Control of Breathing

• Unaware: until something goes wrong -dyspnea [sensation of shortness of breath]

e.g. high altitude / disease

• Aware: scuba divers, professional singers, partners to sleepy snorers, asthmatics …

• Important: cessation = onset of brain death

• Two key tasks:

1) establish automatic rhythm for contraction of respiratory muscles

2) adjust the rhythm to accommodate metabolic [arterial blood gases + pH],
mechanical [postural changes],
episodic non-ventilatory behaviors
[speaking, sniffing, eating,..]
 Complexities

• unlike the pumping of the heart – there is no single pacemaker generating the
basic rhythm of breathing.

• there is no single muscle devoted to the pumping of air- cyclic excitation of many
muscles that are also involved in non-ventilatory functions: [e.g. speech]

• our understanding relies on classic whole animal studies on anesthetized,

decerebrate models (cats) or current work on neonatal brainstem-spinal cord
preparations- i.e. state dependent or highly reduced preparations.

• Jerome Demsey’s 1995 review- over 5000 major references – in an effort to

integrate information into a unifying concept of control of breathing. For other
reviews see Bianchi et al., Feldman et al., & Richter et al.
 Three Basic Elements of the Control System

Sensors:
Sensors Two classes of receptors [chemoreceptors & mechanoreceptors] monitor
the effect of breathing and provide information to the effectors to automatically
control ventilation and maintain stable arterial blood bases
 Chemical Control of Respiration

History: Three Primary Blood Borne Stimuli to Breathe

Hypercapnia, Hypoxia & Acidemia

1) inhalation of gas mixtures ↑ in CO2, ↓ O2 & injection of acid in rabbits stimulates

breathing [Dohmen, Pfluger & Walter; between 1865-1877]

2) localization of chemosensitive area to the head:

Landmark cross perfusion experiments of Léonéo Frédéricq [11 years prior to publication in
Liege,1901]: cross the blood supply to the head of 2 dogs: each dogs head perfused from
the other dog’s trunk but remains neurally connected to its own trunk:

Hyperventilating one animal produced apnea in the other ⇒ changes in blood chemistry to
the head and not neural input are controlling ventilation
Léon Frédéricq [1851-1935]
Professor of Physiology

University of Liège, Belgium

[see Léon Frédericq Foundation]

Les Terrsasses sous la neige

 Chemical Control of Respiration
Central Chemoreceptors

• few µm beneath the ventral surface

of the medulla

VI • close to entry of VIII & XI cranial nerves

VII
VIII
• bilateral pairs: eponyms

IX, X, XI
• stimulated by application of acidic or
high PCO2 solution on the surface:
XII increase in ventilation

• reversibly depressed by application

C cold / anesthetic solution on the
1 surface: decrease in ventilation
Current Controversy: Location

• Eugene Nattie: focal acidification of brain tissue

with acetazolamide, a CA inhibitor in cats &rats

• sites that are deeper, more dorsal and rostral,

examples
nucleus tractus solitarius [NTS]
locus coeruleus [LC]

• more importantly: what are these receptors:

neural elements, ion channels, ion transport proteins…?
 Local Acidosis Stimulates the Central Chemoreceptor

• 1950s Isidore Leusen- infusing cerebral ventricle of dogs with acidic solution with
a high PCO2 caused hyperventilation.

• central chemoreceptors, as part of brain tissue, respond to increases in both

arterial PCO2 and CSF pH.

• most likely the stimulus driving the increase in ventilation is the pH decrease
within the brain tissue that follows the rise in arterial PCO2
 Mechanism of Central Chemoreception

CSF
blood supply CSF
• formed by filtration + secretion from choroid
H2O + CO2 CO2 + H2O plexus (capillaries within the ventricles)
½ ½
• absorbed by arachonoid villi
H2CO3
H2CO3 • amount= 80-150 ml
½ • rate of formation/absorption=20 ml/hour
HCO-3 + H+ ½ • turnover time= 4 hours
HCO-3 + H+
• low in protein, bicarbonate only buffer of
brain consequence, pH 7.32, PCO2=50 mm Hg
tissue i.e acidic relative to blood
(BECF)
• a given acute rise in blood PCO2 results in
a greater PCO2 change in the CSF
choroid
arachnoid villi plexus
BBB • key unanswered questions, how CSF
bicarbonate levels regulated?
 Chemical Control of Respiration
Peripheral Chemoreceptors

• sense PO2, PCO2 and pH of arterial blood

• primarily sensitive to ↓ arterial PO2 ⇒ hyperventilation

• ↑ PCO2 and ↓pH of arterial blood stimulate these receptors to a lesser extent but
make them more responsive to hypoxemia

• in the absence of peripheral chemoreceptors, hypoxia results in CNS neuronal

depression
Peripheral Chemoreceptors: Location

1. Carotid bodies [key role/studied more]

• bilateral, pair
• close to bifurcation of the common carotid artery
• blood supply: small branch of the occipital artery

2. Aortic bodies

• scattered between the arch of the aorta &

the pulmonary artery
• blood supply: small vessels leaving arch of aorta
& branches of the coronary artery

Remind to students: not to confuse with baroreceptors close by

within the walls of the blood vessels (adventitia of arteries)
 Peripheral Chemoreceptors
Afferent Traffic

• Carotid body

carotid sinus nerve (CSN) →

glossopharyngial [IX cranial nerve, cell body
in the petrosal ganglion] → medulla
near nucleus tractus solitarius (NTS)

• Aortic body

join the vagus [X cranial nerve, cell body in

the nodose ganglion] → medulla
near nucleus tractus solitarius (NTS)
 Peripheral Chemoreceptors
Blood Supply

• receive more blood flow

per gram than any other
organ: 2000 ml/100g/min,
extraordinary high, compare
to:
kidney 420 (five fold)
brain 54 (forty fold)
• despite very high
metabolic rate [2-3 fold
greater than the brain],
capillary PO2, PCO2 is
close to arterial values
due to the blood flow
 Peripheral Chemoreceptors
Carotid Bodies Key Features & History

• small; 10 micron diameter- hard to dissect but studied more extensively

“ganglion minutuum” Wilhelm Ludwig Taube, 1743 [credit to supervisor von Haller]

• rediscovered periodically:
1800s- Hubert Luschka “glandular carotida” ? endocrine function

• 1926-Fernando de Castro y Rodriguez: clearest morphological description extensive

thorough histology-proposes a function “a sensory organ that tastes blood” – disruption
of work during the Spanish Civil War at the Cajal Institute, Madrid- 1960 E.M. study of
glomus cells began a few days prior to his death.

• Nobel Prize in PHYL& MED, 1939 to Corneille Heymans [Belgian]- demonstrated its
physiologic role: serendipitous: examining baroreceptor response while injecting KCN
in the carotid artery→↑breathing frequency [unilateral CSN cut, maintained ventilatory
response, bilateral denervation→ no ventilatory response
 Type I & Type II cells of the Carotid Body

Type I [Glomus cell]

• sensitive to local changes in
PO2 [mainly], PCO2 & pH
• prominent cytoplasmic granules
[DA,NE,Ach, neuropeptides]
• closely associated with both
myelinated & unmyelinated
afferent fibers
Type II [sustentacular cell]
• interstitial cell wraps around glomus
and nerve endings
• no cytoplasmic granules
• function ? Type II
 Mechanism of Peripheral Chemoreception
Signal Transmission in the Glomus Cell
A Chronology of Hypotheses

Which neurotransmitter?

Cholinergic Hypothesis: Ach release from glomus cell stimulates the CSN.
• evidence for: both hypoxia & Ach stimulate CSN afferent activity
• evidence against: Ach antagonist blocks Ach response but not the hypoxic response
• refinement: pre synaptic (autoreception) Ach receptors on glomus cells, modulate release
of other neurotransmitter from glomus cell

Dopaminergic Hypothesis: 10X more DA than Ach. Dose dependent CSN activity [excitatory
at high and inhibitory at low doses]
• complication: co-release of substance P, VIP, serotonin-antagonist study hard to do.
• complication: gap junctions between glomus cells masking electrochemical coupling effects
• suggestive: only neurotransmitter that has both pre and post synaptic receptors
 Mechanism of Peripheral Chemoreception
Signal Transmission in the Glomus Cell
A Chronology of Hypotheses

The rest of the signal transduction pathway?

Metabolic Hypothesis: Metabolic poisons: cyanide and hypoxia lead to ↓ ATP in glomus
cells and an ↑CSN activity. Perhaps common pathway is through inhibition of electron
transport chain activity in the mitochondria by a low O2 affinity cytochrome oxidase→ less
H+ pumped out due to reduced oxidative phosphorylation → mitochondrial Ca2+ release
into cytoplasm → neurotransmitter release.

• refinement: source of Ca2+ is typically extra cellular.

Can there be a common element to the three triggers, hypoxia,
hypercapnia & acidemia that stimulate ventilation via the carotid bodies?

Heme containing protein unbinds from O2 or binds to H+ and CO2 → conformational change
→ → neurotransmitter release
 Mechanism of Peripheral Chemoreception
Signal Transmission in the Glomus Cell
The Role of Potassium Channels

Evidence:
Evidence Reduction in PO2 will reduce potassium currents in Type I cells
thereby depolarize them.

Current Hypothesis: Potassium channel inhibition the hub of the

signal transmission pathway. pH & CO2 may act independently from the
heme containing membrane protein (see next slide for current hypotheses)
Signal Transmission in the Glomus Cell
Inhibiting K+ Channels leads to Depolarization
 The Integrated Response to an Acute Change in Blood Gases
The Hypercapnic Ventilatory Response

• linear-slope= a measure of sensitivity to CO2

variability humans: 1-6 L/min/mmHg
• hypoxia accentuates the response [↑slope=sensitivity]
• dog leg seen with hypoxia
• steep portion of the curves converge to a
set point (threshold) on the abscissa
• sensitivity and set point can be measured-
effect of drugs on ventilation
• progesterone ↑ slope
• sleep, anesthetics, narcotics ↓ slope

• peripheral chemoreceptor denervation studies:

20-30 % of the response from carotid bodies
[rapid]; the remaining 80% from central chemoreceptors [slow] Nielson & Smith, 1952
 The Integrated Response to an Acute Change in Blood Gases
The Hypoxic Ventilatory Response

• hyperbolic relationship

• little but not zero activity at PO2 as high as 500 mmHg

• marked activity at PO2 < 60 mmHg

• maximum activity at PO2 ≈ 30 mmHg

• response is accentuated by with ↑PCO2

• mimics the impulse activity of CSN to hypoxia

 Mechanical Control of Respiration
Receptors in Lung Tissue and Airways

• in the lungs and airways three types of mechanoreceptors have been

characterized by their response to lung inflation

™ slowly adapting
™ rapidly adapting
™ c-fiber endings

• all three are innervated by fibers of the vagus nerves [X cranial nerve]
 Mechanical Control of Respiration- Slowly Adapting Stretch Receptors
a.k.a. “bronchopulmonary stretch receptors”

• slowly adapting: continue to fire sensory signals as long as the stretch is held
• myelinated afferent fibers

• nerve endings within the smooth muscle surrounding the extra-pulmonary airways

• responsible for respiratory sinus arrhythmia [ tachycardia during I relative to E]

stretch→↑ afferent vagal discharge→ medullary CV centre → ↓parasympathetic +
↑sympathetic activity → ↑HR
• responsible for the Hering-Breuer reflex [1868]
 The Hering Breuer Inflation & Deflation Reflexes

Tracheal occlusion at different lung volumes in anesthetized dogs:

• at FRC: no effect on TI & TE

• at peak inspiration: increased TE
• by lung deflation by 100 ml + occlusion: TE shortened

Important in regulation of phase timing in some mammals & human neonates

nb: in adult humans, operate at VT thresholds > 800ml
 Mechanical Control of Respiration- Rapidly Adapting Stretch Receptors
a.k.a. “irritant receptors”

• nerve endings between airway epithelia close to the mucosal surface

• myelinated afferent fibers

• stimulated by a host of irritants: cigarette smoke, gases: sulphur dioxide, ammonia,

antigens, inflammatory meditators: histamine, serotonin, prostaglandins

• depending on the stimulus may result in cough, rapid shallow breathing or mucus secretion
• state dependent: reflex cough in awake state versus apnea when asleep/anesthetized
 Mechanical Control of Respiration- C-fiber endings

• unmyelinated free nerve endings in two areas based on vascular accessibility:

1. Pulmonary C-fibers [“juxta alveolar” or “J”-receptors within the walls of pulmonary capillaries]
• sensitive to products of inflammation [histamine, serotonin, bradykinin, prostaglandin
- reflex results in rapid shallow breathing]
• ? sensitive to pulmonary vascular congestion + pulmonary edema- reflex results in
dyspnea associated with LVF or severe exercise

2. Bronchial C-fibers [in the conducting airways]

• sensitive to products of inflammation-result in bronchoconstriction + ↑airway vascular
permeability
 Mechanical Control of Respiration—Upper Airway Irritant Receptors

• myelinated nerve endings

• respond to chemical and mechanical irritants [a.k.a irritant receptors]

Nasal receptors: afferent pathway in the trigeminal + olfactory nerves

1. sneezing reflex
2. diving reflex: stimulus water instilled into the nose ⇒ apnea, laryngeal closure,
bronchoconstriction+ bradycardia, vasoconstriction in skeletal muscle, kidney + skin [not
brain/heart: protection of vital organs from apnea]- diving mammals, ducks + humans.

Pharyngeal + Laryngeal receptors: afferent pathway in the laryngeal + glossopharygeal nerves

1. aspiration (from epipharynx to pharynx)/sniff/swallowing reflexes
2. negative pressure induced abduction [ensure UAW patency during inspiration]
Three Basic Elements of the Control System
 The Effectors: The Muscles of Respiration
The Diaphragm

• principle inspiratory muscle in man

• dome shaped skeletal muscle

separating thoracic from
abdominal cavity

• contraction-shortening → descent of the

diaphragm ≈ 1-2 cm during quiet breath→
compression of the abdominal content→ resist
further descent→ elevation of lower
ribs→↑vertical + transverse dimension of thorax
 The Diaphragm

Crural
origin = lumbar vertebrae;
insertion: central tendon;
opening for esophagus,
abdominal aorta & inferior
vena cava

Costal
origin=sternum & lower ribs
insertion=central tendon

Innervation
-bilateral
-phrenic nerves
-phrenic motor nuclei in
spinal cervical
segments [C3,C4,C5]
 Bilateral Innervation of the Diaphragm by the Phrenic Nerves

• How would the diaphragm move if one of the

phrenic nerves was during a deeply & briskly
inspiration: ie, sniffs ?

• Diaphragmatic paresis following trauma to the

phrenic nerves is a rare complication after neck
surgery [ 8%* - hopefully transient] paresis of the left hemi-diaphragm

• The resulting elevation of the ipsilateral hemi-

diaphragm is diagnosed on post-operative chest
radiography and may be confirmed by ultrasound
or fluoroscopy

*de Jong A, Manni J, Phrenic nerve paralysis following neck

dissection. Eur Arch Otorhinolaryngol 1991; 248: 132-4 restoration of function- left hemi-diaphragm
 Inspiratory Muscles other than the Diaphragm

External intercostals
• connect adjacent bony (interosseous) ribs
• innervated by the intercostal nerves
[motor nuclei in the thoracic ventral horns]
• contraction upward + down ward motion of the ribs
• ribs pivot from the vertebral column in a bucket-handle fashion
• active during quiet breathing +
recruited further with greater inspiration

Parasternal intercostals
• are intercostal muscles that connect the
cartilagenous portions of the upper ribs
• active during quiet breathing +
recruited further with greater inspiration

Scalene + Sternocleidomastoid [accessory muscles of inspiration-- in the neck)

• scalene: innervated by the brachial plexus [C3-C8]
• scalene: active during quiet inspiration and further with greater inspiration
• sternocleidomastoid: innervated by the accessory nerve (CN XI)
• sternocleidomastoids: not active during quiet breathing but with greater ventilation
• elevate the thorax by elevating the sternum and the first two ribs
 Exthrathoracic Airway Muscles Recruited During Inspiration

• during inspiration the potential collapse

of the upper airways is actively opposed
by the dilator (abductor) muscles of the
pharynx + larynx, e.g: genioglossus
protrudes of the tongue= pharyngeal dilator

• innervated by cranial nerves or their branches:

e.g. recurrent laryngeal nerve,RLN (arising from
the vagus, CN X) supplies the larynx

nb. denervation of RLN ⇒closure of vocal cords

 Expiratory Muscles
Recruited during Active Expiration

Internal intercostals
• beneath the external intercostals
inner surface in contact with the pleura
• connect the ribs at nearly right angles to the
external intercostals
• contraction pulls the ribs downward + inward
• innervated by the intercostal nerves [motor
nuclei in the thoracic ventral horns]

Triangularis sterni
• innervation by intercostal nerves
• connects the inside of the sternum to the
cartilagenous portion of the ribs 3-7;
contraction pulls these ribs down

Abdominal wall muscles

• innervation by intercostal + other spinal nerves
motor nuclei in thoracic + lumbar ventral horns]
• contraction lowers the ribs + compresses the abdomen
Three Basic Elements of the Control System
 The Central Controller
Involuntary (a.k.a Metabolic or Automatic) Control of Breathing

• rhythmic output of the CNS to the muscles of ventilation takes place automatically
& subconsciously.

• this respiratory rhythmogenesis takes place in the medulla oblongata, beneath the
floor of the IVth ventricle- historically inferred from alterations in ventilation following
transection/ ablation of brainstem regions with or without sensory input from the vagus
nerve [vagotomy]
• neurons within the medulla generate signals that are distributed to pools of cranial +
spinal motoneurons
Lumsden (1923/cats): spinomedullary transection → ventilation ceases [loss of the
descending input to the phrenic+ intercostal motor neurons in the spinal cord]

nb: respiratory activity continues in muscles innervated by motor neurons with cell bodies
in the brain stem: nares, tongue, pharynx + larynx- this was noted much earlier by Galen,
physician or gladiators in Greek city of Pergamon: breathing stops with a swords blow to te
high cervical spine but blow to the lower cervical spine resulted in paralysis of the arms
and legs but respiration was intact
 The Central Controller
Effect of Brainstem Transections [1920-1950s]

I: separation of brainstem from rostral CNS structures ⇒ normal rhythm

I + vagotomy ⇒ notion of inspiratory offswitch

II: mid pontine transection similar to

I + vagotomy ⇒ notion of pneumotaxic
centre or pontine respiratory group
[PRG] ⇒ an earlier inspiratory cutoff,
contributing to inspiratory offswitch

II + vagotomy: apneusis [Gk: holding of

the breath] prolonged inspiration, rapid
expiration

III: separation at ponto-medullary junction:⇒ rhythmicity is independent of ascending vagal input

IV: see Lumsdens spino-medullary transection on the previous slide
Midline section + vagotomy each side maintains its own independent breathing rhythm.
 The Respiratory Related Neurons [RRN]
The Pontine and the Medullary (Dorsal & Ventral) Respiratory Groups contain
Neurons that Fire in phase with the Respiratory Cycle

• RRN in the brain stem (pons & medulla) exhibit

bursts of action potentials in synchrony with the
activity of a nerve supplying a respiratory muscle.

A simple classification:

• I-inspiratory: fire in phase with phrenic nerve impulse activity

• E-expiratory: fire during the silent phase of phrenic nerve impulse activity
• Phase Spanning: fire during both phases with peak firing rates at the transition
between phases
Characteristics of Phrenic Nerve Impulse Activity

Integrated phrenic nerve activity

Raw phrenic nerve activity

INSP EXP 5 sec

• abrupt onset of inspiratory activity

• ramp like, gradual increase in activity
• abrupt decline to silence during the expiratory phase
 PHRENIC NERVE ACTIVITY

Examples of Neural Activity

during the Respiratory Cycle in RRN INSPIRATORY RAMP NEURON

EARYLY INSPIRATORY NEURON

Potential Axonal Projections of RRN

• Bulbospinal premotor neurons: project to cell body CONSTANT INSPIRATORY NEURON

of motoneurons / interneurons within the spinal cord
at the cervical, thoracic, and lumbar regions that
courses through the ventrolateral column and
innervate the respiratory muscles LATE ONSET INSPIRATORY NEURON

• Propriobulbar interneurons: relay sensory input

EARYLY EXPIRATORY NEURON
to 1) other motoneurons 2) bulbospinal neurons

• Cranial motoneurons: branches of vagus + facial

EXPIRATORY RAMP NEURON
nerve that project to the upper airway muscles
 The DRG Processes Sensory Input & Contains Primarily I-neurons

• bilateral-dorso-medial in the medulla, close to NTS

• majority of cells show I activity

• project to VRG,PRG + spinal respiratory motonueuons

• site of termination of afferents from the peripheral

chemoreceptors, SAR of the lungs + afferents of the
arterial baroreceptors, hence integration of sensory
information
• nb NTS receives sensory input form all viscera of thorax + abdomen.
NTS is one of the key nuclei of the autonomic nervous system,
viscerotopically organized- with respiration portion being VL to TS,
just beneath the floor of the caudal end of the IV ventricle
 The VRG Is Primarily Motor & Contains Both I & E Neurons

• bilateral- ventrolateral, extending from the bublbospinal to

bulbo-pontine border, close to NA + NRA

• divided into 3 functional parts

-rostral: primarily E (a.k.a. Bötzinger complex

drives the E activity of the caudal region)

-intermediate: primarily I, somatic motoneurons

supplying the upper airways + maximizing airway
caliber during inspiration; one group of I neurons,
the pre-Bötzinger complex
.
-caudal: almost exclusively E, premotor neurons
impinging on spinal motoneurons that innervate the
E muscles of respiration
 The Respiratory Related Neurons [RRN] in the Medulla
The Dorsal & Ventral Respiratory Groups contain Neurons that Fire in Phase with
the Respiratory Cycle
 Determinants of RRN Firing Pattern
Intrinsic Membrane Properties & Patterned Synaptic Input

Intrinsic membrane property: the complement + distribution of ion channels

present in a neuron & how they affect firing patterns in response to synaptic input.
e.g DRG neurons with transient A-type K + currents & late onset inspiratory activity

Patterned synaptic input: that RRN receive from other respiratory neurons including
the excitatory (EPSP) + inhibitory (IPSP) that arrive at a given time during the
respiratory cycle . e.g. the early burst activity of the early inspiratory neuron parallels
the strong excitatory synaptic input that the neuron receives early in inspiration + the
inhibitory synaptic input that it receives during expiration
 Determinants of Respiratory Rhythm
Intrinsic Membrane Properties & Patterned Synaptic Input

Intrinsic membrane properties: simplest pattern generator are pacemaker cells,

e.g cardiac myocyte and its pacemaker currents, a single spike for each cardiac
cycle;respiratory pacemakers show bursting pacemaker activity (found in brain stem
slice preparations-examples 1) pre-Bötzinger complex 2) NTS with TRH presence

Synaptic Inputs: pattern generation is

possible in neural circuits without
pacemaker neurons-example-synaptic
input between DRG & VRG generate
EPSP + IPSPs with a timing that can
explain the neurons’ oscillatory
behavior.

Controversy: Which
model? network vs
pacemaker vs hybrid
 The Central Controller
Voluntary Control of Breathing

• arising from higher centres (primary motor, premotor, supplementary & parietal cortex;
basal ganglia & cerebellum-areas known to control skilled motor movement)

• provides feed-forward input to the respiratory muscles

• axons descent as corticospinal fibers in the dorsolateral columns of the spinal cord,
bypassing the involuntary respiratory system [coursing through the ventrolateral columns]

How can you demonstrate that there is voluntary control of breathing?

Ondine’s Curse

• Ondine, a play by Jean Giraudoux based on La Motte Fouque’s

German legend about a beautiful water nymph- without a soul
until she marries a mortal-falls in love with a knight- marries him
becomes mortal-pregnant & not so beautiful after a while- he is
unfaithful…
“You swore faithfulness to me with every waking breath, and I accepted your oath. So be it.
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!” . “And so it was.”

• The term coined in 1962 by Severighaus & Mitchell having seen the play & studied 3
patients with high cervical cordotomy [VL tracts cut for treatment of intractable pain]- loss of
automatic breathing: can breathe when awake but not during sleep.
• Later used to describe cases with Congenital Hypoventilation Syndrome: rare individuals
born without ventilatory chemosensitivity-breathing adequate when awake, but not when
asleep [require mechanical ventilation during sleep--no response to hypercapnia, hypoxia,
metabolic acidosis, administered respiratory stimulants: theophylline, progesterone,
methylphenidate, dopamine, almitrine bismesylate? Integration of chemosensitivity?]