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Breathing and the Nervous System
Respiration involves pulmonary ventilation, gaseous exchange between lung alveoli and blood, and transport of oxygen and carbon dioxide between the blood, tissues, and interstitial fluids. The nervous system plays a pivotal role in controlling pulmonary ventilation as it exerts both automatic and voluntary control over breathing. The anatomic pathways involve the cerebral hemispheres, pons, medulla, spinal cord, anterior horn cells, nerves, and neuromuscular junctions, as well as peripheral chemoreceptors and lung mechanoreceptors and the respiratory muscles themselves. Several central and peripheral neurologic disorders can affect respiration adversely, and hypoxia and hypercapnia resulting from respiratory dysfunction may affect the nervous system and produce neurologic complications.
Physiology of Breathing
Breathing is a predominantly involuntary, rhythmic phenomenon that can be overridden by voluntary control. Although the pathways for automatic and voluntary breathing are anatomically separate, they demonstrate significant functional integration ( Fig. 1-1 ).
Respiratory Rhythm Pattern Generators
The respiratory rhythm originates in the medulla and neuronal activity in the brainstem can be divided into inspiratory, postinspiratory, and preinspiratory (or late expiratory) neural activities. Two main groups of neurons in the medulla are implicated in the regulation of respiration, namely the dorsal respiratory group (DRG) and the ventral respiratory group (VRG). The DRG is thought to be activated prior to inspiration, and the VRG is considered to modulate expiration. N -methyl- d -aspartate (NMDA) receptors are the major mediators of VRG ventilatory drive, with modulation by non-NMDA glutamate systems. In addition, recent studies have identified several other respiratory pattern generators (RPGs) in the medulla. Among these, the pre-Bötzinger complex is considered to be the primary RPG that provides the inspiratory rhythm, and the retrotrapezoid nucleus and parafacial respiratory group, which contain chemosensitive neurons, are thought to provide rhythmic expiratory drive by producing tonic excitation to the pre-Bötzinger and Bötzinger complexes. In addition, located rostrally in the pons, the pneumotaxic center, comprised of the Kölliker-Fuse and parabrachial nuclei, are suggested to be the relay nuclei for reflex and higher-order control of breathing. The Kölliker-Fuse nuclei are also crucial for transition from inspiration to expiration and for modulation of airway patency during breathing. Overall, respiratory rhythm generation is controlled by multiple factors including noradrenergic, serotonergic, peptidergic, and cholinergic neurons.
Control of Breathing
The control of breathing occurs at multiple levels of the respiratory system through a negative feedback system that ensures precise control of arterial PO 2 , PCO 2 , and pH. This homeostasis is maintained by an integration of chemical, metabolic, and mechanical inputs and adjusting the ventilatory output to meet the metabolic demands ( Fig. 1-1 ).
Chemical Control of Breathing
Peripheral and central chemoreceptors monitor afferent inputs (arterial PO 2 and PCO 2 ). The central chemoreceptors modulate respiration based on changes in CO 2 /pH detected in the brain, whereas the peripheral chemoreceptors, which act faster, sense changes in the periphery.
Central chemoreceptor sites are responsible for approximately two-thirds of the ventilatory response to CO 2 /pH. Eight major central chemoreceptor sites have been reported and these are distributed throughout the lower brainstem. Peripheral chemoreceptors are located in the carotid body, bifurcation of the carotid artery, and the arch of the aorta. The carotid bodies are the major chemoreceptor sites for hypoxia and are very sensitive to changes in partial pressure of arterial oxygen (PaO 2 ), arterial carbon dioxide (PaCO 2 ), and H + . Peripheral and central chemoreceptors are anatomically linked, and this interdependence determines the normal respiratory drive in eupneic and hypoxic conditions. Carotid bodies have been shown to exert a tonic drive on the output of central chemoreceptors, and the magnitude of sensory input from the carotid chemoreceptor is known to influence the central chemoreceptor response.
Mechanical Inputs from Airways, Lungs, and Chest Wall
Inputs from the chest wall and respiratory muscles predominantly affect the pattern of breathing and are most evident when there is an increased ventilatory demand. Respiratory muscles play a significant role in respiration by aiding in the expansion and contraction of the thoracic cavity. The main inspiratory muscles include the diaphragm, external intercostal and scalene muscles, with accessory inspiratory muscles being the sternocleidomastoid, pectoralis major and minor, serratus anterior, latissimus dorsi, and serratus posterior superior. The expiratory muscles are the internal intercostals, external oblique, internal oblique, rectus abdominis, transverse abdominis, and serratus posterior inferior. Muscles of the upper airway do not have a direct action on the chest cage or intrathoracic volume, but are crucial to keep the airway open during inspiration, regulate airway resistance, and partition airflow through nasal and oral pathways. These are muscles of the soft palate, pharynx, larynx, trachea, nose, and mouth, and are innervated by cranial nerves V, VII, IX, X, and XII. At the level of airways, the Hering–Breuer reflex, which is elicited by inflation of slow-adapting pulmonary stretch receptors, causes inhibition of inspiratory effort following stretching of the airway. In addition, the laryngeal chemoreflex, which produces reflexive central apnea, bradycardia, and glottis closure on exposure of the laryngeal mucosa to acidic or organic stimuli, plays a protective role. However, this reflex has been considered to play a role in the pathogenesis of sudden infant death syndrome.
Voluntary Control of Breathing
Voluntary control of breathing is mediated by the descending corticospinal tract and its influence on the motor neurons innervating the diaphragm and intercostal muscles. The rate and rhythm of breathing are influenced by the forebrain, as observed during voluntary hyperventilation or breath-holding, as well as during the semivoluntary or involuntary rhythmic alterations in ventilatory pattern that are required during speech, singing, laughing, and crying.
Electrophysiologic and imaging studies have shown that specific areas of cortex are involved in different phases of voluntary breathing. The diaphragm can be activated by stimulation of the contralateral motor cortex using transcranial magnetic stimulation. The diaphragm lacks significant bilateral cortical representation, consistent with the finding of attenuation of diaphragmatic excursion only on the hemiplegic side in patients with hemispheric stroke, and intercostal muscles are similarly affected by hemispheric lesions. Positron emission tomographic studies have shown an increase in cerebral blood flow in the primary motor cortex bilaterally, the right supplementary motor cortex, and the ventrolateral thalamus during inspiration; and the same structures, along with the cerebellum, are involved in expiration.
The involvement of the forebrain in the regulation of breathing is further substantiated by the induction of apnea that follows stimulation of the anterior portion of the hippocampal gyrus, the ventral and medial surfaces of the temporal lobe, and the anterior portion of the insula.
Factors Influencing the Control of Breathing
Several factors including but not limited to sleep, cerebrovascular responsiveness, age, sex, and genetic factors influence the control of breathing.
Sleep
During sleep, owing to the loss of wakefulness stimuli, breathing is entirely dependent on stimuli from chemoreceptors and mechanoreceptors. Transient central apnea and breathing instability can frequently occur during the transition from wakefulness to sleep. During nonrapid eye movement (NREM) sleep, loss of the wakefulness drive to breathe renders respiration highly dependent on metabolic and chemical influences, particularly PaCO 2 . During REM sleep, respiratory control is insensitive to changes in PaCO 2 , and is predominantly under behavioral control. Owing to this, central sleep apnea (CSA) is relatively uncommon in REM compared to NREM sleep. Due to the increased ventilatory motor output and reduced chemosensitivity, the hypercapnic and hypoxic ventilatory drive are blunted in REM sleep.
Cerebrovascular Responsiveness
Cerebrovascular responsiveness to CO 2 is a crucial determinant of hypercapnic ventilatory response and eupneic ventilation. A reduction in cerebral blood flow results in accumulation of CO 2 which stimulates the medulla, whereas an increase in blood flow depresses ventilation owing to a rapid removal of CO 2 . Hence, alteration in blood flow lead to variations in cerebrovascular responsiveness to CO 2 which may contribute to respiratory abnormalities.
Age
Older adults are more prone to sleep apnea because cerebral blood flow regulation and cerebrovascular responsiveness are reduced in them, and sleep state oscillations may precipitate apnea. Transient instability in breathing and central apnea may often occur during transitions from wakefulness to NREM sleep. As sleep oscillates between the above-mentioned states, PaCO 2 is at or below the apneic threshold, that is, the level required to maintain rhythmic ventilation during sleep, and this results in central apnea. Recovery from this is associated with transient hyperventilation and wakefulness.
Sex
Experimental evidence has suggested a role of sex hormones in alteration of the hypocapnic apneic threshold during sleep, and women have been reported to be less susceptible than men to develop hypocapnic central apnea during NREM sleep.
Genetic Factors
A significant number of transcription factors are known to play a role in the control of breathing. The most clinically relevant is the PHOX2B , which is involved in the development of the retrotrapezoid nucleus, and mutations of this gene have been documented to produce congenital central hypoventilation syndrome.
Evaluation of Pulmonary Function
A detailed discussion of the evaluation of pulmonary function is beyond the scope of this chapter. The following is a summary of an approach to evaluating patients with impaired breathing in the setting of neurologic illness. The onset, distribution, character, and accompaniments of weakness may suggest the underlying cause. History obtained from a bed-partner or caregiver is important in determining the presence of sleep-disordered breathing.
Clinical Assessment
A detailed clinical history should be obtained and importance paid to any history of breathing or cardiac problems. The time of onset and temporal relationship to neurologic symptoms should be ascertained. Furthermore, the presence of any illness (such as infections) that may have preceded the onset of muscle weakness (e.g., in Guillain–Barré syndrome) should be recorded.
The respiratory and cardiac systems are examined to determine the respiratory rate and volume, pattern of breathing, heart rate, blood pressure, temperature, and presence of cyanosis. Bedside assessments should also include a single-breath counting exercise, observation of chest expansion, and testing of cough strength. Diaphragmatic weakness may give rise to paradoxical inward movement of the abdomen during inspiration. The presence of hypophonia, nasal intonation, dysarthria, dysphagia, and pooling of secretions suggest bulbar dysfunction. Auscultation of the chest may reveal features of bronchoconstriction, pulmonary congestion, or consolidation.
Tests of Pulmonary Function
Pulmonary Function Tests
Pulmonary function tests can be used to provide quantitative information about pulmonary function. Bedside spirometry is useful to assess pulmonary function, especially in neuromuscular disorders. Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and maximal inspiratory force (MIF) should be measured. In neuromuscular disorders, a “restrictive” pattern of respiratory dysfunction is seen, evidenced by a normal or sometimes higher ratio of FEV1 to FVC. MIF is an indicator of the strength of the respiratory muscles.
Arterial Blood Gas Studies
Arterial blood gas analysis (pH, PaCO 2 , PaO 2 ) is required for patients with impending respiratory failure to determine the need for ventilatory support. Overnight pulse oximetry is useful in patients with sleep-related breathing problems.
Imaging
Imaging plays a major role in the assessment of pulmonary function and diseases. Although a wide range of imaging techniques are available, computed tomography (CT) is still the mainstay of imaging as it allows high-resolution and quick assessment of the lung parenchyma and its surrounding structures. A CT scan of the thorax may sometimes be useful to detect small pleural effusions as well as mediastinal masses and lymphadenopathy. Functional imaging of the diaphragm using fluoroscopy or ultrasound is undertaken to evaluate diaphragmatic dysfunction, specifically diaphragmatic weakness secondary to phrenic nerve palsy.
Polysomnography
Polysomnography is useful to study abnormalities of breathing during different stages of sleep. Breathing is monitored by recording the airflow at the nose and mouth using thermal sensors and a nasal pressure transducer, effort is recorded using inductance plethysmography, and oxygen saturation is also measured. The breathing pattern is analyzed for the presence of apneas and hypopneas.
Patterns of Respiratory Dysfunction
Disorders of the peripheral and central nervous system (CNS) may result in respiratory insufficiency through different mechanisms. The pattern of respiratory dysfunction primarily depends on the site of the lesion rather than the underlying etiology, whereas prognosis depends on both factors. Weakness of respiratory muscles may result in a restrictive pattern of ventilatory insufficiency. Oropharyngeal and laryngeal weakness can result in an obstructive pattern, especially during sleep. Patients with neuromuscular diseases and bulbar involvement are at risk of recurrent aspiration pneumonia and acute upper airway obstruction.
Central Nervous System Lesions
As discussed in an earlier section, the neurons responsible for generation of respiratory rhythm are located in the medulla, and their output to respiratory muscles through the reticulospinal tract is modulated by chemical and neural afferents. Specific breathing patterns have been reported in neurologic diseases based on the site of lesion.
Cheyne–Stokes Breathing
Cheyne–Stokes breathing is characterized by a cyclical escalation of hyperventilation followed by decremental hypoventilation and finally apnea ( Fig. 1-2 ). In humans, cycle lengths from 40 to 100 seconds may occur. During Cheyne–Stokes breathing, analysis of arterial blood gases shows cyclical variations. In the hyperventilation stage, there is a decrease in PaO 2 and pH and an increase in PaCO 2 , which is followed by an increase in PaO 2 and pH, and a declining PaCO 2 during the decremental hypoventilation phase. This pattern may be observed with bilateral cortical or diencephalic dysfunction caused by either structural damage or metabolic problems. It can also occur in patients with cardiac failure and in most normal individuals while sleeping at high altitudes.
Hyperpnea
Hyperpnea or hyperventilation with regular deep breaths is indicative of a CNS lesion in rare instances. It is more often observed in patients with underlying medical conditions including sepsis and liver failure.
Apneustic Breathing
This is a pattern characterized by prominent, prolonged end-inspiratory pauses ( Fig. 1-2 ) and is observed in lesions of rostral pons that involve the pneumotaxic center, that is, the Kölliker-Fuse–parabrachial complex.
Ataxic Breathing
Ataxic or irregular breathing is a pattern of breaths that are irregular in duration, frequency, and depth ( Fig. 1-2 ). This pattern is usually observed with lesions of the pontomedullary junction and frequently heralds the onset of respiratory failure.
Disorders of Involuntary Respiratory Control
Congenital Central Hypoventilation Syndrome
Congenital central hypoventilation (Ondine curse) is a rare disorder characterized by intact volitional breathing with the inability to maintain respiration during sleep. Patients experience apnea or hypopnea during sleep, most often during NREM sleep. Mutations of the PHOX2B gene have been implicated in this autosomal dominant disease.
Acquired Central Hypoventilation
A phenomenology similar to congenital central hypoventilation syndrome has been described in bilateral or unilateral medullary infarction, bulbar poliomyelitis, neurodegenerative disorders such as multiple system atrophy (MSA), syringobulbia, paraneoplastic brainstem syndromes, and idiopathic sleep apnea. Iatrogenic injury has been reported following bilateral cervical tractotomy performed for intractable pain, presumably as a result of damage to the descending reticulospinal tracts which activate phrenic motor neurons and the ascending spinoreticular fibers that carry afferent information to brainstem centers.
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