Control of BreathingControl 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,..]

ComplexitiesComplexities

• 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 SystemThree Basic Elements of the Control System

SensorsSensors: 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 RespirationChemical Control of Respiration

History: Three Primary Blood Borne Stimuli to BreatheHistory: Three Primary Blood Borne Stimuli to BreatheHypercapniaHypercapnia, Hypoxia & , Hypoxia & AcidemiaAcidemia

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 Léoéon Fréédééricq [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

LéonLéon FrédéricqFrédéricq [1851[1851--1935]1935]Professor of PhysiologyProfessor of Physiology

University of University of LiègeLiège, Belgium, Belgium[see [see LéonLéon FrédericqFrédericq Foundation]Foundation]

Les Terrsasses sous la neige

Chemical Control of RespirationChemical Control of RespirationCentral Central ChemoreceptorsChemoreceptors

IX, X, XI

VIIVIII

VI

C1

XII

• few µm beneath the ventral surface of the medulla

• close to entry of VIII & XI cranial nerves

• bilateral pairs: eponyms

• stimulated by application of acidic or high PCO2 solution on the surface: increase in ventilation

• reversibly depressed by applicationcold / anesthetic solution on the surface: decrease in ventilation

Current Controversy: LocationCurrent Controversy: Location

• Eugene Nattie: focal acidification of brain tissuewith 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 ChemoreceptorLocal 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 ChemoreceptionMechanism of Central Chemoreception

H2O + CO2

H2CO3

HCO-3 + H+

blood supply

BBB

CSF

brain tissue(BECF)

CO2 + H2O

H2CO3

HCO-3 + H+

arachnoid villichoroidplexus

CSF• formed by filtration + secretion from choroid

plexus (capillaries within the ventricles)

• absorbed by arachonoid villi

• amount= 80-150 ml• rate of formation/absorption=20 ml/hour• turnover time= 4 hours

• low in protein, bicarbonate only buffer of consequence, pH 7.32, PCO2=50 mm Hgi.e acidic relative to blood

• a given acute rise in blood PCO2 results in a greater PCO2 change in the CSF

• key unanswered questions, how CSF bicarbonate levels regulated?

Chemical Control of RespirationChemical Control of RespirationPeripheral Peripheral ChemoreceptorsChemoreceptors

• sense PO2, PCO2 and pH of arterial blood

• primarily sensitive to ↓ arterial PO2 ⇒ hyperventilation

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

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

Peripheral Peripheral ChemoreceptorsChemoreceptors: : LocationLocation

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

1. Carotid bodies [key role/studied more]

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 Peripheral ChemoreceptorsChemoreceptorsAfferent TrafficAfferent Traffic

• Carotid body

carotid sinus nerve (CSN) →glossopharyngial [IX cranial nerve, cell bodyin the petrosal ganglion] → medulla near nucleus tractus solitarius (NTS)

• Aortic body

join the vagus [X cranial nerve, cell body inthe nodose ganglion] → medulla near nucleus tractus solitarius (NTS)

• 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)

Peripheral Peripheral ChemoreceptorsChemoreceptorsBlood SupplyBlood Supply

• 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 Peripheral ChemoreceptorsChemoreceptorsCarotid Bodies Key Features & HistoryCarotid 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

• 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 ventilatoryresponse, bilateral denervation→ no ventilatory response

• 1926-Fernando de Castro y Rodriguez: clearest morphological description extensivethorough histology-proposes a function “a sensory organ that tastes blood” – disruptionof work during the Spanish Civil War at the Cajal Institute, Madrid- 1960 E.M. study ofglomus cells began a few days prior to his death.

Type I & Type II cells of the Carotid BodyType 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 & unmyelinatedafferent fibers

Type II [sustentacular cell]

Type II

• interstitial cell wraps around glomusand nerve endings

• no cytoplasmic granules• function ?

Mechanism of Peripheral ChemoreceptionMechanism of Peripheral ChemoreceptionSignal Transmission in the Signal Transmission in the GlomusGlomus CellCell

A Chronology of HypothesesA Chronology of Hypotheses

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 [excitatoryat 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

Which neurotransmitter?

The rest of the signal transduction pathway?Metabolic Hypothesis: Metabolic poisons: cyanide and hypoxia lead to ↓ ATP in glomuscells 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 ChemoreceptionMechanism of Peripheral ChemoreceptionSignal Transmission in the Signal Transmission in the GlomusGlomus CellCell

A Chronology of HypothesesA Chronology of Hypotheses

Mechanism of Peripheral ChemoreceptionMechanism of Peripheral ChemoreceptionSignal Transmission in the Signal Transmission in the GlomusGlomus CellCell

The Role of Potassium ChannelsThe Role of Potassium Channels

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

Current Hypothesis: 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 Signal Transmission in the GlomusGlomus CellCellInhibiting KInhibiting K++ Channels leads to DepolarizationChannels leads to Depolarization

The Integrated Response to an Acute Change in Blood GasesThe Integrated Response to an Acute Change in Blood GasesThe The HypercapnicHypercapnic VentilatoryVentilatory ResponseResponse

• hypoxia accentuates the response [↑slope=sensitivity]

• peripheral chemoreceptor denervation studies: 20-30 % of the response from carotid bodies[rapid]; the remaining 80% from central chemoreceptors [slow]

• progesterone ↑ slope• sleep, anesthetics, narcotics ↓ slope

• linear-slope= a measure of sensitivity to CO2variability humans: 1-6 L/min/mmHg

• sensitivity and set point can be measured-effect of drugs on ventilation

• dog leg seen with hypoxia

• steep portion of the curves converge to aset point (threshold) on the abscissa

Nielson & Smith, 1952

The Integrated Response to an Acute Change in Blood GasesThe Integrated Response to an Acute Change in Blood GasesThe Hypoxic The Hypoxic VentilatoryVentilatory ResponseResponse

• 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 RespirationMechanical Control of RespirationReceptors in Lung Tissue and AirwaysReceptors in Lung Tissue and Airways

• in the lungs and airways three types of mechanoreceptors have been characterized by their response to lung inflation

slowly adaptingrapidly adaptingc-fiber endings

• all three are innervated by fibers of the vagus nerves [X cranial nerve]

• myelinated afferent fibers

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

• responsible for the Hering-Breuer reflex [1868]

Mechanical Control of RespirationMechanical Control of Respiration-- Slowly Adapting Stretch ReceptorsSlowly Adapting Stretch Receptorsa.k.a. “a.k.a. “bronchopulmonarybronchopulmonary stretch receptors”stretch receptors”

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

• responsible for respiratory sinus arrhythmia [ tachycardia during I relative to E] stretch→↑ afferent vagal discharge→ medullary CV centre → ↓parasympathetic + ↑sympathetic activity → ↑HR

The The HeringHering BreuerBreuer Inflation & Deflation ReflexesInflation & 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 neonatesnb: in adult humans, operate at VT thresholds > 800ml

Mechanical Control of RespirationMechanical Control of Respiration-- Rapidly Adapting Stretch ReceptorsRapidly Adapting Stretch Receptorsa.k.a. “irritant 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 RespirationMechanical Control of Respiration-- CC--fiber endingsfiber 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 vascularpermeability

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

Mechanical Control of RespirationMechanical Control of Respiration——Upper Airway Irritant ReceptorsUpper Airway Irritant Receptors

Nasal 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: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 SystemThree Basic Elements of the Control System

The Effectors: The Muscles of RespirationThe Effectors: The Muscles of RespirationThe DiaphragmThe Diaphragm

• principle inspiratory muscle in man

• dome shaped skeletal muscleseparating thoracic fromabdominal 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

Cruralorigin = lumbar vertebrae;insertion: central tendon; opening for esophagus,abdominal aorta & inferiorvena cava

Costalorigin=sternum & lower ribsinsertion=central tendon

Innervation-bilateral-phrenic nerves-phrenic motor nuclei inspinal cervical

segments [C3,C4,C5]

Bilateral Bilateral InnervationInnervation of the Diaphragm by the of the Diaphragm by the PhrenicPhrenic NervesNerves

• How would the diaphragm move if one of the phrenic nerves was during a deeply & briskly inspiration: ie, sniffs ?

• Diaphragmatic paresis following trauma to thephrenic nerves is a rare complication after necksurgery [ 8%* - hopefully transient]

• The resulting elevation of the ipsilateral hemi-diaphragm is diagnosed on post-operative chest radiography and may be confirmed by ultrasound or fluoroscopy

paresis of the left hemi-diaphragm

restoration of function- left hemi-diaphragm*de Jong A, Manni J, Phrenic nerve paralysis following neck dissection. Eur Arch Otorhinolaryngol 1991; 248: 132-4

InspiratoryInspiratory Muscles other than the DiaphragmMuscles 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

ExthrathoracicExthrathoracic Airway Muscles Recruited During InspirationAirway Muscles Recruited During Inspiration

• during inspiration the potential collapseof the upper airways is actively opposedby the dilator (abductor) muscles of thepharynx + larynx, e.g: genioglossusprotrudes 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 MusclesExpiratory MusclesRecruited during Active ExpirationRecruited during Active Expiration

Internal intercostals• beneath the external intercostalsinner 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]

Abdominal wall muscles • innervation by intercostal + other spinal nerves

motor nuclei in thoracic + lumbar ventral horns]• contraction lowers the ribs + compresses the abdomen

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

Three Basic Elements of the Control SystemThree Basic Elements of the Control System

• this respiratory rhythmogenesis takes place in the medulla oblongata, beneath the floor of the IVth ventricle- historically inferred from alterations in ventilation followingtransection/ ablation of brainstem regions with or without sensory input from the vagusnerve [vagotomy]

The Central ControllerThe Central ControllerInvoluntary (a.k.a Metabolic or Automatic) Control of BreathingInvoluntary (a.k.a Metabolic or Automatic) Control of Breathing

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 tehigh cervical spine but blow to the lower cervical spine resulted in paralysis of the arms and legs but respiration was intact

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

• neurons within the medulla generate signals that are distributed to pools of cranial +spinal motoneurons

The Central ControllerThe Central ControllerEffect of Brainstem Effect of Brainstem TransectionsTransections [1920[1920--1950s]1950s]

I: separation of brainstem from rostral CNS structures ⇒ normal rhythmI + vagotomy ⇒ notion of inspiratory offswitch

II: mid pontine transection similar toI + vagotomy ⇒ notion of pneumotaxiccentre 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 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) exhibitbursts 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 Characteristics of PhrenicPhrenic Nerve Impulse ActivityNerve Impulse Activity

Integrated phrenic nerve activity

Raw phrenic nerve activity

• abrupt onset of inspiratory activity• ramp like, gradual increase in activity• abrupt decline to silence during the expiratory phase

INSP EXP 5 sec

Examples of Neural ActivityExamples of Neural Activityduring the Respiratory Cycle in RRNduring the Respiratory Cycle in RRN

PHRENIC NERVE ACTIVITY

INSPIRATORY RAMP NEURON

EARYLY INSPIRATORY NEURON

LATE ONSET INSPIRATORY NEURON

CONSTANT INSPIRATORY NEURON

EARYLY EXPIRATORY NEURON

EXPIRATORY RAMP NEURON

Potential Axonal Projections of RRN

• Bulbospinal premotor neurons: project to cell bodyof motoneurons / interneurons within the spinal cordat the cervical, thoracic, and lumbar regions that courses through the ventrolateral column and innervate the respiratory muscles

• Propriobulbar interneurons: relay sensory input to 1) other motoneurons 2) bulbospinal neurons

• Cranial motoneurons: branches of vagus + facial nerve that project to the upper airway muscles

The DRG Processes Sensory Input & Contains Primarily IThe DRG Processes Sensory Input & Contains Primarily I--neuronsneurons

• 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 thearterial 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

• 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 complexdrives the E activity of the caudal region)

-intermediate: primarily I, somatic motoneuronssupplying the upper airways + maximizing airway caliber during inspiration; one group of I neurons,the pre-Bötzinger complex.

-caudal: almost exclusively E, premotor neuronsimpinging on spinal motoneurons that innervate the E muscles of respiration

The VRG Is Primarily Motor & Contains Both I & E NeuronsThe VRG Is Primarily Motor & Contains Both I & E Neurons

The Respiratory Related Neurons [RRN] in the MedullaThe Respiratory Related Neurons [RRN] in the MedullaThe Dorsal & Ventral Respiratory Groups contain Neurons that Fire in Phase with

the Respiratory Cycle

Determinants of RRN Firing PatternDeterminants of RRN Firing PatternIntrinsic Membrane Properties & Patterned Synaptic InputIntrinsic 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 RhythmDeterminants of Respiratory RhythmIntrinsic Membrane Properties & Patterned Synaptic InputIntrinsic 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 ControllerThe Central ControllerVoluntary Control of BreathingVoluntary 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’sOndine’s CurseCurse

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

• The term coined in 1962 by Severighaus & Mitchell having seen the play & studied 3patients with high cervical cordotomy [VL tracts cut for treatment of intractable pain]- loss ofautomatic breathing: can breathe when awake but not during sleep.

• Later used to describe cases with Congenital Hypoventilation Syndrome: rare individualsborn without ventilatory chemosensitivity-breathing adequate when awake, but not whenasleep [require mechanical ventilation during sleep--no response to hypercapnia, hypoxia,metabolic acidosis, administered respiratory stimulants: theophylline, progesterone, methylphenidate, dopamine, almitrine bismesylate? Integration of chemosensitivity?]

“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.”