Control of Breathing – Key Vocabulary

Respiratory Control Centres

• Breathing must continuously match metabolic O₂ demand and CO₂ removal to maintain blood gas homeostasis.

• Skeletal respiratory muscles, such as the diaphragm and intercostals, are entirely dependent on motor output from specialised brain-stem nuclei collectively called the respiratory centre (autonomic).

• This centre functions involuntarily and rhythmically but can be modulated by various inputs (e.g., chemoreceptors, mechanoreceptors, higher brain centres).

• Major anatomical subdivisions:

  • Medullary respiratory centre (medulla oblongata)

    • Dorsal respiratory group (DRG)

    • Ventral respiratory group (VRG)

    • Pre-Bötzinger complex (within the VRG)

  • Pontine respiratory group (PRG) (located in the pons)

Medullary Respiratory Centre Details

1. Dorsal Respiratory Group (DRG) – “Quiet-breathing driver”

• Generates the basic rhythm for eupnea (normal quiet breathing, approx. 12-20 breaths per minute).

• Sends rhythmic bursts of action potentials, known as the inspiratory ramp signal:

  • \text{ON \approx 2 s}: The frequency of action potentials gradually increases over 2 seconds, leading to a smooth, gradual contraction of inspiratory muscles. Impulses travel via phrenic nerves (innervating the diaphragm) and intercostal nerves (innervating the external intercostals) → inspiration occurs.

  • \text{OFF \approx 3 s}: Cessation of impulses allows inspiratory muscles to relax → passive elastic recoil of the lungs and chest wall → expiration.

• This cycle repeats continuously (total length approx. 5 seconds for a breath, yielding 12 breaths min⁻¹).

• Everyday reinforcement example: while sitting/watching this video, your DRG is following the 2 s/3 s pattern to maintain quiet breathing.

2. Ventral Respiratory Group (VRG)

• Generally quiescent during quiet breathing except for the Pre-Bötzinger sub-region, which is active as the rhythm generator.

• Activated primarily during conditions requiring forced or active breathing, such as exercise, speaking loudly, or playing a wind instrument.

• Contains two functional neuron pools:

  • Forced-inspiration neurons → activate accessory inspiratory muscles (e.g., sternocleidomastoid, scalenes, pectoralis minor, erector spinae) to increase the force and depth of inspiration.

  • Forced-expiration neurons → drive accessory expiratory muscles (e.g., internal intercostals, rectus abdominis, obliques, transversus abdominis) once inspiratory activity ceases, actively depressing the rib cage and compressing abdominal contents to force air out more rapidly.

3. Pre-Bötzinger Complex

• Recognized as the intrinsic pacemaker/rhythm generator for respiration – functionally analogous to the SA node of the heart.

• Contains a specialized network of pacemaker neurons that exhibit inherent bursting activity.

• Provides the fundamental rhythmic drive to the DRG and VRG; the exact cellular mechanisms contributing to its rhythmicity are still a subject of ongoing research.

Pattern Generation Summary

• Quiet Breathing (Eupnea)

  • DRG inspiratory neurons fire for approximately 2 seconds (inspiratory ramp) → diaphragm and external intercostals contract → quiet inspiration.

  • DRG inspiratory neurons become silent for approximately 3 seconds → passive elastic recoil of the lungs and chest wall → quiet expiration.

• Forced Breathing (Active)

  1. Forced Inspiration: DRG is strongly activated, and VRG inspiratory neurons are recruited and fire vigorously → accessory inspiratory muscles contract forcefully → significantly larger tidal volume achieved.

  2. Forced Expiration: DRG and inspiratory VRG neurons fall silent; simultaneously, VRG expiratory neurons fire actively → accessory expiratory muscles contract forcefully → active and more rapid expulsion of air.

Pontine Respiratory Group (PRG)

• Located in the pons, it sends modulatory impulses to both the inspiratory (DRG, VRG inspiratory) and expiratory (VRG expiratory) neuron pools in the medulla.

• Function: Smooths the transition between inspiration and expiration, preventing prolonged inspiration or expiration; essentially “fine-tunes” the basic medullary rhythm.

  • The pneumotaxic center (a component of the PRG) primarily inhibits inspiration, allowing expiration to occur earlier and preventing lung overfilling, leading to shorter, more rapid breaths.

  • The apneustic center (also sometimes functionally associated with the pons, though its precise location and role are debated) prolongs inspiration, leading to deep breaths.

• Lesion effect: Damage to the pontine respiratory group (e.g., due to trauma or stroke) causes long, deep gasping inspirations interrupted by sporadic, brief expirations → this characteristic breathing pattern is known as apneustic breathing (a significant clinical marker of pontine/upper medullary damage, as the inhibitory input to inspiration is lost).

Higher Brain & Other Modulatory Influences

• Cortical (voluntary) control

  • The cerebral cortex can temporarily override the brain-stem pattern generators, allowing for conscious control of breathing (e.g., breath-holding when diving, speaking, singing, playing a wind instrument, or consciously avoiding inhalation of noxious fumes/aerosols).

  • This voluntary control is limited; eventually, the build-up of CO₂ and drop in O₂ will stimulate chemoreceptors, forcing an involuntary breath (the "breaking point").

  • The hypothalamus and limbic system provide pathways for emotional states (e.g., fear, excitement, stress) to influence breathing patterns (e.g., gasping, sighing, hyperventilating).

• Temperature

  • ↑ Body/core T° (e.g., fever, exercise) → ↑ respiratory rate, influenced by direct effects on respiratory neurons and via hypothalamic thermoregulatory centers to increase heat dissipation.

  • Sudden cold immersion (e.g., polar plunge) → transient intense stimulation followed by apnea (the 'cold shock response') due to a vagal reflex.

• Pain

  • Severe, sudden pain may transiently inhibit breathing due to strong afferent inhibitory signals.

  • Chronic or moderate pain usually elevates the respiratory rate.

• Airway irritation

  • Irritant receptors in the airways respond to noxious stimuli (e.g., dust, smoke, chemicals).

  • Activation of these receptors triggers protective reflexes like the cough or sneeze reflex → brief apnea followed by explosive expiration to expel the irritant.

• Arterial blood pressure (minor influence)

  • Baroreceptors, sensitive to blood pressure changes, provide weak feedback to the respiratory center.

  • ↑ BP → mild ↓ breathing rate; ↓ BP has the opposite effect (a relatively minor contribution compared to chemoreceptors).

Chemoreceptor Regulation – The Most Powerful Feedback

Chemoreceptors are the primary sensors for blood gas and pH status, providing critical feedback to the respiratory centres.

Central Chemoreceptors

• Location: Primarily found on the ventral surface of the medulla oblongata, bathed in cerebrospinal fluid (CSF).

• Primary stimulus: Directly sensitive to CSF [H^+] (pH).

• Indirectly sense P{CO2}: Arterial CO₂ is highly lipid-soluble and readily diffuses across the blood-brain barrier into the CSF. In the CSF, CO₂ reacts with water to form carbonic acid (\mathrm{H2CO3), which then dissociates into H⁺ and HCO₃⁻ (catalyzed by carbonic anhydrase):
  \mathrm{CO2 + H2O \leftrightarrow H2CO3 \leftrightarrow H^+ + HCO_3^-}

• Because CSF has very limited protein buffering capacity, even small increases in P{CO2} lead to significant increases in CSF [H^+] and a drop in pH, powerfully stimulating these chemoreceptors.

Peripheral Chemoreceptors

• Carotid bodies: Located at the bifurcation of the common carotid arteries; afferent signals transmitted to the medulla via the glossopharyngeal nerve (CN IX).

• Aortic bodies: Located in the aortic arch; afferent signals transmitted to the medulla via the vagus nerve (CN X).

• Response profile:

  • Primarily sensitive to arterial P{CO2} (the strongest and most rapid stimulus for peripheral chemoreceptors).

  • Also respond to arterial [H^+].

  • Sensitive to arterial P{O2} (oxygen partial pressure) specifically when P{O2} falls significantly, typically below 100 mmHg, becoming a strong stimulus when it drops to 60-50 mmHg or lower (hypoxic drive).

Key point

• Arterial P{CO2} ( ext{normal } \approx 40 ext{ mmHg}) is the single most important and potent chemical driver of ventilation, primarily detected by central chemoreceptors via CSF pH changes.

Hypercapnia Feedback Loop

1. Stimulus: An increase in arterial P{CO2} above normal (hypercapnia, e.g., >40-45 \text{ mmHg}), or a significant decrease in pH ([H^+] increase, acidosis), or a substantial drop in P{O2} (hypoxemia).

2. Chemoreceptor activation: Both central (primarily) and peripheral chemoreceptors are strongly stimulated and increase their firing rate.

3. Afferent signals: Nerve impulses are sent from the chemoreceptors to the DRG in the medulla.

4. Respiratory response: The DRG increases the frequency and depth of ventilation (hyperventilation, increased minute ventilation) to expel excess CO₂ and take in more O₂.

5. Result: Increased ventilation leads to a decrease in arterial P{CO2}, an increase in pH, and an increase in P{O2}. These changes reduce the stimulation of the chemoreceptors, causing them to relax and signalling the DRG to return ventilation towards homeostasis.

Hypocapnia

• When arterial P{CO2} falls below normal (<40 \text{ mmHg}, hypocapnia, often due to hyperventilation), chemoreceptors are quieted.

• The DRG re-establishes a moderate rhythm, leading to a temporary decrease in ventilation or even apnea, until CO₂ levels normalize (e.g., as seen after voluntary hyperventilation).

Proprioceptor & Baroreceptor Reflexes

• Proprioceptors (muscle & joint receptors)

  • Located in muscles, tendons, and joints, they detect body and limb movement.

  • At the onset of exercise, these receptors send immediate excitatory signals to the respiratory control centers, causing a rapid, anticipatory increase in ventilation before any significant changes in blood gases (O₂ or CO₂) metabolic by-products occur.

  • This mechanism is a feed-forward control ensuring adequate oxygen supply as activity increases.

• Pulmonary stretch (baro)receptors (located in the walls of bronchi and bronchioles)

  • Activated when the lungs are significantly over-inflated (stretch).

  • Vagal afferent fibres (via CN X) send inhibitory signals to the DRG, effectively terminating inspiration and initiating expiration.

  • This reflex is called the Hering–Breuer (inflation) reflex; it serves as a protective mechanism to prevent excessive lung inflation and potential damage, particularly during strenuous breathing or in infants (where it's more prominent during quiet breathing).

  • In adults, this reflex is typically not active during normal quiet breathing but becomes significant at larger tidal volumes (e.g., during intense exercise).

Types of Hypoxia (↓ tissue O₂)

Hypoxia is a condition where tissues are deprived of adequate oxygen supply, categorized by the underlying cause:

Breathing & Exercise

• Moderate exercise

  • Tidal volume (amount of air per breath) increases significantly, and breathing frequency may also increase, leading to a substantial rise in minute ventilation (total air moved per minute).

  • Importantly, arterial P{O2} and P{CO2} remain essentially constant (at or very near normal levels) during moderate exercise. This is because the enhanced alveolar ventilation precisely matches the increased metabolic demand, effectively clearing CO₂ and delivering O₂ to maintain blood gas homeostasis.

• Temporal phases of ventilatory increase during exercise

  1. Abrupt initial rise (seconds after exercise onset)

     • Primarily a neurogenic phase, driven by immediate excitatory input from:

       • Limbic anticipation (psychological arousal, preparedness for exertion).

       • Proprioceptor discharge (from moving muscles and joints sending feed-forward signals).

       • Primary motor cortex outflow (co-activation of respiratory centers along with motor commands for limb movement).

  2. Gradual secondary rise (minutes, continues until a plateau is reached during steady-state exercise)

     • Due to metabolic by-products and other factors accumulating over time, stimulating various receptors:

       • Slight decreases in P{O2} and increases in P{CO2} (though kept tightly regulated).

       • Increase in [H^+] (due to lactic acid production from anaerobic metabolism).

       • Increase in body temperature.

       • Increases in plasma K^+ concentration.

     • These factors increasingly stimulate central and peripheral chemoreceptors, as well as receptors in the muscles and joints, further driving ventilation.

Age-Related Changes in the Respiratory System

• With increasing age, the connective tissues of the airways, alveoli, and thoracic cage become notably less elastic and more rigid due to changes in elastin and collagen content.

• The vital capacity (VC = Tidal Volume + Inspiratory Reserve Volume + Expiratory Reserve Volume), a measure of maximum exhalable air after a maximal inhalation, typically falls by approximately 35\% by age 70.

• Consequences of these changes:

  • Decreased maximal P{O2} achievable in blood: Reduced elastic recoil, decreased surface area for gas exchange, and increased alveolar-arterial gradient lead to less efficient oxygen uptake.

  • Decreased efficiency of alveolar macrophages & cilia: Structural changes and reduced immune surveillance increase the risk of respiratory infections (e.g., pneumonia, bronchitis) and chronic inflammatory conditions like emphysema.

  • Diminished exercise tolerance & cardiovascular reserve: The increased work of breathing and reduced ventilatory capacity limit physical activity, and the heart has to work harder to compensate for reduced respiratory efficiency.

Key Terminology

• Eupnea – The normal, quiet, unconscious breathing pattern, typically about 12-20 breaths per minute.

• Apnea – A temporary absence or cessation of breathing.

• Apneustic breathing – An abnormal breathing pattern characterized by prolonged inspiratory gasps with occasional, brief expirations; a clinical sign strongly indicative of damage to the pons or upper medulla, specifically loss of inhibitory input to inspiration.

• Hypercapnia – A condition where arterial P{CO2} is above the normal range (typically > 45 \text{ mmHg}) due to insufficient CO₂ removal.

• Hypocapnia – A condition where arterial P{CO2} is below the normal range (typically < 35 \text{ mmHg}) due to excessive CO₂ removal.

• Hering–Breuer reflex – An inflation reflex mediated by pulmonary stretch receptors and the vagus nerve, which inhibits inspiration when the lungs are over-distended, protecting them from damage. More prominent in infants and during deep breaths in adults.

• Pre-Bötzinger complex – A crucial medullary neuronal network recognized as the intrinsic pacemaker that generates the fundamental inspiratory rhythm of breathing.

Clinical & Everyday Connections

• Voluntary breath-holding: Activities like swimming or consciously avoiding pathogen inhalation (e.g., passing someone unmasked) rely on cortical override of the brain-stem respiratory centres. This control is temporary, eventually overcome by the powerful chemoreceptor drive for breathing when CO₂ levels rise critically.

• Cold-water immersion: The initial physiological response to a polar bear plunge or cold-water triathlon includes a gasp followed by momentary apnea (the "cold shock response"), primarily due to the sudden stimulation of temperature receptors and strong vagal reflexes.

• Stroke and ischemic hypoxia: Patients who have experienced a stroke resulting in ischemic hypoxia may present with normal hemoglobin levels and intact lung function. However, the problem lies in the localized lack of blood flow, which prevents oxygen from reaching specific tissues.

• Carbon monoxide (CO) alarms: These are essential safety devices because CO poisoning produces anemic hypoxia without typically causing dyspnoea (shortness of breath) until severe. This is because CO binds to hemoglobin with an affinity approximately 200 times greater than oxygen, causing oxygen starvation at the cellular level. Standard (pulse oximetry) measures of P{O2} would likely be normal as the blood is still saturated, just with CO instead of O₂.

• Elderly clients and pulmonary health: Older adults often require vaccine prophylaxis (e.g., pneumococcal vaccine, annual flu shots) and may benefit from pulmonary rehabilitation programs. This is crucial to offset their naturally reduced vital capacity, compromised immune surveillance (less efficient alveolar macrophages and cilia), and increased susceptibility to respiratory infections.