Neural control of respiration (like neural control of many other physiological functions, micturition, for example) is highly complex and not fully elucidated. Research is still going on to determine the centers in the brain and their complex interactions. There may be variations of opinion between different researchers depending on newer findings. Every effort has been made to keep this information as current and authoritative as possible, yet in a simple enough form for the student to understand and digest the information. Dr Sanjoy Sanyal, Professor and Course Director of Neuroscience and FCM-III Neurology in Caribbean created this PPTX after studying this complex topic for a very long time. Tags: Respiration, Breathing, Respiratory Centers, Brainstem, Apneustic Breathing, Biots Breathing, Cheyne-Stokes, Ataxic, Agonal, Kussmaul, Brainstem Reticular Nuclei, NTS, Locus Ceruleus, Fastigial, Raphe nucleus, Vagus, RTN nucleus, pFRG nucleus, Kolliker-Fuse, PBC nucleus, RVL nucleus "Copyright Disclaimer Under Section 107 of the Copyright Act 1976, allowance is made for "fair use" for purposes such as criticism, comment, news reporting, teaching, scholarship, and research. Fair use is a use permitted by copyright statute that might otherwise be infringing. Non-profit, educational or personal use tips the balance in favor of fair use." Educational Value: A very complex and poorly understood topic has been rendered in as simple a format and style as possible, so as to make it easily digestible to any Basic Science medical student and Medical Resident

1. Dr Sanjoy Sanyal, MBBS, MS (Surgery), MSc (Royal College
of Surgeons of Edinburgh), ADPHA
Professor and Course Director of Neuroscience and FCM-
III Neurology
It’s as natural as breathing.
Well, maybe not!

2. Chemoreceptors (CR)
 Chemoreceptors (CRs)
monitor Body Fluid chemistry
and respond to their H+ (pH),
PCO2, PO2 concentrations
 Input from CRs to CNS and
Output from CNS to Lungs
drive Alveolar Ventilation
Types of CR:
 Central CR
(CCR)
 Peripheral CR
(PCR)

3. Central Chemoreceptors (CCRs)
1. Pre-Bötzinger Complex (PBC) in Rats
2. Retrotrapezoid Nucleus (RTN) in
Pons
3. Parafacial Respiratory Group (pFRG)
in Medulla
4. Raphe Nuclei in Brainstem Reticular
Formation
5. Locus Ceruleus in Pons
6. Nucleus Tractus Solitarius (NTS) in
Medulla
7. Fastigial Nucleus in Cerebellum
(PBC, RTN, pFRG, Locus Ceruleus are
also Respiratory Rhythm centers)
Location: Close to
CSF surfaces
of Medulla,
Pons,
Cerebellum;
Bathed in CSF;
Monitors CSF
H+ and PCO2
directly

4. Central Chemoreceptors (CCRs)
Receptor Type: H+ / PCO2 Receptor;
NO PaO2 receptors in CCR
Stimulus: CSF H+ (Most Sensitive),
CSF PCO2, Arterial PCO2
(Indirectly); NOT Arterial PO2
Less Sensitive To: Systemic Arterial
pH (Because H+ passes very slowly
across Blood-CSF Barrier)
Adaptation: within 12-24 hrs; Due to
pumping of HCO3
- in/out of CSF
There are NO
PO2
Receptors in
the CCR

5. CCR – Bottom Line
 CCRs are very sensitive
 Provide main drive to ventilation under normal
conditions at Sea Level Atmospheric Pressure
 Ventilation responds much more to moderate
↑Arterial PCO2 (Hypercapnia) than to large ↓in
Arterial PO2 (Hypoxia), because of lack of central
PO2 Receptors in CCR

6. CCR Respiratory Stimulants
 Progesterone acts on CCR via Steroid Receptor-
Mediated Mechanism to help Respiration
 Naloxone is -Opiate Receptor Antagonist, Used
in Opioid-induced Central Respiratory
Depression
 Doxapram is PCR and CCR Stimulant;
Overcomes Opioid-induced Central Respiratory
Depression
 Acetazolamide (Carbonic Anhydrase Inhibitor)
causes Acidification of CSF, acting as CCR
Respiratory Stimulant, especially at High Altitude

7. Peripheral Chemoreceptors (PCR)
Locations: Aortic and Carotid Bodies;
Bathed in Arterial Blood; Monitor
Arterial Blood PO2 directly
1. Aortic Bodies: Near Aortic Arch;
CN10 Afferent
2. Carotid Bodies (Most important):
Near Carotid Sinus at Carotid
Bifurcation; CN9 Afferent
[Very small structure; Receives maximum
Blood per Gm of tissue; Meets metabolic
requirements by utilizing O2 dissolved in
Blood; Type 1 Glomus Cells are main
sensors of Hypoxia]

8. Peripheral Chemoreceptor (PCR)
Receptor Types: PO2 Receptor (Mainly); Also H+ /
PCO2 Receptor
Stimulus: Arterial PO2 (Most sensitive); Monitor
PO2 (Partial Pressure of O2 in Blood, which is O2
Dissolved in blood), NOT O2 Content (O2 in Hb)
Less Sensitive To: Systemic Arterial pH / PCO2;
Very small contribution to normal drive for
ventilation
Adaptation: Nil (Receptor keeps firing so long as
Arterial Hypoxic Stimulus exists)

9. PCR – Bottom Line
When Systemic Arterial PaO2 >100 mmHg:
 There is NO Stimulus to PO2 receptors
 PCRs do NOT contribute to drive for Normal
Ventilation
When Systemic Arterial PaO2 <100 mmHg:
 Strong Stimulus to PO2 receptors, ↑Drive for
Alveolar Ventilation
 Main Drive for ventilation in Hypoxemic Hypoxia
 This drive increases with CO2 Retention
(Hypercapnia)

10. PCR Respiratory Stimulants
 Almitrine Bismesylate is Carotid Body (PCR)
stimulant
 Doxapram is PCR and CCR Stimulant;
Overcomes Opioid-induced Central Respiratory
Depression
General Information:
 Partial Pressure of Gases in Blood / CSF is
measured in Pascals (Pa) / kiloPascals (kPa).
 1 kPa = 7.5 mm Hg; 133 Pa = 1 mm Hg

11. Summary of CCRs and PCRs
CCR PCR
Location Medulla, Pons,
Cerebellum
Aortic / Carotid
Bodies
Samples What CSF Arterial Blood
Receptor Type H+ / PCO2 PaO2
Stimulus CSF H+ (Main);
CSF PCO2;
Arterial PCO2
(Indirectly)
Arterial PO2
(Main); Arterial
pH, PCO2 (Less)
Less Sensitive
To
Systemic Arterial
pH
Systemic Arterial
pH / PCO2
Adaptation 12 – 24 hours Nil

12. Respiratory Rhythm / Control
Afferents: From Mechano-
receptors in:
 Lungs: Via Thoracic
Cardiopulmonary Splanchnic
Nerves (T2-5)
 Intercostal Muscles: Via
Intercostal Nerves
 Diaphragm: Via Phrenic
Nerve (C3-5)
 Overview:
Input from CRs
to CNS and
Output from
CNS to Lungs
drive Alveolar
Ventilation

13. Respiratory Rhythm / Control
Afferents: From Peripheral and
Central Chemo-receptors:
 Carotid Body
 Aortic Body
 CCRs: 7 (Slide #3)

14. Respiratory Rhythm / Control
Rhythm Centers:
 Rostroventrolateral
(RVL) Nucleus in
Medulla
 Kölliker-Fuse Nucleus
 Para-brachial Complex
 Locus Ceruleus in
Pons (This is also a
CCR)
Inspiratory Centers:
 Pre-Bötzinger Complex
(PBC) in rats only (This is
also a CCR)
Expiratory Centers: (These
are also CCRs)
 RTN
 pFRG

15. Respiratory Rhythm / Control
Pathway 1:
 Carotid Body (CN9) / Aortic
Body (CN10)
 → NTS (CCR)
 → RTN (CCR / Expiratory
Center)
 → Respiratory Rhythm

16. Respiratory Rhythm / Control
Pathway 2:
 RVL (Lateral Medulla) →
Lateral Medullary RST
 Rhythmic discharge to
Phrenic Nucleus (C3-5)
 Phrenic Nerve →
Diaphragm
 Spontaneous Respiratory
Rhythm

17. Respiratory Rhythm / Control
Central Respiratory Integration
 Above-mentioned centers in Brainstem Reticular
Formation Generate central Respiratory Drive
 Govern inherent Respiratory Rhythm
 Transmit to Upper Airway and to Main and
Accessory Respiratory Muscles
Bottomline:
 Input from CRs to CNS and Output from CNS to
Lungs drive Alveolar Ventilation

18. Respiratory Rhythm / Control
Autonomic Control:
 SNS: Thoracic CP
Splanchnic Nerve
(Sympathetic from T2-5
Ganglia) relaxes Bronchi
 PSNS: Dorsal Nucleus of
Vagus (Parasympathetic)
constricts Bronchi
Supramedullary
Areas: Cortex / Sub-
cortex Initiate or
Modulate breathing
with Volition,
Emotion, Exercise etc

19. Summary CCR Respiratory Rhythm Centers
CCR Inspiratory
Centers
Expiratory
Centers
Other Rhythm Centers
Pre-Botzinger Complex
(PBC) (Rats)
PBC (Rats) Rostroventrolateral
(RVL) Nucleus in
Medulla
Retrotrapezoid
Nucleus (RTN) in Pons
RTN Kolliker-Fuse Nucleus
Parafacial Respiratory
Group (pFRG)
pFRG Parabrachial Complex
Raphe Nuclei in
Brainstem Reticular
Formation
Locus Ceruleus (Pons) Locus Ceruleus (Pons)
Nucleus Tractus
Solitarius (NTS) in
Medulla
Fastigial Nucleus in
Cerebellum

20. Respiratory Control – Clinical Aspects
Spinal Cord Lesions:
 Complete lesion at or above C3 Spinal Segment
interrupt Diaphragmatic Respiration
 Complete lesion at or below C6 Spinal Segment
will not
Respiratory Depressants:
 Opioids act on -Opiate Receptors in Brainstem
Reticular Formation and Inhibit Brainstem
Respiratory Rhythm (See Naloxone in Slide 24)

21. Respiratory Control – Clinical Aspects
Brainstem Pathology:
 Breathing control can be disturbed by many
Brainstem Pathology.
 Previously undiagnosed such pathology may be
revealed by Abnormal Breathing during Sleep
Sleep-Awake States:
 Important in regulating breathing
 Thus, respiratory control abnormalities are most
often evident during Sleep, or during transition
from Sleep to Wakefulness (Next 2 slides)

22. Respiratory Control – Clinical Aspects
Central (Diaphragmatic) Sleep Apnea:
 Inhibition of ‘Respiratory Center’ (RVL in Caudal
Brainstem Reticular Formation)
 → Intermittent Diaphragmatic Arrest, causing
(a)Cheyne-Stokes Respiration (60-second
Hyperventilation → Apnea) in
(b)Elderly

23. Respiratory Control – Clinical Aspects
Ondine's Curse vs. Locked-in Syndrome: Distinguish
Brainstem (Volitional) from Supramedullary
(Autonomic) regulatory failure
 Former loses Autonomic Respiratory control and
requires Volitional Breathing for survival. So patient has
Hypoventilation during Sleep
 Latter loses CST / CBT in Pons that is required for
Volitional Breathing, but retains Autonomic Control

24. Respiratory Stimulants
 Progesterone acts on CCR via Steroid Receptor-
Mediated Mechanism to help Respiration
 Almitrine Bismesylate is Carotid Body (PCR)
Stimulant
 Naloxone is -Opiate Receptor Antagonist, Used in
Opioid-induced Central Respiratory Depression
 Doxapram is PCR / CCR Stimulant; Overcomes
Opioid-induced Central Respiratory Depression
 Acetazolamide (Carbonic Anhydrase Inhibitor)
causes Acidification of CSF, acting as CCR
Respiratory Stimulant, especially in High Altitude

25. Abnormal Breathing – Apneustic
Description
 Prolonged Inspiration
 Alternating with short Expiration
 (No equivalent Expiration attempt)
Causes
 Loss of normal balance between Vagal Input and
the Pons-Medullary Interactions
 Lesion usually in Caudal Pons

26. Abnormal Breathing – Biot’s (Cluster)
Description
 Several Breaths of identical Rate and Depth
 Alternating with irregular periods of Apnea
Causes
 Increased ICP
 Midbrain Lesions
 Serious Head Trauma with Medullary Injury
 Brainstem Strokes

27. Abnormal Breathing – Cheyne-Stokes
Description
 A type of Periodic Breathing:
60-Second Hyperventilation
followed by Apnea
 Cycles of gradually increasing
Depth and Frequency
 Followed by gradual decrease
in Depth and Frequency
 Between periods of Apnea
Causes
 Midbrain Lesions
 Head Trauma
 Stroke
 Infants and During Sleep,
especially High Altitudes
 Central (Diaphragmatic)
Sleep Apnea in Elderly
 With Type-B ICP Waves in
Normal Pressure Hydrocephal

28. Abnormal Breathing – Ataxic / Agonal
Description
 Ataxic Breathing: Irregular breathing
intermixed with irregular periods of Apnea
 As breathing continues to deteriorate it becomes
Agonal Respirations, and finally Apnea
Causes
 Head Trauma
 Medullary Stroke

29. Abnormal Breathing – Kussmaul
Description
 Deep, Rapid Breathing to expels excess CO2 in
Metabolic Acidosis
Causes
 Diabetic Ketoacidosis (DKA)
 CNS Disorders

30. Reference
 Pattinson KTS. Opioids and the Control of
Respiration. Posted: 10/03/2008; Br J
Anaesth. 2008; 100(6):747-758. © 2008 Oxford
University Press URL: www.medscape.com
 Asher R, Knight A et al. EMT Basic - Airway
Management Module 2.1 URL: http://www.ceu-
emt.com/airway-ceu.php (Accessed 16 Mar 2014)

31. Disclaimer
 Neural control of respiration (like neural control of
many other physiological functions, micturition, for
example) is highly complex and not fully elucidated.
 Research is still going on to determine the centers in
the brain and their complex interactions.
 There may be variations of opinion between different
researchers depending on newer findings.
 Every effort has been made to keep this information
as current and authoritative as possible, yet in a
simple enough form for the student to understand
and digest the information.