Voluntary respiration, in contrast to automatic respiration, does not involve the respiratory control center in the medulla. Instead, the motor cortex initiates the neural activity for voluntary respiration, which then directly communicates with motor neurons in the spine through the corticospinal tracts. These motor neurons, responsible for the respiratory muscles, serve as the final integration site for both voluntary (corticospinal tract) and automatic (ventrolateral tracts) control of ventilation. During breath holding, there is initially a dominance of voluntary control over the spinal motor neurons. However, as the breath hold continues, automatic ventilatory control eventually supersedes voluntary effort, limiting the duration of the breath hold. Motor neurons also innervate the muscles of the upper airway, located near the respiratory control center in the medulla. Through the cranial nerves, they facilitate the dilation of the pharynx and large airways at the onset of inspiration.

Ventilation is regulated by the partial pressure of arterial carbon dioxide (PaCO2), along with PaO2 and arterial pH. Among these regulators, PaCO2 holds the greatest significance. To maintain PaCO2 close to 40 mm Hg, both the rate and depth of breathing are controlled. In a normal awake individual, ventilation linearly increases as PaCO2 reaches and exceeds 40 mm Hg. However, hyperventilation and certain drugs like morphine, barbiturates, and anesthetic agents can reduce the ventilatory drive or response to changes in PaCO2 by depressing the respiratory center. This decrease in ventilatory response to both CO2 and O2 occurs when the stimulus is insufficient to activate the motor neurons responsible for respiration. Additionally, the ventilatory response to changes in PaCO2 is diminished during sleep and can be further reduced in individuals with chronic obstructive pulmonary disease (COPD) due to increased work of breathing, which limits the effectiveness of the respiratory center's neural output in promoting ventilation.

Central and peripheral chemoreceptors detect changes in PaCO2 and transmit this information to the medullary respiratory centers. The respiratory control center then regulates minute ventilation to maintain PaCO2 within the normal range. With a normal PaO2, ventilation typically increases by approximately 3 L/minute for every 1 mm Hg rise in PaCO2. The response to an increase in PaCO2 is amplified when PaO2 is low, resulting in greater ventilation for any given PaCO2 and an enhanced increase in ventilation for a specific increment in PaCO2. The slope of the minute ventilation response to inspired CO2 is known as the ventilatory response to CO2 and serves as a test for CO2 sensitivity. It is important to note that low O2 further amplifies this relationship.
In contrast to automatic respiration, voluntary respiration bypasses the respiratory control center in the medulla. The neural activity controlling voluntary respiration originates in the motor cortex, and signaling passes directly to motor neurons in the spine through the corticospinal tracts. The motor neurons to the respiratory muscles act as the final site of integration of the voluntary (corticospinal tract) and automatic (ventrolateral tracts) control of ventilation. Voluntary control of these muscles competes with automatic influences at the level of the spinal motor neurons, and this competition can be demonstrated by breath holding. At the start of the breath hold, voluntary control dominates the spinal motor neurons. However, as the breath hold continues, the automatic ventilatory control eventually overpowers the voluntary effort and limits the duration of the breath hold. Motor neurons also innervate muscles 490 SECTION5Berne & Levy Physiology 15 10 5 0 25 35 45 55 65 PaCO2 (mm Hg) Alveolar ventilation (L/min) Metabolic acidosis Awake normal Sleep Morphine, barbiturates COPD Anesthetic agents •Fig. 25.1 Relationship between Partial Pressure of Arterial Carbon Dioxide (PaCO2) and Alveolar Ventilation in Awake Normal States, during Sleep, after Narcotic Ingestion and Deep Anesthesia, and in the Presence of Metabolic Acidosis. Boththeslopesoftheresponse(sensitivity)andthepositionoftheresponsecurves(threshold,thepointatwhichthecurvecrossesthex-axis[notshown])arechanged,whichindicatesdifferencesinventilatoryresponsesandresponsethresholds.COPD,chronicobstructivepulmonarydisease.
of the upper airway. These neurons are located within the medulla near the respiratory control center. They innervate muscles in the upper airways through the cranial nerves. When activated, they dilate the pharynx and large airways at the initiation of inspiration.
Response to Carbon Dioxide
Ventilation is regulated by PaCO2, PaO2, and pH in arterial blood. PaCO2 is the most important of these regulators. Both the rate and depth of breathing are controlled to maintain PaCO2 close to 40 mm Hg. In a normal awake individual, there is a linear rise in ventilation as PaCO2 reaches and exceeds 40 mm
Hg (Fig. 25.1 ). The ventilatory drive or response to changes in PaCO2 can be reduced by hyperventilation and by drugs that depress the respiratory center and decrease the ventilatory response to both CO2 and O2, such as morphine, barbiturates, and anesthetic agents. In these instances, the stimulus is inadequate to stimulate the motor neurons that innervate the muscles of respiration. It is also depressed during sleep. In addition, the ventilatory response to changes in PaCO2 is reduced if the work of breathing is increased, which can occur in individuals with chronic obstructive pulmonary disease (COPD). This effect occurs primarily because the neural output of the respiratory center is less effective in promoting ventilation as a result of the mechanical limitation to ventilation.
Changes in PaCO2 are sensed by central and peripheral chemoreceptors, and they transmit this information to the medullary respiratory centers. The respiratory control center then regulates minute ventilation and thereby maintains PaCO2 within the normal range. In the presence of a normal PaO2, ventilation increases by approximately 3 L/minute for each 1 mm Hg rise in PaCO2. The response to an increase in PaCO2 is further increased when the PaO2 is low (
Fig. 25.2, ). With a low PaO2, ventilation is greater for any given PaCO2, and the increase in ventilation for a given increment in PaCO2 is enhanced. The slope of the minute ventilation response as a function of the inspired CO2 is termed the ventilatory response to CO2 and is a test of CO2 sensitivity. It is important to recognize that this relationship is amplified by low O2 (see