XIV.

Control of Breathing
Learning objectives:
P51. Describe the functions of the neural control centers for breathing
including the ventral respiratory group (VRG), dorsal respiratory
group (DRG) and pneumotaxic center of the brainstem.
P52. Explain how a patient with bilateral paralysis of the diaphragm is
able to breathe.
P53. Describe the innervation of muscles used for breathing and predict
the effects of spinal cord injuries at different levels on the ability of
patients to breath; e.g., transection at C2 versus transection at C6.
P54.Contrast the primary stimuli, thresholds, nerve pathways, and
response times of central and peripheral chemoreceptors.
P55. Describe the location and pattern of breathing elicited by irritant and
mechanical receptors.
P56. Explain why O2 therapy may decrease breathing in a patient with
chronic obstructive lung disease; e.g., emphysema.
P57. Contrast the acute vs. chronic effects of hypoxia and hypercapnia
on ventilation. Describe the functions of the neural control centers for
breathing.

H. Shams 1
 Respiratory center & afferent and efferent inputs
Cortex
(exercise, voluntary)
Brainstem
Central (Emotion,Temperature)
input

Rhythm generator

Efferent
output

Afferent
Respiratory
input muscles

Mechanoreceptors in
lung and thorax

Chemoreceptors

Respiratory stimuli: Mechanoreceptors in

With feedback muscloskeletal system
Without feedback

I. Introduction
The amount of O2 uptake and CO2 elimination by your body changes dramatically from rest to heavy exercise, yet
there is normally no change in arterial blood gases. This requires a very precise control of breathing. This lecture
will cover the neural and chemical control systems that regulate breathing. The control of respiration is both
voluntary and involuntary. Voluntary control allows us to hold our breath and accomplish special uses of breathing
like talking, singing, playing instruments, etc. Understanding the normal control systems is essential to
understanding clinical disorders related to control of breathing including asthma, emphysema, sleep apnea;
sudden infant death syndrome (SIDS); and adult respiratory distress syndrome (ARDS).

II. Neural Control of Breathing

A. Respiratory Centers of the Brainstem
The rate and volume of pumping air are under both voluntary and involuntary control. The afferent and efferent
pathways of the respiratory center of the medulla are shown in the figure. The respiratory center consists of
interconnected groups of respiratory neurons in the medulla and pons. Neural information about breathing is
relayed to the cortex which also exerts voluntary control over the respiratory muscles. The spinal origin of the
motor nerves to respiratory muscles dictates the effects of spinal cord injuries at different levels on the ability of
patients to breath; e.g., transection at C2 versus transection at C6.

The efferent output of the respiratory center goes to the respiratory muscles. At rest, only inspiration requires
muscular effort. The muscles used are the diaphragm and the external intercostals muscles. Accessory
muscles are available for heavy exercise and breathing against some resistance. Expiratory accessory muscles
are the abdominal muscles and internal intercostals muscles. Inspiratory accessory muscles are the scalene,
sternocleidomastoid, trapezius, and external intercostal muscles. Accessory muscles for inspiration can provide
normal tidal volume in patients with bilateral paralysis of the diaphragm, although the patients have tachypnea and
show paradoxical inward movement of the abdomen with inspiration.

The afferent input to the respiratory center includes irritant, mechanical, and chemical receptors from the lungs,
airways, pharynx, blood vessels, and from higher centers. The integrating centers are located in the pons and
medulla. There are 3 groups of neurons involved in respiratory control.

H. Shams 2
 3 groups of neurons control
respiration

Inhibitory effects:
Pons Pneumotaxic Off switch of
Center inspiration, control
of FR

Medulla • Basic rhythm

• Cardiorespiratory, symp.
Integration DRG VRG and parasymp. coupling
of inputs (NTS) • Basic activity of bronchial
muscle cells
Vagus & • Extra drive: exercise, high
Glossopharyngeal altitude
Respiratory
Motor Paths
Basic
rhythm

“ramp” signal

1. Ventral Respiratory Group of Neurons: In each side of the medulla, some 5 mm anterior to the
DRG is the ventral respiratory group (VRG) of neurons. The VRG is composed of three cell groups:
the rostral nucleus retrofacialis, the caudal nucleus retroambiguus, and the nucleus
paraambiguus. The VRG contains both inspiratory and expiratory neurons that are believed to be
primarily involved in rhythm generation. They are capable of emitting repetitive bursts of inspiratory
signals even when all of the afferent nerves have been severed and the brain stem has been
sectioned above and below the medulla. The inspiratory signal generated by the neurons of VRG is a
“ramp” signal, beginning weakly and getting progressively stronger for about 2 seconds. It then
ceases abruptly for the next 3 seconds. This results in a steady increase in lung volume, rather than a
gasp, during inspiration, followed by expiration due to passive elastic recoil of the lungs. The VRG
neurons play also a great role when respiratory drive becomes greater than normal; e.g., during
exercise or high altitude, and are especially important in driving the accessory expiratory muscles of
the abdomen. Thus, these neurons serve as an “overdrive” mechanism when demand to breathe is
increased. These neurons are also involved in “cardio respiratory coupling” that occurs during
stimulation of the sympathetic nervous system. This is the locus of increased central respiratory drive
that occurs during dyspnea due to sympathetic stimulation caused by heart failure, hypertension,
anemia, exercise, etc.
1. Dorsal respiratory group of neurons: The neurons of dorsal respiratory group (DRG) are located
in the Nucleus Tractus Solitarus (NTS). The NTS is the termination of sensory input from the vagus
and glossopharyngeal nerves coming from peripheral chemoreceptors, baroreceptors, and lung
receptors – stretch and nocioceptive. Neurons in the NTS integrate the sensory inputs from airways,
lungs and chemoreceptors and modify breathing accordingly.
2. The pneumotaxic center: is located dorsally in the nucleus parabrachialis of the upper pons. This
center controls the “switch off” point of the inspiratory ramp, therefore controlling inspiratory volume.
This also ends up controlling respiratory rate. A strong pneumotaxic signal can increase the rate of
breathing to 30 or 40 breaths per minute; while a weak signal may produce a respiratory rate of only 3
to 5 breaths per minute.

H. Shams 3
 Pulmonary Reflexes:

1. Slowly Adapting Stretch Receptors (Hering-

Breuer reflex):

Location: Airway smooth muscles, innervated by large myelinated

vagal fibers

Activation:
a) Lung distension (inspiration)
b) Breath holding (lack of movement)
c) Deflation of the lung below FRC
Functions:
a) Terminates inspiration (prevent the lung from
overstretching)
b) Terminates large expiration as well

B. Pulmonary Receptors
1. Slowly Adapting Pulmonary Stretch Receptors:
These receptors lie in the smooth muscle of the airway. They are innervated
by large myelinated vagal fibers. They are activated by lung distension.
When activated, they fire at a high frequency, but if inflation is maintained,
they will slowly adapt to a lower frequency.
High activity (high lung volume) inhibits further inspiration, thereby turning
inspiration off and beginning expiration. This reflex is called the Hering-
Breuer reflex. These receptors are also activated by lack of movement of the
lung as in breath holding and by deflation of the lung to volumes less than
FRC. Thus, the Hering Breuer reflex is both an inspiratory terminating and
expiratory terminating reflex.

H. Shams 4
 Lung stretch reflex
Rhythm generator
(Respiratory center)
-

+
Inspiratory Lung distension
muscles
+

H. Shams 5
 2. Rapidly Adapting Stretch Receptors (irritant
receptors):

Location: Airway epithelium, innervated by myelinated vagal

fibers

Activation: Lung distension, also known as pulmonary distension, refers to the abnormal
a) Lung distension expansion or stretching of the lung tissue.
b) Irritants An irritant refers to a substance or stimulus that causes irritation or discomfort to the
body.

Functions:
a) Cough reflex
b) Gasp and bronchoconstriction by high activity
“gasp” refers to a sudden, sharp intake of breath

2. Rapidly Adapting Pulmonary Stretch Receptors:

These receptors are located in the epithelium of the airways. They are also
innervated by myelinated vagal fibers and are activated by lung distension
and by irritants (also called pulmonary irritant receptors). When activated,
they produce a brief increase in activity that suddenly disappears even if
inflation is maintained. High activity may cause a gasp and
bronchoconstriction. They are involved in a cough reflex. Individuals who
have had lung transplants do not have vagal connections to the CNS
controllers. They have diminished cough reflexes and can develop bronchial
inflammation or infection with little cough.

H. Shams 6
 3. C-Fiber or J-Receptors (J = Juxta capillary):

Location: Near capillaries, innervated by non-myelinated vagal

fibers

Activation:
a) Increases in interstitial fluid (congestion or edema)
b) Pulmonary embolism

Functions:
a) Rapid shallow breathing
b) Bronchoconstriction
c) Cardiovascular depression

Pulmonary embolism is a serious medical condition that occurs when one or more arteries in the lungs become
blocked.
Cardiovascular depression refers to a condition characterized by a decrease in the function of the cardiovascular system,
leading to a reduction in blood pressure and heart rate
3. C-Fibers or Type J-Receptors (J = Juxta capillary):
These receptors are innervated by non-myelinated vagal fibers. They cause
rapid shallow breathing, bronchoconstriction and cardiovascular
depression. They are activated by an increase in interstitial fluid (congestion
or edema). Pulmonary embolism also activates these receptors causing
tachypnea and hyperventilation.

4. Muscle Spindles:
Gamma spindle fibers are located in the intercostals and diaphragm. They
respond to increases in resistance and compliance. Simultaneous stimulation
of gamma and alpha motor neurons allows the spindle to track inspiration
and to aid in increased contraction if inspiration is impeded. When a given
level of motor activity fails to produce the appropriate shortening of
inspiratory muscles, the inspiratory effort is suspended and expiration
follows. In restrictive pulmonary disease, the muscles fail to shorten because
of the stiffer lung, and inspiration stops prematurely. Tidal volume is small
and frequency is high. In obstructive lung disease, gamma fibers continue to
shorten, but because lung volume changes are lagging behind, the muscles
continue to shorten beyond normal. Tidal volume is large and frequency is
low.

H. Shams 7
Caudal...>Posterior
Rostral...>Towards nose

III. Chemical Control of Breathing

A. Central Chemoreceptor (CCR) for CO2:
Chemosensitive neurons are located on the ventrolateral surface of the
medulla and in the medullary raphe. They build three groups of neurons in
the rostral, intermediate and caudal areas of the medulla. They are
superficial (< 0.2 mm deep). They are located very close to the vessels in the
tissue (shown as green close to the vessels red in the picture). They are
stimulated by H+ and inhibited by cold or anesthetics. They are not
stimulated by hypoxia. Anesthetics is loss of feeling or sensation, often used to prevent pain during surgery
Increases in PaCO2 causes a pH decrease in CSF and stimulates breathing. As a
result, both VT and FR are increasing.
Changing plasma hydrogen ion concentration causes no immediate effect on
the composition of the CSF because these ions do not readily penetrate the
blood brain barrier.
Some human diseases may be due to defects in these H+ sensitive neurons.
These include sleep apnea, panic disorder, epilepsy, migraine and sudden
infant death syndrome (SIDS). Each of these diseases is also affected by
CO2 or related to defects in CO2 chemoreception.

H. Shams 8
 Peripheral chemoreceptors
N.IX (Glossopharyngial nerve)
External carotid artery
Internal carotid artery
Carotid
body
Carotid sinus
N.X (vagus nerve)
Left subclavian
artery
Common carotid
artery Brachiocephalic
trunk
Aortic
bodies
Aortic arch
Pulmonal artery

B. Peripheral Chemoreceptors:
Within seconds after the onset, systemic hypoxia stimulates breathing and
raises blood pressure. The primary chemoreceptors in the periphery are
located in the carotid body. The aortic chemoreceptors are not very important
in humans.

The carotid bodies are located on the external carotid arteries near their
bifurcation with the internal carotids. Each carotid body is a few millimeters in
size and has the distinction of having the highest blood flow per tissue weight
of any organ in the body.
Afferent nerve fibers join with the sinus nerve before entering the
glossopharyngeal nerve. A decrease in arterial PO2 or a decrease in carotid
body perfusion results in cellular hypoxia, hypercapnia, and decreased pH
that lead to an increase receptor firing. The threshold PO2 for activation is
about 80 mmHg (normal arterial PO2 is about 95 mmHg), although significant
activity does not occur until PO2 is about 65 mm Hg. These receptors also
respond to PCO2 and pH. An elevation of PCO2 above a normal value of 40
mmHg, or a decrease in pH below 7.4 causes receptor firing.

H. Shams 9
 Peripheral Chemoreceptors

Carotid body Carotid

(glomus caroticum) sinus
nerve

Capillary

Type I cell

Type II cell

Stimuli for increased ventilation

A. Hypoxia
The chemoreceptor tissue is primarily composed of two cell types: type I and
type II. Type I cells (also called glomus cells) are the primary oxygen-sensing
cells. Exactly how glomus cells do this is unclear. A hypothesis describing O2
sensing is shown in the next slide.

H. Shams 10
 Mechanism of Peripheral Chemoreception

pH Action
potential
PCO 2

O2
Transmitter
pHi release

Cai2+ Type I cell

K+ Outflux
Depolarization Ca2+ Influx

One hypothesis suggests that a K+ channel protein is the primary oxygen

sensor and that inhibition of this channel by hypoxia or acidosis leads to
depolarization of the cell which in turn activates a voltage gated Ca++
channel. Finally Ca++ entry into the cell causes the release of transmitter
dopamine that stimulates the nerve endings. This is the same kind of oxygen
sensitive K+ channel that is present in the pulmonary vascular smooth
muscle.

H. Shams 11
 Ventilation Response to hypoxia

60

PaCO2 = 40 mmHg
40
.
PaO2 VA
.
VA PaCO2
20
.
PaCO2 VA

PaCO2 falls
0
90 70 50 30 10
PaO2 (mmHg)

The Ventilatory response to PO2 is not linear; there is little increase in ventilation
until PO2 declines to about 60 mmHg (lower curve). As shown in the figure, the
increase in ventilation in response to hypoxia is much greater when PCO2 is kept
constant at normal value of 40 mmHg (upper curve). Normally, this does not happen
because hyperventilation mediated by hypoxia lowers the PCO2, as shown in the
lower curve. With low PCO2 and high pH, the hypoxic drive is countered by
alkalosis.

H. Shams 12
 Chemical stimuli of breathing

A: CO2 Response B: pH Response C: O2 Response

80

60 PaCO2 = 40 mmHg

PaCO2 = 40 mmHg

40

20
PaCO2 falls
PaCO2 falls
0
40 50 60 70 80 7.40 7.30 7.20 90 70 50 30 10
PaCO2 (mmHg) pHa PaO2 (mmHg)

B. PCO2 and pH:

Carotid body chemoreceptors respond to changes in PCO2 and H+ as well as to
changes in PO2. Increases in PaCO2 and decreases in pHa causes ventilation to
increase by increasing both VT and FR (similar to the effects mediated by CR). This
effect of PCO2 is primarily a pH effect. Also a decrease in pH causes ventilation to
increase and results in a subsequent decrease in PCO2 (lower curve). Therefore,
the ventilation response to a decrease pH is highest if PCO2 is kept constant at 40
mmHg (upper curve).

Comparison between central and peripheral ventilatory responses to CO2 and

O2:

Property Central CR Peripheral CR

Signal responded to [H+] PCO2, [H+], Low PO2

% of total response to PCO2 80 % 20 %
% of total response to PO2 0% 100 %

) Central chemoreceptor is H+ receptor and accounts for 80% of the total ventilatory
response to altered PCO2

H. Shams 13
 Acute vs. chronic hypercapnia
[ HCO3- ]
CSF and blood pH = 6,1 + log
[ CO2 ]
PCR &
CCR stimulated
Only PCR
Ventilation stimulated

 PCO2

Time, days 20

Hypercapnia is a medical condition characterized by an excessive level of carbon dioxide in the bloodstream.

Acute vs. Chronic Hypercapnia:

An increase in arterial PCO2 will cause an immediate increase in CSF [H+]
due to CO2 diffusing into the CSF across the blood brain barrier. Increased
H+ stimulates central receptors and enhances ventilation. Both increases in
arterial PCO2 and arterial H+ would also stimulate peripheral chemoreceptors
and further enhances ventilation. After 12 to 24 hours, however, the pH of
the body is partially compensated by the kidney and thus the stimulus to
central chemoreceptors lessens. Similarly H+ mediated stimulus to peripheral
chemoreceptors weakens, whereas their PCO2 mediated stimulation remains
intact. These changes in stimulation of central and peripheral
chemoreceptors reduce respiration compared to its level at the beginning of
hypercapnia. Therefore patients with chronic hypercapnia have a reduced
ventilatory response to PCO2. These patients are usually hypoxic as well and
may have a significant drive to breathe from their low arterial PO2 as well.
This can create a complication if the patient is given oxygen (instead of air) to
breathe to relief his symptoms of hypoxia. In this case the removal of hypoxia
mediated stimulation of receptors may result in cessation of breathing. The
patient should then be artificially ventilated.

Hypoxia increases ventilation, which results in a decreased PCO2 and an increased pH. This increase in
pH inhibits ventilation. Kidney compensates the pH change within a few days, which causes the relief of
ventilatory inhibition and results in a further increase in ventilation.

H. Shams 14
 Acute vs. chronic hypoxia
Alkalosis from hyper
ventilation inhibits
response to hypoxia during
first few days

Days

Acute vs. Chronic Hypoxia

For hypercapnia, acute exposure is a more potent stimulus to breathe than
chronic exposure. For hypoxia, the opposite is true. As shown in the figure,
there is a brief increase in ventilation immediately after exposure to low PO2.
This hyperventilation is beneficial by lowering alveolar PCO2 (which raises
alveolar PO2) but causes respiratory alkalosis which, in turn inhibits the
peripheral and central CO2/pH receptors leading to decreases in ventilation.
After a few days of exposure to low PO2, the pH is compensated and the pH
inhibition of ventilation ceases. Then, the ventilation increases to a steady
state value. This higher level of ventilation can persist for life if the person
reside at high altitude.

H. Shams 15
 Regulation of breathing during exercise

Cerebral cortex

sensory motor

"direct stimulation"
Rhythm
generator „Stimulation through
feedback"

Respir. Mechano working

muscles receptors muscles
Musculoskeletal system

C. Exercise:
Ventilation increases during exercise. the maximum exercise ventilation
depends on the maximum O2 uptake. The average maximum ventilation is
about 100 L/min for men and 70 L/min for women. The increase in ventilation
is so closely matched with the increase in CO2 production that there is no
change in arterial PCO2, pH, or PO2 until the exercise intensity reaches the
anaerobic threshold. After that point, muscles produce lactic acid which
dissociates to H+ and lactate. H+ stimulates the peripheral and central
chemoreceptors leading to hyperventilation and reduced PaCO2. The
increase in ventilation during exercise is mediated through stimulation of
rhythm generator from cerebral cortex neurons which innervate motor units
for performing muscular work . The rhythm generator also receives afferent
signals from working muscles.

H. Shams 16
 Stimuli for ventilation
suggested he could “make it to the top of Mount Everest”. He wrote a protocol for an experiment for the next day, but his colleagues had difficulty reading it. Not only the content was

Voluntary control
Maximum VE response to stimuli

160
Ventilation, L/min
140
120
100
80
60
40
20
0
Rest PO2 pH PCO2 Exer MVV

D. Voluntary Control
Notice that exercise has a greater effect on ventilation than any of the
chemical signals. However, the greatest increase in ventilation results from
voluntary increases.
Maximum voluntary ventilation is a clinical pulmonary function test that
measures overall condition of the respiratory apparatus including mechanical
properties of chest and lungs, strength of respiratory muscles, and flow
resistance properties of the airways.
It is measured by asking a subject to breath as deeply and rapidly as they
can for 10 seconds and calculating the ventilation per minute. For healthy
adults, the value is about 160 L/min.

H. Shams 17