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Respiration
Chapter · November 2013
DOI: 10.1007/978-1-4614-1997-6_49
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Respiration
45
John J. Greer and Gregory D. Funk
Abbreviations
5-HT
AMPA
ATP
B€
otC
cAMP
CCHS
CCK
CNS
cVRG
Dbx1
DRG
GABA
KF
LPBr
LRt
Mcp
MeCP2
Mo5
MPBr
NK1R
NTS
OSA
P cells
PaCO2
PAO2
Serotonin
2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl)propanoic acid
Adenosine triphosphate
B€
otzinger complex
Cyclic adenosine monophosphate
Congenital central hypoventilation syndrome
Cholecystokinin
Central nervous system
Caudal division of ventral respiratory group
Developing brain homeobox protein
Dorsal respiratory group
g-aminobutyric acid
K€
olliker-Fuse nucleus
Lateral parabrachial nucleus
Lateral reticular nucleus
Medial cerebellar peduncle
Methyl-CpG-binding protein 2
Motor nucleus of the trigeminal nerve
Medial parabrachial nucleus
Neurokinin 1 receptor
Nucleus of the solitary tractus
Obstructive sleep apnea
Pump cells
Partial pressure of arterial carbon dioxide
Partial pressure of alveolar oxygen
J.J. Greer (*) • G.D. Funk
Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta,
Edmonton, Canada
e-mail: john.greer@ualberta.ca, jgf@ualberta.ca
D.W. Pfaff (ed.), Neuroscience in the 21st Century,
DOI 10.1007/978-1-4614-1997-6_49, # Springer Science+Business Media, LLC 2013
1423
1424
PaO2
pFRG/RTN
Pn
preB€
otC
PRG
RAR
REM
Robo3
rVRG
SAR
scp
SIDS
SO
Sol
SolC
SolVL
sp5
SubP
TASK
TRH
VE
vlPons
VRC
J.J. Greer and G.D. Funk
Partial pressure of arterial oxygen
Parafacial respiratory group/retrotrapezoid nucleus complex
Basilar pontine nuclei
Pre-B€
otzinger complex
Pontine respiratory group
Rapidly adapting receptor
Rapid eye movements
Roundabout homolog 3
Rostral division of ventral respiratory group
Slowly adapting receptor
Superior cerebellar peduncle
Sudden Infant Death Syndrome
Superior olive
Solitary tract
Commissural subdivision of the nucleus of the solitary tract
Ventrolateral subdivision of the nucleus of the solitary tract
Spinal trigeminal tract
Substance P
Acid-sensitive two-pore domain K+
Thyrotropin-releasing hormone
Minute ventilation
Ventrolateral pontine region
Ventral respiratory column
Brief History
Introduction and Historical Perspective
Breathing is the “simple” rhythmic act of moving air through the airways and into and
out of our lungs. A striking feature of the neuronal network controlling this behavior is
that it is incredibly robust. In humans, it begins in utero with the onset of fetal
breathing movements in the first trimester and continues largely uninterrupted after
birth under a very wide range of metabolic demands and behavioral states. The quest
to find where within the CNS this life-long, repetitive respiratory rhythm is generated
has an extensive history. This includes the writings of Galen, the physician to the
gladiators, who noted that a breathing rhythm continues as long as nervous tissue
above the lower neck region is intact. Animal experimentation in the 1790s demonstrated that a breathing rhythm persisted after removal of the cerebrum and cerebellum
in rabbit preparations. Refinement of this approach in the early 1800s, also using
the rabbit model, narrowed the critical region to the medulla and lower pons. A few
decades later, Flourens reported persistent breathing movements of the mouth with
only a limited portion of the medulla remaining intact. He referred to this medullary
45
Respiration
1425
region as the “noeud vitale.” The fact that each half of the brainstem could independently generate respiratory rhythms was shown in 1880 after midsagittal division of
the rabbit medulla. Experiments involving sectioning of the anesthetized cat brainstem
at several levels generated data suggesting that the pons plays an important role in the
generation of a normal respiratory rhythm. The importance of the pons was challenged
during that era, and it was concluded that the basic respiratory rhythm is indeed
generated in the medulla, and the pons provides important conditioning input. The late
nineteenth century saw the advent of electrical stimulation as an approach to investigate brainstem respiratory centers. This approach was not particularly useful for
identifying a discrete region controlling rhythm generation; however, it did reveal
that there are multiple regions in the brainstem that influence respiratory rate and
pattern when stimulated. Ramon y Cajal, who made early contributions to many
concepts in this textbook, contributed an anatomical perspective to the question. He
examined the efferent and afferent connections of respiratory-related nerves in rats and
cats and came up with a network model of respiratory pattern generation between
various brainstem nuclei. Variations on that network model were in vogue for many
years prior to the series of experiments described in the “Discovery of the RespiratoryRhythm-Generating Center” section below. In hindsight, given the current models of
respiratory rhythmogenesis, it is remarkable how insightful those early investigators
were based on data from relatively rudimentary experimental approaches.
The respiratory network that produces and controls breathing can be divided into
5 main components as diagrammed in Fig. 45.1: (1) rhythm-generating networks
that produce the basic neural oscillation that underlies the rhythmic act of breathing; (2) pattern forming systems that translate the basic oscillation
into a coordinated pattern of activity in the various motoneuron pools innervating
the respiratory muscles; (3) respiratory muscles, which comprise pump, airway, and
accessory muscles that generate inspiratory and expiratory airflow; (4) regulatory
elements that respond to and process chemosensory and mechanosensory information from the CNS and periphery; and (5) integrative components that coordinate
respiratory movements with other movements such as locomotion, speech,
chewing, and swallowing. Each of these topics will be discussed in the following
sections, and relevant historical context is provided within.
Respiratory Rhythm Is Generated within the Brainstem
Discovery of the Respiratory-Rhythm-Generating Center
As outlined above, the pons and medulla have been a long-standing focus of
investigation. There are three main interconnected regions of the brainstem that
contain concentrated populations of respiratory neurons classified based on the
phase in which they are active (e.g., inspiratory, expiratory, phase-spanning) and
their firing patterns (e.g., decrementing or augmenting). The pontine respiratory
group (PRG) is located within the dorsolateral pons and includes the parabrachial
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J.J. Greer and G.D. Funk
Fig. 45.1 The respiratory
control network can be
divided into five main
components: (1) a rhythmgenerating network that
produces the basic oscillation;
(2) a pattern-forming system
that produces a coordinated
pattern of activity in the
respiratory muscles;
(3) respiratory muscles;
(4) mechanosensory and
chemosensory regulatory
elements; and (5) integrative
components coordinate
breathing with other
behaviours
and K€
olliker-Fuse nuclei (Fig. 45.2). The dorsal respiratory group (DRG) is located
within the nucleus of the solitary tract (NTS). The ventral respiratory column (VRC) is
a column of ventrally located medullary neurons extending from the facial nucleus to
the spinal cord. A series of systematic studies addressed the specific question of which
of these neuronal populations are essential for generating the basic respiratory rhythm.
Following decades of combining neuronal recordings with stimulation, lesioning,
cooling, and ablations within the brainstem of anesthetized or decerebrate animal
models, a major advance resulted from experiments utilizing an in vitro brainstemspinal cord preparation isolated from neonatal rats (Fig. 45.3). Remarkably, the
45
Respiration
1427
Fig. 45.2 Respiratory-related regions of the brainstem of the rat shown in horizontal (a) and
sagittal (b) views. Respiratory-related regions comprise a nearly continuous column in the
lateral brainstem. The boundaries depicted between the various brainstem compartments reflect
functional distinctions between adjacent regions relative to their impact on breathing. Abbreviations: 5n trigeminal nerve, 7 facial nucleus, 7n facial nerve, A5 A5 noradrenergic neuronal
group, AmbC compact part of nucleus ambiguus, AP area postrema, B€
otC B€
otzinger complex,
cVRG caudal division of ventral respiratory group, DRG dorsal respiratory group,
I5 intertrigeminal area, icp inferior cerebellar peduncle, KF K€
olliker-Fuse nucleus, LPBr lateral
parabrachial region, LRt lateral reticular nucleus, mcp medial cerebellar peduncle, Mo5 motor
nucleus of the trigeminal nerve, MPBr medial parabrachial region, NTS nucleus of the solitary
tract, pFRG parafacial respiratory group, Pn basilar pontine nuclei, preB€
otC pre-B€
otzinger
complex, PRG pontine respiratory group, RTN retrotrapezoid nucleus, rVRG rostral division
of ventral respiratory group, scp superior cerebellar peduncle, SO superior olive, sol solitary
tract, SolC commissural subdivision of the nucleus of the solitary tract, SolVL ventrolateral
subdivision of the nucleus of the solitary tract, sp5 spinal trigeminal tract, vlPons ventrolateral
pontine region, VRC ventral respiratory column of the medulla, VRG ventral respiratory
group (Adapted with permission from Alheid and McCrimmon (2008) Respir Physiol Neurobiol.
64:3–11)
1428
a
J.J. Greer and G.D. Funk
b
X
IX
c1
5 sec
c5
T2
T8
5 sec
Fig. 45.3 In vitro brainstem spinal cord preparation isolated from newborn rats. Photomicrographs of (a) in vitro brainstem-spinal cord preparation with recording suction electrodes.
(b) Spontaneous respiratory discharge generated by brainstem spinal cord preparation. Distribution of spontaneous motor activity is illustrated by recordings of cranial (IX, X) and spinal
motoneuron discharge (C1, C4, C5, T2, and T8) on ventral roots (Adapted with permission from
Smith et al. (1991) J Neurophysiol. 64:1149–1169)
preparation, when bathed in an oxygenated modified Krebs solution, spontaneously
generates robust rhythmic respiratory-related activity for several hours. The activity
can be readily monitored by simply watching the rhythmic rib cage movements if the
rib cage is left intact. More precise monitoring is made by recording rhythmic neuronal
discharges from axons contained in ventral roots and cranial nerves that innervate the
diaphragm, respiratory rib cage, and upper airway musculature (Fig. 45.3). This
experimental model provided the opportunity to carefully dissect away various parts
of the brainstem respiratory groups while monitoring for perturbations of the respiratory
rhythm. Removal of the PRG and DRG did not significantly alter rhythmic respiratory
activity. This left the VRC as the likely candidate for containing the neuronal
populations generating the basic rhythm. The VRC is a long column of cells that
extends the rostrocaudal length of the medulla and is comprised of several groups of
neurons based on anatomical and functional criteria. Specifically, from rostral to
caudal, there are the parafacial respiratory group/retrotrapezoid nucleus complex
(pFRG/RTN), the B€
otzinger complex, the pre-B€otzinger complex (preB€otC), the
rostral ventral respiratory group (rVRG), and the caudal ventral respiratory group
(cVRG). The sequential sectioning of fine slices of tissue along the rostrocaudal extent
45
Respiration
1429
Fig. 45.4 Medullary slice preparation containing the preB€
otC complex generates spontaneous
respiratory rhythm. Left panel – imaging of preB€
otC neuronal activity in a medullary slice preparation
using a calcium-sensitive dye. Center panel – schematic of medullary slice that contains the preB€
otC
and hypoglossal (XII) motoneurons. Right panel – whole-cell patch recording of a preB€
otC inspiratory neuron that fires action potentials in approximate synchrony with the inspiratory motor discharge
recorded from the hypoglossal (XII) nerve root of medullary slice preparation (Adapted with
permission from Thoby-Brisson et al. (2005) J Neurosci. 25:4307–4318)
of the VRC revealed that the well-delineated region of the preB€otC was the source of
the basic inspiratory rhythm. In fact, a thin medullary slice of tissue containing the
preB€
otC region, isolated from the remainder of the CNS, will generate robust inspiratory neuronal activity in vitro that can be monitored via electrophysiological recordings
or imaging using voltage- or calcium-dependent dyes (Fig. 45.4). The critical role of the
preB€
otC was further demonstrated in the intact nervous system of adult rodents by
Feldman and colleagues. The first strategy was to determine if rhythmogenic preB€otC
neurons could be differentiated from surrounding cells by the types of neurotransmitters
and receptors they express. It became apparent that many preB€otC neurons expressed
the neurokinin 1 receptor (NK1R), the neurotransmitter somatostatin, and transporters
identifying them as glutamate releasing neurons. The NK1R expression was utilized for
the second strategic study. Normally, the neurotransmitter substance P (SubP) released
at a synapse binds to NK1R and is then internalized while bound to the receptor. In this
series of experiments, the plant toxin saporin was attached to SubP and applied to the
preB€
otC region. This resulted in the internalization of the toxin and subsequent perturbation of protein synthesis and cell death. The selective killing of preB€otC neurons
resulted in a marked destabilization of breathing rhythm. The third strategic study
utilized the somatostatin expression of preB€
otC neurons. Experiments were performed
to induce the expression of the Drosophila allatostatin receptor in somatostatinexpressing preB€
otC neurons. The allatostatin receptor, when expressed in neurons, is
coupled to GIRK channels (inward-rectifying K+ channels). However, there are no
natural ligands for the allatostatin receptor in the mammalian CNS, and thus, neuronal
function is not affected. In this study, exogenous allatostatin was administered to
activate the receptors which induced a hyperpolarization of the cell membrane due to
the increase in potassium conductance. The ensuing silencing of preB€otC neurons led to
the rapid suppression of rhythmic inspiratory drive that was reversible upon the removal
of allatostatin.
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J.J. Greer and G.D. Funk
Fig. 45.5 Two regions of the
VRC that generate rhythmic
respiratory-related activity.
Imaging of respiratory
activity in the pFRG/RTN and
preB€otC regions detected in
the brainstem of a newborn rat
in vitro preparation using
a voltage-sensitive dye
(Adapted with permission
from Oku Y et al. (2007)
J Physiol. 15;585:175–186)
The data from in vitro and in vivo rodent studies was subsequently extended
to the examination of human tissue. A concentrated cluster of NK1R-positive
neurons were found in a region of the human brain that correlates well with the
rodent preB€
otC. In addition, autopsy studies from patients with the neurodegenerative disorder, multiple system atrophy, demonstrated a significant loss of
NK1R expressing neurons in the region of the preB€otC. This is consistent with
the severe respiratory disorders, including central sleep apnea, associated with
the disease.
The model of rhythmogenesis subsequently has become more complicated
with evidence suggesting that a second site contributes to the rhythm of breathing.
Studies utilizing imaging (Fig. 45.5) and recording of respiratory neuronal
activity demonstrate rhythmic activity in the rostral region of the VRC adjacent
to the facial nucleus, referred to as the pFRG/RTN (shown in Fig. 45.2). The
pFRG/RTN rhythmic activity starts slightly prior to preB€otC discharge and
persists when the preB€
otC rhythm has been blocked pharmacologically with
opiates. Lesioning experiments have demonstrated synaptic connections between
the two nuclei, and removal of input from pFRG/RTN to the preB€otC can
modulate the frequency of inspiratory rhythm. More strikingly, the removal of
pFRG/RTN input results in the complete loss of active expiratory activity
(Fig. 45.6). Further, stimulation of the pFRG/RTN area leads to the expression
of previously subthreshold expiratory phase activity and a resetting of the respiratory rhythm. The current proposal is that the preB€otC generates inspiratory
rhythm and the pFRG/RTN generates expiratory activity during forceful, active
exhalation and that these two oscillators are coupled. There is further speculation
that a phylogenic relationship exists between these two coupled mammalian
oscillators and the rhythm generators in the developing amphibian brainstem
that independently, although in a coordinated manner, regulate lung and buccal
respiratory patterns.
45
Respiration
1431
Fig. 45.6 Functional data showing differential roles of pFRG/RTN and preB€
otC in control of
active expiration and inspiration. (a) Transection rostral to the facial nucleus, that leaves the
pFRG/RTN and preB€
otC intact, does not affect breathing pattern. (b) Transection at the caudal end
of the facial nucleus, to remove input from the pFRG/RTN, but not the preB€
otC, eliminates active
expiratory EMGABD bursts while maintaining robust inspiratory activity. (c). Schematic showing
the levels of transections with accompanying histological verification of location. V motor
trigeminal nucleus, VII facial nucleus, LRN lateral reticular nucleus, preB€
otC pre-B€
otzinger
complex, B€
otC B€otzinger complex, pFRG parafacial respiratory group, RTN retrotrapezoid
nucleus, SO superior olivary complex, Ac ambiguus nucleus compact (Adapted with permission
from Janczewski and Feldman (2006) J Physiol. 15;570:407–420)
Neuronal and Network Properties Underlying Respiratory
Rhythmogenesis
The question of how neurons are organized and function within the preB€otC to
generate inspiratory rhythmogenesis has not been fully answered. Early models
proposed that respiratory rhythm emerged as the result of synaptic interactions
between distinct populations of neurons that formed a network within the brainstem.
A central component of those models was that inhibitory neurotransmission was
necessary for the phase transition between inspiration and expiration. This concept
was tested by blocking multiple types of inhibitory neurotransmission. While the
motor pattern is markedly altered under those conditions, the basic respiratory rhythm
persists. This led to the establishment and testing of the hypothesis that rhythm was
1432
J.J. Greer and G.D. Funk
generated by the action of neurons with pacemaker properties, similar to what is
present in a number of invertebrate rhythmic neuronal systems. Indeed, whole-cell
intracellular recording studies identified two classes of respiratory neurons with
bursting-pacemaker properties within a subpopulation of preB€otC neurons in medullary slice preparations. One class depends on a persistent Na+ current (INaP) and the
other on Ca2+ and/or Ca2+-activated nonselective and voltage-insensitive cation
(ICAN) currents for their bursting activity. However, rhythmic inspiratory activity can
persist under some conditions when both types of bursting-pacemaker neurons are
pharmacologically blocked. This has led to the group-pacemaker hypothesis. In this
model, the emerging respiratory rhythm depends on recurrent glutamatergic excitatory
synaptic inputs between many preB€
otC neurons. In addition, the INaP and ICAN that
promote the bursting properties act to amplify the synaptic depolarizations and are
important for the full inspiratory drive potential characteristic of preB€otC neurons.
The preB€
otC and pFRG/RTN in the intact behaving organism function within
a much broader neural system. The generation of completely normal or eupneic
breathing requires inputs from many other central and peripheral network
elements. Synaptic inputs (both excitatory and inhibitory) from the PRG and
DRG are particularly important for respiratory sensorimotor integration and the
shaping of the various phases of inspiratory and expiratory motor patterns. There
are inputs from other brainstem regions and higher centers that regulate respiratory
output and reconfigure the rhythmogenic activity to accommodate behaviors such
as suckling, swallowing, sniffing, chewing, coughing, vomiting, and vocalization.
The modification of rhythmic preB€
otC output for the generation of gasping
is particularly important for autoresuscitation and survival during extreme
tissue hypoxia.
Neuromodulation of Central Respiratory Rhythmogenesis
Which neurotransmitter is primarily essential for generating the basic respiratory
rhythm within the preB€
otC? The answer is glutamate. Among the various types
of glutamate receptors, it is the block of AMPA [2-amino-3-(5-methyl-3-oxo-1,2oxazol-4-yl)propanoic acid] receptors alone that causes a dose-dependent decrease
and ultimate cessation of respiratory frequency. The inspiratory drive potential
generated via activation of AMPA receptors is further enhanced by activation of
NMDA and group I metabotropic glutamate receptors. In addition, preB€otC
neurons receive multiple modulatory inputs from many areas outside and within
the vicinity of the preB€
otC. The neurotransmitters acetylcholine, norepinephrine,
histamine, serotonin (5-HT), dopamine, adenosine triphosphate (ATP), SubP, and
cholecystokinin (CCK), often by converging onto similar second messenger
systems, can increase frequency, regularity, and amplitude of respiratory activity.
The medullary raphe nuclei are an important source of neuromodulatory input
regulating respiratory rhythmogenesis. The three major neurotransmitters released
from the raphe complex, 5-HT, thyrotropin-releasing hormone (TRH), and SubP,
all have excitatory actions on respiratory rhythmogenesis. The noradrenergic
45
Respiration
1433
control of respiratory frequency via synaptic inputs from neurons belonging to the
locus coeruleus and the pontine A5 and A6 nuclei is variable with the predominant
excitatory versus inhibitory action being determined by the relative activation of
medullary a1 (excitatory) and a2 (inhibitory) receptors. The neurotransmitters
g-aminobutyric acid (GABA) and glycine, the principal mediators of fast
chloride-mediated inhibitory transmission in the mammalian CNS, modulate respiratory rhythmogenesis and the patterning of motor output. In addition, GABAA
receptor-mediated control of respiratory activity is markedly enhanced by
neurosteroids released during stress induced by hypoxia, asphyxia, parturition,
ethanol exposure, and infection.
Opiates, used widely as analgesics to treat acute and chronic pain, are powerful
respiratory depressants. Balancing the trade-off between analgesia and sedation and
respiratory depression is one of the major clinical challenges of anesthesiology,
pain, and intensive care medicine. A significant component of the suppression of
respiratory rhythmogenesis results from activation of m-opiate receptors specifically within the preB€
otC. The mechanism of action includes presynaptic mediated
suppression of glutamate release and postsynaptic hyperpolarization of
rhythmogenic preB€
otC neurons. There are also indirect contributions to opioidinduced respiratory depression from other neuronal regions, including cortical
inputs, chemoreceptors, and NTS. Similarly, anesthetics, many of which act
via activation of GABAA receptors, inhibit preB€
otC neuronal function and thus
respiratory rhythmogenesis.
The activation of somatostatin receptors has potent inhibitory effects on respiratory rhythm generation. Acetylcholine has excitatory actions via activation of
nicotinic (nACh) and M3 muscarinic (mACh) receptors, while M2 receptor activation is inhibitory to respiratory rhythm. The purinergic control of respiratory
frequency is complex, with ATP being excitatory and its degradation product
adenosine being inhibitory.
Breathing Movements Are Generated by a Pattern Generator That
Underlies the Coordinated Recruitment of Rib Cage, Abdominal and
Upper Airway Muscles
The respiratory rhythmogenic drive generated in the brainstem is transmitted via
networks of interneurons and premotoneurons to several respiratory motoneuron
populations. At each synapse leading up to the neuromuscular junction, synaptic
and intrinsic membrane properties interact to produce the muscle-specific patterns
of respiratory activation. This includes neurons controlling rib cage, abdominal and
upper airway musculature. Respiratory pattern generating neurons, motoneurons,
and the muscles they innervate are typically active either during the inspiratory
(inhalation) or expiratory (exhalation) phase of the breathing cycle. The expiratory
phase often displays two distinct components. Some respiratory neurons have
a higher intensity of activation during the early stage of expiration (stage I or
postinspiratory), for example, neurons controlling upper airway muscles that aid in
1434
J.J. Greer and G.D. Funk
slowing expiratory flow rate, while other neurons have the predominance of their
activity during the late (or stage II) phase of expiration, for example, those
controlling the internal intercostal muscles.
Respiratory Muscles Controlling the Rib Cage and Abdomen
Air flow in and out of the lungs is regulated by the mechanical action of the
rib cage moving in axial and radial directions. Inspiration is an active phase
controlled by the contraction of the diaphragm, levator costae, scalene, and
parasternal and external intercostals muscles (i.e., pump muscles). In addition,
the sternocleidomastoid, pectoralis, serratus anterior, and trapezius muscles are
recruited during forceful inspiration (i.e., accessory muscles). Expiration is
largely passive. During forced expiration, for instance during strenuous exercise,
the rib cage movements are also controlled by abdominal and internal intercostal
muscles (Fig. 45.7).
Respiratory Spinal Motoneurons
Phrenic motoneurons innervate the diaphragm muscle. They receive their phasic
inspiratory drive from axons that descend from the medulla to the cervical spinal
cord. Specifically, the descending medullary neurons are located in the DRG and
rVRG. The majority of connections from the medulla to phrenic motoneurons are
monosynaptic. Glutamate is the main neurotransmitter mediating the transmission
of inspiratory drive from medullary neurons to phrenic motoneurons, largely via
AMPA receptors. There are also descending inhibitory synaptic inputs from the
medulla onto phrenic motoneurons. The primary inhibitory sources arise from
brainstem neurons located in the cVRG and B€
otC. The inhibitory drive during the
expiratory phase ensures that the diaphragm does not contract during exhalation.
Interestingly, there is also inhibitory drive to phrenic motoneurons during the
inspiratory phase. It is the balance of inhibitory versus opposing excitatory synaptic
drive that determines the activity of phrenic motoneurons and diaphragm contraction. This “push-pull” balance of excitation and inhibition is a strategy widely used
by the CNS to further enhance the potential for regulating motoneuron excitability.
In addition to the fast excitatory and inhibitory inspiratory drives mediated by
the amino acid transmitters, synaptic endings converge onto the phrenic motoneuron pool that contain a multitude of neurotransmitters, including 5-HT, TRH,
norepinephrine, SubP, met-enkephalin, cholecystokinin, galanin, neuropeptide Y,
and adenosine. The neuromodulators regulate phrenic motoneuron excitability on
a slower time scale relative to the amino acid transmitters. In addition, the activity
of these modulatory neurons often varies between states (e.g., sleep-wake cycling).
Internal and external intercostals, as well as triangularis sterni and parasternal
motoneurons, are located in the ventromedial region of the spinal cord that corresponds to the intercostal space in which the muscle is located. Inspiratory drive
45
Respiration
1435
Sternocleidomastoid
Scalene
Parasternal
Serratus
anterior
Internal
intercostal
External
Intercostal
Diaphragm
Rectus
abdominis
INHALATION
EXHALATION
Fig. 45.7 Respiratory muscles innervated by spinal respiratory motoneurons that are recruited
during inhalation and exhalation. Levator costae (occupying most rostral regions of each intercostal space), triangularis sterni (underlie parasternal muscles), and other abdominal muscles
besides rectus abdominis not shown (Copyright 2004 Pearson Education, Inc. publishing as
Benjamin Cummings)
transmission to intercostal respiratory motoneurons arises from the rVRG and
DRG. Expiratory drive arises from the cVRG. Unlike phrenic motoneurons, there
seems to be very little monosynaptic input to intercostal respiratory motoneurons
from the medulla. Rather, there is a segmental network of interneurons that transmit
reciprocal inhibition between inspiratory and expiratory intercostals motoneurons.
The neurochemical control of respiratory motoneurons controlling intercostal
musculature has not been studied in detail, but AMPA receptor activation seems
to be an important contributor.
Abdominal muscles are primarily innervated by motoneurons located in the
lower thoracic and upper lumbar spinal cord. Premotoneurons supplying abdominal
motoneurons are localized in the cVRG. Contraction of the rectus abdominis,
oblique abdominis, and transversus abdominis muscles increases intra-abdominal
pressure that causes upward displacement of the diaphragm muscle during forceful
expiration.
Control of the Upper Airway
In order to maintain adequate ventilation, the upper airway must remain open across
different postural positions and sleep-wake cycles. This is accomplished by contraction of upper airway muscles, such as the genioglossus (tongue) and the hyoid
1436
J.J. Greer and G.D. Funk
muscles. The airway muscles are typically activated prior to the main inspiratory
pump muscle, the diaphragm, and this decreases airway resistance to facilitate
airflow generated by the downward contraction of the diaphragm. The respiratory
modulation of upper airway muscles is superimposed on a background of tonic
activation. This is important for setting baseline airway size and stiffness necessary
for counteracting the subatmospheric collapsing pressures generated during inspiration. Glutamate, acting largely via AMPA receptors, is an important component
of basic inspiratory drive transmission to hypoglossal motoneurons. Suppression of
upper airway muscle activation during sleep can result in episodes of decreased
muscle tone that leaves the upper airspace vulnerable to collapse (Obstructive Sleep
Apnea discussed below).
Spinal Cord Injury and Breathing
The relative importance of each population of respiratory motoneurons for breathing movements is clearly evident from the effects of spinal cord injury. With
a spinal cord injury at the level of C4 and higher, all of the major muscles
controlling rib cage expansion (diaphragm, external intercostal, and parasternal)
are paralyzed. Patients will require the use of a mechanical ventilator except for
short durations where a combination of the recruitment of neck inspiratory
accessory muscles (sternocleidomastoid and scalenus) in combination with
glossopharyngeal breathing can produce adequate ventilation. Glossopharyngeal
(or frog) breathing uses the muscles of the tongue and the throat to force air into the
lungs through repetitious cycles of 6–10 gulps of air followed by exhalation.
Injuries between C4 and T6 leave the diaphragm functioning, but the loss of
intercostal activity results in the patient experiencing a sensation of breathlessness
(dyspnea) despite having adequate gas exchange. Injuries between T6 and T12 do
not normally affect quiet breathing; however, the ability to cough is impaired.
Normal breathing and cough reflexes are preserved with injuries below T12.
Respiratory Rate and Pattern Are Regulated by Chemoreceptive
and Mechanoreceptive Feedback
Chemoreception
The respiratory system works in conjunction with the cardiovascular system to
provide oxygen to cells for cellular metabolism, remove the waste product CO2 and
maintain proper pH levels. For the system to work efficiently, feedback from
sensors that constantly monitor levels of O2, CO2, and pH in the blood and brain
is necessary. There are two main groups of chemoreceptors that perform this
function. The peripheral chemoreceptors detect changes in these variables in the
blood, while central chemoreceptors monitor the CNS. When the chemoreceptors
detect that O2, CO2, and/or pH levels deviate from normal baseline levels, they
45
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1437
transmit nerve signals through a feedback loop to induce compensatory changes in
the depth and/or rate of breathing. Thus, chemoreceptors are key to the homeostatic
control function of the respiratory network.
Hypoxia
Breathing is typically described in terms of the number of breaths taken per minute
(frequency) and the size or depth of each breath (tidal volume). A 70-kg person at rest
typically has a tidal volume of 500 ml per breath and takes 12 breaths per minute.
The product of the two variables is referred to as the minute ventilation (V_ E).
Measurement of blood gases is reported in partial pressures. For example, the measurement of oxygen and carbon dioxide in the arterial blood is reported as PaO2 and
PaCO2, respectively. The relationship between V_ E and the partial pressure of oxygen
in the alveoli (PAO2) is shown in Fig. 45.8 (in healthy individuals, PAO2 is a reasonable estimate of arterial PaO2). This relationship is measured in a laboratory setting by
monitoring a subject’s ventilation when they breathe air containing different levels of
oxygen. Under normal conditions, PaO2 drops when a subject does not breathe
sufficiently to match metabolic demand. This drop in PO2 is detected, the neuronal
feedback loop is activated, and ventilation increases, restoring PaO2. Experimental
control over the O2 level of the inspired air “short-circuits” the normal feedback loop
because no matter how much subjects increase ventilation, they will not be able to
restore PaO2. The resultant relationship describes the potency of hypoxia as a source
of respiratory drive. The experiment is performed under two conditions. In the first, the
only manipulation is to alter the level of hypoxia and monitor ventilation. The resultant
relationship is shown in Fig. 45.8 (blue curve). There are two main points. At resting
levels of PO2 (near 100 mmHg), the relationship is quite flat, indicating that the system
is not very sensitive to changes in PO2 in this range. However, as hypoxia becomes
increasingly severe near PaO2 levels of 60 mmHg, the sensitivity increases, as
indicated by the progressive increase in the slope of the V_ E/PO2 relationship. In the
second experimental condition, CO2 is added to the inspired air to prevent the fall in
CO2 that results from the increased ventilation (Fig. 45.8, red curve). This curve
reveals the true sensitivity of ventilation to hypoxia.
A key feature of the hypoxic ventilatory response is that it is biphasic (Fig. 45.9). In
most adult mammals, it is characterized by an initial increase in ventilation that peaks
within the first 1–2 min and then decreases over the next 2–5 min to a level that
remains above control. This secondary decrease in ventilation, referred to as hypoxic
ventilatory depression, is more pronounced in newborn and premature mammals such
that ventilation can actually fall below baseline levels (as shown for an 8-day-old
infant in Fig. 45.9). Part of this decrease in ventilation is due to the fact that hypoxia
actually depresses metabolism. The reduced metabolism is an appropriate adaptive
response to reduce the use of oxygen that is in short supply. However, the inhibition of
respiratory networks is clearly not adaptive as it does not meet the demand for bringing
in more oxygen via increased ventilation. This disadvantageous suppression of ventilation may be due to the hypoxic-induced release of inhibitory neuromodulators
within the brainstem respiratory circuitry, including adenosine, taurine, neurosteroids,
opioids, prostaglandins, and GABA.
1438
60
PCO2 held constant at 42.6 mmHg
40
Minute Ventilation
Fig. 45.8 Ventilatory
response to hypoxia of
a human subject. The red
curve is the ventilatory
response when PCO2 is kept
constant by adding CO2 to the
inspired gas. The blue curve is
the response when PCO2 was
not maintained constant. In
this case, as ventilation
increases in response to
the decrease in PO2, PCO2
continues to decrease. The
ventilatory response to
hypoxia is therefore blunted
because the CO2 drive to
breathe is constantly falling
and offsetting the increased
hypoxic drive. The numbers
next to the blue curve
represent the PCO2 measured
at each point (Adapted with
permission from Loeschcke
and Gertz (1958) Pfleugers
Archiv. 267:460–477)
J.J. Greer and G.D. Funk
20
30
37
PCO2 allowed to decrease
0
20
60
39
100
140
PO2 (mmHg)
Hypercapnia
Feedback signals in response to an increase in the levels of CO2 (hypercapnia)
cause an increase in ventilation. This respiratory response to hypercapnia is attributed 20% to peripheral and 80% to central chemoreceptors. The relationship
between V_ E and PaCO2, measured in a similar manner to the hypoxic sensitivity,
is shown in Fig. 45.10 at three different levels of PaO2. At normal levels of oxygen
(normoxia), the relationship is characterized by a hockey-stick-shaped curve with
two key features. First, near baseline levels of CO2, the relationship is linear with
a significant slope meaning that even small changes from baseline will evoke
a significant compensatory ventilatory response. This differs markedly from the
V_ E/PO2 relationship and illustrates that under normal conditions, CO2/pH is the
primary regulated variable. Second, ventilation decreases linearly with PCO2 until
26 mmHg when the relationship becomes flat (the blade of the hockey stick).
Over this range, CO2 is so low that it no longer provides a chemical drive to breathe.
The level of ventilation observed here is determined by PaO2.
The relationship between V_ E and CO2 when there is also hypoxia is similar to
that in normoxia with two noteworthy differences. First, the slope of the V_ E/PaCO2
relationship is steeper, indicating a positive nonlinear interaction between
45
Respiration
1439
8 days old
18 days old
+40
+20
% Change in
Ventilation
0
−20
−40
O2(%) 21
15
Hypoxia
21
Hypoxia
15
5 min
Fig. 45.9 Ventilatory responses to mild (15%) hypoxia in premature infants. In the youngest
group, an initial increase in ventilation is followed by a respiratory depression in which ventilation
falls below baseline during the hypoxic exposure and often remains below baseline after returning
to normoxia. In older infants, the ventilatory increase is more sustained, remaining above baseline
throughout the period of hypoxia (Adapted with permission from Waters and Gozal (2003) Respir
Physiol & Neurobiol. 136:115–129)
the O2 and CO2 respiratory drives (i.e., there is a larger change in ventilation for the
same change in PCO2). Second, the flat “blade” component of the hockey stick is
still present, but it occurs at a higher level of V_ E, and the inflection point in the stick
is at lower levels of PaCO2, reflecting the higher O2 drive in this condition. In
hyperoxia (curve 3), the slope of the linear V_ E/PaCO2 relationship is reduced from
that in hypoxia and normoxia, again indicative of the interaction between CO2 and
O2 drives. In addition, the relationship is linear throughout. When PaCO2 falls to
<28 mmHg, the relationship intersects with the x-axis; ventilation falls to zero.
This illustrates a very important feature of the central respiratory network; while
capable of generating a rhythm when isolated from all peripheral inputs in vitro, it
requires a baseline level of tonic drive to operate. Chemoreceptor input is a major
source of this tonic drive in vivo; if blood PaO2 is maintained and PCO2 is reduced,
central respiratory rhythm and breathing will cease.
Peripheral Chemoreceptors
In mammals, the main group of peripheral chemoreceptors is located bilaterally in
the carotid body where the common carotid artery bifurcates into the internal and
external carotid arteries (Fig. 45.11a, b). The carotid bodies are small sensory organs,
but per gram of tissue, they are the most highly perfused structure in the body. This along
with their position between the heart and the CNS places them ideally as monitors of
blood en route to the brain. In addition, there are contributions from chemosensing
aortic bodies that are exposed to blood flowing out of the heart through the aortic arch to
the remainder of the body. Even at rest, the ongoing feedback from the peripheral
chemoreceptors contributes approximately 20% to the ventilatory drive. This has been
demonstrated by the experimental manipulation of briefly having the subject breathe
100% O2 which momentarily silences the feedback from peripheral chemoreceptors.
1440
60
hypoxia
normoxia
40
Minute Ventilation
Fig. 45.10 Ventilatory
response of a human subject
to hypercapnia at three levels
of PO2: hypoxia, normoxia,
and hyperoxia. The response
to PCO2 is linear at each level
of PO2, but the slope of the
relationship increases with
increasing hypoxia (Adapted
with permission from Nielsen
and Smith (1952) Acta
Physiologica Scand.
24:293–313)
J.J. Greer and G.D. Funk
20
hyperoxia
0
20
40
30
PCO2 (mmHg)
50
Carotid bodies contain two main types of cells, neuron-like glomus (type I) cells
and glia-like sustentacular (type II) cells (Fig. 45.11c). Sustentacular (derived from
the Latin word for “support”) refers to cells that provide a supportive function,
similar to those of astrocytes in the CNS. However, just as astrocytes in the CNS
are emerging as important participants in information processing, involvement of
sustentacular cells in signal processing in the carotid body is under intense
investigation.
Glomus type I cells are the actual sensory cells, detecting primarily changes in
PO2 but also PCO2/pH. They have a fine granular appearance due to their high
content of neurotransmitter-containing vesicles. The molecular mechanisms underlying hypoxia sensing are not completely known but appear to involve closure of
a K+ (TASK) channel that is normally open at rest (most likely an acid-sensitive
two-pore domain K+ [TASK] channel) (Fig. 45.11c). These channels are very
sensitive to inhibition of mitochondrial energy metabolism. They close in response
to hypoxia via unknown mechanisms and are the major contributor to the hypoxiaevoked depolarization of glomus type I cells. Elevated CO2 and the resultant
decrease in pH directly inhibit these acid-sensitive K+ channels causing the
CO2-dependent depolarization of glomus type I cells (Fig. 45.11c). Regardless of
the stimulus, glomus type I cell depolarization opens voltage-gated Ca2+ channels,
leading to Ca2+ influx which triggers vesicle fusion with the cell membrane and
45
Respiration
1441
Fig. 45.11 Carotid body chemoreceptors: location, transduction mechanisms, and central projections. The carotid bodies are located bilaterally in the neck (a) at the bifurcation of the common
carotid artery into the internal and external carotid arteries. (b) Enlarged view of the box in
(a) showing the carotid body and its afferent innervation via the carotid sinus nerve. (c) Enlarged
view of a cross section through the carotid body (at the blue line in b) showing arrangement of
glomus cells (type I; the sensor), sustentacular cells (type II; glia-like), capillaries, and carotid
sinus nerve endings. Signal transduction pathways for conversion of increased CO2 (upper glomus
cell [steps i-vii] and decreased O2 (lower glomus cell [steps 1–7]) into transmitter release
and action potential generation in carotid sinus nerve are depicted. (d) Central projections of
carotid sinus nerve afferent fibers in the medulla. The first-order excitatory synapse is in the NTS.
These neurons project to the pontine respiratory group (PRG) and chemosensitive neurons in
the pFRG/RTN which in turn send excitatory projections to the preB€
otC and possibly other regions
of the VRC
neurotransmitter release in proportion to the magnitude of the hypoxic (or hypercapnic) stimulus. Glomus cell vesicles contain a host of neurotransmitters, but it is
primarily ATP and acetylcholine that excite afferent terminals of the carotid sinus
nerve (a branch of glossopharyngeal nerve) by activating P2X (ATP-gated ion
channels) and acetylcholine receptors, respectively. Impulses conduct centrally
1442
J.J. Greer and G.D. Funk
and make excitatory synapses in the caudal NTS (Fig. 45.11d, see also Fig. 45.2).
The NTS is a major integration site for visceral sensory information from the
pharynx, larynx, respiratory tracts, heart, and large blood vessels coming through
the vagus (X), glossopharyngeal (IX), and facial (VII) nerves. From this first-order
synapse in the NTS, second-order neurons synapse in the RTN (important central
chemoreceptive site discussed below) and pontine respiratory groups, which in turn
project to the VRC and hypothalamus to bring about changes in ventilation.
Central Chemoreceptors
Chemosensitive sites: CO2 diffuses rapidly from blood vessels across the bloodbrain barrier. Thus, elevations in PaCO2 rapidly appear in the poorly buffered
extracellular and cerebrospinal fluid of the brain. Central chemoreception refers
specifically to the feedback process whereby changes in brain CO2 (or pH) evoke
the changes in ventilation that maintain arterial CO2 (or pH) near steady-state
levels. The dominant theory is that CO2, working indirectly through its effect on
pH, stimulates breathing by activating different types of acid-sensitive CNS
neurons located at multiple sites. Initial attention focused on the ventral medullary
surface following the observation of dramatic increases in ventilation in response to
local acidification of two regions on the ventral surface of the medulla. Named after
the investigators that described them in the 1960s and 1970s, Mitchell’s area is in
the rostral medulla (approximately under the facial nucleus) and corresponds
approximately with the RTN, while Loeschcke’s area is in the caudal medulla.
Subsequent to those pioneering studies, a variety of areas that evoke increases in
ventilation upon local acidification have been discovered.
Putative chemosensory sites in the brainstem include the caudal NTS and
adjoining dorsal motor nucleus of the vagus, rostroventrolateral medulla, preB€otC,
medullary raphe, locus coeruleus, and RTN. The relative importance of the different regions may change with sleep-wake state, but, in general, there seems to be
a modest increase in ventilation of 20% in response to acidification of each
individual region. If multiple regions are activated together, the overall change in
ventilation reflects the additive effects from each region. Those observations led to
the view that central chemosensitivity derives from the independent actions of these
multiple sites that then converge on the central respiratory controller to produce an
integrated respiratory response (Fig. 45.12a).
An alternate emerging view is that the RTN is a particularly important site of
central CO2 chemosensitivity and that it extends excitatory glutamatergic projections to the preB€
otC to alter ventilation. This view further proposes that the RTN
acts as an integration center for chemosensory information coming from the
periphery and other sites in the CNS (see Fig. 45.12b). This proposed model is
based on several observations. The RTN, which contains the most thoroughly
characterized group of central chemosensitive neurons, receives axonal projections
from other putative central chemosensitive regions. Experimentalists have selectively
lesioned RTN neurons in adult rats and noted a marked decrease in CO2 sensitivity.
Further, a genetically engineered mouse model that is lacking the Phox2b transcription factor is born without a functioning RTN (i.e., Phox2b is critical for RTN
45
Respiration
1443
Fig. 45.12 Hypothesized configurations of multiple chemosensory sites underlying central
chemoreception. (a) The prevailing view is that multiple sites converge on the central respiratory
controller (preB€otC/VRC) to produce an integrated CO2/pH respiratory response. (b) An emerging
view is that the RTN is a key chemosensory site, but also the central integration site of
chemosensory information arising from the other sites (including peripheral chemoreceptors)
that then influences the respiratory controller. (c) A third possibility represents of hybrid of
(a) and (b) in which only some regions feed through the RTN. Abbreviations: NTS nucleus tractus
solitarius, RTN retrotrapezoid nucleus, RVLM rostroventrolateral medulla, VRC ventral respiratory
column
formation). Those mice are capable of generating a respiratory rhythm but lack
a central CO2 response. In addition, in one of “mother nature’s” experiments, patients
with the rare disorder called congenital central hypoventilation syndrome (discussed
further in Genetics and Breathing Disorders) also lack Phox2b neurons and central
chemosensitivity. A third model states that there is a hybrid organization where only
some chemosensitive regions feed through the RTN and others work independently
to control ventilation (Fig. 45.12c).
1444
J.J. Greer and G.D. Funk
Molecular mechanism of CO2/pH sensing: How do chemosensitive neurons
actually “sense” changes in pH? This basic issue has not been fully resolved, but
acid-sensitive ion channels in the membranes of chemosensitive neurons are currently hypothesized as the proton sensors. Numerous candidate channels have been
described and their pH sensitivity characterized in significant detail. Despite this,
no single ion channel has been shown to directly contribute to central respiratory
chemosensitivity. The search is confounded by the fact that the chemosensitivity of
individual neurons may depend on multiple acid-sensitive ion channels. Also, the
chemosensitivity of the different classes of chemosensitive neurons (e.g., RTN vs.
locus coeruleus vs. raphe neurons) may depend on a different complement of acidsensitive ion channels. Finally, neurons that are not involved in respiratory
chemosensation may also express acid-sensitive channels.
A probable list of candidate acid-sensitive channels includes the following:
specific subtypes of acid-sensitive two-pore domain K+ (TASK) channels (close
with decreased pH); inwardly rectifying K+ channels (Kir1.1, Kir4.1-Kir5.1, close
with decreased pH); acid-sensitive ion channels that open in response to decreased
pH and permeate both Na+ and Ca2+; and ATP-gated P2X2 receptors. However,
knockout mice lacking each of these candidate genes have essentially normal
ventilatory responses to normoxic hypercapnia.
Astrocytes: Chemosensory cells may not be limited to neurons. Within the RTN,
astrocytes are emerging as important contributors to central chemoreception. They
release ATP in response to decreases in pH via Ca2+-dependent, exocytotic release
and possibly also via Ca2+-independent, CO2-sensitive gating of hemichannels (half
of a gap junction that can open independently) (Fig. 45.13). The released ATP excites
local chemosensitive RTN neurons and may account for 20% of the overall CO2
ventilatory response of the RTN. In summary, central chemosensitivity likely derives
from multiple chemoreceptive cells and multiple chemosensory mechanisms.
Mechanoreception
A key component of any motor control system is a sensory network that provides
rapid feedback about the status of the limbs, joints, and muscles to allow for
necessary adjustments. Note that speed is critical since the afferent feedback is
relevant for modification of the behavior as it is happening. For example,
in locomotion, information from muscle spindle afferents provides critical information about muscle length and limb position, Golgi tendon organs provide
information about muscle tension, and cutaneous afferents provide information
about interactions between the limbs/body and the immediate environment.
Similarly, the respiratory network receives breath-by-breath information about
the mechanical status of respiratory muscles, airways, lungs, and thorax, to achieve
efficient breathing. Unlike the locomotor system, however, very little of the afferent
information comes from the muscles per se. The main source of mechanoreceptive
feedback derives from visceral afferents from the lung, chest wall, and airways.
These reflexes can be classified as regulatory or protective.
45
Respiration
1445
Fig. 45.13 Schematic illustration of the hypothetical mechanism(s) underlying the contribution
of chemosensitive RTN neurons and astrocytes to central chemoreception. Elevated CO2 in the
blood diffuses across the blood vessel/capillary wall, increasing CO2 and H+ in the extracellular
space surrounding neurons and astrocytes (1). Astrocytes near the ventral medullary surface
including those in the glia limitans respond in two ways. Depicted in the middle astrocyte, elevated
CO2 (intracellular or extracellular) may evoke release of ATP through CO2-sensitive Cx26
hemichannels (i.e., Cx26 hemichannels act as the CO2 sensor) (2). Depicted in the right astrocyte,
CO2 or H+ causes intracellular Ca2+ release (3) and Ca2+-dependent, exocytotic release of ATP (4).
ATP released via one or both of these mechanisms excites chemosensitive RTN neurons through
a P2Y (5), G-protein-coupled receptor-dependent mechanism that either modulates an unknown
membrane conductance (6) or the acid-sensitive ion channels directly (7). RTN neurons are also
directly sensitive to intra- or extracellular acidification; the H+ sensor may be K+ channels that are
open at rest and close in response to increased H+ (8). Increased output from the RTN to the ventral
respiratory column (VRC) (9) causes ventilation to increase. NOTE: ATP-dependent processes
mediate 20% of the central chemosensory response. The remainder of the response reflects direct
activation of RTN and other chemosensory neurons
Regulatory reflexes are important in controlling both the rate and depth of
normal breathing on a cycle-by-cycle basis. They are mediated by receptors that
provide information relevant to the ongoing breathing (i.e., lung inflation, pressure
in the trachea, chest wall/body position, etc.) and primarily change the pattern of
respiratory motor output rather than the level of ventilation.
The main class of regulatory reflexes is the Breuer-Hering respiratory reflexes that
are mediated by slowly adapting receptors (SARs) located primarily in the smooth
muscle of the airways. These receptors have a background level of tonic discharge
1446
J.J. Greer and G.D. Funk
that increases with lung inflation/airway distension. They are referred to as SARs
because their discharge decays slowly in response to a constant, sustained stimulus.
SAR signals travel in rapidly conducting myelinated axons of the vagus (X) nerve to
the first-order excitatory synapse on pump cells (P cells) in the NTS. Second-order
synapses are on specific types of inspiratory and expiratory neurons in the VRC.
The main impact of SAR feedback on basal breathing pattern is immediately
apparent when input from the vagus nerve is removed. In the majority of mammals,
this results in a very slow breathing frequency with each breath being of large
amplitude (Fig. 45.14a). Surprisingly, in humans after heart-lung transplant, breathing is normal during relaxed wakefulness and sleep despite the absence of a control
loop involving pulmonary mechanoreceptors. This suggests that vagal feedback is
not as critical in adult humans as in other species.
The two main Breuer-Hering reflexes are the inspiratory terminating reflex and
the expiratory prolonging reflex. Both are mediated by SARs, but the evoked reflex
is dependent on the phase of the respiratory cycle in which the afferent information
arrives. The inspiratory terminating reflex is important in the breath-to-breath
control of inspiratory duration (Fig. 45.14b). As the lungs inflate during inspiration,
SAR activity increases, exciting P cells, which in turn excite neurons in the VRC
that discharge late in the inspiratory phase. These “late-inspiratory neurons”
terminate inspiration by inhibiting other inspiratory neurons (Fig. 45.15a).
During expiration, SAR activity typically decreases with lung volume. However, if
there is a sudden increase in SAR activity, or a slowing in the normal decrease in SAR
activity that accompanies expiration, the elevated activity of P cells excites VRC
neurons that show decrementing patterns of discharge during expiration. These
“decrementing E cells” inhibit a type of inspiratory neuron important in terminating
expiration and initiating inspiration. Their inhibition therefore delays the onset of the
next inspiration (Fig. 45.15b). The hypothesized function is that if something limits
expiratory airflow, this reflex extends the expiratory period to allow normal emptying of
the lung.
Proprioceptors in the diaphragm with afferent, myelinated axons in the phrenic
nerve are sparse compared to most skeletal muscles but appear to operate in
a manner analogous to that of the SARs, that is, their activation inhibits inspiratory
neurons and shortens inspiration.
Protective reflexes are mediated by receptors that have a low level of tonic discharge
and become active only in unusual situations. These receptors are often chemoreceptors,
supplied primarily by nonmyelinated fibers. In the upper airway (larynx), multimodal,
nonmyelinated C fibers sensitive to temperature and irritants convey information centrally via the recurrent laryngeal or superior laryngeal nerves (branches of vagus nerve)
and evoke cough, vocal cord adduction, and defensive changes in breathing pattern.
Chemosensitive C fibers with axons in the vagus nerve are also present throughout the
lower respiratory tract from the trachea to the distal portions of the bronchial tree.
Stimulation of these neuron endings in the airways and alveolar wall by chemical
irritants and edema (fluid in the lungs) evokes a brief apnea followed by rapid shallow
breathing. The apnea is achieved through inhibition of central inspiratory and expiratory
neurons. It is protective in that it prevents further inhalation of the offending compound.
45
Respiration
1447
Fig. 45.14 Breathing pattern in the presence of afferent feedback from slowly adapting receptors is
faster and of smaller amplitude due to the SAR-mediated Breuer-Hering inspiratory termination
reflex. (a) Recording of integrated motor activity from the phrenic nerve innervating the diaphragm
in the presence of SAR feedback is faster and of smaller burst amplitude than in the absence of
feedback (Modified with permission from Felman and Gauthier (1976) J Neurophysiol. 39:31–44).
(b) Recordings of integrated nerve activity from the vagus nerve (mainly from SARs) and the motor
activity from the phrenic nerve. In the absence of SAR feedback, inspiratory duration indicated by
phrenic nerve activity reflects the intrinsic period of the rhythm generator (left panel). Normal
incrementing discharge of SARs terminates inspiratory such that the inspiratory period in the
presence of feedback is shorter than in its absence (right panel). (Traces from left are superimposed
as dashed lines in the right panel to facilitate comparison of inspiratory period in the presence and
absence of SAR feedback) (Redrawn from von Euler (1986) Handbook of Physiology, Sect. 3, The
Respiratory System, Vol. II Control of Breathing. p. 1–68. Unpublished observations by C. von Euler
and T. Trippenbach. Am Physiol Soc, used with permission)
Rapidly adapting receptors, which have also been referred to as irritant receptors,
are located in the epithelial and subepithelial layers of the mucosa in the lower
respiratory tract and send myelinated axons centrally via the vagus nerve. They were
first identified by their rapidly adapting response to rapid lung inflation. In addition to
rapid inflation, RARs respond to large lung inflation or deflation, airborne irritants, and
lung edema. Their activation is associated with a rapid burst of activity in phrenic
motoneurons. They initiate multiple reflexes depending on the stimulus and location.
Activation of RARs near the tracheal bifurcation by inhaled irritants elicits cough,
a protective reflex that clears the airway. RARs can elicit rapid breathing and are also
sensitive to changes in lung mechanics. During quiet resting breathing, lung compliance decreases by as much as 30% (i.e., it becomes stiffer). As lung stiffness increases,
RARs discharge high-frequency bursts of action potentials at the peak of each inspiration. At some critical level of activity, the RARs trigger a sigh, or augmented breath,
which restores lung volume and compliance to optimum values.
1448
J.J. Greer and G.D. Funk
a
b
NA
NTS
Exp.
Exp.
neuron
neuron
IV Ventricle
VRC
Area
Area
Postrema
Postrema
Insp.
Insp.
term
term
neuron
neuron
Insp.
Insp.
neuron
neuron
Pump
Pump
cell
cell
Insp.
Insp.
preMN
preMN
excitatory
excitatory
inhibitory
inhibitory
To
To Insp.
Insp.
MNs
MNs
SAR
SAR Feedback
Feedback
c
Lung
Lung inflation
inflation during
during expiration
expiration excites
excites expiratory
expiratory neurons,
neurons,
prolonging
prolonging expiration
expiration
∫Phrenic
∫Phrenic
Nerve
Nerve
–10
–10 mV
mV
Mem.
Mem. Potential
Potential
Exp.
Exp. neuron
neuron
–60
–60 mV
mV
Tracheal
Tracheal
Pressure
Pressure
d
10
10 cm
cm H
H22O
O
Lung
Lung
inflation
inflation
22 sec
sec
Lung
Lung inflation
inflation during
during expiration
expiration inhibits
inhibits inspiratory
inspiratory neurons,
neurons,
prolonging
prolonging expiration
expiration
–40
–40 mV
mV
Mem.
Mem. Potential
Potential
Insp.
Insp. neuron
neuron
–60
–60 mV
mV
∫Phrenic
∫Phrenic
Nerve
Nerve
Tracheal
Tracheal
Pressure
Pressure
10
10 cm
cm H
H2200
Lung
Lung inflation
inflation
22 sec
sec
Fig. 45.15 Breuer-Hering reflex pathways. (a) Dorsal view of rat brainstem showing respiratoryrelated nuclei (from Fig. 45.3) and hypothesized pathways underlying the Breuer-Hering inspiratory termination and expiratory prolonging reflexes. SARs in the large airways activate pump cells in
the NTS. Activation of pump cells during inspiration excites inspiratory terminating neurons in the
VRG. Activation of pump cells during expiration causes subsequent excitation of expiratory neurons
that in turn inhibit inspiratory neurons necessary for initiating and maintaining inspiration; the result
is expiratory prolongation. (b) Image of an expiratory and inspiratory neuron labeled with fluorescent
markers while their respiratory-related changes in membrane potential (shown in the traces in panels
c and d) were recorded with an intracellular electrode. (c) Membrane potential recording of an
expiratory neuron like that shown in (b) along with inspiratory activity from the phrenic nerve.
A recording of tracheal pressure shows that when the lung is inflated during expiration, the expiratory
neurons discharge for much longer than during a normal breath, that is, expiration is prolonged. It is
hypothesized that the increased activity of this type of expiratory cell is responsible for the inhibition
of the inspiratory neuron evoked in (d) by lung inflation during expiration (Adapted with permission
from Hayashi, Coles and McCrimmon (1996) J Neurosci. 16(20):6526–6536)
45
Respiration
1449
Respiratory Network Activity Is Integrated with Networks
Controlling Sleep, Exercise, and Locomotion
Sleep
Sleep is a remarkably complex behavior that occupies approximately one third of
our lives. It is virtually ubiquitous among animals - even fruit flies exhibit periods
of inactivity akin to sleep. The physiological function of sleep is not fully understood; however, its necessity is obvious from the severely impaired mental, physical, and emotional function after even 24 h of sleep deprivation. Sleep can be
divided into two main substates: non-REM (also referred to as slow wave or quiet
sleep) and REM (also referred to as active, paradoxical, or dreaming sleep). NonREM sleep is further divided into four stages (I–IV) that we progress through
sequentially each night to the deepest stage IV sleep. Cortical EEG activity in
non-REM is easily distinguished from that in wakefulness by the emergence of
slow, synchronous oscillations in brain activity. Periods of non-REM alternate with
REM sleep, which in terms of brain activity is much more like wakefulness.
Sleep networks interact significantly with motor and homeostatic control systems. Most significant in the context of respiratory control is that during REM
sleep, most skeletal muscles show dramatic reductions in excitability. The muscle
atonia of REM sleep is a signature feature of this state. The condition known as
REM behavior disorder exemplifies the advantage of remaining motionless during
REM. Those patients lack REM-related atonia and physically act out their dreams
that can involve kicking, screaming, punching, and jumping out of bed. At the same
time, paralysis of all respiratory muscles during sleep presents its own unique set of
problems. Not surprisingly, there is differential sensitivity of respiratory muscles to
this atonia. Phrenic motoneurons driving the main inspiratory pump muscle, the
diaphragm, are least affected by pathways underlying REM sleep atonia. Motoneurons controlling airway muscles, in contrast, are like most other skeletal muscles
and show dramatically reduced excitability in REM sleep. While this is not
a concern for most animals, the highly compliant airway of humans, which evolved
in association with the development of speech, predisposes some individuals with
anatomically compromised airways to sleep-disordered breathing (see below; also
Obstructive Sleep Apnea).
Exercise
Elite athletes can increase ventilation 30–40-fold to support maximum exercise.
Ventilation levels >200 L/min have been recorded in elite cyclists, which compares
with 5 L/min at rest. The respiratory network must control both movement and
homeostasis to achieve this level of dynamic regulation (Fig. 45.16).
The ventilatory response to moderate exercise follows a well-characterized time
course that comprises three distinct phases (Fig. 45.17). At the onset of exercise,
breathing increases rapidly (phase I), that is, within 10–15 s or often with the first
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J.J. Greer and G.D. Funk
Fig. 45.16 Central
respiratory networks control
both movement and
homeostasis, two of the major
controlling functions of the
brain
breath. Minute ventilation and metabolic rate then increase gradually, in parallel
over several minutes (phase II) to reach a steady state (phase III). The same phases
are repeated in the same order when exercise stops, with a rapid phase I decrease in
ventilation followed by a gradual decrease in ventilation and metabolic rate back to
resting levels.
The mechanisms that increase breathing in proportion to the increase
in metabolic rate remain one of the most controversial issues in Physiology.
It is a simple question. What is the trigger to increase ventilation when we exercise?
The most intuitive answer is the decrease in oxygen and buildup of CO2 that result
from increased activity. However, in virtually all animals tested, the ventilatory
control system is so efficient in increasing ventilation during exercise that PaO2
actually increases and PaCO2 decreases. In other words, there is no blood-borne
(humoral) chemical stimulus necessary to evoke the increase in ventilation.
If humoral signals do not cause the initial ventilatory increase, what does? Valuable
insight comes from the kinetics of the three-phase ventilatory response. The rapid
phase I increase in ventilation occurs before any effect of increased muscle metabolism can alter blood gases and circulate to the chemoreceptors. This suggested
to pioneers in the field in the late 1800s that neural (or neurogenic) signals in
the form of feedback signals from the working muscles or feed-forward signals
from locomotor centers in the brain to the respiratory networks may be important
contributors. Hypothesized mechanisms have changed little since this very
early work of Krogh and Lindhard. However, it now appears that the ventilatory
response to exercise reflects coordinated interaction of neurohumoral and multiple
neurogenic mechanisms. What remains is to determine the relative roles of these
mechanisms in each of the different phases.
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Fig. 45.17 Time course of the ventilatory response during moderate exercise and recovery. Phase
I represents the rapid initial increase in ventilation that occurs at the transition from rest to
exercise. Phase II represents the gradual increase into steady-state levels of ventilation that are
achieved in phase III (Adapted from Wasserman, Whipp and Casaburi (1986) Handbook of
Physiology, Sect. 3, The Respiratory System, Vol. II Control of Breathing. p. 595–619. Am
Physiol Soc, used with permission)
The phase I increase in ventilation is neurogenic in origin. An extensive body of
creative experimentation has explored the contribution of various feedback signals to
the phase I increase in ventilation. Activation of type I and II afferent fibers, large
diameter myelinated fibers that carry information from muscle spindles and Golgi
tendon organs, produce only minor increases in ventilation. Thus, these afferents are
not considered as a major contributor; however, they may provide mechanoreceptive
information about the timing of the locomotor cycle important for coordinating
respiration with locomotor rhythm (see Locomotor-Respiratory Coordination).
Type III, or small-diameter myelinated, fibers transmit information from free nerve
endings in the muscle. Type IV, or nonmyelinated, fibers are chemosensitive and
respond to local changes in K+, pH, etc. Approximately half of the type III and IV
fibers respond to ergoreceptive stimuli (nonnoxious stimuli related to muscle
contraction and/or metabolic products of muscle work); these ergoreceptive fibers
are significant contributors to the rapid onset phase I increase in ventilation.
Feed-forward neurogenic mechanisms from locomotor networks also contribute
to the phase I increase in ventilation during exercise. Almost 100 years after it
was originally hypothesized, investigators finally demonstrated in 1983 that parallel
drives from higher centers that activate locomotor networks also activate respiratory centers and contribute to the ventilatory response to exercise. They stimulated
a midbrain locomotor-inducing nucleus, the mesencephalic locomotor region,
in decerebrate animals to activate locomotion. Rapid, parallel increases in ventilation were noted. When stimulation intensity increased, locomotor activity,
metabolic rate, and ventilatory activity all increased in parallel. Under these
conditions, as in intact animals, the increase in ventilation could reflect feedback
or feed-forward processes. In the critical experiment, the animals were paralyzed
and locomotor centers were again stimulated. In this case, in the complete
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absence of all afferent feedback, the activity of central locomotor and respiratory
networks still increased in parallel.
Similar feed-forward mechanisms operate in humans. When conscious, but
completely paralyzed subjects were asked to perform different types of exercise
(handgrip, ankle dorsiflexion, contraction of all limb muscles), phase I increases in
heart rate and blood pressure occurred, despite complete lack of any muscular
contraction. In other words, despite the fact that not a single muscle had contracted,
the mere central command to “exercise” was sufficient to evoke the initial response.
Phases II and III of the ventilatory response are under neurogenic and neurohumoral control. Neurogenic feed-forward and feedback mechanisms continue in
phases II and III. In addition, chemoreceptor mechanisms are implicated in these
later phases. The delayed onset of phase II (10–15 s), which coincides roughly with
delay for blood-borne transfer of chemical signals from exercising muscles to
putative chemoreceptor sites, suggests a significant neurohumoral (blood-borne)
contribution. In addition, the time course of the phase II increase in ventilation is
sluggish in the absence of arterial chemoreceptors. Nevertheless, the precise nature
of the blood-borne signal is uncertain because PO2, PCO2, and pH change little in
submaximal exercise. Possibilities include catecholamines (i.e., epinephrine), O2,
CO2, K+, or oscillations in pH, PCO2, and PO2. Thus, while feedback and feedforward mechanisms give an approximately proportional increase in ventilation and
metabolic rate, peripheral chemoreceptors (with perhaps a small contribution from
central chemoreceptors) appear to ensure precise matching. This interaction
between neurogenic and neurohumoral mechanisms continues into phase III.
Coordination of Breathing with Other Behaviors
Respiratory muscles serve multiple functions outside of breathing. In some cases,
the competing demands cannot be met simultaneously. The tongue, for example, is
important in breathing (maintaining an open airway), suckling, swallowing, and
speech. Breathing is not compatible with most of those behaviors; so only one can
be expressed at a time. Breathing is stopped during swallowing via a reflex from
sensory afferents in the upper airway. Similarly, breathing is stopped during the
Valsalva maneuver which requires that the glottis is closed and thoracic and
abdominal muscles are contracted to increase intrathoracic and intra-abdominal
pressure. In contrast, speech is well coordinated with breathing as it occurs during
the expiratory phase.
Many of the muscles used in respiration also have postural or locomotor roles.
Coordination between locomotor and respiratory rhythms is observed in virtually
all vertebrate phyla. Quadrupeds from the gerbil to the rhinoceros take one breath
per stride during galloping, with the breath always occurring at the same part of the
locomotor cycle. Similarly, in some birds during flight, inspiration is synchronized
1:1 with the upstroke of the wings. Similarly, the number of strides taken per breath
by trained human runners typically shows an integer relationship. A 2:1 ratio
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appears to be preferred, but it is highly variable (4:1, 3:1, 2:1, 1:1, 5:2, and 3:2),
both between and within subjects. This variability indicates the coordination is not
simply due to an obligatory mechanical interaction.
Coordination of locomotor and respiratory rhythms is achieved through
a combination of feedback and feed-forward neural mechanisms. Afferent feedback, most likely from type I and II afferent fibers, entrains respiratory rhythm to
the locomotor cycle via a pathway that involves first the pontine parabrachial
respiratory group and subsequent inhibition of inspiratory neurons in the VRC.
Additional entrainment arises from respiratory mechanoreceptors (SARs, RARs)
that detect cyclic changes in thoracic pressure and volume.
Afferent feedback, however, is not necessary. When “flight” is activated in birds
(Canada geese) after complete muscular paralysis, the relationship between the
neural outputs of the locomotor and respiratory networks to their respective muscles is synchronized (1:1). During free flight, it is primarily 3:1 but varies to 2:1 and
4:1. Thus, while the locomotor and respiratory networks interact centrally to
produce coordinated outputs, under the labile conditions of actual locomotion,
feedback from limb and respiratory mechanoreceptors is likely critical in altering
respiratory timing to adjust the pattern of coordination.
Functionally, such coordination is hypothesized to reduce the work of breathing
by reducing the mechanical interference between locomotion and respiration and
transferring part of the work of breathing from respiratory to locomotor muscles.
For example, by acting as a bellows, the action of bending and extending the trunk
during galloping in the horse may relieve the work of the diaphragm. Similarly,
inertial oscillations of the viscera in hopping wallabies and trotting dogs may act as
a piston mechanism that assists in producing respiratory airflow.
One of the most intriguing examples of coordination between multiple motor
networks is in insectivorous microchiropteran bats that use extremely highfrequency sound pulses to provide information about the location of airborne
prey. Breathing and wingbeat are synchronized, with expiration occurring during
downstroke. Vocalization is also synchronized such that the high-frequency echolocation pulses, which require extremely high rates of expiratory airflow, are only
emitted during the downstroke of the wingbeat. The energetic demands of echolocation are extremely high for these bats at rest, but it comes at virtually no extra cost
during flight due to this precise coordination of activities in these three networks.
The Respiratory Control Network Is Highly Plastic
Perinatal Environment
Research into the developmental origins of health and disease has established that
the environment in utero and during the postnatal period can have long-term
effects on physiological processes. This includes the respiratory system that
exhibits considerable plasticity in response to perinatal experiences. The effects
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of hypoxia are a clear example. In utero hypoxia can lead to longer-term modifications of respiratory control that extend into the newborn period causing
persistent hyperventilation and an exaggerated response to hypoxia. Repeated
bouts of hypoxia in the immediate newborn period, such as those that occur with
apnea of prematurity, can lead to a long-term increase in baseline ventilation,
significantly heightened sensitivity to opiate-induced respiratory depression, and
a decreased ventilatory response to hypoxia. Exposure to drugs in utero is another
example, with nicotine being the best studied. Nicotine exposure in utero leads to
the suppression of fetal breathing movements necessary for proper lung development. Longer-term effects that appear in the newborn period include reduced
baseline ventilation, a more unstable breathing pattern, increased bouts of apnea,
a diminished capacity for autoresuscitation following severe hypoxic exposure
(e.g., face in pillow), and increased risk for sudden infant death syndrome (SIDS,
discussed below).
Plasticity in the Adult System
It is only within the last 15 years that the conventional view of respiratory control
networks as rigid, largely immutable structures has been replaced with the current
view that recognizes the enormous capacity of the mature respiratory control
system to undergo plasticity. For example, when goats and humans undergo
repeated exercise trials (20–70) with added dead space (i.e., they breathe through
a tube), the ventilatory response to exercise is enhanced. The enhanced response
persists in subsequent baseline exercise trials after the dead space is removed.
This persistent enhancement of the ventilatory response is referred to as longterm facilitation and is a form of motor learning or neuroplasticity.
Long-term modulation of the ventilatory response to exercise in human has
also been observed in response to repeated pairings of exercise with increased
inspired CO2 (high number of pairing appears critical) and with inspiratory
resistive loading (without an elevated CO2 stimulus). This latter finding is significant because it suggests that long-term modulation of ventilatory control is not
limited to conditions associated with long-term disruptions in blood-gas homeostasis; it may extend to conditions in which respiratory system mechanics are
altered for prolonged periods. In other words, respiratory plasticity (long-term
modulation) may help individuals adapt and maintain appropriate respiratory
responses to mechanical challenges that arise through weight gain, aging, and
lung disease.
The field of respiratory plasticity has advanced enormously over the last decade.
Many of the intracellular signaling pathways responsible for the adaptive changes
in the healthy nervous system of animal models of respiratory plasticity are being
resolved. There is considerable excitement about the potential of exploiting these
mechanisms to address clinical conditions, including traumatic injury (including
spinal cord injury), obstructive sleep apnea, amyotrophic lateral sclerosis, and other
neurodegenerative diseases in which respiration is compromised.
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Respiratory Pathologies Result from Abnormal Neural Control
Mechanisms
Apnea, the term comes from the Greek word meaning “without wind.” Sleep apnea
is a disorder characterized by abnormal pauses in breathing during sleep. There are
three forms of sleep apnea: central, obstructive, and complex or mixed sleep apnea
(i.e., a combination of central and obstructive).
Sleep-disordered breathing describes a group of disorders characterized by
abnormalities of respiratory pattern (pauses in breathing) during sleep. One of the
most common and most serious of these conditions is obstructive sleep apnea
(OSA; Fig. 45.18b). It affects upwards of 10% of adult males (5% of females) and
is characterized by repeated episodes (hundreds/night) of airway obstruction,
apnea, decreased blood O2, elevated CO2, blood pressure swings, and sudden
arousals. This nightly series of harmful metabolic insults often lead to cardiovascular disease including angina, myocardial infarction, stroke, left ventricular dysfunction, and sustained daytime hypertension. Further, the loss of quality sleep
results in a very marked increase in motor vehicle and occupational accidents.
Mechanistically, it is important to emphasize that OSA is specific to
sleep. Even patients with the most severe cases breathe normally when awake.
The neurotransmitters that provide modulation of hypoglossal motoneuron activity,
and presumably the activity of other airway motoneurons, change dynamically
across sleep-wake states. The excitatory drive to upper airway motoneurons from
medullary raphé neurons (release 5-HT, TRH, and SubP) and the locus coeruleus
complex (release noradrenalin) declines from wakefulness to non-REM sleep, with
minimal firing in REM. This loss of excitatory input during sleep is referred to as
disfacilitation. In addition, there is active inhibition of upper airway motoneurons
during sleep. Specifically, activation of a subset of cholinergic neurons involved in
the generation of REM sleep causes net decreases in respiratory-related motoneuron activity, with muscarinic receptor-mediated suppression predominating
over nicotinic excitation. Further active inhibition arises from the release of glycine
from the nucleus pontis oralis that is activated during REM sleep. The relative
importance of disfacilitation versus active inhibition in upper airway atonia
during sleep and the potential role of other neurotransmitter systems are not fully
understood. This, in part, explains the current lack of success in developing an
effective pharmacological therapy for OSA.
Central apnea occurs when there is a lack of respiratory drive from brainstem
regions to pump and airway muscles (Fig. 45.18a). Conditions that can cause or
lead to central sleep apnea include bulbar poliomyelitis, encephalitis affecting the
brainstem, neurodegenerative illnesses such as Parkinson’s disease and multiple
system atrophy, stroke affecting the brainstem, congestive heart failure, and use of
certain medications such as narcotic-containing analgesics.
Cheyne-Stokes respiration, whose description is attributed to the Irish physicians
John Cheyne and George Stokes in the nineteenth century, is a specific pattern of
breathing characterized by progressively deeper (increased tidal volume) and
sometimes faster breathing followed by central apnea (Fig. 45.18c). The pattern
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Fig. 45.18 Pathological patterns of breathing. (a) Central apnea is characterized by lack of
central drive to respiratory muscles and thus loss of rib cage movement and air flow.
(b) Obstructive apnea is associated with activation of respiratory rib cage and muscles as evident
from movements of the thorax and abdomen, but there is reduced or no airflow due to obstruction
of the airway. (c) Cheyne-Stokes respiration is characterized by repeated waxing and waning of
progressively deeper breaths followed
by apnea. (d) Left panel shows normal (eupnea) breathing
R
pattern as detected by integrated ( PN) and raw phrenic nerve recording (PN). Right panel shows
experimentally induced apneusitic breathing pattern induced in anesthetized animal model after
pontine lesion and cutting of the vagus nerve (Adapted with permission from Haji et al., Neurosci
Res. 1998, 32:323–331)
repeats with each cycle typically lasting 0.5–2 min and can occur during sleep and
wakefulness, although more common during sleep. This pattern of breathing is
thought to be caused by altered chemosensitivity to hypoxia and hypercapnia,
together with a prolonged circulatory time, and is observed in association with
heart failure and brainstem injury caused by stroke, tumors, or toxins. CheyneStokes respiration is also present in healthy individuals in the hypoxic environment
of very high altitudes.
Apneustic breathing (or apneusis – derived from the Greek word for breathholding) is characterized by a very prolonged inspiratory effort (Fig. 45.18d). In
animal models, it is observed after concurrent removal of network elements that
normally regulate the termination of inspiration, that is, SAR mechanosensory
feedback from the vagus nerve and pontine respiratory groups. However, in the
vast majority of human cases, vagal input is intact and trauma or stroke in the pons
or medulla is the primary cause of apneusis.
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Apnea of prematurity is defined as cessation of breathing by a premature infant
that lasts for more than 15 seconds and is accompanied by low blood oxygen levels
(hypoxemia) and lowered heart rate (bradycardia). Apnea of prematurity, which can
be obstructive, central, and mixed, occurs to varying degrees in more than 85% of
infants who are born at less than 34 weeks of gestation (full term is considered
between 37 and 42 weeks). The incidence of apneas in premature infants is most
common during REM sleep. Aside from conditions such as congenital abnormalities (e.g., cervicofacial malformations, laryngomalacia, vocal cord paralysis), there
are two primary mechanisms involved in mixed/obstructive apneas in the newborn.
The most frequently recognized mechanism is passive upper airway collapse during
inspiration, which can occur under conditions such as flexion of the neck, nose
obstruction, or lack of upper airway muscle tone. In addition, there can be active
closure of the airway as part of the laryngeal chemoreflexes triggered by stimulation
of laryngeal mucosal receptors in response to salivary or respiratory secretions,
gastroesophageal reflux, and during feeding.
Methylxanthines (theophylline and caffeine) are effective treatments for apnea
of prematurity. Administration results in improved respiratory drive and reduced
need for ventilation and diminishes the likelihood of chronic lung disease, cerebral
palsy, and cognitive delay. Mechanisms of action are thought to include blockade of
adenosine receptors that act through both peripheral and central effects and the
additional increase in respiratory neuronal excitability associated with an elevation
of cAMP levels. The currently recognized unwanted side effects include increased
heart rate (tachycardia) and disruption of sleep-state architecture. The apneas
typically subside as the infant matures during the first several postnatal weeks.
It should be made clear that sudden infant death syndrome (SIDS), defined
clinically as a sudden death of an infant that is unexpected by medical history
and remains unexplained after postmortem investigation, is not correlated with
apnea of prematurity. In fact, few infants die of SIDS under 1 month of age; rather,
the incidence peaks between 2 and 4 months and then declines again after 5 months.
The underlying cause(s) is/are unknown, but failed autoresuscitation from hypoxicinduced apnea sleep has been postulated to be involved in the sequence of events
leading to SIDS. Major risk factors for SIDS include prone sleeping, maternal
smoking, recent infection, and prematurity. The decline in the incidence of SIDS
with the adaptation of positioning sleeping infants on their back or side has been
very significant. Presumably, this has led to a decrease in the obstruction of
breathing that can trigger the fatal hypoxic event in susceptible infants.
Genetics and breathing disorders: In human infants, dysfunction of the neural
control of breathing is seen in a variety of genetic diseases that include congenital
central hypoventilation syndrome (CCHS), Rett syndrome, and Prader-Willi
syndrome. CCHS is a rare condition typically caused by a mutation of the
PHOX2B gene that encodes a transcription factor expressed in central and peripheral neurons involved in respiratory chemoreception, including those in the pFRG/
RTN. CCHS is characterized by adequate (although still compromised) ventilation
while the patient is awake and by hypoventilation and apnea during sleep that often
requires intervention with mechanical ventilation. CCHS was previously referred to
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as Ondine’s curse in reference to the German folktale of Ondine, a water nymph
who cursed her unfaithful husband. “As long as you are awake, you shall have your
breath, but should you ever fall asleep, then that breath will be taken from you and
you will die!”
Rett syndrome results from a mutation in the X-linked gene encoding the
transcription factor methyl-CpG-binding protein 2 (MeCP2) in neurons. Children
with Rett syndrome typically appear normal until 6–18 months of life, when there is
a prolonged period of regression characterized by a loss of communication and
motor skills, onset of stereotyped hand movements, gait disturbances, and irregular
breathing patterns that include periods of hyperventilation, breath-holding, and lifethreatening apneas. Unlike many CNS disorders of breathing which are specific or
exaggerated in sleep, the breathing abnormalities are most prominent during wakefulness. This suggests an abnormality in regulatory inputs to the respiratory rhythm
generating center that are most prominent when awake (e.g., associated with stress).
Prader-Willi syndrome is a genetic disorder in which genes located on a specific
region of chromosome 15 (q11-13) are deleted or unexpressed on the paternal
chromosome. Prader-Willi syndrome patients typically have some degree of
learning disabilities, low muscle tone, short stature if not treated with growth
hormone, incomplete sexual development, and a chronic feeling of hunger that
can lead to marked obesity. In addition there is an abnormally high incidence
of central and obstructive apneas.
Each of the above mentioned genetic conditions has provided insights into
transcriptional control of neurons that modulate breathing. However, none of the
genes underlying the respiratory phenotypes are expressed in the preB€otC per se.
Recent insight into the transcriptional control of preB€otC development has been
made with the observation that a deletion of the gene encoding the transcription
factor Dbx1 (developing brain homeobox protein 1) in mice results in the loss of
glutamatergic preB€
otC neurons and inspiratory rhythmogenesis. Further, expression of the Robo3 (roundabout homolog 3) gene is necessary for guiding the axons
that cross the midline and ensure bilateral synchronous activity of preB€otC neurons.
Summary of Major Concepts
An understanding of the neural control of breathing starts with an appreciation of
the source of basic respiratory rhythmic drive within the ventrolateral medulla.
A network of neurons within the preB€
otC is necessary for the generation of the
primary active phase of breathing, inspiration. The current hypothesis is that
a second rhythmogenic circuit within the pFRG/RTN is important for generating
the expiratory phase of activity during forceful breathing (i.e., active expiration).
However, the final pattern of rhythmic drive that emerges and coordinates the
activation of the rib cage and abdominal and upper airway musculature to produce
normal (eupneic) breathing in intact mammals is ultimately determined by complex
synaptic interactions between those rhythmogenic centers and other parts of the
VRC, as well as the DRG and PRG. Further, similar to all motor systems, there is
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a continuous feedback of afferent signals that tune the respiratory neural output. In
the specific case of respiration, the concentration (or partial pressure) of oxygen and
carbon dioxide and pH levels in blood, tissue, and the brain are the key components
being regulated, and thus, feedback on their levels is particularly critical for the
homeostatic control of respiratory network activity. This feedback arises from
peripheral and central sources. Peripheral chemosensory information regarding
plasma oxygen and carbon dioxide levels arises primarily from the aortic and
carotid bodies. Centrally, there are multiple brainstem regions that contain neurons
(and astrocytes) sensitive to pH that ultimately converge directly or indirectly on
the central respiratory controller. Mechanoreceptive feedback from the lung, airways, and respiratory muscles further regulates breathing rate and pattern. During
exercise, there is a very efficient neural feed-forward system in place whereby
motor centers responsible for driving locomotor activity send parallel signals to
respiratory networks and concomitantly respiratory activity. Afferent feedback
from working muscles contributes to this neural drive and, in combination with
chemoreceptor feedback, provides a precise matching of ventilation and metabolic
rate. In addition, the respiratory control system is not hardwired and immutable. It
can undergo long-term adaptive changes in response to environmental, physiological, and disease challenges. Thus, in general, the respiratory system is extremely
robust, but also highly adaptable, operating efficiently in a seamless manner to meet
a very wide range of metabolic and behavioral demands. However, there are certain
developmental, state-dependent, and disease-related conditions where there are
impairments in respiratory rhythmogenesis, afferent feedback, and/or drive to
respiratory muscles. This is exemplified by the instability in respiratory rhythm
and inability to keep the airways open in prematurely born infants. In adults, the
trade-off of having a compliant upper airway necessary for speech has the downside
of a susceptibility to airway obstruction during certain sleep states. Neuronal
damage or deficiencies in key transcriptional control mechanisms, particularly
within the brainstem, can affect chemoreception or the proper balance of synaptic
drive from multiple brainstem regions and neuromodulators necessary for stable
rhythmogenesis.
Outlook
In the context of understanding the organization and function of mammalian motor
systems, the respiratory field is at a relatively advanced stage (e.g., compared to the
locomotor system). However, there remain significant deficits in our understanding
of some very fundamental mechanisms, including the following.
Rhythmogenesis: The discovery of the preB€
otC was a seminal advancement in
the field of respiratory neural control. The challenge going forward will be to
determine the cellular and synaptic mechanisms within this region that are responsible for rhythm generation. There are sufficient data to provide a foundation for the
group-pacemaker hypothesis, but it remains to be rigorously tested. Further, it is
important to note that much of the cellular data on which current models of how
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the respiratory rhythm is generated are derived from in vitro experiments using
reduced perinatal rodent preparations. A thorough investigation of respiratory
neuronal properties within the preB€
otC in intact models is lacking. Further, the
underlying mechanisms may vary under different behavioral states and with age
and disease.
The proposal that the pFRG/RTN is a second oscillator responsible for the
expiratory phase of breathing requires further verification. Very little is known
about how rhythmogenesis is generated within the pFRG/RTN and how it couples
with the preB€
otC. There are also questions regarding the relative role of the two
oscillators at different developmental stages (i.e., the pFRG/RTN may play a more
important role during the immediate newborn period) and behavioral states. How
the respiratory activity within the PRG and DRG interacts and modulates preB€otC
and pFRG/RTN rhythmic activity is not well understood. These regions are clearly
essential in producing a fully evolved pattern of normal breathing. Application of
novel methods such as optogenetics that allow neurons to be switched on and off in
milliseconds using light could greatly facilitate a deeper understanding of the
importance of these various brainstem nuclei.
Neurochemical control: There are a multitude of neuromodulators that regulate
breathing over multiple time scales. In addition, the relative balance of excitatory
versus inhibitory synaptic input to rhythm-generating centers and respiratory motoneurons fluctuates across age (e.g., apnea of prematurity) and sleep-wake states
(e.g., OSA). Further, there is a diverse number of receptor subtypes for each
neurotransmitter family, and they have yet to be delineated among various respiratory nuclei. Developing drug therapies for central respiratory disorders
is a serious unmet medical need, and advances will depend on a much more
comprehensive understanding of the neurochemical control of breathing. This
may require, for instance, the further development of microdialysis approaches
and novel methods for measuring neurotransmitter levels in the extracellular space
of respiratory nuclei in behaving animal models.
The role of astrocytes in the modulation of respiratory network activity is also of
emerging interest. Astrocytes express many of the same transmitter receptors as
neurons, respond to the activation of these receptors, and in turn release neuroactive
compounds that modulate synaptic function. Our understanding of their role will
accelerate as pharmacological, molecular, and imaging (including optogenetic)
approaches are developed that permit their selective manipulation.
Chemoreception: Central and peripheral chemoreceptors are very active areas of
investigation due to their critical role in respiratory homeostasis and respiratory
disorders. Yet, the relative importance of the RTN, raphe complex, locus coeruleus,
and other brainstem regions for central chemoreception is unclear. The role of
glia in the processes has only recently gained attention. The most basic mechanisms
by which changes in hydrogen ion concentration are detected and translated into
changes in neuronal excitability and subsequently transmitted to induce a change
in ventilation remain unresolved. Similarly, the mechanisms by which peripheral
chemoreceptors respond to changes in PaO2 and PaCO2 are only partially
understood.
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Development and genetics: From a developmental perspective, the timing of
preB€
otC formation, at least in the rodent, is fairly well understood. However, little
is known about the development of other respiratory brainstem nuclei. Further, the
genetic control mechanisms underlying the development of preB€otC and other
respiratory nuclei are a newly emerging field. The recent discovery of the critical
role of the DBX1 gene for preB€
otC formation is an important foundation. The
deficiencies underlying abnormal breathing in genetic disorders such as Rett
syndrome, Prader-Willi syndrome, and CCHS will hopefully be advanced by
investigations of genetically engineered mouse models that replicate some of
the disease characteristics. Importantly, those models provide opportunities for
evaluating therapeutic interventions.
Breathing in the newborn: Infants born prematurely are prone to having their
central respiratory drive shut down and their airways collapse while sleeping. It is
unclear whether this is due to an immaturity of the respiratory control network or
a lack of appropriate balance of excitatory/inhibitory synaptic drive. Exposure to
a hypoxic in utero environment alters the response to hypoxia after birth. The
mechanisms underlying this clinically problematic phenomenon are not
understood.
A main predisposing factor to SIDS is prenatal nicotine exposure. However, it is
not clear how this exposure alters the neural networks controlling breathing.
Further, how those changes impair the infant’s ability to autoresuscitate in the
presence of a hypoxic event is unknown. If SIDS is related to a failure of
the respiratory system to mature properly, why is the peak period of deaths delayed
to the 1–3-month period; what is critical about the time window?
Further Reading
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