45: The Sensory, Motor, and Reflex Functions of the Brain Stem

• The Cranial Nerves Are Homologous to the Spinal Nerves

  • Cranial Nerves Mediate the Sensory and Motor Functions of the Face and Head and the Autonomic Functions of the Body

  • Cranial Nerves Leave the Skull in Groups and Often Are Injured Together

• Cranial Nerve Nuclei in the Brain Stem Are Organized on the Same Basic Plan As Are Sensory and Motor Regions of the Spinal Cord

  • Adult Cranial Nerve Nuclei Have a Columnar Organization

  • Embryonic Cranial Nerve Nuclei Have a Segmental Organization

  • The Organization of the Brain Stem and Spinal Cord Differs in Three Important Ways

• Neuronal Ensembles in the Brain Stem Reticular Formation Coordinate Reflexes and Simple Behaviors Necessary for Homeostasis and Survival

  • Cranial Nerve Reflexes Involve Mono- and Polysynaptic Brain Stem Relays

  • Pattern Generator Neurons Coordinate Stereotypic and Autonomic Behaviors

  • A Complex Pattern Generator Regulates Breathing

• An Overall View

In primitive vertebrates—reptiles, amphibians, and fish—the forebrain is only a small part of the brain and is devoted mainly to olfactory processing and to the integration of autonomic and endocrine function with the basic behaviors necessary for survival. These basic behaviors include feeding, drinking, sexual reproduction, sleep, and emergency responses. Although we are accustomed to thinking that human behavior originates mainly in the forebrain, many complex responses, such as feeding—the coordination of chewing, licking, and swallowing—are actually made up of relatively simple, stereotypic motor responses governed by ensembles of neurons in the brain stem.

The importance of this pattern of organization in human behavior is clear from observing infants born without a forebrain (hydrancephaly). Hydrancephalic infants are surprisingly difficult to distinguish from normal babies. They cry, smile, suckle, and move their eyes, face, arms, and legs. As these sad cases illustrate, the brain stem can organize virtually all of the behavior of the newborn.

In this chapter we examine the role of the brain stem in reflex behavior. We also review the cranial nerves, their origin in the brain stem, as well as the ensembles of local circuit neurons that organize the simple behaviors of the face and head.

The brain stem is the rostral continuation of the spinal cord and its motor and sensory components are similar in structure to that of the spinal cord. But the portions of the brain stem that control the cranial nerves are much more complex than the corresponding parts of the spinal cord that control the spinal nerves because cranial nerves mediate more complex behaviors. The core of the brain stem, the reticular formation, is homologous to the intermediate gray matter of the spinal cord but is also more complex. Like the spinal cord, the reticular formation contains ensembles of local-circuit interneurons that generate motor and autonomic patterns and coordinate reflexes and simple behaviors. In addition, it contains clusters of dopaminergic, noradrenergic, and other modulatory neurons that act to optimize the functions of the nervous system. The modulatory actions of these nuclei are described in the next chapter.

Because the spinal nerves reach only as high as the first cervical vertebra, the cranial nerves provide the somatic and visceral sensory and motor innervation for the head. Two cranial nerves, the glossopharyngeal and vagus nerves, also supply visceral sensory and motor innervation of the neck, chest, and most of the abdominal organs with the exception of the pelvis. Unlike the spinal nerves, which supply all sensory and motor functions for specific body segments, each cranial nerve is associated with one or more functions and may therefore overlap the physical territory of another cranial nerve.

Assessment of the cranial nerves is an important part of the neurological examination (see Appendix B) because abnormalities of function can pinpoint a site in the brain stem that has been damaged. Therefore, it is important to know the origins of the cranial nerves, their intracranial course, and where they exit from the skull.

The cranial nerves are traditionally numbered I through XII in rostrocaudal sequence. Cranial nerves I and II enter at the base of the forebrain. The other cranial nerves arise from the brain stem at characteristic locations (Figure 45–1). All but one exit from the ventral surface of the brain stem. The exception is the trochlear (IV) nerve, which leaves the midbrain from its dorsal surface just behind the inferior colliculus and wraps around the lateral surface of the brain stem to join the other cranial nerves concerned with eye movements. The cranial nerves with sensory functions (V, VII, VIII, IX, and X) have associated sensory ganglia that operate much as dorsal root ganglia do for spinal nerves. These ganglia are located along the course of individual nerves as they enter the skull.

The olfactory (I) nerve, which is associated with the forebrain, is described in detail in Chapter 32; the optic (II) nerve, which is associated with the diencephalon, is described in Chapters 25 and 26. The spinal accessory (XI) nerve can be considered a cranial nerve anatomically but actually is a spinal nerve originating from the higher cervical motor rootlets. It runs up into the skull before exiting through the jugular foramen to innervate the trapezius and sternocleidomastoid muscles in the neck.

Cranial Nerves Mediate the Sensory and Motor Functions of the Face and Head and the Autonomic Functions of the Body

The ocular motor nerves —the oculomotor (III), trochlear (IV), and abducens (VI) nerves—control movements of the eyes. The abducens nerve has the simplest action; it contracts the lateral rectus muscle to move the globe laterally. The trochlear nerve also innervates a single muscle, the superior oblique, but its action both depresses the eye and rotates it inward, depending on the eye's position. The oculomotor nerve supplies all of the other muscles of the orbit, including the retractor of the lid. It also provides the parasympathetic innervation responsible for pupillary constriction in response to light and accommodation of the lens for near vision. The ocular motor system is considered in detail in Chapter 39.

The trigeminal (V) nerve is a mixed nerve (containing both sensory and motor axons) that leaves the brain stem in two roots. The motor root innervates the muscles of mastication (the masseter, temporalis, and pterygoids) and a few muscles of the palate (tensor veli palatini), inner ear (tensor tympani), and upper neck (mylohyoid and anterior belly of the digastric muscle).

The sensory fibers arise from neurons in the trigeminal ganglion, located at the floor of the skull in the middle cranial fossa, the central division of the skull, adjacent to the sella turcica, which houses the pituitary gland.

Three branches emerge from the trigeminal ganglion. The ophthalmic division (V₁) runs with the ocular motor nerves through the superior orbital fissure (Figure 45–2A) to innervate the orbit, nose, and forehead and scalp back to the vertex of the skull (Figure 45–3). Some fibers from this division also innervate the meninges and blood vessels of the anterior and middle intracranial fossas. The maxillary division (V₂) runs through the round foramen of the sphenoid bone to innervate the skin over the cheek and the upper portion of the oral cavity. The mandibular division (V₃), which also contains the motor axons of the trigeminal nerve, leaves the skull through the oval foramen of the sphenoid bone. It innervates the skin over the jaw, the area above the ear, and the lower part of the oral cavity, including the tongue.

Complete trigeminal sensory loss results in numbness of the entire face and the inside of the mouth. One-sided trigeminal motor weakness does not cause much weakness of jaw closure because the muscles of mastication on either side are sufficient to close the jaw. Nevertheless, the jaw tends to deviate toward the side of the lesion when the mouth is opened because the internal pterygoid muscle on the opposite side, when unopposed, pulls the jaw toward the weak side.

The facial (VII) nerve is also a mixed nerve. Its motor root supplies the muscles of facial expression as well as the stapedius muscle in the inner ear, stylohyoid muscle, and posterior belly of the digastric muscle in the upper neck. The sensory root runs as a separate bundle, the nervus intermedius, through the internal auditory canal and arises from neurons in the geniculate ganglion, located near the middle ear. Distal to the geniculate ganglion the sensory fibers diverge from the motor branch. Some innervate skin of the external auditory canal whereas others form the chorda tympani, which joins the lingual nerve and conveys taste sensation from the anterior two-thirds of the tongue. The autonomic component of the facial nerve includes parasympathetic fibers that travel through the motor root to the sphenopalatine and submandibular ganglia, which innervate lacrimal and salivary glands (except the parotid gland) and the cerebral vasculature.

The facial nerve may suffer isolated injury in Bell's palsy, a common complication of certain viral infections. Early on the patient may complain mainly of the face pulling toward the unaffected side because of the weakness of the muscles on the side of the lesion. Later the ipsilateral corner of the mouth droops, food falls out of the mouth, and the eyelids no longer close on that side. Loss of blinking may result in drying and injury to the cornea. The patient may complain that sound has a booming quality in the ipsilateral ear because the stapedius muscle fails to tense the ossicles in response to a loud sound (the stapedial reflex). Taste may also be lost on the anterior two-thirds of the tongue on the ipsilateral side. If the Bell's palsy is caused by a herpes zoster infection of the geniculate ganglion, small blisters may form in the outer ear canal, the ganglion's cutaneous sensory field.

The vestibulocochlear (VIII) nerve contains two main bundles of sensory axons from two ganglia. Fibers from the vestibular ganglion relay sensation of angular and linear acceleration from the semicircular canals, utricle, and saccule in the inner ear. Fibers from the cochlear ganglion relay information from the cochlea concerning sound. A vestibular schwannoma, one of the most common intracranial tumors, may form along the vestibular component of cranial nerve VIII as it runs within the internal auditory meatus. Most patients complain only about hearing loss, as the brain is usually able to adapt to the gradual loss of vestibular input from one side.

The glossopharyngeal (IX) nerve and vagus (X) nerve are mixed but are predominantly autonomic. These closely related nerves transmit sensory information from the pharynx and upper airway as well as taste from the posterior third of the tongue and oral cavity. The glossopharyngeal nerve transmits visceral information from the neck (for example, information on blood oxygen and carbon dioxide from the carotid body, and arterial pressure from the carotid sinus), whereas the vagus nerve transmits visceral information from the thoracic and abdominal organs except for the distal colon and pelvic organs. Both nerves include parasympathetic motor fibers. The glossopharyngeal nerve provides parasympathetic control of the parotid salivary gland, whereas the vagus nerve innervates the rest of the internal organs of the neck, thorax, and abdomen. The glossopharyngeal nerve innervates only one muscle of the palate, the stylopharyngeus, which raises and dilates the pharynx. The remaining striated muscles of the larynx and pharynx are under control of the vagus nerve.

Because many of the functions of nerves IX and X are bilateral and partially overlapping, unilateral injury of nerve IX may be difficult to detect. Patients with unilateral cranial nerve X injury are hoarse, because one vocal cord is paralyzed, and may have some difficulty swallowing. Examination of the oropharynx shows weakness and numbness of the palate on one side.

The spinal accessory (XI) nerve is purely motor and originates from motor neurons in the upper cervical spinal cord. It innervates the trapezius and sternocleidomastoid muscles on the same side of the body. Because the mechanical effect of the sternocleidomastoid is to turn the head toward the opposite side, an injury of the left nerve causes weakness in turning the head to the right. A lesion of the cerebral cortex on the left will cause weakness of muscles on the entire right side of the body except for the sternocleidomastoid; instead, the ipsilateral sternocleidomastoid will be weak (because the left cerebral cortex is concerned with interactions with the right side of the world).

The hypoglossal (XII) nerve is also purely motor, innervating the muscles of the tongue. When the nerve is injured, for example during surgery for head and neck cancer, the tongue atrophies on that side. The muscle fibers exhibit twitches of muscle fascicles (fasciculations), which may be seen clearly through the thin mucosa of the tongue.

Cranial Nerves Leave the Skull in Groups and Often Are Injured Together

In assessing dysfunction of the cranial nerves it is important to determine whether the injury is within the brain or further along the course of the nerve. As cranial nerves leave the skull in groups through specific foramina, damage at these locations can affect several nerves.

The cranial nerves concerned with orbital sensation and movement of the eyes (III, IV, VI, and the ophthalmic division of the trigeminal nerve, V₁) are gathered together in the cavernous sinus, along the lateral margins of the sella turcica, and then exit the skull through the superior orbital fissure adjacent to the optic foramen (Figure 45–2A). Tumors in this region, such as those arising from the pituitary gland, often make their presence known first by pressure on these nerves or the adjacent optic chiasm.

Cranial nerves VII and VIII exit the brain stem at the cerebellopontine angle, the lateral corner of the brain stem at the juncture of the pons, medulla, and cerebellum (Figure 45–2B), and then leave the skull through the internal auditory meatus. A common tumor of the cerebellopontine angle is the vestibular schwannoma (sometimes erroneously called an "acoustic neuroma"), which derives from Schwann cells in the vestibular component of nerve VIII. If the tumor is large, it may not only impair the function of nerves VII and VIII but may also press on nerve V near its site of emergence from the middle cerebellar peduncle, causing facial numbness, or compress the cerebellum or its peduncles on the same side, causing ipsilateral clumsiness.

The lower cranial nerves (IX, X, and XI) exit through the jugular foramen (Figure 45–2B) and are vulnerable to compression by tumors at that site. Nerve XII leaves the skull through its own (hypoglossal) foramen and is generally not affected by tumors located in the adjacent jugular foramen, unless the tumor becomes quite large. If nerve XI is spared, the injury is generally within or near the brain stem rather than near the jugular foramen.

Cranial nerve nuclei are organized in rostrocaudal columns that are homologous to the sensory and motor laminae of the spinal cord (see Chapters 22 and 34). This pattern is best understood from the developmental plan of the caudal neural tube that gives rise to the brain stem and spinal cord.

The transverse axis of the embryonic caudal neural tube is subdivided into alar (dorsal) and basal (ventral) plates by the sulcus limitans, a longitudinal groove along the lateral walls of the central canal, fourth ventricle, and cerebral aqueduct (Figure 45–4). The alar plate forms the sensory components of the dorsal horn of the spinal cord, whereas the basal plate forms the motor components of the ventral horn. The intermediate gray matter is made up primarily of the interneurons that coordinate spinal reflexes and motor responses.

The brain stem shares this basic plan. As the central canal of the spinal cord opens into the fourth ventricle, the walls of the neural tube are splayed outward so that the dorsal sensory structures (derived from the alar plate) are displaced laterally whereas the ventral motor structures (derived from the basal plate) remain more medial. The nuclei of the brain stem are divided into general nuclei, which serve functions similar to those of the spinal cord laminae, and special nuclei, which serve functions unique to the head (such as hearing, balance, taste, and control of the branchial musculature).

Adult Cranial Nerve Nuclei Have a Columnar Organization

Overall, the brain stem nuclei on each side are organized in six rostrocaudal columns, three of sensory nuclei and three of motor nuclei (Figure 45–5). These are considered below, in dorsolateral to ventromedial sequence. The columns are discontinuous—the nuclei are not packed solidly along the rostrocaudal axis of the brain stem. Nuclei with similar functions (sensory or motor, somatic or visceral) have similar dorsolateral-ventromedial positions at each level of the brain stem.

Within each motor nucleus, motor neurons for an individual muscle are also arranged in a cigar-shaped longitudinal column. Thus each motor nucleus in cross section forms a mosaic map of the territory that is innervated. For example, in a cross section through the facial nucleus the clusters of neurons that innervate the different facial muscles form a topographic map of the face.

General Somatic Sensory Column

The general somatic sensory column occupies the most lateral region of the alar plate and includes the trigeminal sensory nuclei (N. V). The spinal trigeminal nucleus is a continuation of the dorsal-most laminae of the spinal dorsal horn (Figure 45–5A) and is sometimes called the medullary dorsal horn. Its outer surface is covered by the spinal trigeminal tract, a direct continuation of Lissauer's tract of the spinal cord (see Chapter 24), thus allowing some cervical sensory fibers to reach the trigeminal nuclei and some trigeminal sensory axons to reach the dorsal horn in upper cervical segments. This arrangement allows dorsal horn sensory neurons to have a range of inputs that are much broader than that of individual spinal or trigeminal segments, and ensures the integration of trigeminal and upper cervical sensory maps.

The spinal trigeminal nucleus receives sensory axons from the trigeminal ganglion (N. V) and from all cranial nerve sensory ganglia concerned with pain and temperature in the head, including geniculate ganglion (N. VII) neurons that relay information from the external auditory meatus, petrosal ganglion (N. IX) cells that convey information from the posterior part of the palate and tonsillar fossa, and nodose ganglion (N. X) axons that relay information from the posterior wall of the pharynx. The spinal trigeminal nucleus thus represents the entire oral cavity as well as the surface of the face.

The somatotopic organization of the afferent fibers is inverted: The forehead is represented ventrally and the oral region dorsally. Axons from the spinal trigeminal nucleus descend on the same side of the brain stem into the upper spinal cord, where they cross the midline in the anterior commissure with spinothalamic axons and join the opposite spinothalamic tract. (For this reason, upper cervical spinal cord injury may cause facial numbness.) The trigeminothalamic axons then ascend back through the brain stem, providing inputs to brain stem nuclei for reflex motor and autonomic responses in addition to carrying pain and temperature information to the thalamus.

The principal sensory trigeminal nucleus lies in the mid pons just lateral to the trigeminal motor nucleus. It receives the axons of neurons in the trigeminal ganglion concerned with position sense and fine touch discrimination, the same types of sensory information carried from the rest of the body by the dorsal columns. The axons from this nucleus are bundled with those from the dorsal column nuclei in the medial lemniscus, through which they ascend to the ventroposterior medial thalamus.

An additional component of the trigeminal sensory system, located at the midbrain level in the lateral surface of the periaqueductal gray matter, is the mesencephalic trigeminal nucleus, which relays mechanosensory information from the muscles of mastication and the periodontal ligaments. The large cells of this nucleus are not central neurons but primary sensory ganglion cells that derive from the neural crest and, unlike their relatives in the trigeminal ganglion, migrate into the brain during development. The central branches of the axons of these pseudo-unipolar cells contact motor neurons in the trigeminal motor nucleus, providing monosynaptic feedback to the jaw musculature, critical for the precise control of chewing movements.

Special Somatic Sensory Column

The special somatic sensory column has inputs from the acoustic and vestibular nerves and develops from the intermediate region of the alar plate. The cochlear nuclei (N. VIII), which lie at the lateral margin of the brain stem at the pontomedullary junction, receive auditory afferents from the spiral ganglion of the cochlea. The output of these nuclei is relayed through the pons to the superior olivary and trapezoid nuclei and bilaterally on to the inferior colliculus (see Chapter 31). The vestibular nuclei (N. VIII) are more complex. They include four distinct cell groups that relay information from the vestibular ganglion to various motor sites in the brain stem, cerebellum, and spinal cord concerned with maintaining balance and coordination of eye and head movements (see Chapter 40).

Visceral Sensory Column

The visceral sensory column is concerned with special visceral information (taste) and general visceral information from the facial (VII), glossopharyngeal (IX), and vagus nerves (X). It is derived from the most medial tier of neurons in the alar plate. All of the afferent axons terminate in the nucleus of the solitary tract. The solitary tract is analogous to the spinal trigeminal tract or Lissauer's tract, bundling afferents from different cranial nerves as they course rostrocaudally along the length of the nucleus. As a result, visceral sensory information from different afferent nerves produces a unified visceral sensory map of the body in the nucleus.

Special visceral afferents carrying taste information from the anterior two-thirds of the tongue reach the nucleus of the solitary tract through the chorda tympani branch of the facial nerve, whereas those from the posterior parts of the tongue and oral cavity arrive through the glossopharyngeal and vagus nerves. These afferents terminate in roughly somatotopic fashion in the anterior third of the nucleus of the solitary tract. General visceral afferents are relayed through the glossopharyngeal and vagus nerves. Those from the rest of the gastrointestinal tract (down to the transverse colon) terminate in the middle portion of the solitary nucleus in topographic order, whereas those from the cardiovascular and respiratory systems terminate in the caudal and lateral portions.

The solitary nucleus projects directly to parasympathetic and sympathetic preganglionic motor neurons in the medulla and spinal cord that mediate various autonomic reflexes, as well as to parts of the reticular formation that coordinate autonomic and respiratory responses. Most ascending projections from the viscera to the forebrain are relayed through the parabrachial nucleus in the pons, although some reach the forebrain directly from the solitary nucleus. Together the solitary and parabrachial nuclei supply visceral sensory information to the hypothalamus, basal forebrain, amygdala, thalamus, and cerebral cortex.

General Visceral Motor Column

All motor neurons initially develop adjacent to the floor plate, a longitudinal strip of non-neuronal cells at the ventral midline of the neural tube (see Chapter 52). Neurons fated to become the three types of brain stem motor neurons migrate dorsolaterally, settling in three distinct rostrocaudal columns. The neurons that form the general visceral motor column migrate to the most lateral region of the basal plate, just medial to the sulcus limitans.

The Edinger-Westphal nucleus (N. III) lies next to the oculomotor complex just below the floor of the cerebral aqueduct. It contains preganglionic neurons that control pupillary constriction and lens accommodation through the ciliary ganglion.

The superior salivatory nucleus (N. VII) lies just dorsal to the facial motor nucleus and comprises parasympathetic preganglionic neurons that innervate the sublingual and submandibular salivary glands and the lacrimal glands and intracranial circulation through the sphenopalatine and submandibular parasympathetic ganglia.

Parasympathetic preganglionic neurons associated with the gastrointestinal tract form a column at the level of the medulla just dorsal to the hypoglossal nucleus and ventral to the nucleus of the solitary tract. At the most rostral end of this column is the inferior salivatory nucleus (N. IX) comprising the preganglionic neurons that innervate the parotid gland through the otic ganglion. The rest of this column constitutes the dorsal motor vagal nucleus (N. X). Most of the preganglionic neurons in this nucleus innervate the gastrointestinal tract below the diaphragm; a few are cardiomotor neurons.

The nucleus ambiguus (N. X) is a cluster of neurons that runs the rostrocaudal length of the ventrolateral medulla and contains parasympathetic preganglionic neurons that innervate thoracic organs, including the esophagus, heart, and respiratory system, as well as special visceral motor neurons that innervate the striated muscle of the larynx and pharynx, and neurons that generate respiratory motor patterns (see below). The parasympathetic preganglionic neurons are organized in topographic fashion, with the esophagus represented most rostrally and dorsally.

Special Visceral Motor Column

The special visceral motor column includes motor nuclei that innervate muscles derived from the branchial (pharyngeal) arches. Because these arches are homologous to the gills in fish, the muscles are considered special visceral muscles, even though they are striated in mammals. During development these cell groups migrate to an intermediate position in the basal plate and are eventually located ventrolaterally in the tegmentum. The trigeminal motor nucleus (N. V) lies at midpontine levels and innervates the muscles of mastication. Associated with it are the accessory trigeminal nuclei that innervate the tensor tympani, tensor veli palatini, and mylohyoid muscles, and the anterior belly of the digastric muscle.

The facial motor nucleus (N. VII) lies caudal to the trigeminal motor nucleus at the level of the caudal pons and innervates the muscles of facial expression. During development facial motor neurons migrate medially and rostrally around the medial margin of the abducens nucleus before turning laterally, ventrally, and caudally toward their definitive location at the pontomedullary junction (Figure 45–6A). This sinuous course of the axons forms the internal genu of the facial nerve. The adjacent accessory facial motor nuclei innervate the stylohyoid and stapedius muscles and the posterior belly of the digastric muscle.

The nucleus ambiguus contains branchial motor neurons with axons that run in the glossopharyngeal and vagus nerves. These neurons innervate the striated muscles of the larynx and pharynx. During development these motor neurons migrate into the ventrolateral medulla, and as a consequence their axons form a hairpin loop within the medulla, similar to those of the facial motor axons.

General Somatic Motor Column

The neurons of the somatic motor column migrate the least during development, remaining close to the ventral midline. The oculomotor nucleus (N. III) lies at the midbrain level; it consists of five rostrocaudal columns of motor neurons innervating the medial, superior, and inferior rectus muscles, the inferior oblique muscle, and the levator of the eyelids. The motor neurons for the medial and inferior rectus and inferior oblique muscles are on the same side of the brain stem as the nerve exits, whereas those for the superior rectus are on the opposite side. The levator motor neurons are bilateral.

The trochlear nucleus (N. IV), which innervates the trochlear muscle, lies at the midbrain/rostral pontine level also on the opposite side of the brain stem from which the nerve exits. The abducens nucleus (N. VI), which innervates the lateral rectus muscle, is located at the midpontine level. The hypoglossal nucleus (N. XII) at the caudal end of the medulla consists of several columns of neurons, each of which innervates a single muscle of the tongue.

Embryonic Cranial Nerve Nuclei Have a Segmental Organization

Although the sensory and motor nuclei in the adult hindbrain are organized rostrocaudally, the arrangement of neurons at each level derives from a strikingly segmental pattern in the early embryo. Before neurons appear, the future hindbrain region of the neural plate becomes subdivided into a series of eight segments of approximately equal size, known as rhombomeres (Figure 45–6A).

Each rhombomere develops a similar set of differentiated neurons, as if the hindbrain is made up of series of modules. The even-numbered rhombomeres differentiate ahead of the odd-numbered ones. This is most clearly seen in the branchial (special visceral) motor neurons, which are readily identified early in development. Rhombomeres 2, 4, and 6 form the branchial motor nuclei of the trigeminal, facial, and glossopharyngeal nerves, respectively. Later, rhombomeres 3, 5, and 7 contribute motor neurons to these nuclei; in each case the axons of individual motor neurons extend rostrally as they join those of their even-numbered neighbor. At this developmental stage each of these nuclei is composed of homologous neurons derived from two adjacent segments. This early transverse segmental organization changes as rhombomere boundaries disappear and the dorsolateral migration of the cell bodies aligns the cells into rostrocaudal columns. The migration of the facial motor neurons of rhombomere 4 around the abducens nucleus (Figure 45–6A) generates the internal genu of the facial nerve.

The combination of the neurons of two rhombomeres into a single cranial nerve nucleus also corresponds to the relationship of the rhombomeres with the branchial arch muscles that are the targets of these motor neurons. For example, rhombomeres 2 and 3 (trigeminal) register with branchial arch 1 (mandibular), which forms the muscles of mastication; rhombomeres 4 and 5 (facial) register with branchial arch 2 (hyoid), which forms the muscles of facial expression (Figure 45–6A). Furthermore, neural crest cells from each rhombomere migrate into the corresponding branchial arches where they provide positional cues that determine the development and identity of the arch muscles.

The Organization of the Brain Stem and Spinal Cord Differs in Three Important Ways

One major difference between the organization of the brain stem and that of the spinal cord is that the long ascending and descending sensory tracts that run along the outside of the spinal cord are incorporated within the interior of the brain stem. Thus the ascending sensory tracts (the medial lemniscus and spinothalamic tract) run through the reticular formation of the brain stem as do the auditory, vestibular, and visceral sensory pathways.

A second major difference is that, in the brain stem, the cerebellum and its associated pathways form additional structures that are superimposed on the basic plan of the spinal cord. Fibers of the cerebellar tracts and nuclei are bundled with those of the pyramidal and extrapyramidal motor systems to form a large ventral portion of the brain stem. Thus, from the midbrain to the medulla the brain stem is divided into a dorsal portion, the tegmentum, which follows the basic segmental plan of the spinal cord, and a ventral portion, which contains the structures associated with the cerebellum and the descending motor pathways. At the level of the midbrain the ventral (motor) portion includes the cerebral peduncles, substantia nigra, and red nuclei. The base of the pons includes the pontine nuclei, corticospinal tract, and middle cerebellar peduncle. In the medulla the ventral motor structures include the pyramidal tracts and inferior olivary nuclei.

A third major difference is that, although the hindbrain is segmented into rhombomeres during development, there is no clear repeating pattern in the adult brain. In contrast, the spinal cord is not segmented during development but the final pattern consists of repeating segments. The prominent ladder-like arrays of ventral root axons and dorsal root ganglia suggest that segmentation is imposed by a polarizing effect of the adjacent somites into which they migrate—in each somite the rostral part attracts axonal growth cones and neural crest cells, whereas the caudal part is repulsive (see Figure 52–1). In the head such patterning is lacking as the cranial mesoderm is not segmented into somites but rather develops under the influence of the rhombomeres.

A variety of reflexes and simple behaviors are mediated by the cranial nerves. These range from simple autonomic and motor responses to more complex patterns of facial expression and more complex behaviors such as breathing and eating, which in turn come under voluntary control by the forebrain. The stereotypic motor responses that make up these behaviors are controlled by neurons in the brain stem reticular formation. Impairment of cranial nerve reflexes and motor patterns in patients with neurological disease can be used to identify the precise site of brain stem damage.

Cranial Nerve Reflexes Involve Mono- and Polysynaptic Brain Stem Relays

The response of the pupils to light (pupillary light reflexes) are determined by the balance between sympathetic tone in the pupillodilator muscles and parasympathetic tone in the pupilloconstrictor muscles of the iris. Sympathetic tone is maintained by postganglionic neurons in the superior cervical ganglion, which in turn are innervated by preganglionic neurons in the first and second thoracic spinal segments. Parasympathetic tone is supplied by postganglionic ciliary ganglion cells under the control of preganglionic neurons in the Edinger-Westphal nucleus and adjacent areas of the midbrain.

Light impinging on the retina activates a special class of retinal ganglion cells that act as brightness detectors. These ganglion cells receive inputs from rhodopsin-containing rods and cones, but also have their own photopigment, melanopsin, which allows them to respond to light even in patients who have degeneration of the rods and cones. These cells send their axons through the optic nerve, chiasm, and tract, bypassing the lateral geniculate nucleus to the olivary pretectal nucleus, where they synapse onto neurons whose axons travel through the posterior commissure to contact the preganglionic neurons in the Edinger-Westphal nucleus (Figure 45–7). Thus injury to the dorsal midbrain in the region of the posterior commissure can prevent pupillary light responses (midposition, fixed pupils), whereas injury to the oculomotor nerve eliminates parasympathetic tone to that pupil (fixed and dilated pupil). The melanopsin-containing retinal ganglion cells also project to the suprachiasmatic nucleus of the hypothalamus, where they entrain circadian rhythms to the day-night cycle.

Vestibulo-ocular reflexes stabilize the image on the retina during head movement by rotating the eyeballs counter to the direction of rotation of the head. These reflexes are activated by pathways from the vestibular ganglion and nerve to the medial, superior, and lateral vestibular nuclei, and from there to neurons in the reticular formation and ocular motor nuclei that coordinate eye movements. The reflex movements are seen most clearly in comatose patients, in whom turning the head will elicit counter-rotational movements of the eyes (so-called doll's eye movements). Damage to these pathways in the pons impairs these movements.

The corneal reflex involves closure of both eyelids as well as upward turning of the eyes (Bell's phenomenon) when the cornea is gently stimulated (eg, with a wisp of cotton). The sensory axons from the first division of the trigeminal nerve terminate in the spinal trigeminal nucleus, which relays the sensory signals to pattern generator neurons in the reticular formation adjacent to the facial motor nucleus. The pattern generator neurons provide bilateral inputs to the motor neurons that innervate the orbicularis oculi, which controls eye closure, and to the oculomotor nuclei, causing the elevation of the eyes. Because the output of the pattern generator is bilateral, damage along the sensory pathway prevents the reflex in both eyes, whereas damage to the facial nerve prevents closure on the same side only.

The stapedial reflex contracts the stapedius muscle in response to a loud sound, thus damping movement of the ossicles. The sensory pathway is through the cochlear nerve and nucleus to the reticular formation adjacent to the facial motor nucleus, and from there to the stapedial motor neurons, which run in the facial nerve. In patients with injury to the facial nerve (eg, Bell's palsy) the stapedial reflex is impaired, and the patient complains that sounds in that ear have a "booming" quality (hyperacusis).

A variety of gastrointestinal reflexes are controlled by multisynaptic brain stem relays. For example, the taste of food causes neurons in the solitary nucleus that project to the reticular formation adjacent to the nerve VII and IX nuclei to stimulate the preganglionic salivary neurons. The taste of food can also elicit gastric contractions and acid secretion, presumably through inputs from the solitary nucleus directly to parasympathetic preganglionic gastric neurons in the dorsal motor vagal nucleus.

The gag reflex protects the airway in response to stimulation of the posterior oropharynx. The afferent sensory fibers in the glossopharyngeal and vagus nerves terminate in the spinal trigeminal nucleus, whose axons project to the reticular formation adjacent to the nucleus ambiguus. Branchial motor neurons in the nucleus ambiguus innervate the posterior pharyngeal muscles, resulting in elevation of the palate, constriction of pharyngeal muscles (to expel the offending stimulus), and closure of the airway. Loss of the gag reflex on one side of the throat indicates injury to the medulla or to cranial nerves IX and X on that side.

Pattern Generator Neurons Coordinate Stereotypic and Autonomic Behaviors

Reflex responses such as the corneal or gag reflex are mediated by complex spatial and temporal patterns of activity in multiple motor nuclei. These patterns of activity are coordinated by pattern generator neurons in the adjacent reticular formation. Similar mechanisms control a variety of simple, stereotypic behaviors. For example, pools of pattern generator neurons in the reticular formation adjacent to the facial nucleus control facial expressions through stereotypic patterns of contraction of facial muscles simultaneously on the two sides of the face.

The patterns are so characteristic that Charles Darwin in his book on Expression of the Emotions in Man and Animals claimed that he could identify emotional states in animals like dogs and monkeys on the basis of contraction of homologous groups of facial muscles. Pattern generator neurons on each side of the brain stem project to the facial motor neurons on both sides of the brain, so that spontaneous facial expressions are virtually always symmetric. Even patients who have had major strokes in the cerebral hemispheres and cannot voluntarily move the contralateral orofacial muscles still tend to smile symmetrically when they hear a joke and can raise their eyebrows symmetrically.

Many orofacial movements involved in eating are produced by pattern generator neurons in the reticular formation near the cranial motor nuclei that mediate the behaviors. Licking movements are organized in the reticular formation near the hypoglossal nucleus, chewing movements near the trigeminal motor nucleus, sucking movements near the facial nucleus, and swallowing near the nucleus ambiguus. Not surprisingly, neurons in these reticular areas are closely interconnected with each other and receive inputs from the part of the nucleus of the solitary tract concerned with taste and the part of the spinal trigeminal nucleus concerned with tongue and oral sensation.

A variety of responses organized by the brain stem require coordination of cranial motor patterns with autonomic and sometimes endocrine responses. A good example is the baroreceptor reflex, which insures an adequate blood flow to the brain (see Chapter 47). The nucleus of the solitary tract receives information about stretch of the aortic arch through the vagus (X) nerve and stretch of the carotid sinus through the glossopharyngeal (IX) nerve. This information is relayed to neurons in the ventrolateral medulla that produce a coordinated response that protects the brain against a fall in blood pressure.

Reduced stretch of the aortic arch and carotid sinus reduces drive to the parasympathetic preganglionic cardiac-vagal neurons in the nucleus ambiguus, resulting in reduced vagal tone and increased heart rate. Simultaneously, increased firing of neurons in the rostral ventrolateral medulla drives sympathetic preganglionic vasoconstrictor and cardioaccelerator neurons. This combination of increased cardiac output and increased vascular resistance elevates blood pressure. Meanwhile, other neurons in the ventrolateral medulla increase the firing of hypothalamic neurons that secrete vasopressin from their terminals in the posterior pituitary gland. Vasopressin also has a direct vasoconstrictor effect, and it maintains blood volume by reducing water excretion through the kidney.

Vomiting is another example of a coordinated response mediated by pattern generator neurons. Toxic substances that enter the blood stream can be detected by nerve cells in the area postrema, a small region adjacent to the nucleus of the solitary tract along the floor of the fourth ventricle. Unlike most of the brain, which is protected by a blood–brain barrier (see Appendix D), the area postrema contains fenestrated capillaries that allow its neurons to sample the contents of the blood stream. When these neurons detect a toxin, they activate a pool of neurons in the ventrolateral medulla that control a pattern of responses that clears the digestive tract of any poisonous substances. These responses include reversal of peristalsis in the stomach and esophagus, increased abdominal muscle contraction, and activation of the same motor patterns used in the gag reflex to clear the oropharynx of unwanted material.

A Complex Pattern Generator Regulates Breathing

One of the most important functions of the brain stem is control of breathing. The brain stem automatically generates breathing movements beginning in utero at 11 to 13 weeks of gestation in humans, and continues nonstop from birth until death. This behavior does not require any conscious effort, and in fact it is rare for us to even think about the need to breathe. The primary purpose of breathing is to ventilate the lungs to control blood levels of oxygen, carbon dioxide, and hydrogen ions (pH), normal levels of which are essential for survival. (These are often measured together clinically and referred to as "blood gases.") Breathing movements involve contraction of the diaphragm, which is achieved by activating the phrenic nerve. The diaphragm is assisted when necessary by accessory muscles of respiration, including the intercostal muscles, pharyngeal muscles (to change airway diameter), some neck muscles (which help expand the chest), the tongue protruder muscles (to open the airway), and even some facial muscles (which flare the nares).

Respiratory activity can be generated by the medulla even when it is isolated from the rest of the nervous system. Within the medulla many neurons have patterns of firing that correlate with inspiration or expiration (Figure 45–8A). Some neurons have more complicated patterns, such as firing only during early inspiration or late inspiration. These respiratory neurons are concentrated in two regions. The dorsal respiratory group, located bilaterally in and around the ventrolateral part of the nucleus of the solitary tract, receives respiratory sensory input, including afferents from stretch receptors in the lungs and peripheral chemoreceptors. Neurons in the dorsal respiratory group contribute to reflexes such as limitation of lung inflation at high volume (the Hering-Breuer reflex) and the response to low oxygen (hypoxia). The ventral respiratory group, a column of neurons in and around the nucleus ambiguus, coordinates respiratory motor output. Some of these neurons are motor neurons with axons that leave the brain through the vagus nerve and innervate accessory muscles of respiration.

Respiratory neurons within the medulla in the rostral part of the ventral respiratory group, in an area called the pre-Bötzinger complex, are important components in the network that generates the respiratory rhythm. When transverse brain slices are prepared from the rostral medulla, neurons in the pre-Bötzinger complex are able independently to generate a respiratory rhythm that can be recorded in the XII cranial nerve rootlets that emerge from the ventral surface of the slices (Figure 45–8B). When neurons in this cell group are selectively killed acutely in intact animals, the animals are unable to maintain a normal respiratory rhythm. However, other areas of the medulla, such as the parafacial respiratory group, also contribute to respiratory rhythm generation. The exact roles of each of these areas, and their contributions to normal breathing, remain an active area of investigation.

The most important input into the respiratory pattern generator comes from chemoreceptors that sense oxygen (O₂) and carbon dioxide (CO₂). Under normal conditions ventilation is primarily regulated by the levels of CO₂ rather than O₂ (Figure 45–9A). However, breathing is strongly stimulated if O₂ becomes sufficiently low, such as at high altitude or in people with lung disease. The peripheral chemoreceptors in the carotid and aortic bodies respond primarily to a decrease in blood oxygen. During hypoxia they also respond to the increased acidity that results from an increase in CO₂ (water and CO₂ combine to form bicarbonate and hydrogen ions). Afferent fibers from peripheral chemoreceptors travel in the glossopharyngeal and vagus nerves and contact neurons in the dorsal respiratory group.

Central chemoreceptors in the brain stem respond to the decrease in pH induced by an increase in CO₂ (hypercapnia) but do not respond to hypoxia. Breathing increases when acidic solution is applied to the ventral surface of the medulla lateral to the pyramidal tract. Within this region and within the midline raphe nuclei are serotonergic neurons that are sensitive to acidosis (Figure 45–9B). Because these neurons surround large arteries (Figure 45–9C) and project to respiratory neurons, they are thought to be central chemoreceptors that sense hypercapnia in the blood. Indeed, genetic deletion or silencing of all central serotonergic neurons in mice reduces the ventilatory response to hypercapnia by 50%. Glutamatergic neurons in the nearby retrotrapezoid nucleus of the rostral ventrolateral medulla, as well as in other areas of the brain stem, are also central chemoreceptors, and current work is aimed at determining the relative importance of each of these chemoreceptor pools to the overall ventilatory response to hypercapnia.

Breathing must be coordinated with many motor actions that share the same muscles. To accomplish this coordination, respiratory neurons in the medulla receive input from neuronal networks concerned with vocalization, swallowing, sniffing, vomiting, and pain. For example, the ventral respiratory group is connected with a part of the parabrachial complex in the pons termed the pontine respiratory group or pneumotaxic center. These pontine neurons coordinate breathing with behaviors such as chewing and swallowing. They can cause holding of the breath at full inspiration (called apneusis) during eating and drinking. The reserve of air in the lungs permits a cough, if necessary, to expel any food or drink that may enter the airway. Other neurons in the intertrigeminal zone, between the motor and principal sensory trigeminal nuclei, receive facial and upper airway sensory fibers and project to the ventrolateral medulla to temporarily stop breathing to protect against accidental inspiration of dust or water.

The motor pattern generated by the respiratory centers is remarkably stable in normal people, but a variety of abnormal patterns can emerge under some conditions (eg, during disease). One of the most easily recognized is the Cheyne-Stokes respiratory pattern, which is characterized by repeated cycles of gradually increasing then decreasing ventilation, alternating with cessation of breathing (apnea). At the peak of each cycle a high CO₂ level at the central chemoreceptors causes hyperventilation. The hyperventilation leads to a decrease in CO₂ in the capillaries of the lung, but it takes several breaths before this blood reaches the central chemoreceptors. By this time the subject has overcompensated, so that the CO₂ in the pulmonary capillaries is now too low. When that blood finally reaches the chemoreceptors, the low CO₂ causes apnea (Figure 45–10). This in turn causes an increase in CO₂ in the lung capillaries, and when this blood reaches the chemoreceptors it initiates another cycle.

Cheyne-Stokes breathing can be seen in patients with congestive heart failure in whom a decrease in cardiac output causes an increase in the delay between gas exchange in the lungs and the change in CO₂ at the central chemoreceptors in the brain stem. It is commonly seen in hospitalized patients. Although not dangerous in itself, it can indicate that there is a serious underlying cardiorespiratory problem that needs to be corrected. In normal healthy individuals this cycle does not occur because it is suppressed by other sensory afferents to the ventral respiratory group.

Conversely, at altitudes greater than 10,000 feet even normal individuals experience Cheyne-Stokes breathing, particularly during sleep, probably because the relative hypoxia sensitizes the CO₂ receptors. A variety of other symptoms (headaches, insomnia, breathlessness, nausea) also result from the hypoxia at high altitude. Many of these symptoms can be prevented by taking acetazolamide, which causes a decrease in brain pH. The decrease in pH stimulates central chemoreceptors, which increase ventilation and maintain blood O₂ levels closer to normal. When severe, the best treatment is to breathe oxygen or to return to lower altitude.

A variety of descending inputs can influence the brain stem respiratory system. Voluntary motor pathways can take over the control of breathing during talking, eating, swimming, or playing a musical instrument. Descending inputs cause hyperventilation at the onset of exercise, in anticipation of an increase in oxygen demand. In fact, this leads to a sustained drop in blood CO₂ during exercise—the opposite of what would be expected for a negative feedback control system. Other descending inputs from the limbic system produce hyperventilation in connection with pain or anxiety, and in some people may be responsible for causing spontaneous panic attacks, characterized by hyperventilation and a feeling of suffocation. These various descending inputs allow seamless integration of breathing with other brain functions, but they are superseded by the need to maintain blood gas homeostasis, as even a small increase in CO₂ produces severe air hunger or dyspnea. Thus the respiratory control system is a fascinating example of a brain stem pattern generator that must be sufficiently stable to insure survival yet flexible enough to accommodate a wide variety of behaviors.

The plan for the brain stem and the cranial nerves unfolds early in development, as neurons assemble into clusters that come, in time, to assume their functional organization. Building on the basic plan of the spinal cord, motor and sensory neurons concerned with the face, head, neck and internal viscera form into discrete nuclei with specific functions and territories of innervation.

Neurons in the reticular formation surrounding these cranial nerve nuclei develop into ensembles of neurons that can generate patterns of autonomic and motor response that subserve simple, stereotyped, coordinated functions ranging from facial expression to feeding and breathing. These behavior patterns are sufficiently complex and flexible to represent the entire behavioral repertory of a newborn baby. As the forebrain develops and exerts its control over these brain stem pattern generators, a variety of more complex responses and ultimately volitional control of behavior evolves.

Even a skilled actor, however, finds it difficult to produce the facial expressions associated with specific emotions unless he recreates the emotional states internally, thereby triggering the pre-patterned facial expressions associated with those feeling states. Thus, some of the most complex human emotions and behaviors are played out unconsciously by means of stereotypic patterns of motor and autonomic responses in the brain stem.