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Control%20of%20 Breathing


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Control%20of%20 Breathing

  1. 1. 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,..]
  2. 2. 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.
  3. 3. Three Basic Elements of the Control System Sensors: Two classes of receptors [chemoreceptors & mechanoreceptors] monitor Sensors the effect of breathing and provide information to the effectors to automatically control ventilation and maintain stable arterial blood bases
  4. 4. 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 Léon Frédéricq [11 years prior to publication in éo 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
  5. 5. Léon Frédéricq [1851-1935] Professor of Physiology University of Liège, Belgium [see Léon Frédericq Foundation] Les Terrsasses sous la neige
  6. 6. 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
  7. 7. 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…?
  8. 8. 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
  9. 9. Mechanism of Central Chemoreception CSF blood supply CSF • formed by filtration + secretion from choroid H2O + CO2 CO2 + H2O plexus (capillaries within the ventricles) • absorbed by arachonoid villi H2CO3 H2CO3 • amount= 80-150 ml • rate of formation/absorption=20 ml/hour HCO-3 + H+ • 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?
  10. 10. 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
  11. 11. 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)
  12. 12. 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)
  13. 13. 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
  14. 14. 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
  15. 15. 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
  16. 16. 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
  17. 17. 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
  18. 18. Mechanism of Peripheral Chemoreception Signal Transmission in the Glomus Cell The Role of Potassium Channels Evidence: Reduction in PO2 will reduce potassium currents in Type I cells Evidence 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)
  19. 19. Signal Transmission in the Glomus Cell Inhibiting K+ Channels leads to Depolarization
  20. 20. 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
  21. 21. 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
  22. 22. 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]
  23. 23. 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]
  24. 24. 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
  25. 25. 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
  26. 26. 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
  27. 27. 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]
  28. 28. Three Basic Elements of the Control System
  29. 29. 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
  30. 30. 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]
  31. 31. 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
  32. 32. 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
  33. 33. 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
  34. 34. 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
  35. 35. Three Basic Elements of the Control System
  36. 36. 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
  37. 37. 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.
  38. 38. 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
  39. 39. 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
  40. 40. 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
  41. 41. 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
  42. 42. 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
  43. 43. The Respiratory Related Neurons [RRN] in the Medulla The Dorsal & Ventral Respiratory Groups contain Neurons that Fire in Phase with the Respiratory Cycle
  44. 44. 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
  45. 45. 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
  46. 46. 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?
  47. 47. 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?]