17.1: Central Control Mechanisms

Introduction

Although control of breathing is fundamentally reflexive to maintain blood gases and pH, there are underlying complexities that, despite decades of research, are still not clear. At the foundation of ventilatory control is an underlying respiratory rhythm that can be modulated by chemoreflexes to maintain blood homeostasis, overridden by emotion or other higher brain functions, be ignored while we finish speaking a sentence (but for only so long), or be trusted to control breathing throughout the night as the rest of the brain sleeps.

In this chapter we will have a look at the regions of the nervous system that control breathing and how they interact or override each other.

The Role of the Brainstem

It has long been known that the brainstem contains critical centers for the control of breathing. These regions produce what is often referred to as the reflex drive to breathe, or brainstem drive to breathe. Despite its critical nature for survival, this involuntary motor drive that operates the respiratory muscles is barely understood.

What we will do here is summarize some basic information to create a coherent and accurate overview.

The reflex drive to breathe is a typical reflex arch, with receptors in the vasculature and lung reporting to a central controller in the brainstem that implements its effects via the respiratory muscles. What is different from most simple reflexes is that the controller is rather complex and can be thought of as a central hub that integrates inputs from multiple sources.

Many visceral sensors supplying the controller in the brainstem send their afferent signals via the glossopharyngeal and vagus nerves to the nucleus tractus solitaries, or NTS. This input station is part of an anatomically indistinct region on the dorsal surface of the medulla, called the dorsal respiratory group or DRG. The DRG connects to motor neurons that lead to the inspiratory muscles.

These DRG (figure 17.1) neurons show ramp-like bursts of activity that cause inspiratory muscle contraction to induce inspiration, then stop, allowing the inspiratory muscles to relax and passive exhalation to begin. This intermittent ramp of activity can be modulated by input from the sensors or other regions of the central nervous system, but it is not spontaneous; rather this activity is initiated by another respiratory pacemaker. It was this pacemaker that eluded physiologists for decades.

On the other side of medulla is the ventral respiratory group (figure 17.1), which has been known for a long time to contain circuits that contribute to the control of breathing within its rostral, intermediate, and caudal regions. Within the intermediate region a cluster of neurons called the pre-Bötzinger complex (figure 17.1) with apparently spontaneous activity is currently thought to be the respiratory pacemaker. The pre-bötzinger complex is likely responsible for the activity of the DRG inspiratory neurons to produce the ramping activity.

The ventral respiratory group also contains neurons with inspiratory-related activity and connections to the inspiratory motor neurons. It is better known for its expiratory neurons, however, which are capable of activating the expiratory muscles when expiration must become active rather than remain passive. During quiet resting breathing, these expiratory neurons remain dormant.

This medullary circuitry can be influenced by other brainstem centers thought to be responsible for fine-tuning the breathing rhythm.

The Apneustic center in the lower pons (figure 17.1) excites the inspiratory neurons and prolongs the ramp activity they produce; this inevitably produces a prolonged inspiratory period. Higher up in the pons is the Pneumotaxic center (figure 17.1), which acts as an off switch for inspiratory neurons; thus it regulates inspiratory volume and indirectly influences the rate of breathing, tending to increase it. This is a very basic overview of the breathing circuitry that is capable of generating inspiration and active expiration when needed. But these centers take information and direction from other neural influences, including chemoreceptors, receptors in the lung, and higher brain centers. We will look at the latter two now.

Figure 17.1: Brainstem respiratory network.

Pulmonary and Higher Brain Influences

The brainstem drive to breathe can be modulated from above and from below. The literature about whether these influences increase or decrease the drive to breathe is often confused, perhaps because of the wide range of experiments performed and the different species used.

We will have a look at some of the most consistent and clinically pertinent aspects here, starting in the lung and three populations of intrapulmonary neural receptors.

Pulmonary stretch receptors are mechanoreceptors found in airway walls and smooth muscle. As their name suggests, they respond to expansion of the lung, and their afferent activity to the brainstem increases with lung volume, as figure 17.2 shows. Upon arrival at the NTS the PSR activity tends to inhibit inspiratory neurons and can stop inspiratory activity completely in other species (the Hering–Breuer reflex).

Figure 17.2: Lung volume and pulmonary stretch receptor firing. The top tracing represents lung volume with two full inflations followed by a sustained inflation. In response to the increases in lung volume, pulmonary stretch receptors depolarize, producing action potentials, which are shown in the lower trace as upward spikes. The increase in action potentials with increased lung volume is seen as more densely clustered spikes. Note how the sustained inflation causes an initial high frequency of action potentials that gradually falls as the receptor adapts to the high lung volume.

However, their influence on the control of breathing in humans is weak, and while they might not contribute to the control of breathing in man, they likely influence respiratory sensations, such as shortness of breath.

Irritant receptors are found in the airway epithelium and are ideally placed to perform their role of detecting harmful substances entering the lungs, such as noxious gases, particulates, and even cold air. They generally have an inhibitory influence on the drive to breathe, perhaps as an attempt to limit the amount of noxious substance entering the lung. Other components to their defensive strategies are bronchoconstriction and induction of the cough reflex. Their response to inflammatory mediators also suggests they may play a role in asthma.

J-receptors, or Juxtacapillary receptors, are found at the junction of the pulmonary capillaries and alveoli. These receptors respond to increases in interstitial pressure so are likely to play a role in the response to pulmonary edema. Their effect on the drive to breathe can be regarded as excitatory as they cause an increase in breathing rate as part of the J-reflex, which includes cardiac components and is intended to prevent over-exercising and cardiopulmonary collapse. As such the J-receptors may also contribute to generating the sensation of shortness of breath.

These three pulmonary receptor groups are the three that usually appear in textbooks, perhaps because of their clinical pertinence, but perhaps because we know most about these. Others exist, and details can be found in other sources. We will now focus briefly on the influence of higher centers on breathing, and these are generally all positive (i.e., cause an increase in breathing). Cortical influences are numerous and undefined, that collectively they produce what is referred to as the wakeful drive to breath. The extent of cortical influence is best illustrated by sleep, when the higher brain is unconscious and any wakeful drive is removed. During sleep breathing is significantly reduced—enough so that arterial PCO₂ is several mmHg higher than during wakefulness. This suggests that cortical influences on breathing are enough to cause a lower P_aCO₂ than would be determined by chemoreflexes alone.

More specific influences from higher centers include emotions; anger, anxiety, sadness, happiness, and sexual arousal all influence the drive and pattern of breathing. This is perhaps best exemplified by emotionally driven sighs or the frankly bizarre activity of laughter. But the list of higher center influences does not stop there; indeed it is likely that we still yet do not know where it stops. Changes in light changes breathing, a sudden loud sound changes breathing, doing a mathematical problem changes breathing… and so on. And unfortunately for clinicians and pulmonary physiologists, the act of measuring breathing changes breathing. So it is likely that all those textbook numbers for normal respiratory rate and depth are all too high, as telling someone you are going to measure their breathing usually causes them to hyperventilate.

Breathing is also a rare incidence of being able to voluntarily control a normally reflex activity (e.g., we can willfully override reflex breathing to perform speech or a breath-hold). In fact, we have as precise control over our respiratory muscles as we have control over the muscles in our hands. Humans maybe be exclusive in this respect because of our elaborate speech, but again, this is another unknown. However, eventually reflex breathing will always reclaim its command over breathing—as anyone who has performed a prolonged breath-hold will know.

Summary

So we have seen that at the heart of the control of breathing there is a pacemaker establishing a basic rhythm and depth of breathing, but this is influenced by numerous other factors from both the lung and higher brain. These influences adjust breathing via the brainstem to produce respiratory responses to the environment and changes in emotional state, and contribute to efficient and appropriate levels of ventilation.