The brainstem is a complete central nervous system including all afferent and efferent systems necessary for survival of individual and species. These systems include somatosensory, taste, auditory, vestibular, and visual systems as well as somatic and emotional motor systems controlling all parts of the body. In mammals many parts of the brainstem are “copied” into the cerebral cortex, but the basic systems still function and are used as tools for the cortex. The brainstem is located caudal to the diencephalon, (thalamus and hypothalamus), ventral to the cerebellum, and rostral to the spinal cord. From caudal to rostral the brainstem consists of the medulla oblongata or myelencephalon, the pons or metencephalon, and the midbrain or mesencephalon. Especially in humans a large portion of the pons consists of pontine nuclei, which are cells that relay information from various sources to the cerebellum. In this article we will not further discuss these pontine nuclei or any other precerebellar structures in the brainstem. For these nuclei we refer to the article about the cerebellum.
Spinal cord and brainstem
The brainstem is the rostral continuation of the spinal cord. In order to understand the function of the brainstem, we will consider the spinal cord and caudal brainstem as one entity. The spinal cord on each side consists of neurons in its central parts, the so-called gray matter, and of fibers in the periphery, the so-called white matter. In the caudal brainstem a similar organization exists with, on each side, neurons centrally and fibers peripherally.
The two laws of the brain
The central nervous system is built according to two laws; law # 1, survival of the individual, and law # 2, survival of the species. All brain systems, including those in the brainstem, function in the context of these two laws. In this chapter we will describe the brainstem from caudal to rostral in the context of these two laws and of the phylogenic development of animals including humans.
Spinal cord continues into medulla oblongata and pons
Although immediately rostral to the upper cervical segment of the spinal cord, the central nervous system is not called spinal cord anymore, but medulla oblongata, the function of both parts of the central nervous system is very similar. As shown below the dorsal horn of the spinal cord continues rostrally as the spinal trigeminal nucleus, the lateral ventral horn as the lateral tegmental field, and the medial ventral horn as the dorsomedial tegmentum of medulla and caudal pons. The regions that integrate the function of spinal cord and medulla into behavior that obeys laws #1 and #2, are only located rostral to the pons.
Spinal dorsal horn continues into the trigeminal nucleus
Neurons in the dorsal part of the spinal cord form the dorsal horn. They are involved in processing incoming or afferent information that enters the dorsal horn by way of fibers from neurons in spinal ganglia outside the spinal cord. Neurons in spinal ganglia send their peripheral axons via nerves to all parts of the body including skin, muscles and organs, where they accumulate information. The same neurons in the spinal ganglia send fibers centrally to relay this information to the dorsal horn. Information concerning fine touch and position sense is processed in central parts of the dorsal horn (mainly laminae II-IV of Rexed). Nociception including pain, on the other hand, is processed in other parts of the dorsal horn (mainly laminae I and V). Nociception is a measurable physiological event, that might represent immediate danger for survival of the individual (law #1). Therefore, neurons in especially laminae I and V send ascending fibers to brainstem and thalamus to inform the brain about such eventual threats. The individual becomes aware of this information as pain, agony or distress. The most caudal parts of the spinal cord (lumbosacral cord) process information from the lowest parts of the body, including bladder, genitals and other pelvic organs as well as of the distal parts of the legs and feet. More rostrally in the spinal cord (thoracolumbar cord) enters information concerning back and abdomen. At lower cervical levels the spinal cord receives information from hands and arms and at upper cervical segments from the muscles and skin of the neck. Afferent fibers from head and face do not enter the spinal cord but the brainstem at the level of the lateral pons ( Figure 1).
The ganglion involved is the trigeminal ganglion of which the peripheral fibers form the trigeminal or fifth (V) cranial nerves. The proximal fibers of the trigeminal ganglion enter the brainstem as a bundle of trigeminal fibers descending through the caudal brainstem as the spinal trigeminal tract. These fibers terminate in the spinal trigeminal nucleus just medial to the trigeminal tract. This trigeminal nucleus is called “spinal” because it is the rostral continuation of the spinal dorsal horn. From the first cervical spinal segment it extends rostrally until the site of entrance of the trigeminal fibers in the lateral pons. The nucleus is subdivided from caudal to rostral into three subdivisions, the pars caudalis, the pars interpolaris and the pars oralis. The function of the pars caudalis is the same as the spinal dorsal horn, consisting of five different laminae, of which laminae I and V process nociceptive information from all parts of the face. At the level of entrance of the trigeminal fibers in the lateral pons there is also another nucleus, the principal trigeminal nucleus, that relays information from the trigeminal fibers to the thalamus. Thus, after entering the brainstem some trigeminal fibers terminate in the principal trigeminal nucleus and in the adjacent spinal nucleus pars oralis, but many descend laterally in the spinal trigeminal tract through caudal pons and medulla to terminate in interpolar and caudal parts of the spinal trigeminal nucleus. Afferent fibers from some specific head regions as palate and throat do not enter the brainstem via the trigeminal (V) but via other cranial nerves as facial (VII), glossopharyngeus (IX) and vagus (X), but within the brainstem they terminate in the spinal trigeminal nucleus also. Remarkably, the ganglion cells that receive afferent information from the chewing muscles are not located outside, but inside the brainstem at the lateral border of the periaqueductal gray (PAG; see below). They are called mesencephalic trigeminal ganglion cells. Their peripheral fibers leave the brainstem to run together with the third branch of the trigeminal nerve to the chewing muscles. The proximal fibers of these ganglion cells project to the motoneurons innervating the chewing muscles and to their premotor interneurons in the caudal pontine and medullary lateral tegmental field.
Lateral ventral horn continues into the lateral tegmental field
The ventral part of the spinal gray matter is called the ventral horn, with somatic motoneuronal cell groups, called lamina IX. These motoneurons send their fibers via peripheral nerves to striated muscles. Each muscle has its own motoneuronal cell group in the ventral horn. Motoneurons in the medial ventral horn innervate the axial and proximal musculature (muscles of back and trunk), and those in the lateral ventral horn innervate distal muscles (arms, hands, legs and feet). The premotor interneurons projecting to these motoneurons are located in the adjoining laminae V-VIII. Somatic motoneurons in the sacral cord innervate striated muscles of the pelvic floor including the urethral and anal sphincters, as well as muscles of the most distal parts of the legs, including feet. At a slightly higher level the somatic motoneurons innervate the hindlimb muscles. Somatic motoneurons in upper lumbar and thoracic spinal segments innervate the axial and abdominal muscles. At low cervical levels the somatic motoneurons innervate arms and hands and at upper cervical levels neck muscles. The somatic motoneurons innervating the head muscles are located in the brainstem. Similar to the dorsal horn continuing rostrally as the trigeminal nucleus, the lateral part of the spinal ventral horn (laminae V to IX) continues rostrally as the lateral tegmental field ( Figure 2), with its rostral end bordering the so-called parabrachial nuclei. The lateral tegmental field lies medial to the spinal trigeminal nucleus and tractus, and, similar to spinal laminae V to IX, contains motoneuronal cell groups and their premotor interneurons. In contrast to the spinal cord, the motoneurons in the brainstem do not form a continuous column, but are located in distinct motoneuronal cell groups. From caudal to rostral these motoneuronal cell groups innervate tongue, throat (pharynx and larynx) and vocal cord, facial, and chewing muscles. The most caudal motor nucleus is the hypoglossal or XIIth nucleus located at the level of the obex, the transition of fourth ventricle into spinal canal. The hypoglossal motoneurons innervate the intrinsic and extrinsic muscles of the tongue. The hypoglossal nucleus is located medially, the other cell groups laterally in the lateral tegmental field. The nucleus ambiguus is located at the same level and rostral to the hypoglossal nucleus. Its name comes from “ambiguous” meaning vague, unclear or indistinct, because the nucleus is sometimes difficult to distinguish in a histological section. At certain levels it contains only very few motoneurons. The somatic motoneurons of the nucleus ambiguus innervate the muscles of pharynx, larynx, and upper esophagus. Close to these motoneurons are located the parasympathetic preganglionic motoneurons innervating heart, lungs and gastrointestinal tract (see below). According to some authors these parasympathetic motoneurons also take part in the nucleus ambiguus, which sometimes gives rise to confusion. The motoneurons in the more rostrally located facial nucleus innervates, via the facial or seventh nerve, all facial muscles, including those of the forehead, around the eye and mouth, and of chin and cheek. Even the thin platysma skin muscle in front of the neck is innervated by the facial nerve. The most rostral of these nuclei is the motor trigeminal nucleus, which sends its fibers along with the third branch of the trigeminal nerve, to the jaw muscles, including the mouth closing and mouth opening muscles.
There are also so-called autonomic, sympathetic and parasympathetic motoneurons. In fact, the autonomic motoneurons are not at all autonomous, but function under strong supraspinal control, albeit not under voluntary control. The sympathetic preganglionic motoneurons are especially active when the survival of the individual is threatened, i.e. when “action” is necessary. They are located laterally in lamina VII at thoracic and upper lumbar levels and innervate heart, lungs, gastrointestinal tract organs, bloodvessels, etc. In case the individual is not treatened the parasympathetic preganglionic motoneurons take care of "digestion". Most of them are located in the brainstem, but some in the sacral cord. These sacral parasympathetic motoneurons innervate the smooth musculature of the bladder and other pelvic organs. Parasympathetic motoneurons in the rostral brainstem send their fibers via the oculomotor nerve to the sphincter pupillae where they produce pupillary constriction and accomodation of the lens of the eye for near vision. Those in the upper medullary lateral tegmental field innervate the salivatory and lacrimal glands. Most parasympathetic motoneurons, however, are located in the caudal medulla in the so-called dorsal vagal nucleus, and scattered in the lateral tegmental field. Together they innervate all parts of the digestive tract as well as the heart, lungs and other organs as pancreas and liver. Since these parasympathetic motoneurons innervate these organs, afferent input from these organs enter the brainstem via the vagal nerve to terminate in the so-called solitary nucleus in the caudal medulla. Neurons in the solitary nucleus relay this incoming information to higher levels in brainstem and diencephalon, but also to the parasympathetic motoneurons in the brainstem. For the parasympathetic motoneurons that innervate the salivatory glands taste information is important. Fibers relaying this information enter the brainstem via the facial, glossopharyngeal and vagal nerves and terminate in the rostral portion of the solitary nucleus from where it is relayed to the parasympathetic motoneurons innervating the salivatory glands and to more rostral levels as parabrachial nuclei, medial thalamus and hypothalamus.
The premotor interneurons for all these motoneurons are located in the lateral tegmental field. Since direct projections to somatic motoneurons are scarce and only from the motor cortex in humans and monkeys, they serve as relay cells between incoming information from the trigeminal or other afferent systems, but also from motor and premotor cortex, prefrontal cortex, amygdala, bed nucleus of the stria terminalis and the lateral hypothalamus. The lateral tegmental field also contains premotor interneurons for certain groups of motoneurons in the spinal cord in the context of blood pressure and heart rate control, micturition, respiration and sexual activities. Premotor interneurons for the sympathetic motoneurons in the thoracolumbar cord are located in ventrolateral part of the lateral tegmental field caudal to the facial nucleus, premotor interneurons for the sacral parasympathetic motoneurons are found in the pontine micturition center, premotor interneurons for the phrenic motoneurons are present in the rostral retroambiguus and rostral solitary nucleus and premotor interneurons for the abdominal motoneurons are located in the caudal nucleus retroambiguus.
Medial ventral horn continues into the dorsomedial tegmental field
The medial part of the spinal ventral horn contains motoneurons and premotor interneurons involved in the control of proximal and axial muscles of back and neck. They not only control body posture but also the position of the head, and, thus, of the visual field of the individual. Later in phylogeny the position of the eyes was also determined by eye muscles in the orbit. Since both eye- and neck muscles determine the position of the visual field, it is apparent that the eye muscle motoneurons and premotor interneurons are located in a region that is strongly connected with the ventromedial ventral horn of the spinal cord. The medial ventral horn extends rostrally into the brainstem as the medullary and caudal pontine dorsomedial tegmentum ( Figure 2). Within this region the motoneurons of the lateral rectus muscle of the eyeball (nucleus abducens) are located. The motoneurons of the other eye muscles can be found in the trochlear (IV) and oculomotor (III) nuclei. Phylogenetically they are a later development, which is the reason that they are not located in the caudal brainstem, but further rostrally in the mesencephalon. The premotor interneurons of all these motoneurons not only have connections with the other eye muscle motoneurons, but also with those in the spinal cord innervating neck and axial muscles. A major pathway carrying most of these interconnecting fibers is called medial longitudinal fasciculus (MLF), which runs from the spinal cord rostrally into the most rostral mesencephalon. For example, in order to keep the direction of gaze the same for both eyes, contraction of the lateral rectus muscle of the right eye has to be accompanied by contraction of the medial rectus muscle of the left eye at the same time. This is achieved by internuclear neurons lying in the abducens nucleus whose axons enter the contralateral MLF and terminate on the medial rectus pool of motoneurons in the oculomotor nucleus of the other side. Usually, when visual, auditory, or somatosensory information urges the individual to turn the visual field towards the direction of possible danger, the premotor interneurons in the dorsomedial tegmentum are activated, resulting in movement of eyes and head into that direction. Also the prefrontal eyefield in the cortex projects to the dorsomedial tegmentum, in order to voluntarily change the direction of the visual field.
Vestibular, auditory, and visual information enters the brainstem
The vestibular organ in the os petrosum of the skull, through systems as semicircular canals, utricle and saccule produces information concerning the position or movement of the head in space. This information is important in order to keep the body upright as long as possible in case of danger, but also to keep the visual field into the direction of an eventual threat. Similar to dorsal horn and trigeminal nuclei the vestibular system also makes use of neurons in a ganglion, that relay the vestibular information to the brainstem. The brainstem cell groups receiving the information from the vestibular ganglion, are, therefore, called vestibular nuclei. They are dorsal appendages to the brainstem, dorsal and dorsomedial to the trigeminal tract and nuclei ( Figure 1). Neurons in the vestibular nuclei have access to the neurons involved in the control of the position of the visual field, i.e. the motoneurons innervating eye-, neck- and back muscles. Some of the vestibular fibers, therefore, pass throughout the length of the spinal cord (the ipsilateral lateral vestibulospinal tract), but some only descend to the cervical cord to terminate on especially the neck muscle premotor and motoneurons (the bilateral medial vestibulospinal tract). Other cells in the vestibular nuclei have access to the motoneurons of the eye muscles in nuclei III, IV and VI via the medial longitudinal fasciculus (MLF). Thus, the position of the head (utricle) or a change in this position (semicircular canals) is relayed via the vestibular ganglion, to the vestibular nuclei. These nuclei, via their projections to spinal cord and eye muscle motoneuronal nuclei, can immediately adjust the posture of the body and the position of head and eyes, in order to prevent damage to the individual (law #1). This reflex is phylogenically very old; part of it is called the vestibulo-ocular reflex (VOR), which is so basic to the elementary wiring of the brainstem that it occurs even in a state of unconciousness. Some vestibular pathways ascend to the thalamus and convey information about the orientation of the head in space to the cerebral cortex.
Auditory information is also very important for detecting danger (law #1) or contacting an eventual mating partner (law #2). The auditory organ (cochlea), together with the vestibular organ, is located in the os petrosum of the skull. As usual, it uses a ganglion, (the so-called spiral ganglion in the center of the cochlea) to transmit information from the auditory cells in the organ of Corti in the cochlea to the brainstem. This information is received by cell groups, so-called cochlear nuclei, forming, similar to the vestibular nuclei, appendages of the brainstem ( Figure 1), but now on the lateral side. One of the structures to which these cochlear nuclei convey the auditory information are the superior olivary nuclei in the pontine brainstem. These nuclei are able to determine from which direction the auditory stimulus, that might represent a threat, is coming from. The cochlear nuclei also relay information to the more rostrally located inferior colliculus in the caudal mesencephalon. The inferior colliculus has access to other brainstem mechanisms such as the startle reflex in order to immediately cope with a threatening stimulus. It also transmits auditory information to the deep layers of the superior colliculus, and in higher order animals as mammalians, to cortical levels.
The brainstem also contains a visual system. Similar to the somatosensory, auditory, and vestibular systems, the visual system also uses ganglion cells to convey visual information to the brainstem. These ganglion cells are located in the retina where it receives information from the various retinal layers and relay that information to the superficial layers of the superior colliculus as well as to a set of accessory optic nuclei ( the dorsal lateral, medial and interstitial accessory optic nuclei) and the nucleus of the optic tract, ( Figure 1). These nuclei are specifically activated by horizontal or vertical movements of very large visual fields, and send the information to the dorsal tegmentum. In life movements of very large visual fields is exactly what happens to the visual field when one moves the head. So these visual reflexes compliment the vestibular reflexes. Cells in the accessory optic nuclei and the nucleus of the optic tract can also register smaller movements in the visual field, which movements might represent danger. These nuclei relay this information to the dorsomedial tegmental field, in order to immediately adjust the posture of body and position of the head towards the direction of these movements. The superficial collicular layers receive information from all parts of the retina, and relay it to the deep layers of the superior colliculus. Importantly, these deeper layers are not specifically involved in visual information, but also receive projections from the auditory, vestibular, and somatosensory systems (see below).
Ventromedial tegmentum of medulla and pons
This region, including the raphe nuclei magnus, pallidus and obscurus, but especially the adjacent tegmental regions, has a completely different function than the dorsomedial tegmentum, which controls body posture and the position of head and eyes. One might consider the ventromedial tegmentum as the rostral extension of spinal lamina X, albeit that lamina X is rather small in more developed animals. Neurons in the ventromedial tegmentum do not project to a certain system in spinal cord and brainstem, but to all parts of the spinal gray and lateral tegmentum. One particular cell in this area projects to all levels of the spinal cord and lateral tegmentum of the brainstem, showing how diffuse this projection system is. The rostral half of the ventromedial tegmentum, including the nucleus raphe magnus and adjoining regions, projects to the dorsal horn and caudal spinal trigeminal nucleus, as well as to spinal and medullary preganglionic motoneurons. The cells in the caudal half of the ventromedial tegmentum, with nucleus raphe pallidus and obscurus and adjoining areas, project to the spinal ventral horn and brainstem lateral tegmental field, including somatic and autonomic motoneurons. The ventromedial tegmentum is not involved in specific motor systems but determines the general level of activity of the spinal cord and caudal brainstem ( Figure 1). These level setting cells are under strong control of more rostral brainstem regions as the periaqueductal gray, hypothalamus, amygdala, bed nucleus of the stria terminalis and the prefrontal cortex.
In contrast to the dorsomedial tegmentum, of which most projecting cells use glutamate or aspartate as a neurotransmitter, the cells in the ventromedial tegmental field contain many different neurotransmitters or neuromodulators, of which the most well known is serotonin, but there are many others as substance P, thyrotropin-releasing hormone (TRH), somatostatin, methionine enkephalin, leucine-enkephalin, calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), cholecystokinin, and galanin. Many of the fibers with these neurotransmitters do not terminate via conventional synapses on distinct neuronal dendrites or somata, but release their content via non-synaptic sites in the neuropil around the somata and dendrites of neurons, which fits with a general level-setting function. With regard to the ascending level-setting projections, there are the raphe nuclei in the mesencephalon, such as the caudal linear, dorsal raphe, and median raphe nuclei. Together they project to almost all structures of di- and telencephalon, including the cerebral cortex, intralaminar nuclei of the thalamus, substantia nigra, striatum, septum, bed nucleus of the stria terminalis, amygdala, and hippocampus. There are even a few projections from these rostral raphe nuclei to caudal brainstem and spinal cord.
Locus coeruleus and nucleus subcoeruleus
Dorsolaterally in the pontine tegmentum a group of nor-adrenergic neurons is located that have similar diffuse projections as the caudal pontine and medullary ventromedial tegmentum, i.e. to all parts of the brainstem and spinal cord. However, in contrast to the cells in the ventromedial tegmentum, the nor-adrenergic neurons in the locus coeruleus and subcoeruleus also contain neurons that have access to most of the di- and telencephalic regions. The nor-adrenergic innervation to all these brain regions is also involved in general level-setting of the various brain regions.
PAG and deep layers of the superior colliculus
The mesencephalon is that part of the brainstem that organizes the different inputs from various sources into a motor output in the context of the two basic laws. First of all a large portion of the mesencephalon, the inferior colliculus and the superficial layers of the superior colliculus process auditory and visual information respectively. The result of this processing is sent to the deeper layers of the superior colliculus where it is decided whether any action has to be taken. For example the deep layers of the superior colliculus send fibers via the tectobulbospinal tract to the dorsomedial tegmentum in order to adjust body posture and the position of head and eyeballs, i.e. changes the position of the body, head, and visual field into the direction of possible danger. Another very important structure is the periaqueductal gray (PAG), which can be considered the emotional output center. It controls heart rate, respiration, vocalization, micturition, nociception, blood pressure and all other systems that are involved in basic survival. Also mating behavior (law #2) is controlled by the PAG. The PAG and the deep layers of the superior colliculus, also called mesencephalic tegmentum, are not completely separate entities, because similar ipsilateral projections to the ventromedial tegmentum of caudal pons and medulla originate from both regions. The PAG also has strong connections with various premotor centers for specific mechanisms as the pontine micturition center for micturition, the retroambiguus for respiration, vocalization, and mating behavior, and the subretrofacial nucleus for the control of blood pressure. Thus all the basic survival mechanisms are coordinated on the level of the PAG and adjoining tegmentum ( Figure 3).
The red nucleus is also located in mesencephalon, ventrolateral to the PAG. The magnocellular red nucleus, in contrast to the dorsomedial tegmentum of caudal pons and medulla, controls the motor output of the limbs, i.e. the fore- and hindlegs. Since the limbs are a phylogenetically later development (see for example the development of tadpole into frog), its supraspinal control center, the red nucleus, is also a later development. Cells in the red nucleus project contralaterally to the premotor and to a limited extent motoneurons of the limb muscles. This rubrospinal projection system is well developed in most mammals, but in humans it is very limited, because this motor control system is taken over by the motor cortex. Although the rubrospinal cells are known to be controlled by motor cortex and deep cerebellar nuclei, it is known that these cells are also activated by other sources, since nociceptive stimuli effect their activity. It is not unlikely that cells in the deep layers of the superior colliculus, receiving visual, auditory, and somatosensory input, have access to the rubrospinal cells, albeit that such a projection has not yet been demonstrated. This way, the mesencephalic tegmentum can produce movements of the back, neck, and head, as well as of the limbs, in order to maintain survival.
Emotional and somatic motor systems
The mesencephalon, including the PAG, adjoining tegmentum (deep layers of the superior colliculus) and the red nucleus can be considered as relatively well developed coordinating brain centers, which also in humans are of crucial importance for basic survival. However, they are under very strong control of supramesencephalic regions. The PAG and adjoining tegmentum receive very strong projections from the limbic system, such as the amygdala, hypothalamus, bed nucleus of the stria terminalis, but the strongest projections are from the prefrontal cortex. All these regions take part in the so-called emotional motor system ( Figure 4).
The red nucleus is under strong control of the motor cortex. In simple terms, the cerebral cortex can be considered as a “copy or rather a replica” of the brainstem, with the visual cortex as a replica of the superficial layers of the superior colliculus, the auditory cortex as a replica of the inferior colliculus. The motor cortex, in this concept, is a replica of the magnocellular red nucleus and dorsomedial tegmentum. These regions together belong to the so-called somatic motor system ( Figure 4).
The extended amygdala (amygdala together with bed nucleus of the stria terminalis) and the medial prefrontal cortex is the replica of the PAG and adjoining tegmentum. There are two important differences. First of all the primary cortical regions are much larger than the equivalent regions in the brainstem, but perhaps the most important difference is the presence of large secondary and tertiary cortical regions. They can be considered as the memory of the primary cortical regions, which allows them to recognize certain events and to produce motor activities from the cortical memory, crucial for typical human activities as speech and understanding language. Nevertheless, the cortex keeps using those brainstem regions of which the functions are so well organized that they don’t have to be improved. Examples are the prefrontal eyefield using the dorsomedial tegmentum for changing the visual field, the prefrontal cortex for producing speech by way of its projections to Broca’s area and at the same time to the PAG-retroambiguus system for producing the sound. Also the emotional motor system with its origin in prefrontal cortex and extended amygdala produces its effects exclusively via the PAG and the basic premotor regions in the caudal brainstem. Only the magnocellular red nucleus motor seems to have become redundant in the human brain, because the motor cortex has taken over all its control mechanisms. In the brains of lower mammals as rat, cat and monkey, however, the magnocellular red nucleus still plays an important role in the somatic motor system.
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