Control of Respiration

I. RESPIRATORY CENTER

1. Dorsal Respiratory Group (DRG)

• Located in the nucleus tractus solitarius (NTS), dorsal medulla
• Primary function: controls inspiration and generates the basic respiratory rhythm
• Receives afferent input from peripheral chemoreceptors, baroreceptors, and lung receptors via vagus (CN X) and glossopharyngeal (CN IX) nerves
• Fires in repetitive bursts even after all peripheral inputs are severed - intrinsic rhythmicity
• The pre-Botzinger complex (rostral ventral respiratory group) contains spontaneously firing pacemaker neurons that project to DRG/VRG and is considered the key component of the central pattern generator for respiratory rhythm

2. Ventral Respiratory Group (VRG)

• Located in the ventrolateral medulla (nucleus ambiguus and nucleus retroambiguus)
• Contains both inspiratory and expiratory neurons
• Largely quiescent during normal quiet breathing
• Activated during increased ventilatory demand (exercise, hypercapnia) - drives accessory muscles of inspiration and muscles of active expiration

3. Pneumotaxic Center

• Located dorsally in the superior pons
• Primary role: limits inspiration - signals the inspiratory neurons to switch off, controlling inspiratory duration
• Higher pneumotaxic activity -> shorter inspiratory time -> faster respiratory rate
• Works with the apneustic center (lower pons): if pneumotaxic center is removed and vagus is cut, sustained inspiratory spasm (apneusis) occurs

II. GENERATION OF RESPIRATORY RHYTHM

• Instead of firing abruptly, the DRG sends a progressively increasing (ramp) signal to inspiratory muscles over ~2 seconds
• This causes smooth lung inflation
• The ramp is "switched off" abruptly, allowing elastic lung recoil for expiration
• Expiration is normally passive (no active muscle firing)
• The cycle: ~2 s inspiration, ~3 s expiration = normal ~12 breaths/min

III. CHEMICAL CONTROL OF RESPIRATION

A. Central Chemoreceptors

• Located on the ventral surface of the medulla, separate from the respiratory center itself
• Stimulus: H+ ions in CSF (NOT CO2 directly)
• CO2 rapidly crosses the blood-brain barrier (BBB) -> reacts with water to form H2CO3 -> dissociates into H+ -> stimulates central chemoreceptors
• H+ ions themselves cross the BBB very slowly, so CO2 is the dominant acute chemical signal
• Powerful, fast-acting: a rise in arterial PCO2 of 5 mmHg nearly doubles ventilation

• CSF has very little protein buffering (unlike blood), so even small CO2 rises cause significant H+ increase in CSF
• This makes the central system exquisitely sensitive to CO2

B. Peripheral Chemoreceptors

• Respond primarily to PO2 fall below 60 mmHg (below the flat part of the oxyhemoglobin dissociation curve)
• Above PO2 of 100 mmHg - essentially no stimulation
• High blood flow relative to O2 consumption -> respond to PO2 (dissolved O2), NOT SaO2
• Also respond to rising PCO2 and falling pH, but weaker effect than central chemoreceptors for CO2

IV. EFFECTS OF CO2, O2, AND pH ON VENTILATION

CO2 / H+ (Most Powerful Stimulus)

• Normal PaCO2 = 40 mmHg is the "set point"
• A rise of 5-10 mmHg PCO2 can double alveolar ventilation
• Acts via both central (H+ in CSF) and peripheral chemoreceptors
• Very high CO2 (>70-80 mmHg) becomes narcotic - depresses the respiratory center

O2 (Hypoxic Drive)

• Minimal effect until PaO2 falls below 60 mmHg
• At PaO2 = 40 mmHg: ventilation doubles
• At PaO2 = 20 mmHg: ventilation increases ~6-fold
• Hypoxic ventilatory response is entirely peripheral (carotid bodies)
• In COPD patients who chronically retain CO2, the central receptors "reset" to high PCO2 and the hypoxic drive becomes the primary stimulus - giving supplemental O2 can dangerously suppress respiration

pH

• Unrelated to CO2 changes: metabolic acidosis (e.g., diabetic ketoacidosis) lowers blood pH -> stimulates peripheral chemoreceptors -> increases ventilation (Kussmaul breathing)
• Effect is mainly via peripheral chemoreceptors (H+ crosses BBB slowly)

V. COMPOSITE / INTERACTIVE EFFECTS

• Low O2 + high CO2 produce greater ventilation than either alone
• At lower pH (7.3 vs 7.4), ventilation curves for PCO2 shift to the left (more ventilation for any given PCO2)
• Acclimatization to altitude: over 2-3 days, central chemoreceptors lose ~80% sensitivity to CO2 (CSF pH normalizes via bicarbonate secretion), allowing low PO2 to drive ventilation up 400-500% (vs only 70% acutely)

VI. OTHER REFLEX CONTROLS

VII. REGULATION DURING EXERCISE

• Primary stimulus is neural: motor cortex sends collateral signals to respiratory center simultaneously with movement commands (neurogenic drive)
• Proprioceptors in limbs provide early stimulation
• The slight rise in CO2/H+ and fall in O2 that do occur amplify the response further
• Epinephrine and body temperature also stimulate breathing

VIII. VOLUNTARY AND HIGHER CENTER CONTROL

• Cerebral cortex: Can override automatic control (voluntary breath-holding, hyperventilation); essential for speech, singing, coughing, Valsalva maneuver
• Hypothalamus: Adjusts respiration during emotion (fear, pain - increases rate) and temperature regulation (panting)
• Limbic system: Emotional modulation of breathing patterns
• Voluntary control is limited by chemical stimuli: breath-holding ends when CO2/H+ reach threshold ("breaking point")

IX. APPLIED / CLINICAL CORRELATES

SUMMARY DIAGRAM (Conceptual)

Rising PCO2 / H+ ──► Central Chemoreceptors (medulla) ──┐
                                                          ├──► DRG/VRG ──► Phrenic/Intercostal nerves
Falling PO2 ────► Peripheral Chemoreceptors ─────────────┤             ──► Breathing ↑
                  (carotid/aortic bodies)                 │
Neural input ──► Motor cortex / Proprioceptors ──────────┘
(exercise)
             ▲
Pneumotaxic (pons) limits inspiration duration
Hering-Breuer reflex terminates inspiration

1. Pre-Botzinger complex = pacemaker for respiratory rhythm
2. Central chemoreceptors sense H+ (from CO2 crossing BBB), not O2
3. Peripheral chemoreceptors (mainly carotid bodies, CN IX) respond to low PO2 (<60 mmHg), high PCO2, low pH
4. CO2 is the most powerful chemical controller of breathing
5. Hering-Breuer is protective; proprioceptors drive early exercise hyperpnea
6. Voluntary override (cortex) possible but limited by chemical "breaking point"