In one breath
Breathing has two controllers: the cerebral cortex for voluntary breathing and the brainstem for automatic breathing. The medulla makes the basic rhythm, through a pacemaker network in the pre-Bötzinger complex (the central pattern generator) that sits among the dorsal and ventral respiratory groups and drives the phrenic and intercostal motor neurons. The pons only tunes that rhythm: the apneustic center prolongs inspiration, while the pneumotaxic center and vagal stretch input cut it short. Cutting the brainstem at different levels shows which center does what.
Leads to: Chemical control of breathing · Non-chemical control: reflexes and sleep · Abnormal breathing patterns
General concepts
- Breathing is unusual among body functions: it runs automatically, yet you can also control it at will.
- Automatic breathing comes from rhythmic firing of the motor neurons that drive the respiratory muscles. Their cyclic contraction changes the volume of the thorax, and air follows.
- That firing is set by the brain, chiefly the brainstem. So a cut through the cord where it leaves the brain (the medullary–spinal junction) stops breathing altogether.
- The centers are adjusted by the blood’s chemistry (PO₂, PCO₂ and pH) and by nonchemical inputs such as impulses from proprioceptors.
- J.S. Haldane (1860–1936), working with Priestley, showed in a 1905 paper that the trigger for breathing is too much CO₂ in the blood, not too little O₂. The Haldane effect carries his name, and he is called the “Father of Oxygen Therapy”.
Overview of the control loop
- Neurons in the medulla produce the motor signals for the cranial and spinal motor neurons of the breathing muscles. The rhythm-making area is the central pattern generator (CPG).
- In quiet breathing, inspiration is active: the inspiratory muscles, above all the diaphragm, contract. When their excitation stops, expiration follows passively: the stretched lungs and chest wall simply spring back.
- When the body needs more air, as in exercise, the expiratory muscles join in and expiration turns active.
- Medullary output changes the activity of the chest wall, the diaphragm and the conducting airways.
- The ventilation that results alters blood PO₂, PCO₂ and pH. Peripheral and central chemoreceptors feed this back to the CPG and the other pontomedullary centers.
- More feedback arrives through the vagus, the spinal nerves and proprioceptive pathways, and the centers adjust their output to what the body needs.
| Kind of control | Works through | Read it in |
|---|---|---|
| Neural | brainstem centers; cortex for voluntary breathing | this page |
| Chemical | peripheral and central chemoreceptors | Chemical control of breathing |
| Nonchemical | reflexes from lungs, airways, chest wall | Non-chemical control: reflexes and sleep |
Neural control: voluntary and automatic
- Voluntary control: centers in the cerebral cortex, acting on the respiratory muscles through the corticospinal tract.
- Automatic control: centers in the brainstem.
- Brainstem neurons converge on the spinal motor neurons:
| Phase | Spinal motor neurons | Muscles |
|---|---|---|
| Inspiration | C3–C5 (phrenic) and thoracic | diaphragm, external intercostals |
| Expiration | mainly thoracic | internal intercostals |
Medullary respiratory centers
The medulla sets the basic rhythm. It holds two neuron groups named for their position, the dorsal and ventral respiratory groups, and the CPG lies in and around them.
Dorsal respiratory group (DRG)
- Site: both sides of the dorsal medulla, in and around the nucleus tractus solitarius (NTS).
- Neurons: mostly inspiratory.
- Inputs: the NTS receives sensory input from all the thoracic and abdominal viscera. The DRG gets input from the respiratory system, including the peripheral chemoreceptors, through cranial nerves IX and X.
- Job: mainly inspiration, and integrating the sensory information that comes from the respiratory system.
- Output: projects straight to the cell bodies of the phrenic motor neurons in the spinal cord.
Ventral respiratory group (VRG)
- Site: ventrolateral medulla, around the nucleus ambiguus (its retroambiguus and para-ambiguus parts) and the nucleus retrofacialis.
- A bigger column than the DRG, running almost the full length of the medulla, with both inspiratory and expiratory neurons.
- The retrofacialis and retroambiguus fire in expiration; the para-ambiguus fires in inspiration.
| VRG region | Fires in | Drives |
|---|---|---|
| Rostral (Bötzinger complex) | expiration | the caudal region |
| Middle | inspiration | inspiratory muscles; pharynx and larynx muscles |
| Caudal | expiration | motor neurons of expiratory muscles |
- Because the middle region also drives the pharyngeal and laryngeal muscles, it widens the upper airway during inspiration as well as powering it.
- The DRG and VRG of each side run the breathing apparatus of that side. Cross-connections keep the two sides in step, so both halves of the chest move together and symmetrically.
- Worth knowing, though not in your pages: the three regions match the nuclei above: the Bötzinger complex lies in the retrofacialis, the middle region in the para-ambiguus and the caudal region in the retroambiguus.
Central pattern generator (CPG)
- It seems to sit in the pre-Bötzinger complex: pacemaker cells on each side, between the nucleus ambiguus and the lateral reticular nucleus.
- How it works is not fully known, but it is widely accepted as the source of the normal respiratory rhythm. Its pacemaker cells fire rhythmically and switch on the phrenic motor neurons.
- The evidence: destroying the pre-Bötzinger complex, or cutting between it and the phrenic motor neurons, abolishes the rhythmic inspiratory firing of those motor neurons.
- An integrator in the medullary reticular formation shapes the CPG. It gathers input from chemoreceptors, cortex, hypothalamus and limbic system, and sets mainly the rate and depth (frequency and amplitude) of breathing.
Bötzinger or pre-Bötzinger?
The Bötzinger complex is the rostral, expiratory part of the VRG. The pre-Bötzinger complex is the pacemaker: the CPG. Mixing the two up is a common viva slip.
Pontine respiratory centers
The pons has two centers, pneumotaxic and apneustic. They modulate the medulla’s output, but the medulla does not need them to produce a normal rhythm.
Pneumotaxic center
- Site: upper (rostral) pons, in the nucleus parabrachialis medialis and the Kölliker–Fuse nucleus.
- Its neurons are active in both inspiration and expiration.
- Its exact role is not settled, but it coordinates the cycle by switching between inspiration and expiration.
- It normally inhibits the apneustic center.
- In animals, a lesion above the pons leaves the rhythm unchanged, so centers higher up add little to the basic rhythm.
Apneustic center
- Site: lower (caudal) pons.
- Stimulating it gives apneusis: long, held inspiratory efforts broken only by brief expirations. So it strongly excites the medullary inspiratory center.
- The pneumotaxic center inhibits it tonically, which keeps its inspiratory drive in check.
Role of the vagus nerve
The vagus carries afferents from the lungs and airways. As the lung stretches during inspiration, these fibers fire faster.
- Their impulses inhibit the medullary inspiratory neurons. So stimulating the vagus inhibits breathing, and cutting it (vagotomy) makes each inspiration bigger.
- Removing vagal feedback lengthens the phrenic nerve’s firing without making it any stronger.
- The vagus and the pneumotaxic center together hold the apneustic center in check. Since the apneustic center drives inspiration, vagotomy releases inspiration.
- Vagotomy after a lesion of the pneumotaxic center produces apneusis.
- Henry Head (1861–1940) showed the vagus’s part in regulating breathing (1889). He also studied referred pain and aphasia.
- Worth knowing, though not in your pages: cutting both vagi with the brainstem intact makes breathing slower and deeper.
"Bigger breaths" but "no stronger phrenic firing"?
Both are true. Without vagal feedback the phrenic nerve fires for longer, not harder. Each inspiration lasts longer, so more air goes in.
Control by higher centers
- Higher control is more complex than the rhythm itself. Many areas act on the medullary centers; the reticular activating system (RAS) and the limbic system matter most.
- The RAS gives the CPG a tonic drive, which rises when you wake from sleep.
- The limbic drive rises during emotion.
Integration of the neural mechanisms
What brainstem cuts show
- A cut below the medulla stops breathing. After a lesion above the medulla breathing goes on, though irregularly. So the rhythm generator is in the medulla.
- A lesion above the pons leaves breathing unchanged, so the controlling centers lie in the pons and medulla.
| Cut | Breathing | What it shows |
|---|---|---|
| S1: below medulla | stops | rhythm is made at or above the medulla |
| S2: below pons | rhythmic but irregular | medulla makes the rhythm; higher centers refine it |
| S3: upper pons | deeper breaths | pneumotaxic center normally restrains the apneustic |
| S3 + both vagi cut | apneusis | the vagus also restrains the apneustic |
| S4: above pons | normal | centers lie in pons and medulla |
| S4 + both vagi cut | deeper breaths | vagal input normally limits inspiration |
S2 lies just below the apneustic center; S3 lies just below the pneumotaxic center.
A slip in your book's figure caption
For the last row, the caption says the vagus inhibits the pneumotaxic center’s output. That cannot explain the result: if it were so, cutting the vagi would free the pneumotaxic center and make breaths shallower, not deeper. The reading that fits the rest of the chapter is that the vagus and the pneumotaxic center both hold inspiration back.
Inspiration
- Normal breathing is stereotyped, with two phases. The pre-Bötzinger pacemakers fire and drive the phrenic motor neurons, which start each inspiration.
- Phrenic activity climbs steadily over about 2 seconds, then stops abruptly as expiration begins.
- Two kinds of inspiratory neuron:
- constant neurons fire steadily all through inspiration;
- ramp neurons fire in a rising ramp that tracks phrenic activity, so lung volume rises smoothly.
- The phrenic nerve is silent through expiration, apart from a short burst at its very start.
- There are expiratory ramp neurons too, which fire during expiration.
Expiration
- Early phase: some inspiratory muscle activity carries on (or restarts) and keeps the first part of the outflow in check. It fades as lung volume falls.
- Late phase: inspiratory activity stops completely. Air leaves by passive recoil in quiet breathing, or by expiratory muscle contraction in forced breathing.
- What sets its length: how strongly the DRG–VRG inspiratory neurons are inhibited. The inhibition is strongest as expiration begins and then wanes; when it can no longer hold them, the next inspiration starts. Several factors shape how fast it wanes.
- Its length also depends on nerve signals arriving during expiration and on the pattern of the breath before.
Control mechanisms of breathing
- The CPG makes the basic pattern, and many control mechanisms act on it.
- A proposed integrator (controller), also in the medulla, projects to the CPG. Its inputs come from the cortex and limbic system, proprioceptors, receptors inside the lungs, and blood gases.
- In exercise:
- cortical input makes the pattern generator drive the working muscles in step with the effort;
- the generator senses the CO₂ load in the blood and sets ventilation to match;
- receptors in the lungs, and proprioceptors in the moving joints, add feedback.
- The controller also picks the rate and depth that deliver the needed ventilation for the least work. For this it uses mechanoreceptor signals from the lungs and chest wall on lung volume, how fast it is changing, and transpulmonary pressure.
- Upper airway: the same generator drives the muscles of the nose, pharynx and larynx. Their contraction in inspiration widens the airway and lowers resistance from the nostrils to the larynx.
| Breathing | Vocal cords in expiration | Effect |
|---|---|---|
| Quiet | actively adducted early on | expiratory braking |
| Exercise hyperpnea | kept apart throughout | lower resistance, easier outflow |
Draw it: brainstem centers and the four cuts
Draw a side view of the brainstem: midbrain on top, then pons, medulla and spinal cord. Write “pneumotaxic” in the upper pons, “apneustic” in the lower pons, and “DRG, VRG, pre-Bötzinger (CPG)” in the medulla. Draw an arrow from the apneustic center to the medullary inspiratory neurons marked (+), one from the pneumotaxic to the apneustic center marked (−), and vagal afferents from the lung entering the medulla marked (−). Draw S4 above the pons, S3 between the two pontine centers, S2 between pons and medulla and S1 below the medulla. Beside each line sketch the breathing trace: normal, deeper, irregular, flat. Add apneusis beside S3 for the vagi cut.
Exam-answer skeleton: "Describe the neural regulation of respiration" (long essay)
- Two systems: voluntary (cortex, corticospinal tract) and automatic (brainstem); the final paths to the phrenic and intercostal motor neurons.
- Medullary centers: DRG (NTS, inspiratory, inputs via IX and X, output to phrenic) and VRG (nucleus ambiguus and retrofacialis, three regions, upper-airway role).
- The CPG in the pre-Bötzinger complex, and the integrator that sets rate and depth.
- Pontine centers: pneumotaxic and apneustic, their sites and how they interact (diagram).
- Role of the vagus: stretch afferents inhibit inspiration; the effects of vagotomy.
- Brainstem cuts at S1–S4, with and without vagotomy (diagram and table).
- Higher centers: RAS, limbic system, cortex.
- The breathing cycle: ramp neurons, the two phases of expiration and the controller; close with a line on chemical and reflex control.
Asked in exams
- Respiratory centres and the neural control of breathing: Nov 2012, 10 marks · Nov 2017, 10 marks · Oct/Nov 2018, 4 marks · Jan/Feb 2022, MCQ · May 2022, 5 marks · Dec 2023, MCQ · Mar 2024, MCQ · Aug 2024, MCQ · Oct 2024, 5 marks