inputs
to E-BS neurons?
What are the eects of hypoxia and CO2 on these
neurons?
How is descending drive distributed to abdominal
interneurons and motoneurons?
Are there abdominal interneurons and, if so, what
roles do they play not just in `normal' respiration
but in the other behaviors in which abdominal
motoneurons participate?
What are the projections (ipsilateral, contralateral, same or other segments) of abdominal muscle
spindles? Tendon organs? Do projections dier in
the lumbar and thoracic segments?
In the thoracic segments, do intercostal and abdominal muscle spindles and tendon organs modulate the discharge of both abdominal and intercostal
interneurons and motoneurons? Do thoracic interneurons ``share'' abdominal and intercostal motoneurons?
Does the task specicity (postural versus respiratory) described by Puckree et al. (1998) of abdominal
motor units also apply to dierent experimental respiratory conditions (e.g. hypercapnia, hypoxia, shifts
in lung volume)?
Answers to these and related questions should do
much to advance our knowledge of respiratory control mechanisms in general and of the many non-respiratory functions in which abdominal muscles are
used.
AcknowledgementsThis review is in honour of Morton I.
Cohen, on the occasion of his 75th birthday. My research
has been supported by the Medical Research Council of
Canada, the Ontario Thoracic Society (both directly and
through grants to Queen's University), the Canadian Lung
Association, and Queen's University (the Advisory

491

Research Committee, Botterell Foundation, and R.K.

Start Memorial Fund). I thank Sheila Gordon and Jeremy
Simpson for their assistance with production and/or modication of gures. Many individuals answered, some very
patiently, my questions and several provided access to
unpublished material. I am greatly indebted to (in alphabetical order): Dorothy Ainsworth, David Ballantyne, Albert
Berger, Armand Bianchi, Frank Cerny, Mort Cohen,
Andre De Troyer, Jay Dean, Jerry Dempsey, Jim Dun
(who also reviewed much of the manuscript), Howard
Ellenberger, Jay Farber, Gaspar Farkas, Jack Feldman,
Ralph Fregosi, Laurent Grelot, Gabriel Haddad, Musa
Haxhiu, Mary Ann Jarrell, Peter Kirkwood, Ned Lawson,
Bruce Lindsey, Janusz Lipski, Don McCrimmon, Gene
Merrill, Alan Miller, Roger Monteau, Jacopo Mortola,
Gene Nattie, John Orem, Tito Pantaleo, Julian Paton,
Eliot Phillipson, Jean-Paul Praud, George Richerson,
Diethelm Richter, Barry Sessle, Curtis Smith, Walter St.
John, Rod Suthers, Ryuji Takeda, Jean-Francois Vibert,
David Vicario, David Warner, Bill Whitelaw, Martin Wild,
and Ed Zuperku. All errors of interpretation are, however,
the sole responsibility of the author. I thank the authors
and the publishers (The Physiological Society, the
American Physiological Society, and Elsevier ScienceNL
(Sara Burgerhartstraat 25, 1055 KV Amsterdam, The
Netherlands) for their kind permission to reproduce
gures.

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