46: The Modulatory Functions of the Brain Stem

• Ascending Monoaminergic and Cholinergic Projections from the Brain Stem Maintain Arousal

• Monoaminergic and Cholinergic Neurons Share Many Properties and Functions

  • Many Monoaminergic and Cholinergic Neurons Are Linked to the Sleep-Wake Cycle

  • Monoaminergic and Cholinergic Neurons Maintain Arousal by Modulating Neurons in the Thalamus and Cortex

• Monoamines Regulate Many Brain Functions Other Than Arousal

  • Cognitive Performance Is Optimized by Ascending Projections from Monoaminergic Neurons

  • Monoamines Are Involved in Autonomic Regulation and Breathing

  • Pain and Anti-nociceptive Pathways Are Modulated by Monoamines

  • Monoamines Facilitate Motor Activity

• An Overall View

• Postscript: Evaluation of the Comatose Patient

As we learned in the previous chapter, the brain stem can respond independently to the environment with stereotypic actions. We have also seen, in discussing the sensory and motor systems, that the brain stem is the conduit for all ascending and descending pathways between the forebrain, spinal cord, and peripheral nervous system. In this chapter we examine still a third role of the brain stem, as the modulatory center that orchestrates the activity of the rest of the central nervous system, ensuring that its activity is optimized.

This modulatory function is mediated by several small groups of neurons in the brain stem. These neurons project widely, using as neurotransmitters acetylcholine and the monoamines (norepinephrine, epinephrine, serotonin, dopamine, and histamine). Many of the monoaminergic groups modify pain and help regulate the autonomic nervous system to maintain internal homeostasis. Some are essential for controlling the level of behavioral arousal; and together they influence attention, mood, and memory. Because they are involved in the pathophysiology of many human diseases and are targets of many commonly used drugs, these monoaminergic and cholinergic neurons are also important for clinical care.

Behaviors we regard as uniquely human, such as memory, language, and compassion, depend heavily on modulation of forebrain function by the ascending cholinergic and monoaminergic systems. This dependence is seen clinically in the links between Alzheimer's disease and the acetylcholine system, schizophrenia and the dopaminergic system, and alleviation of depression with drugs that affect serotonergic and noradrenergic synapses. Thus, although the brain stem is phylogenetically primitive, the modulatory systems that project from this region enable and modulate many of the higher-order behaviors that we regard as most human.

Some neurons in the brain stem that project to the forebrain control wakefulness and sleep. In the mid-1930s Frederic Bremer found that transection of the cat's brain stem at the midbrain level produced a continuous sleep-like state, whereas transections that separated the medulla from the spinal cord did not (Figure 46–1). These experiments demonstrate that the portion of the brain stem from the midbrain to the medulla keeps the forebrain awake.

Consistent with this view, experiments in 1949 by Guiseppi Moruzzi and Horace Magoun found that damage to the brain stem reticular formation in cats led to loss of wakefulness. Conversely, stimulating the reticular formation immediately converted the electroencephalogram (EEG) of a sleeping cat to a waking EEG. Transection of the brain stem at the level of the midpons or lower did not cause loss of wakefulness, indicating that the critical structures that need to be connected to the forebrain for wakefulness are located in the rostral pons and caudal midbrain.

Moruzzi and Magoun proposed that this part of the brain stem provides a general activation energy for the entire brain and therefore called it the reticular activating system. Today this system is more accurately called the ascending arousal system, because we know it is not confined to the reticular formation. As we shall learn in Chapter 51, sleep and waking are regulated by interactions between this ascending arousal system and sleep-promoting regions in other parts of the brain. Damage to the ascending arousal system or its projections in the thalamus and hypothalamus leads to coma (Figure 46–1C, and see the postscript, "Evaluation of the Comatose Patient," at the end of this chapter).

The ascending arousal system was originally viewed as a heterogeneous collection of neurons distributed diffusely throughout the brain stem reticular formation, which had widespread projections. This view changed radically in the early 1960s when Nils-Åke Hillarp and his students in Sweden used histofluorescence to discover that the neurons in this brain stem system fall into chemically distinct groups based on their monoamine neurotransmitter content. In a brilliant series of histochemical experiments they defined the location and projections of these neurons based on differences in the fluorescence signals produced by the different monoamines: norepinephrine, dopamine, and serotonin (Figure 46–2).

These findings were later expanded in studies that used antibodies against the synthetic enzymes for the monoamine neurotransmitters (which also allowed visualization of histamine and epinephrine) and acetylcholine. The connectivity of these cell groups is remarkable. Whereas most nuclei in the central nervous system project to specific regions or to a limited set of nuclei, the monoaminergic and cholinergic neurons of the ascending arousal system have widespread projections, some to virtually every part of the central nervous system.

A major part of the ascending arousal system consists of monoaminergic and cholinergic neurons in the brain stem. These neurons are found primarily in four regions (Figure 46–3A):

1. The locus ceruleus, which contains noradrenergic neurons

2. The dorsal and median raphe nuclei, which contain primarily serotonergic, but also some dopaminergic neurons

3. The pedunculopontine and laterodorsal tegmental nuclei, which contain cholinergic neurons

4. The tuberomammillary nucleus, which contains histaminergic neurons

The monoaminergic pathways from the locus ceruleus, and dorsal and median raphe nuclei, are thought to regulate sleep and waking. Other neurons in the parabrachial nucleus in the rostral pons and caudal midbrain, which largely use glutamate as a neurotransmitter, are also thought to contribute to the regulation of wakefulness and sleep. In addition to these reticular neurons, neurons in the lateral hypothalamus that contain the peptide neurotransmitters orexin and melanin-concentrating hormone are important for sleep and waking. Finally, cholinergic and GABA-ergic (γ-aminobutyric acid) neurons in the basal forebrain contribute to arousal through diffuse cortical projections.

Stimulation of noradrenergic neurons in the locus ceruleus or histaminergic cells in the tuberomammillary nucleus causes increases in EEG arousal (Figure 46–3B), indicating that these systems play an important role in cortical and behavioral arousal. However, lesions restricted to one biogenic amine cell group do not cause profound loss of wakefulness, suggesting that the various cell groups probably have overlapping and at least partly redundant roles in sleep/wake regulation. As we will see, the monoaminergic pathways alter specific cellular properties of postsynaptic neurons in the thalamus and cerebral cortex, enhancing alertness and interaction with environmental stimuli.

At the junction of the midbrain and diencephalon the projections from the ascending arousal system split into two major branches, dorsal and ventral. The dorsal branch terminates in the thalamus. The ventral branch travels through the lateral hypothalamic area and is joined by ascending projections from the hypothalamus and the basal forebrain before terminating throughout the cerebral cortex. Lesions that disrupt either of these two branches impair consciousness.

Monoamines are biochemical compounds with an aromatic ring that are synthesized from aromatic amino acids. They include the catecholamines (epinephrine, norepinephrine, and dopamine), serotonin, and histamine. Neurons that use monamines as neurotransmitters share many cellular properties. For example, most continue to fire spontaneous action potentials in a highly regular pattern when isolated from their synaptic inputs in brain slice preparations. Their action potentials typically are followed by a slow membrane depolarization that leads to the next spike (Figure 46–4A).

The spontaneous regular firing pattern of monoaminergic neurons is regulated by intrinsic pacemaker currents. Tonic firing in vivo may be important for ensuring the continuous delivery of monoamines to targets. For example, the basal ganglia depend on continuous exposure to dopamine from the neurons of the substantia nigra to facilitate motor responses.

The properties of monoaminergic neurons are suited to their unique and widespread modulatory roles in brain function. Indeed, some axon terminals of monoaminergic cells do not even form conventional synaptic connections, instead releasing neurotransmitter diffusely to many targets at once (Figure 46–4B). Most monoamine neurotransmission occurs by means of metabotropic synaptic actions through G protein-coupled receptors. Many monoaminergic neurons co-release neuropeptides, which have slow effects through other G protein-coupled receptors. Thus, although some monoamine responses are mediated through fast synaptic mechanisms (see Chapter 10), many involve slower metabotropic and neuromodulatory actions as well (see Chapter 11).

Some cholinergic neurons in the brain stem share certain of these properties. For example, cholinergic neurons in the pedunculopontine and laterodorsal tegmental nuclei have widespread projections, providing the bulk of the cholinergic input to the thalamus, particularly to its relay and reticular nuclei. Many effects of cholinergic neurons also are mediated by G protein-coupled muscarinic receptors.

Many Monoaminergic and Cholinergic Neurons Are Linked to the Sleep-Wake Cycle

Most central neurons fire maximally during waking, decrease firing in a phase of sleep called slow-wave sleep, and then increase firing again during a phase of sleep called rapid eye movement (REM) sleep, the phase of the sleep cycle in which dreams are particularly likely to occur (see Chapter 51). Motor neurons are an exception; they have their lowest firing frequency during REM sleep because they are actively inhibited to prevent the acting out of dreams.

Noradrenergic, serotonergic, and histaminergic neurons are unlike most central neurons and more like motor neurons. They are maximally active during waking, their firing rates progressively decrease with increasing depth of non-REM sleep, and they stop almost completely during REM sleep (Figure 46–4A). Dopaminergic neurons within the dorsal raphe region also are most active during waking, but it has not yet been possible to distinguish their activity patterns during non-REM and REM sleep from those of the serotonergic neurons with which they intermingle.

In contrast to monoaminergic neurons, the firing rates of cholinergic neurons in the pedunculopontine and laterodorsal tegmental nuclei decrease during non-REM sleep but increase during REM sleep (Figure 46–4A). These and other properties indicate that the role of acetylcholine in controlling arousal is different from that of the monoamines.

The sleep-wake cycle has a strong circadian rhythm. The pacemaker for this rhythm is the suprachiasmatic nucleus in the hypothalamus (see Chapter 51). The suprachiasmatic nucleus regulates the circadian rhythm of sleep and waking primarily through connections with other hypothalamic areas, such as the dorsomedial nucleus. The dorsomedial nucleus in turn contacts both sleep- and wake-promoting cell groups in the hypothalamus and brain stem. As a result, the ascending arousal system entrains to the circadian rhythm (Figure 46–4A).

Monoaminergic and Cholinergic Neurons Maintain Arousal by Modulating Neurons in the Thalamus and Cortex

The monoaminergic and cholinergic neurons induce arousal by activating cortical neurons both directly and indirectly. They do this, in part, by modulating the activity of neurons in the hypothalamus, basal forebrain, and thalamus that activate the cerebral cortex.

Ionic mechanisms produce different modes of firing in thalamic neurons during sleep and wakefulness; during sleep the neurons fire in bursts, and during wakefulness they fire single spikes (see Chapter 51). Thalamic relay neurons exhibit activity in vitro that is similar to that seen in the intact brain during slow-wave sleep. When these neurons in brain slices are depolarized by injection of current, their firing pattern converts from burst mode to single-spike mode (like waking activity). Similarly, the firing pattern of thalamic and cortical neurons in brain slices changes from burst mode to single-spike mode when the cells are depolarized following application of acetylcholine, norepinephrine, serotonin and histamine (Figure 46–5A). Thus these neurotransmitters of the ascending arousal system regulate cortical activity in part by altering the firing of thalamic neurons.

Many pharmacological agents that target monoamines and acetylcholine influence arousal. For example, antihistamines cause drowsiness, serotonin reuptake blockers decrease the amount of REM sleep, and nicotine is a powerful stimulant. In addition, arousal is induced by amphetamines, cocaine, and other drugs that block dopamine reuptake; mice lacking the dopamine transporter are insensitive to such drugs.

Patients with Parkinson disease, who lose dopaminergic neurons in the substantia nigra, also lose noradrenergic neurons in the ascending arousal system and tend to be abnormally sleepy during the day. Some drugs used to treat Parkinson disease activate the D₂ dopamine receptor on presynaptic terminals of the remaining dopaminergic arousal neurons, which results in presynaptic inhibition, thus reducing dopamine release. As a result, although these drugs may make the movement disorder better (through their effects on postsynaptic D₂ receptors on neurons in the striatum), the inhibitory effect on remaining dopaminergic cells in the arousal system may exacerbate daytime sleepiness.

In addition to their well-defined role in regulating arousal, monoaminergic neurons also regulate cognitive performance during waking and affect a variety of other central nervous system functions. We illustrate these effects with four examples.

Cognitive Performance Is Optimized by Ascending Projections from Monoaminergic Neurons

Although the monoamines and acetylcholine each induce arousal, they have different effects on cognitive function during waking. This occurs in part because each of the monoamines, and acetylcholine, uses distinct intracellular signaling pathways that act on different complements of ion channels (Figure 46–5B). Thus, in addition to differences in regional distribution, each type of monoamine receptor has a unique cellular and subcellular distribution (Figure 46–6). Hence each part of the brain and each type of neuron is affected differently by monoamines and acetylcholine.

Neurons of the locus ceruleus, which release norep-inephrine, play an important role in attention. These neurons have a low baseline level of activity in drowsy monkeys. In alert monkeys the cells have two modes of activity that correspond to differences in behavior. In the phasic mode the baseline activity of the neurons is low to moderate. Just before the monkey responds to a stimulus to which it has been attentive, the cells are briefly excited. This pattern of activity correlates with and may facilitate selective attention. In contrast, in the tonic mode the baseline level of activity is elevated and does not change in response to external stimuli. This mode of firing may disrupt the ability to maintain attention on a single task and help to search for a new behavioral and attentional goal when the current task is no longer rewarding (Figure 46–7).

Monoaminergic inputs to the dorsolateral prefrontal cortex improve working memory (see Chapters 65 and 67). Microinjection of dopamine-receptor antagonists into the dorsolateral prefrontal cortex of monkeys markedly reduces the animals' ability to remember a location for several seconds. In functional magnetic resonance imaging (fMRI) studies of humans, D₁ agonist drugs increased activation of the dorsolateral prefrontal cortex during a memory task. Injection of agonists of the α₂-adrenergic receptor into the dorsolateral prefrontal cortex of aging monkeys can also improve performance on working memory tasks.

Dopamine also has been linked to reward-based learning. Rewards are objects or events for which an animal will work (see Chapter 49) and are useful in reinforcing behavior. Activity of dopaminergic neurons increases when a reward (such as food or juice) is unexpectedly given. But after animals are trained to expect that a reward will follow a conditioned stimulus, the activity of the neurons increases immediately after the conditioned stimulus rather than after the reward. This pattern of activity indicates that dopaminergic neurons provide a reward-prediction error signal, an important element in reinforcement learning. The importance of dopamine in learning is also supported by observations that lesions of dopaminergic systems prevent reward-based learning. The same dopaminergic pathways that are important for reward and learning are involved in addiction to many drugs of abuse (see Chapter 49)

Monoamines Are Involved in Autonomic Regulation and Breathing

Neurons in the adrenergic C1 group in the rostral ventrolateral medulla play a key role in maintaining resting vascular tone as well as adjusting vasomotor tone necessitated by various behaviors. For example, an upright posture disinhibits neurons in the rostral ventrolateral medulla that directly innervate the sympathetic preganglionic vasomotor neurons, thus increasing vasomotor tone to prevent a drop in blood pressure (the baroreceptor reflex). Neurons in the noradrenergic A5 group in the pons inhibit the sympathetic preganglionic neurons and play a role in depressor reflexes (eg, the fall in blood pressure in response to deep pain).

Serotonin regulates many different autonomic functions including gastrointestinal peristalsis, thermoregulation, cardiovascular control, and breathing. Electrical stimulation of serotonergic neurons within the medullary raphe nuclei increases heart rate and blood pressure. Serotonergic neurons in the medulla also project to neurons in the medulla and spinal cord that regulate breathing (Figure 46–8A), and stimulation of the medullary raphe nuclei increases respiratory motor output (see Chapter 45). Some serotonergic neurons in the medulla are central chemoreceptors (CO₂ sensors), firing faster in response to an increase in CO₂ and in turn stimulating breathing to restore arterial acid/base homeostasis. Serotonergic neurons in the midbrain also sense arterial CO₂ (Figure 46–8B). These neurons may induce arousal, anxiety, and changes in cerebral blood flow when blood CO₂ increases, responses which are important for survival when airflow is obstructed. Consistent with these ideas, genetic deletion of all serotonergic neurons in mice leads to a large decrease in the ventilatory response to breathing air with increased CO₂ (hypercapnia) and these mice no longer wake up when presented with the same stimulus while asleep.

The role of serotonergic neurons as CO₂ receptors may explain why defects in the serotonergic system have been linked to sudden infant death syndrome (SIDS). SIDS is the leading cause of postneonatal mortality in the Western world, responsible for six infant deaths every day in the United States. It was defined by an expert panel of pathologists and pediatricians as "the sudden and unexpected death of an infant under one year of age that remains unexplained after a complete clinical review, autopsy, and death scene investigation and occurs in seemingly healthy infants usually during a sleep period" (Figure 46–8C).

A widely held theory holds that some SIDS cases are due to defective CO₂ chemoreception, breathing, and arousal. An increase in the number of serotonergic neurons with an immature morphology, a decrease in serotonin levels, and changes in serotonergic receptor density are found in the raphe nuclei of infants who die of SIDS. A plausible neurobiological mechanism for SIDS is that a defect in development of serotonergic neurons leads to reduced ability to detect a rise in partial pressure of CO₂ when airflow is obstructed during sleep, thus blunting the normal protective response which should include arousal and increased ventilation (Figure 46–8C). Infants sleeping face down would be unable to arouse sufficiently to change position when bedding blocks the airway. This mechanism could explain the success of the Back to Sleep campaign that encourages mothers to place infants on their backs when put to sleep and has reduced the incidence of SIDS by 50%.

Pain and Anti-nociceptive Pathways Are Modulated by Monoamines

Although pain is necessary for an animal to avoid injury, continued pain following an injury may be maladaptive (eg, if the pain prevents vigorous escape from a predator). Hence the monoaminergic systems include important descending projections to the dorsal horn of the spinal cord that modulate pain perception (see Chapter 24).

The noradrenergic inputs to the spinal cord originate from pontine cell groups, including the locus ceruleus, A5, and A7 cell groups. Similarly, the serotonergic medullary raphe nuclei, particularly the nucleus raphe magnus, project to the dorsal horn where they modulate the processing of information about noxious stimuli. Direct application of serotonin to dorsal horn neurons inhibits their response to noxious stimuli, and intrathecal administration of serotonin attenuates the defensive withdrawal of the paw evoked by noxious stimuli. In addition, intrathecal administration of antagonists of serotonin receptors blocks the pain inhibition evoked by stimulation of the raphe nuclei.

Insight into the role of serotonin in pain processing has been used in treating migraine headaches. In particular, agonists to the 5-HT_1D receptors, the triptans have been found to be therapeutically effective. One of the possible mechanisms of action of this family of tryptamine-based drugs includes presynaptic inhibition of pain afferents from the meninges, preventing sensitization of central neurons. Drugs that block monoamine reuptake, including both traditional antidepressants and selective serotonin reuptake inhibitors, are effective in limiting pain in patients with chronic pain and migraine headaches.

Monoamines Facilitate Motor Activity

The dopaminergic system is critical for normal motor performance. A massive projection ascends from the substantia nigra pars compacta to the striatum. As described in Chapter 43, dopaminergic fibers act on striatal neurons via D₁ and D₂ receptors to release inhibition on motor responses.

As would be expected, patients with Parkinson disease in whom midbrain dopaminergic neurons have degenerated have trouble initiating movement and difficulty sustaining their movements. Such patients speak softly, write with small letters, and take small steps. Conversely, drugs that facilitate dopaminergic transmission in the striatum can result in unintended behaviors ranging from motor tics (small muscle twitches), to chorea (large scale, jerky limb movements), to complex cognitive behaviors (such as compulsive gambling or sexual activity).

As first shown by Sten Grillner, serotonergic neurons play an important role in generating motor programs. Drugs that activate serotonin receptors can induce hyperactivity, myoclonus, tremor, and rigidity, which are all part of the "serotonin syndrome." Increases in the firing of raphe neurons have been observed in animals during repetitive motor activities such as feeding, grooming, locomotion, and deep breathing. Conversely, the atonia and lack of movement that occur during REM sleep are associated with near cessation of firing of raphe neurons.

Noradrenergic cell groups in the pons also send extensive projections to motor neurons. This modulatory input facilitates excitatory inputs to motor neurons by acting on β- and α₁-adrenergic receptors. The sum of these effects is to facilitate motor neuron responses in stereotypic and repetitive behaviors such as rhythmic chewing, swimming, or locomotion. Conversely, increased β-adrenergic activation during stress can exaggerate motor responses and produce tremor. Drugs that block β-adrenergic receptors are used clinically to reduce certain types of tremor and are often taken by musicians prior to performances to minimize tremulousness.

The brain stem contains modulatory neurons with long axons that either ascend to the forebrain where they control various aspects of mood and cognition, or descend to the spinal cord where they regulate autonomic, somatosensory, or motor functions. These monoaminergic and cholinergic systems are also essential components of the ascending arousal system.

The dual roles of the brain stem as a conduit for information flow to and from the forebrain and a modulator of forebrain activity is illustrated poignantly in patients with injury of the midpons. Because the ascending arousal system begins at the upper pontine level, patients remain awake; but the intact and awake forebrain is unable to interact with the external world other than with eye movements, a condition described clinically as the locked-in syndrome. In contrast, patients in a persistent vegetative state have intact brain stems but in most cases have extensive forebrain damage (such as from hypoxia). These patients appear to be alternately awake and asleep but have no outward signs of consciousness.

Hence, normal conscious behavior requires close interaction between the brain stem and the forebrain. The monoaminergic and cholinergic regulatory systems are very important in clinical medicine because their various components are dysfunctional in a variety of neurological and psychiatric diseases, including depression, dementia, migraine, psychosis, and SIDS. They are the targets of a large number of clinically useful drugs.

These neurons play a disproportionately important role in normal brain function and a better understanding of them has great potential for treating neuropsychiatric disease.

Nowhere is knowledge of brain stem anatomy and function more important in clinical neurology than when caring for the comatose patient. Coma is a state of profound unconsciousness from which the patient cannot be aroused by external stimuli. Two neurological principles are important for determining the cause of coma.

First, any decrease in the level of consciousness (decreased arousal) implies dysfunction of either both cerebral hemispheres or of the ascending arousal system (or its projections in the thalamus or hypothalamus). Second, one can pinpoint the levels of the brain stem that are damaged by determining abnormalities of reflexes mediated by cranial nerves, which often accompany coma.

The keys to successful care of a comatose patient are, first, to provide life support if needed, and then to identify the specific etiology of the coma. The cause of coma can usually be determined by obtaining a history from witnesses, an examination focused on brain stem function, and use of targeted laboratory tests. Dysfunction of the ascending arousal system can result either from diffuse impairment of the brain, usually from a pharmacologic, toxic, or metabolic cause, or from a focal lesion that impinges on the upper brain stem, diencephalon, or both cerebral hemispheres.

In the case of coma from diffuse impairment, there are few if any signs of focal brain stem defects. In the case of focal injuries to the upper brain stem or forebrain there are generally locally restricted changes, and the neurological examination can pinpoint the location and give clues to the cause of the problem.

Thus the neurological examination is the critical first step in determining the cause and severity of coma, and its primary purpose is to determine whether there is any evidence of a focal lesion and, if so, at what levels of the brain stem. The neurological examination of comatose patients is much simpler than that of conscious patients because it is not possible to do many portions of a full exam that require patient cooperation. This abbreviated neurological exam is sometimes called the coma exam or the brain stem exam and includes the following.

The level of consciousness is assessed by observing the motor response to external stimuli. If the patient is unable to respond to verbal stimuli or gentle shaking, it may be necessary to apply a local painful stimulus (eg, pressing on a nail bed). The level of consciousness is assessed by the vigor with which the patient responds to the stimulus. Terms used to describe responsiveness include comatose, semi-comatose, obtunded, somnolent, lethargic, and alert, in increasing order of preservation of arousal. However, it is generally more reproducible to describe how the patient responds to a stimulus rather than to use these inexact terms.

Asymmetric motor responses suggest a focal impairment of either the sensory or motor systems responsible for the side of the body that is less responsive but does not help identify the level of the lesion (Figure 46–9). Flexion of both arms at the elbow and extension of both legs, occurring spontaneously or in response to pain, is called decorticate posturing and usually indicates a lesion above the midbrain. Extension of both arms and both legs is called decerebrate posturing and usually indicates a more severe lesion that often affects the upper part of the brain stem.

Abnormal respiratory patterns can help localize lesions and are important to recognize because they can predict whether a patient may later require mechanical ventilation (Figure 46–10). Periodic waxing and waning of respiration (Cheyne-Stokes breathing) can occur in forebrain depression. This must be differentiated from other irregular breathing patterns such as cluster or ataxic breathing, because the latter indicate damage to the lower brain stem and may require intubation.

Examination of cranial nerve function related to the pupillary light response and eye movements can be informative, because these pathways are closely adjacent to the structures of the ascending arousal system in the upper brain stem. The pupillary light reflex is tested by shining a bright light into one eye. Lesions at various levels of the brain stem produce characteristic changes in pupillary light responses that often can pinpoint the location of an injury (Figure 46–11).

Eye movements can also be equally helpful. Slow, roving eye movements are seen in patients with diffuse forebrain impairment but normal brain stem activity. In a more deeply comatose patient, eye movements can be elicited by turning the head, which induces a vestibular response that causes the eyes to rotate in the direction opposite to the movement (see Chapter 40) or by irrigating the external ear canal with cold water, which causes the eyes to turn toward that side. Lack of movement of both eyes toward one side indicates injury to the lower pons, where vestibular inputs reach the medial pontine circuitry that controls lateral gaze. Selective loss of abduction of one eye indicates damage to the abducens nerve, at the lower pontine level, whereas selective loss of conjugate adduction reflects injury to the medial longitudinal fasciculus, which travels in the medial part of the pons to the midbrain to connect the abducens and oculomotor nuclei. Selective loss of vertical eye movements implies an injury to the dorsal midbrain.

This brief explanation of the coma exam illustrates how it can often make it possible to determine the precise level of the affected brain stem. Such information provides important clues as to the type of the injury and the kind of immediate treatment and further evaluation that may be required.