CSB 346H

Neurobiology of Respiration
Lecture 8
Respiratory Control during Sleep

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 Control of Breathing in Sleep

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 Sleep Affects Ventilatory Control

The central questions:

1. What happens to breathing during sleep?

-Altered breathing pattern
-Altered drive to breath
-Altered respiratory network activity
-Reduced chemosensitivity
-Reduced respiratory motor tone, especially in the airways

2. What processes mediate these effects?

-Different neurotransmitters systems affect breathing during
specific sleep states.

3. What impact does sleep-dependent changes in breathing have on

human health?
-Obstructive sleep apnea
-Sudden Infant Death Syndrome
-Central (Congenital) Hypoventilation Syndrome (ondines curse)

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 Sleep Directly Affects the
Respiratory Network

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 Sleep States: Characteristics
NREM Sleep REM Sleep

Includes Stages 1 to 4: Brain waves somewhat similar to

awake state
Stage 1: Mostly theta waves
Rapid eye movements
Stage 2: Sleep spindles and K-
complex waves Loss of muscle tone ("atonia")
Muscle twitches
Stage 3: Mostly delta waves
Penile erections (males) & vaginal
Stage 4: Delta waves; hard to moistening (females)
awaken
Easy to awaken
May involve dreaming
Usually a time of more intensive,
Low muscle tone vivid dreams

EEG: Electroencephalogram EMG: Electromyogram EOG: Electrooculogram

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 Sleep States: Brain Activity (EEG)

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 Example of REM sleep

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 Breathing Patterns in Sleep & Wake

During quiet wakefulness, breathing is

relatively regular and metabolically
regulated; this pattern may vary greatly at
times when respiratory muscles are used
for other behaviors (e.g., speech,
swallowing).

During NREM sleep (slow-wave sleep),

breathing becomes deeper and very regular,
and PetCO2 increases slightly.

During REM sleep, respiratory rate and

depth vary greatly from breath to breath,
there are brief suppressions of respiratory
activity driven by phasic non-respiratory
events characteristic of REM sleep, and
overall ventilation may be dissociated from
metabolism.

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 Breathing Patterns in NREM Sleep

NREM sleep affects breathing.

On the right is an example of breathing

in a healthy human in NREM sleep.

Different sleep states have different

affects on breathing. For example,
during NREM sleep breathing is slow
and deep compared to wakefulness
levels.

Breathing patterns during stable NREM

sleep are remarkably constant.

Typical breathing pattern during steady NREM sleep. CEco2,

CO2 concentration (%) in the face mask; exp, expiration; insp,
inspiration; Sao2, oxygen saturation (%); thor mvt, abd mvt, thoracic
and abdominal movements; V, ventilatory volumes (mL) obtained
from a pneumotachograph attached to a face mask. (From Krieger
J: Breathing during sleep in normal subjects. Clin Chest Med
1985;6:577-594.)

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 Breathing Patterns in REM Sleep

REM sleep has major affects breathing

pattern.

On the left is an example of breathing in

a healthy human in REM sleep.

Compared to NREM sleep and quiet

wakefulness, breathing during REM
sleep is chaotic.

During REM sleep, respiratory frequency

and inspiratory amplitude can change
rapidly and tend to do so during periods
of rapid eye movements.

Typical breathing pattern during REM sleep. CEco2, CO2

concentration (%) in the face mask; exp, expiration; insp, inspiration;
Sao2, oxygen saturation (%); thor mvt, abd mvt, thoracic and
abdominal movements; V, ventilatory volumes (mL) obtained from a
pneumotachograph attached to a face mask.

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 NREM Sleep Respiratory Neurons

Sleep has major effects on the

activity of respiratory neurons in
the VRG. This may explain the
changes in breathing pattern during
sleep.

On the left is an example of how

sleep affects the activity of an
individual inspiratory neuron in the
VRG of a cat.

This neuron discharges vigorously

in wakefulness but stops in sleep.

The activity of a sleep-sensitive respiratory neuron, and the

locations of it and others like it. AMB, Nucleus ambiguus; CN,
cochlear nucleus; FTL, lateral tegmental field; IO, inferior olive; P,
pyramidal tract; RB, restiform body; SOL, solitary tract; 5 SP, nucleus
of the spinal tract of V; 5 ST, spinal tract of V; 7, facial nucleus; 12 N,
hypoglossal nerve. (From Orem J, Montplaisir J, Dement W: Changes
in the activity of respiratory neurones during sleep. Brain Res
1974;82:309-315.)

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 REM Sleep Respiratory Neurons
REM sleep has more profound affects on respiratory neurons than NREM sleep does.

Below is an example that demonstrates that the discharge activity of an inspiratory neuron is
altered in REM sleep.

Note that during REM sleep, an inspiratory neuron is sporadically activated (*). This does not
happen in NREM sleep.

* Half-wave rectified electromyograms and

* * * *
instantaneous discharge rate of an inspiratory
neuron in non-rapid eye movement (NREM) and
rapid eye movement (REM) sleep during
spontaneous respiration (a) and during mechanical
ventilation (b). The figure shows that in REM sleep,
this neuron is driven by endogenous tonic inputs that
account for much of the activity of the neuron during
spontaneous breathing.

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 REM Sleep Respiratory Neurons

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Sleep Affects the Chemical Control of
Breathing

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 Sleep Affects Chemosensitivity

The ventilatory response to

decreasing levels of arterial
oxygen saturation is decreased in
sleep relative to waking.

In waking, decreases in PaO2

induces a robust increase in
minute ventilation.

This response is significantly

suppressed in Stage 2-4 of NREM
sleep and further suppressed in
REM sleep.

Mean relationship between expired ventilation and decreasing O2

saturation in rapid eye movement (REM) sleep, in sleep stages 2 and
3/4, and awake, in 12 subjects, six men1 and six women. (From
Douglas NJ: Control of ventilation during sleep. Clin Chest Med
1985;6:563.)

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 Sleep Affects Chemosensitivity
The ventilatory response to hypercapnia is also suppressed by sleep.

The figure below demonstrates that increasing levels of inspired CO2 activate the
inspiratory activity of the genioglossus muscle the most during wakefulness and
the least during REM sleep. The ventilatory response to CO2 is also suppressed
in NREM sleep.
Genioglossus Activity (mV)
Respiratory-Related

Wakefulness

Non-REM sleep

REM sleep

Inspired CO2 (%)

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 Sleep Affects the Mechanical Reflex
Control of Breathing

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Sleep Reduces Airway Muscle Activity
Awake Non-REM REM

Airway
+++ ++ +

Intercostals
+++ ++ +

Diaphragm ++ ++
+++

Consequences: Upper airway resistance muscle activity

Pump muscle activity
Lung ventilation in sleep
Clinical Relevance: Airway narrowing in sleep, which potentiates
hypopneas and airway obstructions
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Upper Airway is Suppressed in Sleep
The figure on the left
depicts the natural
suppression of muscle
activity, and particularly
genioglossus activity in
both NREM and REM sleep
in a free-behaving rat.

The same type of

suppression of airways
and diaphragm occur in
health humans.

Note: muscle activity is

lowest in REM sleep and
second lowest in NREM
sleep.

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 Sleep & Upper Airway Motor Control

Sleep exerts powerful effects

on upper airway
motoneurons that innervate
upper airway muscles.

What brain regions do this

and what chemicals do they
use?

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Airway Motor Control during Sleep
Inhibition Disfacilitation

Inhibitory Excitatory
Premotor Premotor
Neurons Neurons
Noradrenaline
GABA Glutamate
Glycine - Serotonin +
Motor Motor
Neurons Neurons

Muscle Activity Muscle Activity

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Biochemical Control of Motoneurons in
Sleep
It is hypothesized that specific neurotransmitters groups that generate sleep project
to and alter the excitability of airway motoneurons and muscles in a state-dependent
manner.

For example,
noradrenaline
discharge is highest
in waking and lowest
in sleep. It is
hypothesized the
reductions in
noradrenergic activity
causes a loss of
consciousness and a
reduction in muscle
activity in sleep.

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Disfacilitation of Motoneurons in Sleep
Below is evidence that upper airway motoneurons are under
wake-related noradrenergic and serotonergic excitation, the withdrawal
of which is responsible for the suppression of upper airway motor tone during sleep,
especially REM sleep.

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 Inhibition of Motoneurons in Sleep
Below is evidence that upper airway motoneurons are inhibited during sleep, and especially in REM
sleep. The source of this inhibition could be GABA or glycine, although this is currently unclear.

Intracellular recording from a trigeminal jaw-closer motoneuron: correlation of membrane potential and state changes. The membrane potential
hyperpolarized rather abruptly at 3.5 min in conjunction with the decrease in neck muscle tone and transition from NREM to REM sleep. At 12.5 min,
the membrane depolarized and the animal awakened. After the animal passed into NREM again, a brief, aborted episode of REM sleep occurred at
25.5 min that was accompanied by a phasic period of hyperpolarization. A minute later, the animal once again entered REM sleep, and the membrane
potential hyperpolarized. EEG trace, marginal cortex, membrane potential band pass on polygraphic record, direct current to 0.1 Hz. EEG,
electroencephalogram; EMG, electromyogram; EOG, electrooculogram; PGO, ponto-geniculo-occipital potential. (Reprinted with permission from
Chase MH, Chandler SH, Nakamura Y: Intracellular determination of membrane potential of trigeminal motoneurons during sleep and wakefulness. J
Neurophysiol 1980;44:349-358.)

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 Respiratory Disorders during Sleep

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