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In general terms, in what ways does the brain regulate respiration and how?

As demonstrated in earlier chapters, ventilation is simple
in concept but complex in execution. The brain controls the
basic pattern of breathing, integrating multiple infl uences
within lower motor neurons of the brainstem and spinal cord
to drive pharyngeal, laryngeal, diaphragmatic, intercostal, and
other respiratory muscles. Recall that
E (L/min) = VT · f. The
central nervous system regulates respiration by controlling the
rhythm and pattern of its output to respiratory muscles, adjusting
f, VT or both, depending on overall ventilatory needs for a
greater or lesser
E (Fig. 11.1).


Describe the central rhythm generator, i.e. its name, its function, how its work is modified, its location.

The frequency of respiration, or its rhythm, is intrinsic to the
brainstem. All vertebrates that use tidal oscillations for the
exchange of O2 and CO2 in their lungs have such movements
generated in their medulla oblongata. Indeed surgically
isolated brainstem preparations, lacking afferent inputs from
chemoreceptors and mechanoreceptors, still produce rhythmic
outputs along the same cranial nerves as during normal respiration.
One critical rhythm generator within a small area of the
medulla and rostral to the obex is called the pre-Bötzinger
complex. Bilateral lesions in this portion of the medulla induce
complete respiratory arrest in humans. Whether this rhythmic
discharge initiates within individual pacemaker cells, or from
a network of such cells, remains a matter of debate. At this
point, it is important to understand that a rhythm is constantly
generated by the medulla, a rhythm that is modifi able by afferent
input from sensory receptors.


Describe the central pattern generator. What does it do and why? How does it accomplish this? What things modify both rhythm and pattern? What things modify just pattern?

The central pattern generator, or the brainstem output controlling all muscles involved in respiration, is much more complex. This pattern generator algebraically sums all the
afferent inputs to produce well-coordinated activations of the
diaphragm, intercostal muscles, and abdominal muscles, and
if needed, the accessory muscles of respiration. Like respiratory
rhythm, the goal of such pattern generation is maintenance
of normal Pao2, Paco2, and pHa. Extreme examples
of modulating both the rhythm and pattern of respiration are
seen during rigorous exercise and ascents to high altitude.
The pattern of respiration is also modulated by events like
coughing, speech, sleep, vomiting, micturition, and defecation,
particularly as the latter may mimic a Valsalva maneuver.
Although some of these events are episodic or relatively
infrequent, they can affect the normal respiratory pattern in
dramatic ways.


Describe 8 different define patterns of respiration.

Eupnea: is normal, quiet breathing at rest. Individuals
are usually unaware of it.

Tachypnea or polypnea: is an increase in f without an
increase in VT . Tachypnea is not a normal stress response,unless hyperthermia or other factor has induced panting.

Hyperpnea or hyperventilation: denotes an increase
in pulmonary ventilation involving both VT and f, but
without the subjectively stressful sensations of dyspnea
(Fig. 11.2).

Dyspnea: is the sensation of inadequate or stressful
respiration, with exaggerated awareness of one’s need
for increased respiratory effort. Dyspnea implies labored
breathing, often involving accessory respiratory muscles.
Many stimuli induce dyspnea.

Cheyne-Stokes respiration: is the most common
form of abnormal breathing, with weak respiratory
efforts that decrease to an apnea and then increase
to hyperpnea. The “crescendo-decrescendo”
oscillations of Cheyne-Stokes are most often caused by
hypoxemia and are a frequently encountered symptom
(see Chap. 25) (Fig. 11.2).

Apneusis: is an abnormally patterned breathing
with prolonged inspirations that alternate with short
expiratory movements (Fig. 11.2). Apneustic breathing
is commonly noted after lesions in the pontine
pneumotaxic center discussed below.

Ataxis or ataxic respiration: is an abnormal pattern with
completely irregular breathing and increasing periods
of apnea. As the pattern deteriorates, it may merge with
agonal respiration. It is caused by damage to the medulla
oblongata by stroke or trauma.

Apnea: is the absence of breathing. As generally
used, apnea implies that the cessation is temporary.
A prolonged apnea for any cause is considered
respiratory arrest.


Which spinal cord neurons are most important to respiration? Why? Which neurons innervate the different respiration muscles?

Spinal cord neurons are organized into ventral horn (motor),
dorsal horn (sensory), and lateral horn (autonomic) regions.
Those in the ventral horn are most critical to respiration, since they include lower motor neurons innervating somatic striated muscles (Fig. 11.3). Major somatic striated muscles involved in respiration include:

Diaphragm: its innervating motoneurons exit at C3-C5
as the phrenic nerve.

Intercostal muscles: innervated by motoneurons within
the thoracic ventral horn with axons that exit the spinal
cord and distribute via the intercostal nerves.

Abdominal muscles: their motoneurons have axons that
track within the lower thoracic and upper lumbar cord

Accessory muscles: include all muscles that elevate
and splay the ribs, notably the levator costalis, scalene,
transverse thoracic, and sternocleidomastoid.


What are the major muscles involved in innervation that are innervated by craniel nerves? Which nerves are they innervated by and where do these nerves originate?

In addition to its role as the principal area of sensorimotor
integration for respiration, the medulla contains lower motor neurons with fi bers that exit via cranial nerves to innervate striated muscles in the head and neck (Fig 11.4). Motor neurons innervating the tongue muscles are found in the hypoglossal nucleus, while those innervating laryngeal, pharyngeal and facial muscles are found in the ventrolateral medulla. All of these muscles receive rhythmic central nervous system (CNS) motor input during every breath. Major cranial striated muscles that are involved during normal respiration include:

Laryngeal muscles: both laryngeal abductors and
adductors are innervated by motoneurons in the nucleus
ambiguus, whose axons travel with the vagus nerve.

Pharyngeal muscles: also receive motor input from the
nucleus ambiguus by neurons whose axons exit via the
glossopharyngeal and vagus nerves.

Facial muscles: most notably the m. nasalis, by
motoneurons within the facial motor nucleus whose
axons exit via the facial nerve.

Tongue muscles: principally the genioglossus muscle
by motoneurons in the hypoglossal nucleus whose axons
exit via the hypoglossal nerve.


What are the two recognized groups of neurons in the medulla that are involved in the integration and coordination of breathing? Where are they located? What is their function? What are their main components?

Within the medulla are two recognized groups of neurons
involved in the integration and coordination of breathing,
whose functions continue to be intensively investigated. The fi rst of these, the ventral respiratory column, is a longitudinal array of respiratory-related neurons that fi re synchronously with each phrenic nerve discharge. These neurons are found in the ventrolateral reticular formation of the medulla, generally just ventral to the nucleus ambiguus. A subject’s basic respiratory rhythm persists if only these brainstem neurons are intact, albeit poorly controlled. Four main components of the ventral
respiratory column have been identifi ed (Fig. 11.5):

Caudal ventral respiratory group (cVRG): an expiratory area running from the spino-medullary junction to the obex;
Rostral ventral respiratory group (rVRG): the area of
mixed inspiratory and expiratory respiratory neurons just
rostral to the obex;
Pre-Bötzinger Complex: an area of neurons that is
rostral to the rVRG and considered of central importance
for rhythm generation;
Bötzinger Complex: an expiratory area just caudal to
the facial nucleus.

In addition to the ventral respiratory column, a second
brainstem area of importance to respiratory control contains the dorsal respiratory group (DRG), being inspiratory neurons in the ventrolateral part of the nucleus tractus solitarii (NTS) (Fig 11.5).


Describe the important respiratory areas in the pons? What is their function? Where are they located? What happens if they are injured?

Situated rostral to the VRG and DRG neurons of the brainstem,
the pons contains the parabrachial nucleus and the
Kölliker-Fuse area, a neurophil surrounding the brachium
conjunctivum (Fig. 11.6). These two regions contain neurons
considered important as the main “off-switch” for
spontaneous inspiration, and have been called the pontine
pneumotaxic center because lesions here result in apneustic


What kind of integration of respiration occurs in the brainstem?

Pontine and medullary respiratory neurons are quite interconnected,
making it diffi cult to assign unambiguous functions
to any particular group of neurons. Investigations of respiratory
control usually are conducted while eliminating variables
that are known to affect the rhythm or pattern of respiration.
This usually means maintaining constant Pao2 or Paco2 levels
in animals that are anesthetized, vagotomized, and sometimes
spinalized. Despite such limitations, it is clear that afferent
inputs from higher brain areas, as well as from chemoreceptors
and mechanoreceptors, converge on this network of brainstem
respiratory neurons (Fig. 11.5). There they produce a pattern of
muscle contractions and thus ventilation that are appropriate for
metabolic needs.


In a comatose patients, describe the breathing patterns that might occur in a patient with an injury to the forebrain, midbrain, rostral pons, and caudal pons/upper medulla.

Respiratory pattern is a key indicator of improper brain
functioning in a comatose patient. During diff use forebrain
depression, as in metabolic encephalopathy with liver
failure, breathing may assume the crescendo-decrescendo
pattern of Cheyne-Stokes respiration, with variable periods
of apnea. Midbrain injury can cause hyperventilation, while
injury to the rostral pons may produce apneusis (Fig. 11.2).
Injury to the lower pons or upper medulla frequently
induces ataxic breathing that often heralds complete
respiratory arrest.


How are rhythm generators in the medulla modulated? Where are these modulators located?

Respiratory rhythm generation is intrinsic to the medulla and
proceeds even without additional sensory input. However,
central respiratory neurons are modulated by afferent inputs affecting the depth, rate, and pattern of respiration. Chemoreceptors
respond to changes in the composition of blood or
other fl uids around them. Major groups of chemoreceptors are
located in the peripheral and central nervous systems.


Where are the peripheral chemoreceptors located? What do they respond to? Where do they send their signals? What do they do? What is their main function? What are some functions for which they are less important?

Peripheral chemoreceptors are located in parenchymal
lobules termed the carotid bodies above the bifurcations
of the common carotid arteries (Fig. 11.7), and the aortic
bodies located along the superior aspect of the aortic arch.
Although the lobules are organized similarly at each location,
the carotid bodies send afferent impulses via the carotid sinus
nerve branch of cranial nerve IX, while the aortic bodies send
signals via cranial nerve X to the NTS in the CNS. In general
terms, these peripheral chemoreceptors respond quickly
to decreasing Pao2 and pHa, and increasing Paco2, with discharge
rates alterable during a single respiratory cycle.
Importantly, they cause all increased ventilation in response
to arterial hypoxemia, although their effect is not appreciable
until Pao2 declines to ~40 mm Hg. Thus, their role in regulating
eupneic breathing is small. It is also thought that their
response to increased Paco2 is less important than that of central


Where are the central chemoreceptors located? What do they respond to? How do they work? What is their response?

The major populations of central chemoreceptors are
located near the ventral surface of the medulla, many near
levels of the exiting hypoglossal nerve (Fig. 11.8). They are
bathed in brain extracellular fl uid (ECF) that rapidly equilibrates
with gaseous CO2 diffusing from blood vessels into
cerebrospinal fl uid (CSF). This local rise in Pco2 acidifi es
CSF and thus stimulates the chemoreceptors, even though
[H+] and [HCO3
–] do not readily cross the blood-brain barrier.
In this manner, a reduction in pHa stimulates ventilation centrally
while an increased pHa is inhibitory (Fig. 11.8).


How does the integration of sensory modulation work?

Systemically the body seldom experiences isolated
hypoxia, hypercapnia, or acidemia. Moreover, the ventilatory
response to a set of variables is greater than the response to
each component, due to integration of these modulatory infl uences
within the CNS.


What are the 3 subtypes of lower airway receptors? Which nerve do they use?

There are several important types of sensory receptors associated
with afferent fi bers in the vagus nerve that respond to
either mechanical or chemical stimulation of the tracheobronchial
tree, including its respiratory mucosa (Table 11.1).
Important subtypes of receptors within the lower airways
and/or the lung parenchyma include three main groups:

Slowly adapting pulmonary stretch receptors (SARs):

Rapidly adapting pulmonary receptors (RARs),

Tracheobronchial C Fibers


Describe slowly adapting pulmonary stretch receptors (SARs). Where are they located? What do they respond to? What is their response? When are they active? Inactive?

Slowly adapting pulmonary stretch receptors (SARs):
Myelinated SARs are situated among airway smooth
muscle cells and send afferent fi bers centrally via the
vagus nerve. They discharge in response to distension
of the lung, and show little adaptation over time to
sustained lung infl ation. Activation of SARs reduces
respiratory frequency by increasing the expiratory time
interval, the so-called Hering-Breuer refl ex. These
SARs are inactive in awake subjects unless VT is large
(>1 L), but they may be prominent in anesthetized
animal preparations.


Describe Rapidly adapting pulmonary receptors (RARs). Where are they located? How do they work? What do they respond to? What are their reflex effects?

Rapidly adapting pulmonary receptors (RARs),
also termed by some authors as irritant receptors:
Myelinated RARs lie between airway epithelial cells
and also send afferent fi bers centrally via cranial
nerve X (vagus). Some RARs are mechanoreceptors
that fire during hyperinfl ation or forced deflation of
the lungs. Most are chemoreceptive RARs activated
by exogenous agents (eg, noxious gases, cigarette
smoke, and cold air) and endogenous chemicals (eg,
histamine, prostaglandins, and serotonin). Their refl ex
effects include bronchoconstriction, hyperpnea, and cough. Indeed, a presumptive cough receptor has been
discovered recently. It is not clear whether RARs
function during eupneic respiration. However, their
responsiveness to inflammatory mediators and other
endogenous chemicals indicate they may be important in
disease (Chap. 10).


Describe tracheobronchial C-fibers. How common are the? What do they respond to? What diseases do they probably play a prominent role in? What is their response? When are they active/inactive?

Tracheobronchial C-fi bers: Unmyelinated C-fi bers
comprise >75% of afferent fi bers emerging from
the lungs. Their nerve endings generally function
as chemoreceptors that are sensitive to histamine,
prostaglandins, bradykinin, and serotonin, as well as
cigarette smoke, noxious gases, and capsaicin. Thus
they probably play a prominent role in asthma, allergic
bronchoconstriction, pulmonary vascular congestion, and
pulmonary embolism. Although C-fi bers are relatively
inactive during eupneic breathing, they respond to lung
hyperinfl ation and can induce refl ex apnea (followed
by tachypnea), bronchoconstriction, hypotension,
bradycardia, and mucus secretion.


Describe the receptors of the upper airways. Where are they located? Where do their afferent nerve fibers travel? What kind of stimuli do the respond to? What response do they cause? What do the sensory innervations of the larynx via the superior laryngeal nerve monitor?

Receptors of the upper airways: There are unencapsulated (free) nerve endings arrayed within
the respiratory mucosa from the nasal cavity to the
larynx (Chap. 2). Their afferent fi bers travel via the
trigeminal, glossopharyngeal, and vagus nerves and
respond to chemical and mechanical stimuli. Induced
respiratory responses caused by their stimulation
include sneezing, coughing, bronchoconstriction, and
apnea, depending on stimulus nature and the region
within the upper respiratory tract being stimulated. Such sensory innervations of the larynx via the
superior laryngeal nerve are of considerable clinical
importance, since these receptors monitor airflow,
laryngeal temperature, and other mechanical and
chemical stimuli (Fig. 11.9).


Describe the function of receptors in muscle? What is the effect? What are they like?

Receptors in muscle: Dynamic or static contractions of
limb muscles induce many autonomic effects including
hyperpnea, although Paco2, Pao2, and pHa change little
during moderate exercise. Moreover, experimental data
indicate that neither the carotid chemoreceptors nor
respiratory muscle afferent fi bers provide the primary
stimulus for such hypernea. Rather, most evidence
suggests that the small myelinated and unmyelinated
fi bers of sensory nerves (Groups III and IV) that innervate
striated muscle initiate this response. It also has been
proposed that a central command mechanism may
initiate hypernea during exercise. This topic is addressed
further in Chap. 13.


What are the many different effects of sleep on respiration?

Sleep is a complex diurnal rhythm having a different time
scale that is superimposed on the normal respiratory rhythm.
Although sleep consists of various stages, it is often simplifi ed
to be either rapid eye movement (REM) sleep or non-REM
sleep. Respiration slows and chemoreception is blunted during
sleep, such that prolonged apnea and marked CO2 retention
may occur. From a cardiovascular perspective, sleep also
induces bradycardia and mild hypotension. These autonomic
effects are especially evident during REM sleep, during which
there is atonia or hypotonia of skeletal muscles. This hypotonia
increases upper airway resistance by relaxing pharyngeal
muscles. It is thought that snoring, as well as obstructive
sleep apneas (OSA) is the result of this atonia (Chap. 25).
Perhaps the most important effect of sleep on respiration is
loss of what some researchers refer to as the wakefulness
stimulus, an overriding controller or integrator of all other
respiratory inputs and functions.


Describe the higher neural controls of respiratory functions. What are their functions? What are they less effective at doing?

Eliminating suprapontine inputs to brainstem respiratory centers has only minor effects on resting respiration, suggesting that such areas modulate but do not control basal respiratory patterns and rhythms. Suprapontine areas are active in volitionally altered
respiration associated with speech, singing, and similar activities
(Fig. 11.10). Thus, cortical areas are capable of affecting the pattern
generator and of activating different muscle groups of respiration.
Although little is known currently about the anatomy and
physiology of cerebral cortical areas that modulate respiration,
new imaging methods using functional MRI and/or PET scans
are beginning to identify important regions.


Define periodic breathing. Describe the different types of apnea.

Respiratory rhythm is usually regular and continues throughout
life without conscious effort. Indeed, consciousness of
one’s breathing often signifi es the presence of extreme environmental
conditions or pathological states. When respirations
become arrhythmic, the term periodic breathing is
applied, while apnea refers to an absence of breathing that is
usually temporary. Apneas are obstructive when caused by
upper-airway blockage despite efferent impulses to breathe,
or central when without respiratory movements, or may be of
mixed type. However other apneas exist, including obstructive
expiratory apnea, obstructive hypoventilation, and
central hypoventilation syndrome (“Ondine’s curse”);
these will be discussed in Chap. 25.


Describe dyspnea. How is it defined clinicallyl? What are some possible causes?

The term dyspnea was introduced earlier to describe a
patient’s sensation of inadequate or stressful respiration, or an exaggerated consciousness of a need for increased respiratory
effort. Clinically, dyspnea usually implies labored respiration
and the use of some or all accessory respiratory muscles, as
in many patients with acute lung injury and the acute respiratory
distress syndrome (Chap. 28). Many factors induce dyspnea,
but it is important to remember that it is a sensation that
may not have an underlying pathophysiological explanation
in every case.


Define period breathing clinically. What is an example? What might cause it? When does it usually occur? When can it occur in healthy individuals?

Periodic breathing is characterized as clusters of breaths
separated by intervals of apnea or near-apnea. A clinically useful definition of such periodic breathing might be when at least three respiratory pauses, each lasting 3 seconds or longer, are separated by periods of normal breathing, each lasting less than 20 seconds. Cheyne-Stokes breathing as commonly seen in congestive heart failure is an example of such periodic breathing (Fig. 11.11). Periodic breathing usually occurs during sleep and can occur in healthy individuals, and the apnea there is usually of central rather than obstructive


When does periodic breathing occur in premature and term infants? When does it become abnormal? What might this mean?

Periodic breathing is a normal respiratory pattern in premature infants during active REM-sleep and non-REM sleep. It persists in infants, but decreases as a percentage of the population as children mature. Among term infants, periodic breathing usually is confined to REM sleep. Persistence of periodic breathing during longer portions of sleep may be abnormal, and reflect immaturity or an abnormality of brainstem respiratory
control (Chap. 39).


How common is sleep apnea?

Sleep apnea occurs in 2%-3% of children,
3%-7% of middle-aged adults, and 10%-15% of otherwise
healthy adults who are > 65 years old.


What is periodic breathing generally considered to be a consequence of? Explain.

Periodic breathing is generally considered to be a consequence of chemoreceptor function. When Paco2 or PAco2 is far below normal eupneic values, or when Pao2 or PAo2 is far above, then at least transient apnea will almost certainly ensue. Thus, there are apneic
thresholds for both hypocapnia and hyperoxia that may differ strikingly among healthy individuals. Whether their periodic breathing is more, the result of activation of central versus peripheral chemoreceptors remains unresolved to date.