2. Motor component, including the axons of lower motor neurons (LMNs) and the neuromuscular junction.

 b. Autonomic Component

1. Sympathetic component, including preganglionic axons, ganglion cells, and their postganglionic axons.

2. Parasympathetic component, including preganglionic axons, ganglion cells, and their postganglionic axons.

 2. Gross Anatomy of the PNS

There are two kinds of peripheral nerves, spinal nerves and cranial nerves. There are 31 pairs of spinal nerves. These are all mixed nerves containing more than one of the aforementioned sensory, motor, or autonomic components to the body. The cranial nerves supply these same functional components to the head and neck. The only difference, other than their area of supply, is that the individual cranial nerves are more specialized. Some of them are almost purely sensory, some are purely motor, and some are partially autonomic. Spinal nerves distribute to the body in a fairly regular pattern (called somatotopic distribution), based on their origin from the spinal cord. The 31 spinal nerves are distributed as follows: 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 1 coccygeal.

The cervical nerves leave the spinal canal through the vertebral foramina rostral to their respective vertebrae except for cervical nerve 8, which leaves caudal to vertebra 7 (because there are only 7 cervical vertebrae). The rest of the spinal nerves leave the vertebral column caudal to their vertebrae. These nerves are numbered for their vertebral levels in the following manner. The first cervical nerve is designated C1, the second, C2, and so forth. The first thoracic is T1; the third lumbar is L3. The cervical nerves supply the shoulder and the upper limb. The thoracic nerves supply the body trunk in the thoracic and abdominal region. The lumbar and sacral nerves supply the lower limb and perineal region. Figure 1- 13 shows the spinal nerves as they exit from the vertebral column.

Cranial nerves are designated by Roman numerals I through XII as well as by their individual names. Because their areas of distribution and their functions are not as regular as the spinal nerves, a brief summary has been provided in the section of this chapter on Regional Neuroanatomy (Table 1-4). These cranial nerves have been subdivided into their sensory, motor and autonomic components. For a more complete and detailed review of these nerves as well as the precise distribution of the individual spinal nerves, one of the neuroanatomy textbooks should be consulted. Such detailed consideration is beyond the scope of this overview. Even though cranial nerves I (olfactory) and II (optic) have been included in the summary, they are really peripherally located tracts of the CNS, and should be considered part of the brain.

 3. Sensory Aspects of the PNS

There are many kinds of sensory receptors, but they all have one thing in common- they all act as transducers to convert various types of external stimuli into electrical impulses. We will not describe the anatomy of these receptors because we are more concerned here with the kinds of information they can transform. For a detailed recounting of receptor anatomy, consult one of the major neuroanatomy textbooks. Bear in mind that there is still no absolute correlation of morphological receptor types and the functional transduction they perform for specific modalities. For the body, these types of information (modalities) can be arranged as follows:

1. Fine, discriminative touch, vibration, two-point discrimination, stereognosis (the ability to determine the size, shape, and texture of an object by tough alone)

    

2. Proprioception, information concerning the action and position of muscles and joints
   • (a) Conscious proprioception-joint position
   • (b) Unconscious proprioception-muscle position and movement

b. Protopathic Modalities (Somatic Sensation)

1. Pain (both fast, localized pain and slow, excruciating, poorly localized pain)
2. Temperature
3. Light moving touch

c. Special Senses

1. Vision
2. Olfaction
3. Audition
4. Vestibular proprioception, the position of the head in space (linear and angular acceleration)
5. Taste

1. Painful sensation from the viscera
2. Non-painful sensation from the viscera

Information transduced by the receptor is conveyed into the CNS by a primary sensory axon. Its most distal part is the receptor and the initial segment immediately adjacent to the receptor. The initial segment is the portion of the axon in which the action potential is initiated, analogous to the axon hillock, except that it is not next to the cell body. The receptor functionally can be considered a dendrite. The rest of the neurite can be considered the axon, which continues into the spinal cord as part of a spinal nerve. The cell body of the primary sensory neuron for somatic sensation is in the dorsal root ganglion, near the spinal cord. It does not have a direct role in carrying or initiating the action potential. The primary sensory cell body therefore serves mainly a trophic role to help nourish and maintain the process. After the axon passes through the dorsal root ganglion, it enters the spinal cord through the dorsal root. See Figure 1- 14 for a summary of the anatomy and connections of a primary sensory neuron. The central processing of the information conveyed by the primary sensory neurons will be discussed in more detail under the sections of spinal cord and sensory systems.

The only component of the motor system found in the periphery is the axon of the lower motor neuron (LMN). Cell bodies of LMNs are found in the spinal cord anterior horn (anterior horn cells) and in motor cranial nerve nuclei in the brain stem. The axon leaves the CNS with a cranial nerve, or with a spinal nerve after exiting through a ventral root. LMNs innervate skeletal muscle. Each motor axon innervates more than one muscle fiber and establishes a functional motor unit (the LMN and all muscle fibers it supplies). When the axon carries an action potential to the terminals, all fibers of the motor unit contract together. In conditions in which LMNs are damaged or degenerating, aberrant discharges in LMNs lead to motor unit twitches (fasciculations), which can be visualized directly. The junctional complex, or synapse, between a LMN and the muscle is called a neuromuscular junction (NMJ), and the terminal of the LMN is called a motor end plate.

An action potential arriving at the terminal of a LMN depolarizes the terminal, causing the release of the neurotransmitter acetylcholine (ACh). ACh diffuses across the synaptic cleft, which in the case of the neuromuscular junction is thrown into numerous secondary folds, thus expanding the surface area of muscle membrane possessing receptors with which the ACh will interact. ACh combines with specific receptors on the muscle membrane, causing it to depolarize, resulting in muscle contraction. These ACh receptors can be activated by nicotine, and are called nicotinic (N) cholinergic receptors. In the total absence of ACh or other compounds that would bind with the receptor, the muscle will be unresponsive and flaccid. This is also true if the LMN itself is destroyed so that no neurotransmission can take place. The cholinergic receptors on the muscle also respond to destruction or cutting of the nerve. Normally, receptors are concentrated densely at the NMJ. When the nerve is lost, the nicotinic receptors proliferate across the surface of the muscle, where they are sensitive to ACh or cholinomimetic compounds from any source. Muscle twitches in this circumstance are not the result of normal neurotransmission from an intact nerve, but reflect the denervation hypersensitivity of the receptors. These twitches, called fibrillation’s, cannot be observed visually, but can be detected by electrical recording, called electromyography.

ACh is removed from the synaptic cleft and is broken down by the enzyme acetylcholinesterase (AChE), found also on the muscle membrane and in the motor terminals. It is extremely important for normal nerve function that this enzyme be present and that it break down (hydrolyze) ACh. If it is not present and functioning properly, or if this enzyme is inhibited by an anti-cholinesterase agent (e.g. nerve gas), the ACh persisting at the NMJ will cause continued stimulation of the nicotinic receptors and continued contraction of the muscle that is no longer under complete neural control. With prolonged persistence of ACh in the cleft, the muscle membrane is chronically depolarized, resulting in total muscle paralysis and death.

Certain drugs have been developed that can be used to augment the action of ACh. For example, in the disease myasthenia gravis, there are not enough receptors available to interact with the ACh that is released from the motor end plate because of antibodies against the nicotinic ACh receptors. A drug that blocks the action of AChE, called an anti-cholinesterase (or cholinesterase inhibitor) is given so that the transmitter can persist in the synaptic cleft longer, increasing the chance that it will combine with receptors and will augment muscle contraction. It should be clear that manipulation of the neurotransmitter (its synthesis, release, combination with a receptor, or its removal from the synapse and eventual metabolism) could be extremely important in controlling muscle activity. It also should be clear that without the presence of a LMN, the skeletal muscle can’t be made to function properly, or to respond to commands from the CNS, no matter how much of a drug or manipulative therapy is used. Fortunately, peripheral nerves have the capacity to regenerate and repair themselves to some extent, if the cell body has not been destroyed. In addition, other LMNs may be able to sprout and reinnervate muscles previously denervated, as happens in polio when the polio virus destroys some, but not all, LMNs. However, when the cell bodies have been destroyed, as in polio with total death of LMNs, or a spinal cord crush injury at the level of total destruction, the neurons die and are not replaced. In these cases, no amount of treatment will help muscle tone or will restore even a small degree of movement.

In general, the autonomic nervous system exists as a two-neuron chain. The first neuron has its cell body in the CNS and is called the preganglionic cell. Its axon, the preganglionic axon, is myelinated, leaves the CNS, and synapses in an autonomic ganglion. The ganglion contains cell bodies for the second neuron is called the postganglionic neuron. The postganglionic axons are mainly unmyelinated. The autonomic nervous system has two divisions, the sympathetic and the parasympathetic, which will be discussed separately.

The general action of the sympathetic nervous system is to activate or arouse the organism to prepare for "fight or flight" activity. The response of this system is widespread, preparing the whole body for activity. It usually is activated by the perception of stress and is not so much a reaction to a specific stimulus as a reaction to the nervous system's interpretation of that stimulus. It is particularly important for a therapist to realize that a patient may respond to therapeutic manipulation intended to assist in motor activities as if it were stressful. The resultant activation of the sympathetics, with the concomitant tensing of muscles, increase in heart rate and respiration, and decrease in homeostatic mechanisms such as digestion may be undesirable, and may interfere with therapy.

Some preganglionic axons do not synapse in chain ganglia at all. They pass through the ganglia, forming bundles called splanchnic nerves, and eventually synapse in collateral sympathetic ganglia (prevertebral ganglia) that are near the target organs. The postganglionic axons leave these ganglia to synapse on the target tissue directly. See Figure 1- 15 for a diagram of sympathetic neurons. These synaptic structures are not like the usual motor nerve terminals. They occur along the length of the axon, as illustrated by Figure 1-16. The individual terminals are called varicosities, and this kind of synapse is called a terminal en passage because the axon does not end there. These synapses are different from central synapse; they may have very wide "synaptic clefts" so that the neurotransmitter must diffuse over a much wider area. The presynaptic ending does not always sit in close proximity to the postsynaptic site, as does the cholinergic nerve ending at the NMJ or central synapses.

Because the collateral ganglia are located near the organ innervated, the cell bodies often are intermingled with nerve terminals in this area. This combination of preganglionic axons and terminals, collateral ganglion cells, and postganglionic axons and terminals, is called a plexus. A plexus may contain both sympathetic and parasympathetic components. Therefore, the conglomeration of neural elements found on the ventral surface of the aorta and large blood vessels, and in or near many organs innervated, are located in autonomic plexuses. For details of the anatomy of the many peripheral plexuses, consult one of the major neuroanatomy or gross anatomy textbooks.

The spreading out of the sympathetics from the relatively restricted preganglionic cells to the widely distributed ganglia, and the less specific nature of the synapses, or neuroeffector junctions, provide the anatomical basis underlying the basic principal that the action of the sympathetic nervous system is widespread. In addition, the adrenal medullary chromaffin cells, which produces the hormones epinephrine (80 per cent) and norepinephrine (20 per cent) for release into the blood, can be considered a component of the SNS. The greater splanchnic nerves, arising from the thoracic chain ganglia (but not synapsing in them), contain preganglionic sympathetic axons that synapse on chromaffin cells of the adrenal medulla. Stimulation of these axons results in the release of epinephrine and norepinephrine into the blood, which carries these compounds to effector tissues, augmenting the action of the sympathetic nervous system. These hormones of adrenal derivation can interact with receptors directly, and also can be taken up by the sympathetic postganglionic noradrenergic nerve terminals, stored, and used subsequently for release as a neurotransmitter. This is an example of a compound with both hormonal and neurotransmitter roles. It also should be noted that adrenal glucocorticoids, released by the action of ACTH (adrenal corticotrophic hormone), a stress hormone from the anterior pituitary, can enhance production of catecholamines in the adrenal medullary chromaffin cells, further enhancing general sympathetic arousal.

The peripheral distribution of sympathetic nerves, once they leave the ganglia, usually follows blood vessels. For example, the sympathetic supply to the head comes almost entirely from the superior cervical ganglion, the rostral-most ganglion of the sympathetic chain. Many of the postganglionic fibers travel along the surface of the carotid artery and it branches to reach their eventual terminations on smooth muscles (pupillary dilator muscle) and glands (mucosal glands) of the head. Some sympathetic fibers travel with nerves, but only rarely is a nerve composed mainly of postganglionic sympathetic fibers (the splenic nerve is the best example).

In general, the sympathetic nervous system can function as a single entity to prepare the body to cope with stress, particularly a dangerous or frightening situation. The pupils dilate, skin and gut blood vessels constrict, muscle blood vessels dilate, bronchioles dilate to allow passage of more air, heart rate increases, and more blood is pumped with each beat. Table 1 - 1 summarizes the actions of the sympathetic nervous system on various tissues.

The postganglionic sympathetic fibers achieve their effects on peripheral tissue by releasing the neurotransmitter norepinephrine (except for sweat glands, innervated by ACh fibers). For this reason, they are called noradrenergic or adrenergic neurons. Many available drugs affect these neurons. The preganglionic cells use ACh as their neurotransmitter, as do the LMNs, and are called cholinergic neurons. The receptors on the ganglion cells are different from those on skeletal muscle cells, although they both respond to nicotine and are considered to be nicotinic cholinergic receptors. They respond to the same transmitter ACh, but they respond differently to other drugs that are applied to them. This is important pharmacologically because it allows the manipulation of one kind of receptor without necessarily causing the same effect on the other receptors. For example, a drug might be given that will partially block cholinergic: receptors on muscle, causing relaxation of that muscle, but that drug will not block cholinergic: preganglionic fibers from synapsing with ganglion cells of the autonomic nervous system. More details will be supplied concerning the pharmacological manipulation of the autonomic nervous system following the next section on the parasympathetic nervous system.

The action of the parasympathetic nervous system is mostly homeostatic, allowing the maintenance and repair of the body. This particularly is the case with the process of digestion, which depends extensively on the parasympathetic system. Sympathetic arousal virtually shuts digestion down. Parasympathetic stimulation is necessary for gut contractility, motility, and peristalsis, and secretion of digestive enzymes and other gut secretory products.

Anatomically, the parasympathetics are similar to the sympathetics in having a two-neuron chain, with preganglionic and postganglionic neuronal elements- but there the resemblance stops. The parasympathetic preganglionic neurons have their cell bodies in two areas of the CNS. The first area, the cranial portion, is in the brain stem. Four cranial nerve nuclei contain parasympathetic preganglionic cells. These are: (1) the Edinger-Westphal nucleus, the parasympathetic portion of the oculomotor nucleus that sends fibers with cranial nerve III; (2) the superior salivatory nucleus that sends fibers with cranial nerve VII; (3) the inferior salivatory nucleus that sends fibers with cranial nerve IX; and (4) the dorsal motor (or efferent) nucleus of the vagus, whose fibers contribute to cranial nerve X. Figure 1-17 depicts a schematic view of the brain stem with the approximate locations of preganglionic cell bodies of the parasympathetic nervous system. The second area of preganglionic cell bodies is in the sacral spinal cord. These cells are located in the intermediate gray of levels S2 to S4, the same zone of gray matter that contains some preganglionic sympathetics in the thoracolumbar regions. Because of the two locations of preganglionic cells, this parasympathetic portion of the autonomic system is often referred to as the craniosacral system.

The postganglionic neurons have their cell bodies in ganglia that are usually very close to, or actually part of, the organ innervated. In other words, preganglionic fibers of the parasympathetic nervous system are long, traveling to the organ innervated, while sympathetic preganglionic fibers are short, traveling to chain or collateral ganglia. As a result, the postganglionic parasympathetic fibers are rather short in comparison to the postganglionic sympathetic fibers that must travel to the organ innervated from their position closer to the spinal cord. In the head, there are specific ganglia associated with specifically innervated structures. Most of the remaining postganglionic cell bodies are located in plexuses near the aorta and its branches or in the organs themselves (called intramural ganglia). For example, the parasympathetic supply to the gut is located (1) in a plexus of cells between the longitudinal and circular smooth muscle layers of the gut wall (myenteric plexus, or Auerbach's plexus); and (2) in a submucosal plexus (Meissner's plexus). These particular arrangements allow coordinated constriction of the gut in order to pass its contents along. Table 1-2 gives the location of preganglionic's, postganglionic's, tissues innervated, and function of parasympathetic stimulation in that tissue.

Blood vessels are not supplied with parasympathetic fibers, but stimulation of the parasympathetic nervous system does affect the circulatory system by inhibiting the sympathetics. The result is dilation of gut and skin blood vessels, and dilation of the blood vessels involved in engorgement of erectile tissues.

Preganglionic parasympathetic cells are cholinergic (use ACh as a neurotransmitter) just like the preganglionic sympathetics; the postganglionic cells are also cholinergic, unlike the noradrenergic postganglionic sympathetics. But the cholinergic receptors on effector tissue differ in their chemical and pharmacological characteristics, and are stimulated by muscarine (muscarinic receptors), not nicotine.

Sympathetics and parasympathetics can exert their actions in one of two ways - they can cause primary effects by stimulating the target tissue or one can act to inhibit the other. This accounts for the effects of parasympathetics on blood vessels even though they have no parasympathetic innervation. In this case, parasympathetics inhibit sympathetic tone or constriction and thereby cause dilation. In fact, both of these activities may occur at once. In the gut, sympathetics stop digestive processes partly by direct action and partly by inhibiting parasympathetic action. Often the sympathetics and parasympathetics oppose each other in action, but there are systems in which they complement each other, such as erection and ejaculation. In addition, during some behavioral states such as chronic stress, both systems may be active. The sympathetics may cause the release of catecholamines and generalized arousal, while the parasympathetics increase gastric secretion, contributing to the production of stress ulcers.

It is essential to have a general understanding of the actions of drugs on the autonomic nervous system, because many drugs given to patients affect autonomics either directly or indirectly. Terminology is a problem in discussing autonomic neurotransmission, so the following distinctions should be made before the details are given.

1. Adrenergic (or noradrenergic) neurons are cells that use norepinephrine as a neurotransmitter.

2. Adrenergic receptors (adrenoceptors) are receptors that recognize and respond to norepinephrine, epinephrine, and dopamine, such as the sympathetically innervated effector tissues.

3. Cholinergic neurons are cells that use ACh as a neurotransmitter.

4. Cholinergic receptors are receptors that recognize and respond to ACh, such as those on ganglion cells, on parasympathetically innervated effector tissue, or on skeletal muscles.

Even though all preganglionic autonomic axons, postganglionic parasympathetic axons, and LMN axons use ACh as a neurotransmitter to stimulate postsynaptic receptors, that receptor react differently to other drugs. It is known that nicotine will stimulate the cholinergic receptors normally stimulated by ACh from preganglionic autonomics and from LMNs, but not those normally stimulated by ACh from postganglionic parasympathetics. These postganglionic parasympathetic receptors are instead stimulated by muscarine and are called muscarinic receptors. Receptors sensitive to nicotine are called nicotinic receptors. This choice of designation is perhaps unfortunate because all nicotinic receptors are not equal. While they all respond to nicotine, they respond differently to still other drugs. For example, ganglionic blockers block the nicotinic receptors on ganglion cells normally stimulated by ACh, but not the receptors at the NMJ, which are also nicotinic.

Adrenergic receptors are also of at least two different kinds. These are designated alpha and beta-adrenergic receptors. These types of receptors not only respond to different drugs, but cause different effects on the postsynaptic site. In general, alpha-receptors are excitatory except in the gut, where they are inhibitory; beta-receptors are inhibitory except in the heart, where they are excitatory. Beta-receptors can be further subdivided into beta₁ receptors (Cardiac muscle, fat cells) and beta₂ receptors (bronchi, blood vessels, lymphocytes). Alpha-receptors also have been subdivided into at least two classes, alpha₁ (mainly postsynaptic) and alpha.₂ (mainly presynaptic). These subdivisions are not rigid but may vary from one system to another.

The actions of many drugs take place on the receptors. Drugs that block receptors are usually named for the kind of receptor they block (cholinergic blockers, ganglionic blockers, adrenergic blockers, beta-blockers, alpha-blockers). They are also called antagonists. Two very common antagonists for the cholinergic system are (1) the muscarinic blockers, atropine and scopalarnine; and (2) the nicotinic blocker, curare. Common antagonists for the adrenergic receptors are (1) alpha-blockers, phentolamine and phenoxybenzamine, and (2) the beta-blocker, propranolol. Drugs that mimic the effects of neurotransmitters are called mimetics (sympathomimetics, parasympathomimetics, and cholinomimetics). They also are called agonists.

 6. Response of Peripheral Nerves to Injury

Peripheral neurons can be damaged in a number of ways- trauma, disease, toxic chemicals, and nutritional deficiencies- resulting in a peripheral neuropathy. If the cell body is killed, no regeneration of the neuron can occur. After birth, peripheral neurons do not divide, and new neurons are not usually formed. However, if the injury occurs to the axon, if the damage is not too severe, and if the distal and proximal ends of the neuron are still close together, reinnervation can occur. The distal portion of the axon dies and is phagocytosed by Schwann cells (Wallerian degeneration). Sprouts extend from the proximal end of the damaged axons, grow into the intact "tube" left by the distal basement membrane, and travel to the target effector tissue, where reinnervation occurs. When the whole neuron is killed, it is possible that nearby neurons can sprout axonal processes and reinnervate the tissue. Sympathetic postganglionic axons (noradrenergic) are particularly able to sprout and reinnervate a denervated tissue.

Another kind of injury can occur to peripheral nerves. The neuron is dependent on the integrity of its myelin sheath for proper function. Demyelinating diseases can damage axons secondarily. If the Schwann cells cannot recover and cannot remyelinate the neuron, the neuron will first lose conduction velocity and eventually the unmyelinated segment can die. This problem can alter the function of sensory, motor, and autonomic nerves. However, since only the preganglionic autonomic axons are myelinated within the ANS, this problem is mainly restricted to those components.

D. SPINAL CORD

The spinal cord lies in the vertebral canal, is surrounded by meninges, and is bathed in cerebrospinal fluid (CSF), as is the rest of the central nervous system (CNS). The spinal cord is divided into segments based on the spinal nerves associated with each segment. There are 31 segments grouped into four major regions. From rostral to caudal these divisions are: (1) cervical spinal cord, with 8 segments; (2) thoracic spinal cord, with 12 segments; (3) lumbar spinal cord, with 5 segments; and (4) sacral spinal cord, with 5 segments, and a single coccygeal segment usually grouped with the sacral spinal cord.

During development, the vertebral column grows more rapidly than the spinal cord it encloses. Therefore, in the adult, vertebral levels do not correspond with spinal segments, even though they are often designated in the same way. For example, the designation C7 may refer to a vertebral level, to a spinal nerve, or to a segment of spinal cord. In this chapter we will use such a designation for the spinal segment only and will refer to the others more specifically as C7 vertebral level, or C7 spinal nerve. For example, an injury to an adult patient at the T8 vertebral level will injure the spinal cord at approximately the T10 segment. The spinal nerves are derived from cord segments of the same number. For instance, the T8 spinal nerve is derived from spinal cord segment T8 and must travel caudally within the vertebral canal to the T8 vertebral level (opposite T10 spinal cord segment) before it leaves the canal. In general, the cervical segments are one segment different from the cervical vertebral levels. (The C5 vertebral level is approximately at the C6 spinal cord level.) The thoracic segments are approximately two segments different (the T6 vertebral level is approximately at the T8 spinal cord level). The T11 and T12 vertebral bodies correspond to the five lumbar spinal cord segments. The adult spinal cord ends at approximately the lower Ll vertebral level (see Fig. 1- 13). The tapering end of the spinal cord in this area, composed of sacral spinal segments, is called the conus medullaris.

Caudal to the conus medullaris, the vertebral canal is filled with spinal nerves traveling to their appropriate vertebral levels of exit. This bundle of spinal roots in the vertebral canal is called the cauda equina (or horse's tail). A spinal tap done to remove a sample of CSF is done in this distal lumbar vertebral region because entry of the needle will be below the caudal end of the spinal cord and is unlikely to damage the spinal roots. The spinal nerves consist of components carrying both input and output. The input (sensory component) enters the spinal cord mainly through the dorsal roots. The output (motor and autonomic components) exits the spinal cord through the ventral roots. The dorsal and ventral roots unite for each segment to form the spinal root for that segment. In actuality, the dorsal and ventral root for each segment is made up of six or more rootlets.

The spinal cord consists of two types of tissue, gray matter and white matter, as does the rest of the CNS. The gray matter consists of cell bodies arranged into clusters called nuclei (not to be confused with the nucleus of an individual cell). The white matter consists of axonal processes, appearing white because of the presence of myelin surrounding the larger fibers. Clusters of fibers are arranged into tracts. These tracts are variously called pathways, columns, channels, funiculi, fasciculi, lemnisci, and so on, but they are all axonal processes communicating with other cells at a distance.

In the spinal cord the gray matter is arranged in a butterfly, or "H," pattern in the center of the cord and can be subdivided further into a dorsal horn, a region of intermediate gray, and a ventral horn. In the spinal cord, dorsal is used synonymously with posterior and ventral with anterior. In thoracic and upper lumbar segments, a lateral horn is present at the lateral edge of the intermediate gray. The white matter is arranged into dorsal, lateral, and ventral funiculi, anatomical zones of tracts subdivided by the dorsal and ventral horns. The gray matter can be subdivided further into 10 lamina, or layers, called lamina of Rexed (Fig. 1-18). In the dorsal horn, lamina I (marginal layer) is associated with spinothalamic projections, laminae II and III (substantia gelatinosa) are associated with slow pain processing, and laminae IV and V (nucleus proprius) are associated with the processing of both slow and fast pain. The dorsal horn is separated from the dorsolateral sulcus by the entrance zone of the dorsal root fibers, called Lissauer's zone. In the intermediate gray, laminae VI, VII, and VIII contain interneurons. In the ventral horn interneurons of laminae VII and VIII are present along with clusters of LMNs, which collectively are called lamina IX. Lamina X is the commissural gray found around the central canal, and in its dorsal portion contains some preganglionic autonomic cell bodies.

The spinal cord contains major processing zones for sensory, motor, and autonomic portions of the CNS. Somatic input and some visceral input enter the spinal cord through the dorsal roots, and motor and autonomic output leaves the spinal cord through the ventral roots. In addition, local neuronal processing in the dorsal, intermediate and ventral gray matter regulates reflex activity in the spinal cord. Converging supraspinal influences from the brain regulate the final outflow from motor and preganglionic autonomic neurons. The spinal cord also serves as a diverging channel for ascending sensory information, destined for both unconscious proprioceptive responses and conscious interpretation. These secondary sensory channels and components are understood most easily by subdividing them into their individual components, which include reflex channels, cerebellar channels, and lemniscal channels. Refer to Table 1-3 for a summary of these components.

The tracts listed in Table 1-3, forming the spinal cord white matter, will be discussed under the heading Systemic Neuroanatomy. Specific areas of cells in the gray matter will also be discussed as necessary with their functional descriptions.

A spinal reflex is an appropriate motor response to a sensory stimulus, not requiring supraspinal input or higher processing. Such a reflex will occur even if supraspinal connections are removed or destroyed because of injury or disease. As long as sensory input and lower motor neuron (LMN) output are intact, a spinal reflex can occur. In fact, a spinal reflex may be hyperresponsive in a cord-injured patient (for example, mass reflexes or spastic muscle stretch reflexes). If LMNs are destroyed, as in polio, these reflexes cannot occur because no motor response is possible. Destruction of the sensory input is more difficult because it is often much more diffuse, but if all sensory input is destroyed, the reflex cannot occur. This can occasionally be seen in severe peripheral neuropathies.

The simplest example of a spinal reflex is the monosynaptic reflex. In this reflex, a sensory neuron synapses directly on a LMN. This reflex can be considered a holdover from the primitive two-neuron nervous system. It is fast and effective but not very flexible. In higher animals, upper motor neuronal control, especially through cortical regulation, can over-ride some reflexes or use this circuitry for performing complex movements. However, the supraspinal control present in intact animals makes the study of such reflexes difficult. In order to study spinal reflexes in isolation from upper motor neuronal or supraspinal control, experiments are sometimes done on animals with lesions that cut off supraspinal input (such as spinal or decerebrate preparations). These experiments show what happens locally, either in individual segments or in the whole spinal cord, but do not show how these reflexes are integrated into more complex motor behavior. The following discussion will include only spinal responses, but it should be remembered that upper motor neurons (UMNs) are extremely important for keeping LMNs and reflex pathways in a state of readiness for voluntary movements, as well as for initiating those movements.

There are basically two kinds of spinal reflexes, cutaneous (or exteroceptive) reflexes and muscle reflexes. The cutaneous reflexes are polysynaptic, while muscle reflexes may be polysynaptic (Golgi tendon organ [GTO] reflexes, reciprocal inhibition reflexes, distant responses to muscle stretch reflexes) or monosynaptic (the muscle stretch reflex). The cutaneous reflexes are a motor response to cutaneous stimulation. They also are called withdrawal reflexes or flexor reflexes. The term flexor reflex is actually a misnomer because the motor response does not have to be flexion. The only requirement is that the motor response must be appropriate to the cutaneous stimulus. Most withdrawals are flexion movements, but an extensor muscle may also carry out appropriate movements. The second kind of spinal reflexes, the muscle reflexes, adjust the tone and reactivity of muscles.

Cutaneous reflexes permit withdrawal from noxious or nociceptive stimuli. The sensory input originates from receptors in the skin and deeper tissue. Because these receptors are on the exterior of the body rather than in the viscera, they sometimes are referred to as exteroceptors and the resultant cutaneous reflexes as exteroceptive reflexes. Exteroceptors are responsive to heat, cold, touch, and pain. There are several different morphological types of receptors, and it has been suggested that each type may report a different kind of stimulus. Unfortunately, the question of which receptor reports which stimulus (or even whether a single receptor reports a single modality) has not been answered fully and will not be discussed further. Consult a major textbook for the many receptor types described by anatomists, and bear in mind that few absolute statements regarding modalities conveyed by these receptors can be made at present.

Painful or noxious stimulation of appropriate receptors causes the withdrawal (usually by flexion) of the entire limb, and sometimes of the entire body. Figure 1-19 shows a schematic of the simplest kind of polysynaptic reflex, with a receptor R, a primary sensory neuron S, synapsing on an interneuron I ₁, which in turn synapses on LMN A. LMN A innervates a flexor muscle, F₁. Stimulation of the receptor causes an action potential to fire in the primary sensory neuron. The primary sensory neuron synapses on the interneuron I₁, exciting this neuron. The interneuron synapses on the LMN, causing it to fire an action potential in turn. The LMN action potential depolarizes its terminal at the motor end plate and releases acetylcholine as its neurotransmitter, which crosses the neuromuscular junction and causes the muscle to contract, completing a cutaneous reflex.

The actual mechanism of the reflex is usually more complex than the simple reflex just described. When a finger is burned (a noxious cutaneous stimulus), the whole arm withdraws, not just the finger, or local flexor. Many muscles contract in a coordinated fashion to cause the withdrawal. This is done through interneurons that control the degree to which other LMNs will fire, and therefore the degree to which other muscles will contract. Generally speaking, the stronger, the stimulus, the more interneurons will be recruited, and the more muscles will be involved in the reflex. Figure 1-20 illustrates this principle schematically. This schematic is similar to Figure 1-19, but to it has added an additional excitatory interneuron, I₂ (remember that excitatory neurons are represented by white or undarkened cell bodies and inhibitory neurons have black or darkened cell bodies). A second LMN, B; and a second flexor muscle, F₂, that represents a synergistic muscle; one that works with the first muscle. In this case, excitation of the receptor and the primary sensory neuron causes interneuron I₁ and subsequently LMN A to fire and muscle F₁ to contract; but it also causes the interneuron I₂ to fire, exciting LMN B, resulting in the contraction of muscle F₂. Adding more interneurons increases the possibility of greater responses and provides an appropriate response for a given stimulus. The whole body does not have to withdraw; only the part actually in danger will withdraw, but the withdrawal has to be both effective and quick, and sometimes will involve a total body response.

Withdrawal reflexes affect more than just the muscles on the side of the body that receives the stimulus. Muscles on the opposite side of the body may respond as well, because of activation through interneurons. This is particularly true of withdrawal of the foot and leg, perhaps from stepping on a tack. The foot that steps on the tack withdraws by flexion of that leg, but in order to maintain balance, the other leg must extend to provide a strong pillar to keep the body from falling over. This kind of reflex is called a flexion-crossed extension reflex.

The processing that goes on in the spinal cord is diagrammed schematically in Figure 1-21. On the right side, Figure 1-21 is the same as Figure 1-20. The left side represents the left side of the spinal cord. Stimulation to receptor R will ultimately cause flexion of muscles F₁ an F₂ just as in Figure 1-20, but the primary sensory neuron also stimulates excitatory interneurons 1₃ and 1₄ on the left side of the spinal cord. These interneurons excite LMNs C and D, which in turn cause the contraction of extensor muscle E₁ and its synergistic muscle represented by E₂. Any further processing diagrammed schematically in this manner will become too complex to follow, so the following simplification will be made. Figure 1-22 represents the same system as Figure 1-21. It is understood that the primary sensory neuron excites interneurons that in turn excite LMNs. The LMNs will be designated FLX for those exciting flexor muscles and EXT for those exciting extensor muscles. For simplicity, the muscles have been left out of the diagram.

Not only are flexors on the side of the stimulus and extensors on the side opposite the stimulus excited. In order for them to have optimal effect, the extensors on the side of the stimulus and the flexors on the opposite side from the stimulus are inhibited so that they will not be working against the withdrawal reflex. This process is diagrammed in Figure 1-23. The inhibition of antagonist muscle groups is mediated through inhibitory interneurons (dark circle), and the process is called reciprocal inhibition. If a stimulus is presented on the right, as it is in the diagram, the LMNs for flexor muscles on the right will be excited, while those for extensors on the right will be inhibited. LMNs for extensors on the left will be excited, while those for flexors on the left will be inhibited.

Maintaining balance while withdrawing a whole leg may require more than simply extending the other leg. Movement of the arms may be needed as well, to offset the loss of balance. Therefore, these reflexes can involve all four limbs and the trunk at once. These reflexes are often referred to as long spinal reflexes, but the movement of each limb is appropriate to withdrawal from the noxious stimulus and maintenance of balance during the movement, and will involve both flexion and extension.

The preceding discussion has considered what happens when one noxious stimulus is presented alone. It is important to note that when more than one such stimulus is presented, one stimulus may have priority over the others, preventing appropriate responses to the latter. Pain usually has precedence over other reflexes. For example, if a scratch reflex is being elicited from a dog, pinching the dog’s foot can stop it. The foot will then be withdrawn. When the painful stimulus is stopped, the scratch will resume.

Muscles have two specialized kinds of receptors: muscle spindles and Golgi tendon organs (GTOs). These receptors are responsible for reporting information about muscles to the spinal cord for spinal reflexes and to special nuclei in the spinal cord and medulla that relay the information to the cerebellum (see the discussion of cerebellar channels). Muscle spindles report static information concerning the length or amount of stretch of individual muscle fibers, and dynamic (phasic) information concerning the speed with which an active muscle fiber is being stretched. The GTO reports the amount of tension on a tendon from the passive stretch or contraction of the muscle. This information is called proprioceptive information and is necessary for two kinds of processing: (1) in the spinal cord, it provides input to LMNs and interneurons for local reflexes such as the muscle stretch reflex; and (2) in the cerebellum, via synapses in the spinal cord or medulla, it reports the state of the muscles so that the cerebellum can coordinate the superimposition of voluntary movements directed by the cortex, or adjustments in tone and posture directed by brain stem UMNs.

The muscle spindle is a sophisticated sensory receptor that reports sensory information from muscles to the CNS and has its own motor innervation through by which it can be adjusted by the CNS. This mechanism assists the CNS by providing continuous sensory feedback from the muscles.

(1) Anatomy of the Muscle Spindle. The muscle spindle is made up of special types of muscle fibers called intrafusal fibers, attached in parallel with the skeletal muscle (extrafusal) fibers. It is attached at both ends to inelastic collagen tissue associated with a skeletal muscle fiber. The extrafusal fibers are responsible for generating the contractile power of the muscle (Fig.1-24A). The muscle spindle is surrounded by a capsule, which is attached at each end to the connective tissue of the skeletal muscle fiber about which it is reporting information. The spindle contains two types of intrafusal fibers attached to the capsule on the inside, chain fibers and bag fibers (Fig. 1-24B). These fibers have an equatorial or middle region that contains cell nuclei and a polar or end region that can contract in response to motor input to increase tension on the equatorial regions. The bag fiber has its nuclei arranged bag-like, in a central cluster, and the chain fiber has its nuclei arranged chainlike, in a row. Each muscle spindle usually has four to six chain fibers and one to two bag fibers. Fibers that are intermediate between the bag and chain fibers have been described, but their function is not well understood at present.

(2) Innervation. The muscle spindle has both sensory and motor innervation (Fig. 1-25). The sensory innervation consists of group Ia fibers and group II fibers, which are sensitive to the tension of the equatorial regions of the bag and chain fibers. Group la endings wrap mainly around the equatorial zone of the bag fibers. These Ia fibers are also called primary endings, or annulospiral endings. Group II endings innervate mainly the chain fibers. They are also called secondary endings, or flower spray endings. A stretch or tension on the equatorial region of the group Ia and II fibers will cause them to fire action potentials. The sensory input goes into the spinal cord, as discussed earlier, and synapses on LMNs or their interneurons, and on relay nuclei sending information to the cerebellum.

The motor innervation is derived from two types of gamma motor neurons (fusimotor neurons), gamma₁ and gamma₂, to be distinguished from alpha motor neurons (skeletomotor neurons). Gamma₁ endings, also called plate endings, innervate mainly the polar ends of the bag fibers, and gamma₂ endings, also called trail endings, end mainly on the chain fiber, near the polar region. Firing of these fusimotor neuron's results in contraction of the polar region of the muscle spindle, stretching or putting tensions on the equatorial region. Stretching of the equatorial region causes the sensory la and II fibers to fire. The resultant stimulation of skeletomotor neurons in the anterior (ventral) horn of the spinal cord causes the skeletal muscle fibers to contract. Experimental stimulation of the fusimotor neurons causes spindle fibers to contract, but adds negligible strength or power to the contraction of the skeletal muscle without the stimulation of skeletomotor neurons. A tightening of the muscle spindle causes the Ia and II fibers to report specific kinds of sensory information to the CNS.

(3) Function. Changes in skeletal muscle activity cause changes in the muscle spindle. Passive stretch of the muscle by tapping on a tendon, or experimental stretch of a muscle by hanging a weight on it, will cause the muscle spindle to stretch. As the spindle stretches, tension is put on the equatorial regions, causing firing of la and II fibers. Increased activity in the Ia fiber’s results in contraction of the extrafusal muscle fibers, increasing the tension produced by the skeletal muscle fibers. This shortening of the extrafusal muscle fibers causes the spindle to slacken. Spindle slackening decreases tension on the equatorial region and decreases the firing of Ia and II fibers. In summary, the spindle reflex responds to a stretch on the muscle by contracting the extrafusal fibers, restoring the muscle to its original state before the stretch. The spindle reflex therefore is a mechanism for maintaining a muscle at a fixed state of contraction. Relaxation of a muscle that has been contracted produces a response of the spindle similar to stretching the muscle; the sensory fibers increase their firing.

Gamma motor neurons act to modulate the length, and consequently the tension, in the muscle spindle so that the information reported to the CNS can be controlled. Contraction of a muscle causes slackening of the spindle so that little or no information goes into the CNS. Under these conditions, the spindle would fail to report sensory information whenever the muscle contracts. However, a resetting of spindle sensitivity is achieved by the gamma motor neurons. These neurons, when stimulated, contract the bag and chain fibers of the muscle spindle by the gamma₁ and gamma₂ motor fibers and cause the resumption of sensory information reporting to the CNS. Figure 1-26 shows what happens to the firing of group Ia and group II fibers during various activities. Type II fiber's report only static information; that is, they report the tension of the spindle, corresponding to the length of the extrafusal muscle fiber. Group la fibers also report static information to the CNS, but are even more important in reporting dynamic information as well. In this capacity, they report the speed with which the extrafusal muscle fibers are changing their length (velocity).

In Figure 1-26A, the skeletal muscle is stretched passively to a new length, which also stretches the muscle spindle. The group II fibers respond to the new tension by increasing their base rate of firing. The group Ia fibers also respond with a new rate of firing, but during the time the muscle fiber is changing its length there is a rapid burst of activity that can be equated with velocity (or change in length with respect to time) of muscle stretch. When stretching stops and a new tension is reached, the group la fiber reports that new static tension with a new firing rate. In Figure 1-26B, the skeletal muscle is contracted, causing the muscle spindle to slacken. Group II fiber’s decrease their firing to report the new length. Group Ia fibers are silent during the period of collapse, then resumes firing at a reduced rate corresponding to the new extrafusal fiber length. It should be noted that when contraction is initiated voluntarily or is adjusted by supraspinal signals, those controlling signal’s are sent to both the alpha and gamma motor neuron’s, thereby adjusting both the extrafusal and intrafusal muscle fibers to maintain the muscle spindle afferents in responsive range for the new extrafusal length. In Figure 1-26C, the muscle tendon is tapped in order to elicit a muscle stretch reflex. Group II fibers do not change their firing rate because the tap is too fast for them to respond. Group Ia fibers report a burst of firing during the stretch part of the tap. It is this quick burst of Ia fiber activity during the tap that causes the corresponding LMN to which it projects to fire. This causes contraction of the extrafusal fiber that was stretched originally, returning it to its previous length.

The preceding discussion has not considered what happens when the fusimotor neurons fire. Stimulation of these neurons increases the responsiveness of the spindles. Stimulation of the gamma₁ or plate fibers, increases responsiveness to both static and phasic events, while stimulation of gamma₂, or trail fibers, increases responsiveness to static events. Mainly descending supraspinal channels, particularly those channels that are influenced by cerebellar outflow, fires the fusimotor neurons. On the other hand, stimulation of alpha motor neurons does not influence directly the contractile elements of the muscle spindle. These neurons cause the skeletal muscle extrafusal fibers to contract and indirectly influence the spindle through altered sensory activity caused by shortening of the extrafusal muscle fibers. Figure 1-27 shows an Ia afferent fiber synapsing directly on a LMN in the spinal cord. Ia stimulation is the most powerful driving force for firing LMNs and causing a muscle contraction or an increase in muscle tension. This phenomenon is exploited clinically by vibration, which can drive Ia afferents tonically, enhancing the contraction of the associated muscle group, a process that can be exploited therapeutically to excite a muscle group antagonistic to a spastic muscle group, thereby reducing the spasticity by reciprocal inhibition. It should be clear that the fusimotor neurons, which can control the sensitivity or responsiveness of the Ia afferent fibers, are critical to the responsiveness of the alpha motor neurons and the control of muscle tone.

Control of fusimotor neurons is from UMN systems that in part keep the fusimotor neurons in check (inhibited). Damage of these UMNs can cause a disinhibition of fusimotor neurons, increasing their firing. The resultant increased stimulation causes the muscle spindle to become more sensitive, which produces more vigorous firing of Ia afferents to stretch, and finally results in an increase in muscle tone brought about by increased LMN firing and an exaggerated response to stretch reflexes owing to the increased sensitivity of the muscle spindle. This increased resistance to passive stretch is called spasticity.

When UMN control is present during normal tone and posture and during normal voluntary movements, both skeletomotor and fusimotor neurons are activated at the same time by the UMNs. This alpha-gamma co-activation prevents the muscle spindle from collapsing during the contraction of the skeletal muscle, so that proprioceptive information is reported continuously to the CNS. Therefore, both fusimotor and skeletomotor neurons act in concert to achieve voluntary motor actions and provide optimum sensory information to the CNS for maximum evaluation of current motor activity and for regulation of subsequent motor activity.

The Golgi tendon organ (GTO) is a receptor that is connected in series with the muscle so that contraction of the whole muscle increases tension on the tendon and excites the GTO. Primary sensory afferents from the GTO called Ib fibers, enter the spinal cord and synapse on interneurons associated with LMNs, and in secondary sensory nuclei that relay unconscious proprioceptive information concerning the state of whole muscles to the cerebellum. The GTO is sensitive to tension on the tendon and therefore is active during both passive stretch and contraction. However, it is difficult to elicit a normal GTO response during a clinical examination. The Ib reflex associated with the GTO and the Ib afferent fiber is an inhibitory reflex that prevents the muscle tendon from being damaged due to excessive muscle contraction. Although the GTO is extremely sensitive to tension on the tendon, and may help to regulate inhibition necessary for alternating movements, no single specific reflex for the Ib fiber can be elicited as simply as can the Ia monosynaptic muscle stretch reflex. However, Ib reflex activity can be demonstrated in a patient with spasticity that has greatly increased tone in response to passive stretch. Passive movement of the spastic limb will meet with considerable resistance at first, followed by a collapse of resistance as the passive movement is continued. The collapse is called a clasp-knife reflex (named after the collapsing of the blade in a pocket knife) and is thought to be the result of Ib inhibition, preventing firing of overactive LMNs so that the muscle will not be damaged because of excessive resistance of the spastic muscle.

Each of the three types of afferent fibers just discussed (Ia, II, and Ib) has an effect on several groups of muscles through the LMNs supplying those muscles. LMNs supplying the muscle from which the afferent fiber derives are called homonymous LMNs. LMNs to the muscles that work with the homonymous muscle are called synergist LMNs. LMNs to the muscle groups that work against or opposite to the homonymous muscle are called antagonist LMNs. Figure 1-28 shows schematically how these reflexes affect their appropriate LMNs. Ia afferents excite homonymous LMNs monosynaptically and synergist LMNs polysynaptically through interneurons. Ia afferents also inhibit antagonist muscle LMNs polysynaptically through an inhibitory interneuron. Ib afferents work in the opposite direction. They inhibit homonymous and synergist LMNs disynaptically through inhibitory interneurons and excite antagonist LMNs disynaptically. Group II reflexes doesn’t work like Ia and Ib reflexes. The group II fibers are thought to respond as a unit with a flexor bias. That is, they consistently facilitate flexor LMNs and inhibit extensor muscle LMNs polysynaptically. However, most research on group II responses is conducted in non-primate animal models. The actual role of group II fibers in humans is not understood adequately at present, and definitive pronouncements about their role in normal or neurologically damaged patients are not possible.

The mammalian nervous system is divided into a peripheral nervous system (PNS), in contact with the outside world and the internal world, and a central nervous system (CNS) that provides integrated control of the periphery, interpretation of stimuli, and generation of internal activities and thoughts. The contacts between the outside world and the nervous system constitute the sensory and motor components of the nervous system. The sensory systems respond to stimuli from the external environment or the internal milieu of the body while the motor system causes skeletal muscles to contract, thus permitting movement and behavior in response to the environment or as primary, voluntarily initiated events. In addition, there is an autonomic nervous system that has components in both the CNS and PNS. This third functional component of the nervous system permits the regulation of smooth muscle, cardiac muscle, secretory (exocrine) glands, and other visceral organs (such as the liver and immune organs), and operates as an internal visceral regulatory control system.

The PNS has the following components: (1) primary sensory cell bodies and axons, and associated receptors; (2) axons of lower motor neurons (LMNs) and their neuromuscular junctions (NMJ’s); (3) preganglionic axons, and ganglion cells and their postganglionic axons of the autonomic nervous system; and (4) the enteric nervous system, sometimes called the third division of the autonomic nervous system, a collection of 100 million neurons found in the gastrointestinal tract that aids the many activities of that system.

The CNS can be subdivided into the following major regions, based on the development of the brain:

• Spinal cord
• Rhombencephalon
  • Myelencephalon-medulla
  • Metencephalon-pons and cerebellum
• Mesencephalon-midbrain
• Prosencephalon (forebrain)
  • Diencephalon (between brain)
    • Thalamus
    • Hypothalamus
    • Subthalamus
    • Epithalamus
• Telencephalon (end brain)
  • Olfactory system
  • Limbic system
  • Basal ganglia
  • Neocortex

The human brain possesses surface landmarks that can be used to delineate these subdivisions (see Figs. 1-29 through 1-32). The spinal cord is distinguished from the medulla by the decussation (crossing) of the pyramids (corticospinal tract), seen on the ventral surface of the caudal-most portion of the medulla (Fig. 1-31). There are no clearly distinguishing features on the dorsal surface of the caudal medulla at its boundary with the spinal cord. The internal demarcation of the spinal cord-medulla transition is gradual. Therefore, by convention, an arbitrary division is made by a plane perpendicular to the neuroaxis (long axis of the brain stem) passing through the spinal cord just above (rostral to) the first pair of cervical rootlets.

The demarcation of the rostral medulla from the caudal pons is both clear and consistent. It consists of a plane through the caudal boundary of the basis pontis of the ventral surface of the brain stem, perpendicular to the neuroaxis (Fig. 1-31). This line of separation also marks the point where cranial nerves VII (facial) and VIII (vestibulocochlear) emerge from the brain stem at the medullopontocerebellar (cerebellopontine) angle, and where the VI (abducens) nerve emerges from the ventral surface.

The midbrain contains the cerebral peduncles on its ventral surface. The caudal boundary of the midbrain is the end of the basis pontis at its junction with the caudal-most beginning of the cerebral peduncles. The caudal boundary of the mammillary bodies in the hypothalamus delineates the rostral boundary of the mesencephalon. The dorsal surface of the midbrain contains two sets of small protrusions, or hillocks, the inferior and superior colliculi (Fig. 1-32). The colliculi are called the quadrigeminal bodies, which make up the midbrain tectum.

The diencephalon is a direct rostral continuation of the brain stem. The boundaries of the diencephalon include the mammillary bodies at the caudal end, located at the base of the brain, and the anterior commissure and lamina terminalis, located at the rostral. end of the third ventricle just above the optic chiasm (see Fig. 1-30). A plane passing perpendicular to the ventral surface of the brain at the rostral boundary of the hypothalamus separates the diencephalon caudally from the basal telencephalon rostrally. In addition, surrounding the diencephalon is an outer mantle of telencephalon containing limbic forebrain, basal ganglia, and neocortical structures. In order to dissect specific regions of the thalamus and hypothalamus, it is necessary to remove or cut through an outer telencephalic shell of structures. Further subdivision of the telencephalon is based upon a functional parcellation of structures into the olfactory system, limbic system, basal ganglia, and neocortex.

Each of the regions just noted contains specific areas, tracts, and nuclei that will be considered in further detail. The spinal cord has been discussed in a previous section as a model for CNS organization. In the following section the brain stem (medulla, pons, midbrain, and cerebellum) and forebrain (diencephalon and telencephalon) will be discussed in a regional fashion. Even though regional neuroanatomy is the main focus of this portion of the chapter, the description still contains a strong systemic orientation. With this approach, regional neuroanatomy makes more sense functionally, rather than merely being a recounting of innumerable anatomical structures.

A good atlas and Figure 1-29 through 1-32 should be referred to continually as this section is read so that the structures discussed can be visualized. Because the PNS and the spinal cord already were described in the last section, we will begin here with the brain stem.

The brain stem is made up of the medulla, pons, midbrain, and cerebellum. These regions are so closely related that they are best considered as a functional unit. While some anatomists consider the diencephalon to be part of the brain stem, we do not; the diencephalon is a highly specialized structure that will be considered separately. The nuclei and tracts of the brain stem are intermingled and appear scattered. However, they do follow functional patterns in the medulla, pons, and midbrain. These three major subdivisions contain six major components that form the basis for regional anatomy for each subdivision. There obviously is overlap, in some cases, of certain components (such as the sensory, motor, and autonomic cranial nerve nuclei).

1. Lower Motor Neurons. The cell bodies are located in the brain stem and the axon’s exit through cranial nerves to innervate muscles of the head and neck.
2. Upper Motor Neurons. The cell bodies are located in the brain stem; the axons descend to the LMNs and associated interneurons, which they control.
3. Descending Motor Pathways. The pathways (e.g. corticospinal tract) consist of axons of UMN system’s that are passing through the region on the way to LMNs and associated interneurons at lower levels.

1. Parasympathetic Preganglionic Cell Bodies. The cell bodies are located in specific nuclei in the brain stem and the axons exit through cranial nerves III, VII, IX, and X to terminate in parasympathetic ganglia near the cardiac muscle, smooth muscles, secretory glands, and viscera those ganglia supply (see Fig. 1- 17).
2. Autonomic Centers. These centers regulate major visceral functions such as respiration, cardiac function, blood pressure, and gastrointestinal functions. These centers are sometimes viewed as complex regulatory regions of the reticular formation and can involve integrated sensory, motor, and autonomic activities. The reticular formation will be discussed later in this section.
3. Descending Autonomic Pathways. Cell bodies from the hypothalamus, amygdala, and cerebral cortex, as well as from the brainstem itself, sends axons that descend through the brain stem to terminate in preganglionic autonomic nuclei or associated regions, such as nucleus solitarius.Additional descending pathways can involve polysynaptic channels to the preganglionic neurons.

1. Secondary Sensory Nuclei. These cell bodies receive input from primary sensory axons and send projections toward higher structures, particularly the thalamic sensory projection nuclei. All primary sensory cell bodies are found in ganglia associated with peripheral or cranial nerves, except for the mesencephalic nucleus of V, which is the only primary sensory cell group within the CNS. Primary sensory ganglion cells project to the secondary sensory nuclei through the peripheral and cranial nerves, and associated primary sensory tracts, such as the solitary tract, the descending tract of V, or fasciculi gracilis and cuneatus.
2. Ascending Pathways and Relay Center. The pathways are mainly ascending secondary sensory (lemniscal) channels. The relay centers include tertiary nuclei or nuclei associated with sensory processing, and give rise to tertiary sensory channels.

d. Cerebellar Systems

e. Reticular Formation

This general region, forming the core of the brain stem and the most ancient supraspinal control systems, includes nuclei, pathways, and centers that control visceral, motor, and sensory functions necessary for life. The reticular formation includes a medial two third (mainly motor), a lateral one third (mainly sensory), the midline raphe, and scattered catecholamine systems. It is responsible for maintaining consciousness, maintaining general muscle tone and posture, processing noxious stimuli, regulating major visceral functions, and providing a host of interconnecting links that are reflex and integrative, and allow quick and appropriate adjustments to disturbances in the external or internal environment.

f. Cranial Nerve Nuclei

These nuclei include components of the sensory, motor, and autonomic systems. This category directly overlaps with categories 1, 2, and 3, and is best considered in these other categories.

a. Lower Motor Neurons

Several motor cranial nerve nuclei are found in the medulla. The hypoglossal nucleus (Nucleus XII) is found near the midline and sends axons through the hypoglossal (XII) nerve to innervate the muscles of the tongue.

The nucleus ambiguus is located in the ventrolateral medulla and sends axons through the glossopharyngeal (IX), vagus (X), and spinal accessory (XI) nerves to innervate palatopharyngeal and laryngeal muscles and the esophagus.

The spinal accessory (XI) nucleus is located in the ventral gray matter of the upper cervical spinal cord; it sends axons through the XI nerve to the sternocleidomastoid and the trapezius muscles. Although the LMNs are found in the spinal cord, the axons travel with a cranial nerve.

The gigantocellular reticular nucleus in the medial reticular formation sends axons that run in the medullary (lateral) reticulospinal tract. This tract is mainly excitatory to flexor LMNs through interneurons and aids in the general maintenance of tone.

The lateral vestibular nucleus sends axons that run in the lateral vestibulospinal tract. This tract is mainly excitatory to extensor motor neurons, with a few direct connections and a predominance of indirect connections through interneurons. It aids in the maintenance of antigravity tone, particularly in response to vestibular stimulation.

The medial vestibular nucleus sends axons that run in the medial vestibulospinal tract. This tract terminates both directly and indirectly on cervical LMNs and regulates neck movements in response to vestibular input, for maintenance of head position.

Raphe nuclei of the medulla (obscurus, pallidus, and magnus) send descending axon’s through scattered zones of the medulla and through the lateral and ventral funiculus of the spinal cord. These axons terminate in the ventral horn and aid in the maintenance of tone, perhaps enhancing or reinforcing the action of other neurotransmitters on LMNs (neuromodulatory action). This descending bulbospinal pathway influences sensory functions and is necessary for narcotic analgesia to occur, and also influences preganglionic autonomic activity.

Several pathways descend through the medulla on their way to spinal cord interneurons and LMNs. The corticospinal tract (pyramidal tract) arises in frontal and parietal lobes and descends through the internal capsule, cerebral peduncles, and basis pontis. Continuing its descent in the ventral medulla, 80 per cent of the fibers decussate at the caudal-most midline region of the medulla. The crossed portion continues into the spinal cord as the lateral corticospinal tract. while the uncrossed portion continues as the anterior corticospinal tract and then mainly crosses into the contralateral ventral horn through the anterior white commissure of the spinal cord. The corticospinal tract regulates fine skilled hand and finger movements, with a predominant influence on flexor LMNs.

The rubrospinal tract arises in the red nucleus of the midbrain, crosses the midline in the ventral tegmental decussation of the midbrain, descends through the ventrolateral medulla, and has a predominant influence on flexor LMNs.

The pontine reticulospinal tract arises in the pontine reticular formation, descends through the ventral medulla, and mainly influences extensor LMNs concerned with tone and posture.

The tectospinal tract arises from the superior colliculus and to a lesser extent from the inferior colliculus, crosses the midline in the dorsal tegmental decussation, descends through the medial longitudinal fasciculus, and terminates mainly in the cervical spinal cord. This tract influences neck movements in response to visual and auditory stimuli.

The noradrenergic bulbospinal tract arises in the locus coeruleus and in noradrenergic nuclei of the brain stem tegmentum, descends in the lateral and ventral regions of the medulla, and influences general LMN tone in addition to autonomic functions.

 2. Autonomic Systems

 a. Parasympathetic Preganglionic Cell Bodies

The dorsal motor nucleus of X and related cells in the lateral reticular formation and commissure nucleus send preganglionic parasympathetic fibers through the X nerve to ganglia located near the visceral organs innervated. This system supplies the heart lungs, and gastrointestinal viscera. Cell bodies supplying the heart are found in the lateral reticular formation around the nucleus ambiguus. Cell bodies supplying the lungs and gastrointestinal viscera are found in the main nucleus of the dorsal motor nucleus of X, the commissure nucleus of the caudal medulla, and dorsal lamina X of Rexed of the first six cervical spinal cord segments.

The inferior salivatory nucleus sends preganglionic parasympathetic fibers through the IX nerve to the otic ganglion. This ganglion supplies fibers to the parotid gland, producing salivation.

b. Autonomic Centers

Numerous visceral centers have been described in regions of the reticular formation of the medulla. These centers act through the preganglionic autonomic cells and also influence some LMNs. These regions include centers for blood pressure regulation, heart rate and contractility, respiratory control, and emetic responses.

Processes from cell bodies in the hypothalamus (paraventricular nucleus and several other zones), central amygdaloid nucleus, and cerebral cortex (frontal, cingulate, and insular) descend directly to the dorsal motor nucleus of X and nucleus solitarius. Some of these cell groups send axons down to the spinal cord to end on preganglionic neurons in the intermediolateral cell column. Other systems descend indirectly (anterior hypothalamus) through the dorsal longitudinal fasciculus to the dorsal tegmental nucleus; and then to the dorsal motor nucleus of X. In the lateral aspect of the medulla, central sympathetic fibers polysynaptically descend from the hypothalamus to the preganglionic sympathetic neurons in the thoracolumbar areas of the spinal cord.

The nuclei gracilis and cuneatus are found in the medial portion of the dorsal medulla at its caudal zone. These nuclei receive input from dorsal root ganglion cells carrying epicratic modalities (gracilis, T6 and below; cuneatus, above T6) via fasciculi gracilis and cuneatus, and send crossed fibers through a decussation in the caudal medulla to form the medial lemniscus. The medial lemniscus ascends to the ventral posterolateral (VPL) nucleus of the thalamus. The nuclei gracilis and cuneatus also receive some information about vibratory sensation, joint position, and cutaneous sensation through projections from spinal cord neurons that travel in the dorsolateral funiculus.

The nucleus of the solitary tract, located in the dorsal medulla, receives cardiac and respiratory reflex afferents, and taste fibers from the geniculate, petrosal, and nodose ganglia, via nerves VII (facial), DC, and X, respectively. The rostral portion of this nucleus, subserving taste, gives rise to a crossed projection, the solitariothalamic tract. This tract ascends to the ventral posteromedial (VPM) nucleus of the thalamus, and also sends projections to brain stem nuclei such as the parabrachial complex; the caudal portion of nucleus solitarius. It processes incoming information from sensory systems such as the carotid sinus and carotid body, and regulates autonomic outflow from the parasympathetic vagal complex and the sympathetic intermediolateral cell column of the thoracolumbar spinal cord.

The descending (spinal) nucleus of V (trigeminal nerve), located at the lateral margin of the medulla, receives input from the trigeminal (gasserian or sernilunar) ganglion cells carrying protopathic modalities such as pain and temperature from the face and oral cavity. Some fibers carrying epicratic sensation (touch) from the face, and fibers from the pharynx and posterior 1/3 of the tongue (nerve IX for general sensation) also terminate in this nucleus. This elongated longitudinal nucleus sends crossed fibers into the ventral trigeminothalamic tract (VTTT) which ascends toward the ventral posteromedial (VPM) nucleus of the thalamus. Some fibers from cells of this nucleus also terminate in reticular formation and project toward nonspecific nuclei of the thalamus, as routes for transmission of slow pain.

Vestibular nuclei (medial, lateral, and inferior) are found in the medulla and continue into the pons (superior). These nuclei receive vestibular input from Scarpa's ganglion via the VIII nerve (vestibular part of the vestibulocochlear nerve). This input carries information reporting angular acceleration from the semicircular canals (movement) and linear acceleration from the utricle and saccule (gravitation). The secondary sensory afferents from the vestibular nuclei project to the spinal cord (medial and lateral vestibulospinal tracts), to the cerebellum (along with some ganglion cell projections, through the medial portion of the inferior cerebellar peduncle, the juxtarestiform body). They also project to the reticular formation through local reflex channels, and to the cranial nerve nuclei supplying extraocular muscles (III, oculomotor, IV, trochlear, VI, abducens) via the medial longitudinal fasciculus. These channels permit a coordinated activation of extensor musculature of the body, neck musculature, and extraocular musculature in response to vestibular input.

Several ascending tracts arise in or pass through the medulla. The medial lemniscus carries epicratic modalities from the body. The spinothalamic tract carries protopathic modalities, particularly fast pain, temperature sensation, and light moving touch from the body, while the spinoreticular tract carries slow pain from the body. The ventral trigeminothalamic tract and its additional projections to reticular formation carry protopathic modalities from the face, oral cavity, anterior two-thirds of the tongue, and sinuses. The solitariothalamic tract carries taste and visceral sensory information. The medial longitudinal fasciculus carries unconscious vestibular information to the extraocular cranial nerve nuclei.

The cerebellar cortex, deep nuclei, and peduncles will be considered separately in the section on the cerebellum. In the medulla, several tracts and nuclei project to the cerebellum.

Spinocerebellar tracts carry unconscious proprioceptive information to the cerebellum from the body. This information includes Ia afferents from individual muscle fibers (dorsal spinocerebellar tract from Clark's nucleus of the spinal cord from T6 and below; cuneocerebellar tract from the medullary lateral (accessory) cuneate nucleus for above T6), and Ib afferents from whole muscles (ventral spinocerebellar tract from spinal cord border cells for T6 and below; rostral spinocerebellar tract from spinal cord intermediate gray [mediobasal nucleus] for T6). These tracts enter the cerebellum through the inferior cerebellar peduncle, except for the ventral spinocerebellar tract, which enters through the superior cerebellar peduncle. For a schematic diagram of these cerebellar channels see Figure 1-34.

The inferior olivary nucleus is a large convoluted nucleus in the ventrolateral medulla that sends climbing fiber axons to the contralateral cerebellar cortex through the inferior cerebellar peduncle. This nucleus is an important motor feedback center and a spinal cord relay center for the cerebellum.

The lateral reticular nucleus of the ventrolateral medulla sends mossy fiber axons to the cerebellar cortex through the inferior cerebellar peduncle. This nucleus conveys spinal cord information from widely distributed sensory receptive fields to the cerebellum.

The medullary vestibular nuclei and the vestibular (Scarpa's) ganglion vestibulocerebellar projections through the medial portion of the inferior cerebellar peduncle, the juxtarestiform body.

Thus the inferior cerebellar peduncle is mainly a channel conveying information from the spinal cord and medulla to the cerebellum.

The inferior cerebellar peduncle carries some outflow from the cerebellar cortex and deep nuclei. Some Purkinje cell axons of the flocculonodular lobe and vermis project directly to the ipsilateral laurel vestibular nucleus. Purkinje cell axons from then arm travel to the fastigial nucleus which sends fibers through die ICP to vestibular and reticular nuclei of both sides of the brain stem.

The reticular formation is a collection of longitudinally oriented large neurons with numerous collaterals, giving rise to a tremendous amount of convergent and divergent sensory, motor, and autonomic information. In the medulla, the reticular formation contains several components. The lateral third is a sensory zone, part of the ascending reticular activating system, which receives widespread input from numerous modalities and systems, This system aids in the maintenance of consciousness and attention through projections to the adjacent ascending portions which convey information to nonspecific nuclei of the thalamus. The medial two thirds is a motor zone that gives rise to the medullary reticulospinal tract. This zone aids in the maintenance of tone and posture and exerts a bias toward flexor LMNs.

The midline raphe nuclei and lateral noradrenergic cell bodies give rise to descending serotonergic and noradrenergic pathways. These tracts aid in the maintenance of tone and posture and also play a major role in sensory and autonomic functions. Autonomic centers regulating blood pressure, cardiac function, respiratory function, and emetic function are also found in the reticular formation.

Numerous cranial nerve nuclei are found in the medulla and are discussed in the sections on motor, autonomic, and sensory systems. These nuclei are associated with cranial nerve IX, X, XI, and XII which leave or enter the medulla, and with cranial nerve VIE, found at the medullopontine junction at the cerebellopontine angle.

a. Lower Motor Neurons

Three motor cranial nerve nuclei are found in the pons. The facial nucleus (VII) is found in a lateral position in the pontine tegmentum; it sends axons' dorsomedially to loop around the abducens nucleus (genu of the facial nerve). These axons then exit through the caudal pons ventrolaterally and innervate the muscles of facial expression. The facial nucleus also innervates the stapedius muscle and aids in dampening the ossicles (stapes) in response to loud noises.

The abducens nucleus (VI) is found near the dorsal midline of the rostral pons. Its axons run ventrally through the pons and exit close to the ventral midline. This nucleus innervates the lateral rectus muscle of the eye and is responsible for turning the eye outward (lateral deviation).

The trigeminal motor nucleus (V) is found in the lateral region of the mid pons and sends axons laterally and a bit ventrally to exit through the mandibular division of the V nerve. This nucleus innervates the muscles of mastication and the tensor tympani muscle for additional dampening of the ossicles (malleus) in response to loud noises.

The caudal and rostral (also called oral) pontine reticular nuclei are found in the medial two thirds of the pontine reticular formation. These nuclei send predominantly ipsilateral (uncrossed) axonal projections to the spinal cord, where they terminate on interneurons associated with extensor lower motor neurons (LMNs). This tract has a strong extensor bias; it augments and reinforces the extensor bias of the lateral vestibulospinal tract. The lateral vestibular nucleus and its lateral vestibulospinal tract also are present in the caudal pons. These were considered in the previous section on the medulla.

The locus coeruleus is a pigmented nucleus (melanin) located just beneath the lateral portion of the fourth ventricle in the pons. This nucleus uses norepinephrine as its major neurotransmitter, in addition to co-localized neuropeptides, and sends noradrenergic axons to several structures, including the cerebral cortex, hippocampal formation, cerebellar cortex, and the spinal cord. The pathway to the spinal cord travels through the ventral and lateral brain stem tegmentum and is augmented in part by axons of noradrenergic cells found in the lateral and dorsal medulla. These noradrenergic fibers aid in the maintenance of tone and posture through interneurons and LMNs and also contribute to the regulation of autonomic functions through preganglionic autonomic neurons.

Major motor pathways descend through the pons on their way to interneurons and LMNs of the spinal cord. The corticospinal tract descends through scattered fascicles in the basis pontis. The rubrospinal tract and tectospinal tracts descend through the tegmentum of the pons. These tracts also descend through the medulla. They were discussed in greater detail in that section.

The superior salivatory nucleus is located in the dorsomedial pons as a rostral continuation of the cell column of the dorsal motor nucleus of X and the inferior salivatory nucleus. This nucleus sends fibers through the facial nerve to the pterygopaletine ganglion and the submandibular ganglion. The pterygopaletine ganglion cells supply postganglionic parasympathetic fibers to the lacrimal glands (tear production) and to glands of the nasal mucosa. The submandibular ganglion supplies postganglionic parasympathetic fibers to the submandibular and sublingual salivary glands.

A few additional autonomic centers are found in the pontine reticular formation, rostral to the medullary centers. Some respiratory functions are directed through pontine respiratory centers. In addition, some "centers" for the control of blood pressure has been described in the pons.

Hypothalamic autonomic pathways and descending pathways from limbic zones of the cerebral cortex and from the central amygdaloid nucleus descend through the pontine tegmentum on their way to sympathetic and parasympathetic preganglionic neurons in the spinal cord and rhombencephalon, as discussed earlier.

3. Sensory Systems

Sensory nuclei associated with the V and VIII nerves are found in the pons. The dorsal and ventral cochlear nuclei are located at the extreme lateral portion of the dorsal zone of the caudal pons. They receive auditory input from the cochlea through the spiral (auditory) ganglion and its projections through the VIII nerve. The dorsal and ventral cochlear nuclei send principally contralateral (crossed) fibers through acoustic stria to innervate accessory nuclei or to form ascending sensory channels. The upper part of the dorsal cochlear nucleus gives rise to the dorsal acoustic stria; the lower part of the dorsal nucleus and upper part of the ventral cochlear nucleus give rise to the intermediate acoustic stria, and the lower (anterior) part of the ventral cochlear nucleus gives rise to the ventral acoustic stria, also called the trapezoid body. These striae form the lateral lemniscus, the major ascending auditory pathway. Some fibers of the trapezoid body terminate in the superior olivary nuclei. One portion of this nucleus (dorsal accessory superior olivary nucleus) receives input onto dendrites from both sides and assists in the localization of sound in space. The superior olivary nuclei contribute fibers to both the ipsilateral and contralateral lateral lemniscus. In addition, some lateral lemniscus fibers terminate in accessory auditory nuclei (nuclei of the lateral lemniscus, nuclei of the trapezoid body). These nuclei also contribute both ipsilateral and contralateral fibers to the lateral lemniscus. The lateral lemniscus ascends to the nucleus of the inferior colliculus. This entire auditory system is clearly a bilateral system, accounting for the failure of a lesion above the level of the pons to produce deafness with a discrete localization on one side.

The main sensory nucleus of V is found just lateral to the motor nucleus of V in the lateral portion of the mid-pons, and receives input from trigeminal semilunar ganglion cells carrying epicratic modalities from the face, oral cavity, and anterior two thirds of the tongue via appropriate potions of the three divisions (V₁, ophthalmic; V₂, maxillary; V₃, mandibular) of the trigeminal nerve. The dorsal portion of this nucleus gives rise to the dorsal trigeminothalamic tract (DTTT), which has been reported to travel either ipsilaterally or contralaterally to the ventral posteromedial (VPM) nucleus of the thalamus. It is not yet clear how this projection system is organized, although the face is thought to have epicritic representation onto the lateral portion of the contralateral postcentral gyrus. Resolution of this question awaits further tracing studies in primates. This system carries fine discriminative modalities of the face for conscious interpretation. Some cells of the main sensory nucleus of V send crossed projections into the VTTT.

The descending nucleus of V also is found partially in pons and has been discussed in the section on the medulla, where the major portion of this nucleus is found. This nucleus gives rise to the ventral trigeminothalamic tract (VTTT), which carries mainly protopathic: modalities from the face toward nucleus VPM of the thalamus. Some of the fibers of this system reach nucleus VPM ("fast" pain and temperature sensation) while other fibers ("slow" pain) end in the lateral reticular formation.

The superior vestibular nucleus is located in the pons. It contributes to the same extraocular, reticular formation, and cerebellar channels as the other medullary vestibular nuclei (inferior, lateral, medial). These channels are discussed in further detail in the section on the medulla.

Several sensory tracts ascend through the pons. The medial lemniscus carries epicritic modalities from the body. The spinothalamic tract carries protopathic modalities, particularly fast pain, from the body, while the spinoreticular tract carries slow pain from the body. The ventral trigeminothalamic tract carries mainly protopathic modalities from the face, oral cavity, anterior two thirds of the tongue, and sinuses. The dorsal trigeminothalamic tract carries epicritic modalities from the same regions. The solitariothalamic tract carries taste and visceral sensory information. The lateral lemniscus carries auditory information. The medial longitudinal fasciculus carries unconscious vestibular information to the extraocular cranial nerve nuclei.

The basis pontis contains clusters of neurons located in pontine nuclei. These nuclei act as a cerebral-cerebellar relay channel. The pontine nuclei receive input from all regions of the cerebral cortex and send axonal projections to the cortex of the contralateral cerebellar hemispheres in the form of mossy fibers. These pontocerebellar fibers enter the cerebellum through their own peduncle, the middle cerebellar peduncle. This relay pathway coordinates voluntary motor activity, apparently initiated by the cortex, with tone and position of the muscles at any given moment. This relay pathway is concerned particularly with fine coordinated movements.

The pons also contains passing fibers of the ventral spinocerebellar tract (VSCT), which enters the cerebellum through the superior cerebellar peduncle, and trigeminocerebellar fibers, which enter the cerebellum through both the superior and inferior cerebellar peduncles.

The pontine reticular formation contains the same motor (medial two thirds) and sensory (lateral third) divisions as the medullary reticular formation. The motor division aids in the maintenance of tone and posture, and the sensory division aids in the maintenance of attention and consciousness.

In addition, ascending monoamine pathways arise from reticular formation nuclei of the pons. The locus coeruleus sends ascending noradrenergic fibers that join other ascending fibers from the lateral and dorsal medulla, and distribute to the hypothalamus, thalamus, limbic forebrain, and cerebral cortex through the brain stem tegmentum and the medial forebrain bundle. This system participates in the regulation of neuroendocrine functions and visceral functions (feeding, drinking, regulation, reproductive behavior, autonomic regulation) of the hypothalamus, emotional or affective behavior, and cognitive and intellectual functions. Dysfunction of this noradrenergic system has been implicated in depressive illness. The dorsal raphe nucleus and central superior nucleus send ascending serotonergic axons to the hypothalamus, thalamus, limbic: forebrain, basal ganglia, and cerebral cortex through the brain stem tegmentum and the medial forebrain bundle. This ascending serotonergic system closely overlaps the ascending noradrenergic: system. The serotonergic system has been implicated in neuroendocrine and visceral hypothalamic function, emotional behavior, and cognitive functions. These noradrenergic and serotonergic pathways and their terminals are the major sites of action of the drugs used to treat depressive and other affective disorders.

Numerous cranial nerve nuclei are found in the pons, and they are discussed in the sections on motor, autonomic, and sensory systems. These nuclei are associated with cranial nerves VII and VIII at the cerebellopontine angle and with cranial nerves V and VI of the pons.

a. Lower Motor Neurons

Two motor cranial nerve nuclei of the extraocular system are found in the midbrain. The trochlear nucleus (IV) is found near the midline of the caudal midbrain and innervates the superior oblique muscle of the contralateral side. The fibers of the trochlear nerve cross before exiting the brain stem. The IV nerve is the only cranial nerve to exit the brain stem from its dorsal surface. The superior oblique muscle depresses the eye (moves the eye downward) when it is turned inward. The oculomotor nucleus (III) is found near the midline in the central gray just rostral to the IV nucleus. It innervates the ipsilateral inferior oblique muscle and the medial, superior, and inferior rectus muscles. The inferior oblique muscle elevates the eye when it is turned inward. The inferior rectus muscle depresses the eye when it is turned outward. The medial rectus moves the eye medially, while the superior rectus elevates the eye, particularly when it is turned outward. The oculomotor and trochlear nuclei work with the abducens nucleus to coordinate the six extraocular muscles of each eye for coordinated conjugate movements of the eyes.

The red nucleus is a large cell group found in the medial portion of the ventral midbrain tegmentum. This nucleus sends fibers that cross in the ventral tegmental decussation at the level of the red nucleus and descend as the rubrospinal tract, This tract descends in the lateral brain stem tegmentum and the lateral funiculus of the spinal cord, and terminates at all levels of the spinal cord. The rubrospinal tract has a flexor bias and terminates mainly on interneurons. It aids the corticospinal tract in overcoming antigravity tone and in achieving skilled flexor movements.

The superior colliculus, and to a lesser extent the inferior colliculus, send descending fibers across the midline of the central gray of the midbrain in the dorsal tegmental decussation, to descend as the tectospinal tract. This tract terminates in the cervical spinal cord on interneurons related to LMNs responsible for neck movements. The tectospinal tract conveys visual stimuli and, to a lesser extent, auditory stimuli, to elicit reflex movement of the head and neck in response to these stimuli.

Cortical efferent fibers descend through the midbrain on their way to lower brain stem and spinal cord structures. These cortical fibers are respectively called corticobulbar and corticospinal tracts. The corticospinal and corticobulbar tracts descend through the middle three fifths of the cerebral peduncles on the ventral surface of the midbrain.

The substantia nigra, a dopamine-containing nucleus in the ventral midbrain tegmentum, just above the cerebral peduncle, is a motor structure mainly associated with the basal ganglia. The substantia nigra has reciprocal connections with the caudate nucleus and putamen and helps to regulate the motor activities of these structures. The basal ganglia enhance wanted movements and suppress unwanted movements, working in concert with the cerebral cortex. The importance of the substantia nigra in motor functions has been underscored by the finding of degeneration and depletion of dopamine neurons in this structure in Parkinson's disease, a motor disorder characterized by a resting tremor, muscular rigidity, and an inability to initiate voluntary movements (bradykinesia).

a. Parasympathetic Preganglionic Cell Bodies

The nucleus of Edinger-Westphal is found in the midline of the central gray in the rostral midbrain, as a rostral component of the oculomotor complex. The nucleus of Edinger-Westphal sends axons ventrally, where they exit from the interpeduncular fossa at the ventral surface of the midbrain in the III nerve. These preganglionic parasympathetic fibers terminate in the ipsilateral ciliary ganglion. The ciliary ganglion supplies postganglionic fibers to the pupillary constrictor muscle and the ciliary muscle. Activation of these fibers produces pupillary constriction and accommodation to near vision, respectively.

Pathways descending from the hypothalamus and higher levels to preganglionic neurons of the parasympathetic and sympathetic nervous systems traverse the midbrain as well as the pons and medulla. These systems were discussed in the section on the medulla.

The midbrain colliculi are major visual (superior colliculus) and auditory (inferior colliculus) relay centers. The superior colliculus receives visual input from the optic (II) nerve, and gives rise to both ascending and descending channels. The ascending channel projects to the pulvinar of the thalamus, which in turn conveys the visual information to associative visual cortex (area 18, 19) of the occipital lobe. The descending channels travel to the spinal cord via the tectospinal tract and to the cerebellum via tectocerebellar projections. Some zones of the superior colliculus also are involved in some pain processing via input from spinoreticular projections. The inferior colliculus; sends auditory information to the medial geniculate body (MGB) of the thalamus via the brachium of the inferior colliculus. The MGB in turn projects to the auditory cortex of the temporal lobe.

The mesencephalic nucleus of V is a cluster of cells scattered throughout the mesencephalon at the lateral edge of the periaqueductal gray. Some neurons also are found in the rostral pons just lateral to the lateral portion of the rostral fourth ventricle. These neurons are the only primary sensory cell bodies found within the CNS. Their peripheral processes are Ia afferent fibers that innervate muscle spindles in masticatory and extraocular muscles. The primary sensory axons enter the CNS through the three divisions of the trigeminal nerve and then travel in the tract of the mesencephalic nucleus of V. This unconscious muscle spindle information is then conveyed to other central structures, such as the motor nucleus of V, forming the basis for the jaw jerk monosynaptic: reflex.

The periaqueductal gray of the midbrain is involved in sensory processing of protopathic modalities. The periaqueductal gray receives input from the reticular formation through polysynaptic spinoreticular channels. In addition, very high levels of endogenous opioid peptides, the enkephalins (cell bodies) and the endorphins (nerve terminals from hypothalamic cells) are found in the periaqueductal gray, further suggesting a role for this structure in pain processing and analgesia. Stimulation of specific portions of the periaqueductal gray with electrical current can produce long-fasting analgesia, perhaps through the enhanced activity of the opioid systems in that area.

The ascending pathways in the midbrain include those tracts that ascend through the pons; they are summarized in the section on the pons. In addition, tectal sensory pathways are found. The brachium of the inferior colliculus carries auditory information from the inferior colliculus of the MGB. The tectopulvinar fibers carry visual information from the superior colliculus to the pulvinar of the thalamus.

The superior cerebellar peduncle (SCP) connects the cerebellum with the midbrain. This fiber bundle is mainly an outflow system for the cerebellum but also conveys some input to the cerebellum. The input comes from the ventral spinocerebellar tract and some trigeminocerebellar fibers. The output comes from the deep nuclei, which are in turn regulated by Purkinje cells in the cerebellar cortex and by collaterals of secondary sensory systems projecting to the cerebellum. Purkinje cells in the paravermal region of the cerebellum project to the globose and emboliform nuclei, which in turn project through the SCP to the red nucleus and to a lesser extent to the ventrolateral (VL) nucleus of the thalamus. Purkinje cells in the lateral cerebellar hemispheres project to the dentate nucleus, which in rum projects through the SCP to the ventrolateral (VL) nucleus of the thalamus and to a lesser extent to the rostral third of the red nucleus.

These projections from globose, emboliform, and dentate nuclei cross the midline in the middle of the caudal midbrain tegmentum through the decussation of the SCP. In addition, these deep cerebellar nuclei also project fibers to the reticular formation. The outflow from the deep cerebellar nuclei permits the cerebellum to regulate motor activity through the control of UMN systems, such as the motor cerebral cortex (through the ventrolateral nucleus of the thalamus), the red nucleus, and the brain stem reticular formation.

The midbrain reticular formation conveys axons of the ascending noradrenergic and serotonergic pathways to the forebrain structures, previously described in the section on the pons. In addition, an ascending mesolimbic: and mesocortical dopamine pathway arises from the ventral tegmental area found in the midline of the midbrain surrounding and above the interpeduncular nucleus. This dopamine pathway ascends to nucleus accumbens and the olfactory tubercle (mesolimbic: pathway to limbic forebrain structures), and to cerebral cortex, particularly the frontal and cingulate cortex (mesocortical pathway). This latter pathway has been implicated in emotional and cognitive behavior, some investigators believe that dysfunction of this dopaminergic system and its receptors on target neurons characterizes schizophrenia, since the anti-schizophrenic drugs, the phenothiazines, mainly alter this system. This hypothesis awaits further substantiation.

Several midbrain nuclei that are intimately associated with the hypothalamus and limbic forebrain structures have been described. These midbrain nuclei (and some pontine components) collectively are called the limbic midbrain area of Nauta; they include the interpeduncular nucleus, the ventrolateral periaqueductal gray, the dorsal raphe nucleus, the central superior nucleus, and the dorsal and ventral tegmental nuclei. These nuclei have reciprocal connections with the hypothalamus (mainly the lateral portion) and in turn with the limbic forebrain structures or area (LFA). A schematic of these relationships is found in Figure 1-33. These connections permit an integration of both midbrain and forebrain limbic: structures through the hypothalamus.

Several midbrain structures are also concerned with processing of pain. These regions include the lateral third of the reticular formation, the central (periaqueductal) gray, and part of the tectum, or colliculi. These structures receive input from the polysynaptic spinoreticular system for protopathic modalities and help to integrate the extremely complex and diverse perception of pain. The periaqueductal gray contains high levels of the newly discovered opioid peptides, the enkephalins and B-endorphin. The enkephalins are found in small neurons in this structure, while the B-endorphin is found in nerve terminals whose cell bodies are found in the periarcuate region of the ventrobasal hypothalamus. These endogenous narcotic systems have a predilection for pain-processing areas and may mediate analgesic effects of chronic pain or pain associated with highly stressful, life threatening circumstances. In addition, the lateral third of the midbrain reticular formation is important in the maintenance of attention and consciousness through the ascending reticular activating system. Destruction of this system results in an irreversible comatose state.

Several cranial nerve nuclei are found in the midbrain and are discussed in the sections on motor, autonomic, and sensory systems. These nuclei are associated with cranial nerves III and IV of the midbrain, and to a lesser extend with cranial nerve V of the mid-pons.

The cerebellum is responsible for modulating coordinated and smoothly integrated motor behavior. The major sensory input to the cerebellum consists of: (1) unconscious proprioceptive information channeled through the spinal cord via the four spinocerebellar tracts; (2) vestibular information from the vestibular nuclei and directly from Scarpa's ganglion through the vestibular nerve; and (3) reticular formation projections from prominent medullary reticular nuclei and some pontine reticular nuclei. These inputs inform the cerebellum of the position and state of contraction of the musculature and the tension on the tendons throughout the body, the position of the head in space, and the general activity of total-body sensation from the reticular formation, respectively. They enter the cerebellum through the inferior cerebellar peduncle, except for the ventral spinothalamic tract, which enters through the superior cerebellar peduncle. In addition, trigeminal information (trigeminocerebellar fibers) enters the cerebellum through the inferior and superior cerebellar peduncle and visual and auditory information (tectocerebellar fibers) enters the cerebellum mainly through the superior peduncle. Information from the cerebral cortex also enters the cerebellum, synapsing first in the pontine nuclei, which in turn send axons into the contralateral cerebellar cortex through the middle cerebellar peduncle. This corticopontocerebellar input informs the cerebellum of movements that have been initiated through the descending supraspinal systems such as the corticospinal and corticobulbar tracts. The cerebellum can then coordinate and interpret these planned movements and integrate them with movements already in progress, whose feedback channels relay back to the cerebellum through sensory-cerebellar input systems. It should be noted that each side of the cerebellum receives information from the ipsilateral side of the body. This is the opposite of the cerebral cortex, which receives sensory input from the contralateral side of the body.

The input to the cerebellum distributes to specific layers of the cerebellar cortex (molecular, Purkinje, and granular cell layers) in the form of climbing fibers (from the inferior olivary nucleus), direct noradrenergic coeruleocerebellar fibers (from the locus coeruleus), and mossy fibers (from all other input nuclei). The climbing fibers synapse on the dendrites of the Purkinje cell’s, the main output neurons of the cerebellum, in a manner comparable to a vine adhering to the branches of a tree. The mossy fiber terminate on granular cells of the cerebellum which in turn project parallel fibers into the molecular layer to synapse consecutively on the dendrites of many Purkinje cells, whose dendritic trees are arranged perpendicular to the parallel fibers. These parallel fibers pass through the orderly parallel plane arrangement of the Purkinje cell dendritic trees in a manner similar to telephone wires running across hundreds of telephone poles, all arranged in a straight row. In addition, complex local neurons (basket, stellate, and Golgi II cells) modulate the cerebellar input and processing to achieve a single coordinated and integrated output through the Purkinje cells. The basket cells in the molecular layer mainly inhibit Purkinje cell bodies, the stellate cells in the molecular layer mainly inhibit Purkinje cell dendrites, and Golgi cells in the granular layer mainly inhibit mossy fiber input to granular cells. The output from the cerebellar cortex arises solely from the Purkinje cells and projects to the four deep cerebellar nuclei (fastigial, globose, emboliform, and dentate nuclei) and to the lateral vestibular nucleus (thought by some to be a displaced deep cerebellar nucleus). These nuclei also receive collaterals from the mossy fibers, the climbing fibers, and the noradrenergic coeruleocerebellar fibers; the cerebellar cortical inputs to these deep nuclei may function mainly to modulate this connection from the input fibers to the deep nuclei. The projections of the deep nuclei exit the cerebellum mainly through the superior cerebellar peduncle and the medial portion of the inferior cerebellar peduncle (juxtarestiform body). The cerebellar outflow from the deep nuclei provides control over UMN systems such as the corticospinal, rubrospinal, vestibulospinal, and reticulospinal tracts. The cerebellar outflow does not regulate LMNs directly; it influences these neurons only through the UMN pathway.

The cerebellar cortex is thrown into a series of convolutions, with gyri and sulci. The gyri are called folia of the cerebellum. Grossly, the cerebellar cortex consists of three longitudinal zones: (1) the vermis, in the midline; (2) the paravermis, on either side of the vermis; and (3) the lateral hemispheres, accounting for the bulk of the cerebellar cortex in primates.

The vermal Purkinje cells project mainly to the fastigial nucleus, which in turn regulates reticulospinal and vestibulospinal systems through projections that travel in the medial ICP. Some Purkinje cell axons project directly to the lateral vestibular nucleus. The paravermal Purkinje cells project mainly to the globose and emboliform nuclei, which in turn regulate the rubrospinal system. The lateral hemispheric Purkinje cells project mainly to the dentate nucleus, which in turn regulates the corticospinal system through the ventrolateral nucleus of the thalamus and its motor cortical connections. The outflow of the globose, emboliform, and dentate nuclei travels contralaterally to these target structures through the SCP

An older system of anatomical description divides the cerebellum into anterior, posterior, and flocculonodular lobes. The flocculonodular lobes are phylogenetically the oldest part of the cerebellum and evolved mainly to aid vestibular processing. In general, the paravermis and hemispheres of the anterior and posterior lobes mediate coordination of movements of the extremities. The lateral hemispheres are particularly important for the coordination of complex hand and finger movements. It is therefore no surprise that the cerebellar hemispheres increase in size and importance as the motor portions of the cerebral cortex increase in size and importance throughout phylogeny. Control of trunk musculature and vestibular responses are mediated through the vermis and the flocculonodular lobe.

The cerebellum performs several vital tasks. During normal posture, the cerebellum must aid in the coordination of trunk and proximal limb- muscles to permit smooth tone and posture, a stable upright position of the body, and error correction for minor shifts in posture. The cerebellum must also smooth and coordinate complex movements of the distal extremities, must carry out sophisticated feedback control of dexterous motor activity, and must adjust moment-to-moment motor movements through sensory feedback. The cerebellum must be recruited to achieve control of UMN systems through the initiation of specific neuronal cerebellar "subroutines" before skilled motor acts can be learned and perfected. These numerous tasks account for the need of the multimodal sensory input and cortical input through the pontine nuclei

G. A Summary of the Cranial Nerves, Cranial Nerve Nuclei, and Their Associated Ganglia

The cranial nerves contain only three major functional components: sensory (S), motor (M), and autonomic parasympathetic (A). While other classification systems subdivide these components into numerous categories based upon developmental considerations, they do little to enhance the functional understanding of the cranial nerves. Rather, they obscure a rather simple system with an archaic and confusing exercise in terminology. A summary is given in Table 1-4, based on a straightforward functional classification.

To summarize further, the cranial nerves are mainly sensory, mainly motor, or mixed nerves:

For a summary of cranial nerve motor nuclei, see Table 1-5.

A summary of the cranial nerve sensory nuclei is given in Table 1-6. Nuclei associated with the olfactory and optic nerves are not included in this summary because nerves I and II are CNS tracts and not true peripheral nerves, as are cranial nerves III through XII.

Table 1-7 contains a summary of the cranial preganglionic parasympathetic nuclei.

The diencephalon consists of two major parts, the thalamus and the hypothalamus. In addition, the epithalamus and subthalamus also are classified as part of the diencephalon. The subthalamus is most properly an accessory nucleus associated with the basal ganglia, while the epithalamus, particularly the habenula, is associated with limbic system connections. These two minor components of the diencephalon will not be considered further in this section.

The thalamus is the major sensory relay station to the cerebral cortex, acting as the gateway to neocortex for ascending lemniscal systems. All sensory information except olfactory input must pass through the thalamus and synapse before further processing by the cerebral cortex for conscious interpretation of the outside world. Table 1-8 contains a summary of thalamic nuclei. The sensory lemniscal input to the thalamus terminates in four major nuclei. The ventral posterolateral (VPL) nucleus receives epicritic somatosensory input from the body via the medial lemniscus and the fast component of pain and temperature sensation via the direct spinothalamic tract. Nucleus VPL then projects this information to the postcentral gyrus of the parietal lobe of the cerebral cortex (except to the lateral portion). The ventral posteromedial (VPM) nucleus receives epicritic sensation, temperature sensation, and fast pain sensory information from the head via the trigeminothalamic tracts and taste information via the solitariothalamic projections. Nucleus VPM projects this information to the lateral portion of the postcentral gyrus of the parietal cortex. The lateral geniculate body (LGB) (or lateral geniculate nucleus) receives visual input from the ganglion cell layer of the retina via the optic tract and conveys this information to the primary visual cortex on the banks of the calcarine fissure via the geniculocalcarine tract (optic radiation). The medial geniculate body (MGB) receives auditory input via the brachium of the inferior colliculus and conveys this information to the transverse gyrus of Heschl of the temporal lobe at the edge of the lateral fissure via the auditory radiation. An additional thalamic nucleus, the pulvinar, has part of its projection directed to a sensory cortical structure. The pulvinar receives visual input from the superior colliculus and projects to the visual association cortex of the occipital lobe.

The thalamus also projects motor and autonomic information to the cortex. The ventrolateral (VL) nucleus receives information from the dentate nucleus of the cerebellum and from the globus pallidus of the basal ganglia and projects fibers to the motor cortex on the precentral gyrus of the frontal lobe. The ventral anterior (VA) nucleus receives input mainly from the globus pallidus and projects fibers to the premotor cortex of the frontal lobe. The precentral gyrus and the premotor cortex are major regions of origin of the corticospinal and corticobulbar tracts, and cortical outflow to brain stem UMN systems such as the red nucleus. The anterior nuclei (ANT) receive input from the limbic system (particularly the mammillary bodies of the hypothalamus) and project axons carrying visceral information to the anterior cingulate cortex.

In addition to major sensory, motor, and visceral-autonomic projection nuclei, the thalamus also contains association nuclei that project to association areas of the cerebral cortex. The pulvinar projects to widespread areas of parietal, occipital, and temporal cortex near the supramarginal and angular gyri. The lateral dorsal (LD) nucleus projects fibers to the posterior cingulate cortex while the lateral posterior (LP) nucleus projects fibers to the posterior portion of the parietal cortex. The medial dorsal (MD) nucleus sends fibers to the prefrontal cortex and plays an important role in maintaining the social, intellectual, and personality related functions of prefrontal cortex. All of the projection nuclei of the thalamus, including the association nuclei, receive reciprocal projections from the region of cortex to which they themselves project. Therefore, the cerebral cortex can monitor and influence its own thalamic input.

Finally, the thalamus contains nonspecific nuclei that project only diffuse and sparse fibers to the cortex. They receive input from the reticular formation of the brain stem and from each other and are associated with maintenance of consciousness. They are also instrumental in the conscious interpretation of painful stimuli of deep, long-lasting nature. The main nuclei in this category are the centromedian nucleus, intralaminar nuclei, and reticular nucleus of the thalamus. These nuclei can arouse the cerebral cortex through local connections to the specific projection nuclei and perhaps also through very sparse cortical connections. These nuclei, along with nucleus MD, contain enkephalins and B-endorphin and may mediate the affective or interpretative aspects of pain.

The hypothalamus lies ventral to the thalamus and surrounds the third ventricle. The nuclei of the hypothalamus fall into two main groups: nuclei that are part of the neuroendocrine system and nuclei that regulate autonomic and visceral activities such as feeding, drinking, reproduction, and thermoregulation. The neurosecretory nuclei, the supraoptic (SON) and paraventricular (PVN) nuclei, send axons into the posterior pituitary, where they release the hormones vasopressin (anti-diuretic hormone, ADH) and oxytocin into the general circulation. Additional nuclei from widespread areas of hypothalamus (including the PVN) and other CNS regions release hormonal-releasing factors (or hormones) and inhibiting factors into the hypophyseal portal system at the contact zone of the median eminence. These factors either increase or decrease the release of anterior pituitary hormones into the blood. The arcuate and periventricular nuclei project dopaminergic fibers to the median eminence, where they may influence the release of releasing factors. In addition, dopamine itself may act as the prolactin inhibitory factor. Numerous other fiber systems (serotonin, substance P, and other peptide systems) also converge on the median eminence to influence the release of the releasing factors. B-Endorphin cell bodies in a zone adjacent to the arcuate nucleus (periarcuate region) send opioid-containing terminals to widespread regions of the CNS, where B-endorphin may mediate a wide range of humoral, visceral, affective, or cognitive functions.

Visceral regulatory areas are not always organized into discrete nuclei, and are therefore called areas, although the designation of hypothalamic areas is an oversimplification that has the danger of inaccurate attribution of function to areas based on gross lesion or stimulation studies. The anterior hypothalamic area contributes to the regulation of the parasympathetic nervous system, while the posterior hypothalamic area contributes to the regulation of the sympathetic nervous system. Hunger and thirst and satiety in eating and drinking involve activity of the dorsomedial, ventromedial, and lateral hypothalamic nuclei or areas. The preoptic area contributes to thermoregulation and to the regulation of sexual function, along with the anterior hypothalamic area. In addition, the suprachiasmatic nucleus and the medial preoptic area regulate cyclic activity of the hypothalamus, particularly associated with hormonal outflow. The mammillary nuclei in the caudal hypothalamus are major integrative centers for limbic system connections, receiving input from the hippocampus and projecting to the anterior thalamic nucleus. The hypothalamus also participates in reproductive and social behavior through limbic connections with the amygdala, the septum, limbic midbrain structures, and regions of cortex. This places the hypothalamus in a role as the final zone of limbic convergence.

Some hypothalamic nuclei (such as PVN, and also lateral, dorsal, and posterior regions) send projections to the interomediolateral cell column of the spinal cord and to the vagal complex of the medulla (dorsal motor nucleus of X and nucleus solitarius), thus regulating directly the outflow of autonomic information from the brain stem and spinal cord. A nucleus such as the PVN, thus appears to be highly complex; it has some direct axonal projections to the posterior lobe of the pituitary, some axonal projections to the contact zone of the median eminence, and some descending projections to autonomic preganglionic neurons. These three functional roles for the PVN appear to be regulated from separate neuronal areas that probably are interconnected. Immunocytochemical studies suggest that at least 25 neurotransmitter-specific cell groups co-exist in this single nucleus, PVN, often scattered and intermixed with each other. Thus, a single nucleus may be a highly complex region of integration for a host of neuroendocrine and visceral functions, with many sub-components.

The telencephalon is made up of four major systems: (1) the olfactory system, (2) the limbic system, (3) the basal ganglia, and (4) the neocortex.

The olfactory system is represented by the olfactory nerve (called cranial nerve I, despite the fact that it is actually a CNS tract and not a nerve), the olfactory bulb, the olfactory tract, and an associated area of primitive cortex called the olfactory cortex of the temporal lobe (uncus). In addition, several limbic forebrain subcortical nuclei receive olfactory input, such as the amygdala, septum anterior perforated substance, and anterior olfactory nucleus. The additional connections are numerous and complicated, and are beyond the scope of this neuroanatomical overview. Olfaction is the only sensory system that bypasses the thalamus to enter cerebral cortex directly. Olfaction evolved as a system with important direct connections to limbic forebrain structure. Olfaction plays an important role in feeding and reproductive behavior in many animals and has retained these connections in the course of evolution of the human brain.

The limbic system consists of the following groups of structures:

2. The lateral hypothalamus and selected thalamic nuclei in the diencephalon.

3. Limbic forebrain structures, including non-cortical (amygdala, septum, nucleus basalis, and anterior perforated substance, also called the olfactory tubercle) and cortical (hippocampal formation, parahippocampal cortex, periamygdaloid cortex, cingulate cortex, and prefrontal cortex) areas.

The limbic system controls emotional responsiveness and expression, short-term memory, and responsiveness of the visceral and endocrine hypothalamus. The limbic system provides an individual interpretive response to the outside world and the inside world, releasing the animal from mandatory, built-in, stereotyped responses to stimuli. This system works in concert with other areas of the cerebral cortex to achieve complex behavioral activity and responses. The nuclei and tracts of the limbic system function as a single, holistic system. It is difficult, if not impossible, to specify an exact function for each component of the limbic system. The nuclei and tracts do not function autonomously, but depend upon activity in the total limbic circuitry for any part of the system to function properly. However, a few limbic forebrain structures have been implicated in playing a major role of a few specific functions. The hippocampal formation is necessary for consolidation of short-term memory. The amygdala can regulate emotional responsiveness in the form of docility on one hand or rage on the other. The periamygdaloid cortex can regulate sexual responsiveness. The cholinergic projections of the nucleus basalis to the cerebral cortex are thought to regulate aspects of short-term memory and some cognitive functions, and are thought to be deficient in the brains of some patients with Alzheimer's disease. However, these structures still interact with other limbic structures, and utilize limbic-hypothalamic connections to achieve the expression of such forms of behavior.

The basal ganglia (nuclei) form a phylogenetically old motor system often described as being involved in maintenance and programming of stereotyped, repetitive, and routine motor behavior. The basal ganglia consist of the striatum, made up of the caudate nucleus and the putamen, and the pallidum, consisting of the globus pallidus. The striatum and pallidum have close, reciprocal relationships with the substantia nigra and the subthalamus, respectively. The subthalamus and substantia nigra often are considered to be nuclei associated with the basal ganglia. The basal ganglia outflow, directed from the globus pallidus, influences motor activity through UMN systems, particularly through projections to the ventrolateral thalamic nucleus, which projects to cells of origin in the precentral gyrus of the corticospinal system. The basal ganglia also work in concert with the cerebral cortex to achieve control over voluntary motor activities. The basal ganglia suppress unwanted movements and enhance desired patterns of movement. The basal ganglia therefore work closely with the neocortex, and indeed have evolved to a highly complex and sophisticated level in the human brain. It is probably best not to think of the basal ganglia as an old system merely concerned with stereotyped and repetitive movements. Rather, the highly evolved structure and function of the basal ganglia and their role in aiding neocortical motor activity should be kept in mind. It also is not appropriate to think of the basal ganglia as strictly a motor system. Indeed, a large input to the head of the caudate nucleus arises from limbic cortex and is directed back to such structures through connections with the globus pallidus, while the putamen received information more from true motor regions and is interconnected with them back through the globus pallidus. It is likely that the basal ganglia serve an integrative function that aids the cerebral cortex in a wide range of its activities.

The neocortex is a mantle of gray matter containing six sheets of cells in a laminated pattern. The entire cortical mantle consists of four major lobes: (1) frontal lobe, (2) parietal lobe, (3) temporal lobe, and (4) occipital lobe (see Figs. 1-29 and 1-30). An additional region of cortex, the insula, is sometimes considered to be a fifth lobe of cerebral cortex, but its reported visceral functions are presently poorly understood. The neocortex is the highest center for both voluntary motor activity and sensory integration and interpretation. It is a center for both understanding and initiating speech and written language. The neocortex enables humans to anticipate the future and to remember the distant past, including the ability to pass information from generation to generation. In addition, the neocortex is the neurological source of personality and is also thought to be the source of the highest mental capabilities and intellectual achievements of the human brain. The ability to describe perfectly the function of neocortex would require a perfect understanding of the complexity of human personality, human behavior and its pathology, and interaction of humans with each other, spanning the range of disciplines from psychology to sociology and history. This represents perhaps the most complex and frustrating task of neurobiology, to explain human behavior and its peculiarities and alterations in terms of neuronal structure, function, and chemistry.

As with the regional neuroanatomy section, all structures discussed in the systemic consideration are labeled in standard neuroanatomy atlases. In addition, many of the systems described in this section also are summarized in schematic diagrams, the purpose of which is to provide the reader with an overall representation of the connections and flow of information in that system.

A. Sensory Systems

Sensory information enters the nervous system when a receptor in the periphery is stimulated sufficiently to send an electrical impulse into the central nervous system (CNS). The receptor is a sensory transducer that changes mechanical, heat, or light energy into electrical energy in the form of an electrical potential in the sensory neuron. Information passes along the primary afferent axon toward the CNS. The cell bodies of these primary sensory neurons are found in sensory ganglia located outside the CNS. For spinal nerves, these ganglia are the dorsal root ganglia, located on the dorsal root near the spinal cord. The sensory cranial nerves have sensory ganglia that also are peripheral, located on the cranial nerve either close to the brain stem or at a distance, near the sensory receptors. These ganglia will be discussed in the appropriate sensory sections. The axons of primary somatosensory neurons enter the spinal cord, synapse with secondary sensory neurons, and form three types of functional secondary sensory connections, called channels: (1) reflex channels, (2) cerebellar channels, and (3) lemniscal channels.

Reflexes exist in several forms. The simplest is the monosynaptic reflex. In this reflex, the incoming primary sensory axon terminals, whose cell bodies are in the dorsal root ganglia, synapse directly on a lower motor neuron (LMN) in the anterior horn of the spinal cord. The muscle stretch reflex is an example of a monosynaptic reflex, in which the stretch of a tendon (quadriceps tendon in the knee jerk reflex) excites a primary sensory group Ia axon, which synapses on a lower motor neuron innervating the muscle whose tendon was stretched (quadriceps), resulting in the contraction of that muscle (the knee jerk). Other reflexes in the spinal cord are polysynaptic, requiring the participation of interneurons. These reflexes may function within the same segment of the spinal cord as the sensory input or may involve many segments. For example, withdrawal reflexes elicited by touching a hot object require participation of many interneurons at both local and distant spinal levels compared to the input. These reflexes can even extend upward into the neuroaxis to influence LMNs of the motor cranial nerve nuclei. An example of this is stepping on a tack, resulting in the entire body withdrawing from the stimulus, requiring the movement of skeletal muscles in the body and in the head and neck.

Information going to the cerebellum from the somatosensory system (Fig. 1-34) comes mainly from proprioceptive receptors in the muscles and tendons but can arise from virtually all types of sensory receptors. Information concerning the state of contraction of individual muscle fibers travels mainly along Ia afferent fibers from muscle spindles into the spinal cord, where it synapses with cells of origin of the dorsal spinocerebellar tract (DSCT) in Clarke's nucleus and with the cells of origin of the cuneocerebellar tract in the lateral (accessory) cuneate nucleus of the medulla. Information reporting the state of contraction of whole muscles (tension on tendons) travels mainly along Ib afferent fibers from Golgi tendon organs (GTOs) into the spinal cord, where it synapses with the cells of origin of the ventral spinocerebellar tract (VSCT) (border cells) and the rostral spinocerebellar tract (RSCT) (centrobasal nucleus) in the dorsal and intermediate spinal gray. Proprioceptive information from the body at level T6 and below travels in the dorsal spinocerebellar tract and the ventrospinal cerebellar tract. Proprioceptive information from the body above level T6 travels in the cuneocerebellar tract and the rostral spinocerebellar tract.

Cells of the dorsal spinocerebellar tract receive primary sensory afferents mainly from muscle spindle Ia afferents from levels T6 and below. These afferents enter the spinal cord synapsing in Clarke's nucleus in the gray matter at the medial base of the dorsal horn of the thoracic spinal cord. (This nucleus is actually present from levels T1 to L2.) Cells of Clarke's nucleus send ipsilateral projections that ascend in the peripheral zone of the dorsal half of the lateral funiculus of the spinal cord and enter the cerebellum through the inferior cerebellar peduncle.

Cells of the ventral spinocerebellar tract receive primary sensory afferents mainly from GTO Ib afferents from levels T6 and below. These afferents enter the cord and synapse with cells in the lateral portion of the intermediate gray known as border cells (of Cooper-Sherrington). These cells send projections across the midline of the spinal cord in the anterior white commissure at the level of entry of the primary sensory fibers. The crossed secondary sensory fibers ascend in the peripheral zone of the ventral half of the lateral funiculus of the spinal cord and in the lateral white matter of the rhombencephalon to the level of the rostral pons, where most of them enter the cerebellum through the superior cerebellar peduncle. A majority of these fibers then re-cross the midline to terminate ipsilateral to the source of the primary sensory input

Cells of the cuneocerebellar tract receive mainly primary sensory muscle spindle Ia afferent fibers from levels above T6. These afferents enter the cord and ascend ipsilaterally in the dorsal funiculus to the lateral cuneate nucleus of the medulla, where they synapse. The cells of the lateral cuneate nucleus project fibers ipsilaterally through the cuneocerebellar tract into the cerebellum via the inferior cerebellar peduncle; these cells are close enough to the ICP that their axons merge with the ICP, and do not form a bundle that is a discrete entity that can be described in a cross section.

Cells of the rostral spinocerebellar tract receive mainly primary sensory GTO Ib afferents form levels above T6, which enter the spinal cord and synapse with cells at the base of the intermediate gray matter (centrobasal nucleus). These cells give rise to fibers of the rostral spinocerebellar tract, which ascends ipsilaterally and enters the cerebellum through the inferior cerebellar peduncle.

In addition to the four direct spinocerebellar pathways, there are two indirect spinocerebellar pathways, a spino-olivo-cerebellar system and a spinoreticulo-cerebellar system. In the inferior olivary system, some primary sensory Ia, II, and Ib afferents enter the spinal cord and synapse in the intermediate gray. Fibers from the intermediate gray cross the midline and ascend to the inferior olivary nucleus, where they synapse. Inferior olivary cells send olivocerebellar fibers across the midline, where they enter the cerebellum through the inferior peduncle. It should be kept clearly in mind that the inferior olivary nucleus receives input from areas other than the spinal cord, such as the red nucleus and cerebral cortex. The inferior olivary nucleus therefore serves as a feedback mechanism for the cerebellum integrating a wide range of sensory and motor information from widespread areas of the CNS (see Fig. 1-34).

In the lateral reticular system, flexor reflex afferents and a wide variety of cutaneous informations from all four extremities enter the cord and synapse in the intermediate gray. The intermediate gray cells then project ascending fibers to the lateral reticular nucleus. The lateral reticular nucleus also receives input from sources other than the spinal cord; therefore it is also an integrating system. The large receptor fields (from all four extremities) of these cells also emphasize the integrative nature of this nucleus.

It should be noted that the vast majority of cerebellar input from spinal sources is ipsilateral. Therefore, cerebellar lesions result in symptoms on the same side as the lesion. With truncal ataxia, the patient will fall toward the side of the cerebellar lesion (if the lesion is only unilateral). A lesion of one cerebellar hemisphere or one superior cerebellar peduncle will result in an ipsilateral intention tremor, ipsilateral dysmetria, loss of coordination, loss of rapid alternating movements, and past-pointing (the inability to accurately reach for, or point directly to, a target).

c. Leminiscal Channels

Conscious sensory information is processed through lemniscal pathways from the periphery to secondary sensory nuclei and then via lemniscal pathways to the thalamus. These thalamic nuclei then convey this information to the cortex, either by direct projections (from the ventral posterolateral nucleus [VPL]) or indirectly through nonspecific nuclei of the thalamus. Both light moving touch and pain sensations are considered lemniscal even though some of their projections do not travel in discrete pathways through the brain stem and do not actually reach the thalamus directly, especially in the case of slow pain.

Epicritic: modalities from the body such as fine discriminative touch, pressure, joint position, two-point discrimination, and vibratory sensation travel in a true lemniscal system called the dorsal column system (Fig. 1-35). Primary sensory afferents come mainly from skin, hair follicles, paccinian corpuscles, and joints. These fibers enter the spinal cord through the dorsal roots and travel in the dorsal columns of the dorsal funiculus, where they ascend toward their secondary sensory nuclei in the medulla. Fibers entering the spinal cord below T6 ascend in the fasciculus gracilis and fibers entering at T6 and above ascend in the fasciculus cuneatus. The primary sensory input is somatotopically arranged, with input from the feet ascending most medially and input from the cervical region ascending most laterally. In the medulla, primary sensory afferents from below T6 traveling in fasciculus gracilis synapse in nucleus gracilis, while those from T6 and above traveling in fasciculus cuneatus synapse in nucleus cuneatus. Additional sensory information processed through dorsal horn interneurons is conveyed to the nuclei gracilis and cuneatus through the dorsolateral funiculus, providing an additional route through the spinal cord white matter for joint position, vibratory sensation, and cutaneous sensation to reach the dorsal column nuclei. Nuclei gracilis and cuneatus give rise to axons that decussate in the medulla, just rostral to the decussation of the pyramids, as the internal arcuate fibers; these crossed fibers then ascend toward the thalamus as the medial lemniscus, a topographically organized bundle. Medial lemniscus fibers synapse in the ventral posterolateral (VPL) nucleus of the thalamus. This nucleus projects to the central and medial portions of the postcentral gyrus of the parietal lobe. This entire lemniscal system remains somatotopically arranged all the way from the spinal cord to the cortex. In the cortex, information from the feet terminates most medially in the paracentral lobule, while information from cervical levels terminates more laterally, on the convexity of the postcentral gyrus.

The very specific and direct lemniscal pathway of the dorsal column system contrasts with some of the spinothalamic-spinoreticular pathway (Fig. 1-36) carrying protopathic information (pain, temperature, and light moving touch). Protopathic receptors are generally free nerve endings or small myelinated fibers. Some small myelinated fibers (A-delta fibers) enter the spinal cord in the dorsal roots and terminate on cells of laminae V and I. These spinal cord cells send fibers across the midline in the anterior white commissure that ascends in the spinothalamic tract in the ventrolateral white matter of the spinal cord. These secondary sensory axons ascend to the nucleus VPL of the thalamus, which in turn sends fibers to the postcentral gyrus. This direct lemniscal portion of the protopathic system reports temperature sensation and so-called fast pain. Fast pain is the first sensation of injury or pain, is accurately localized, and does not last longer than the duration of the stimulus. The slow, excruciating pain, outlasting the stimulus, travels by a more polysynaptic route. It is this pain that is so dismaying and difficult to relieve in medical practice.

Unmyelinated axons (C-fibers) of the primary sensory cells, conveying slow pain, enter the spinal cord through the medial portion of the dorsal root, traverse Lissauer's zone above the dorsal horn and either enter the gray matter and synapse at the level of entry, or ascend or descend for a segment or two before entering the gray matter and synapsing. The primary afferents synapse in the dorsal horn, mostly in substantia. gelatinosa (laminae II and III). Cells of substantia gelatinosa project to deeper layers of the dorsal horn called the nucleus proprius (laminae IV and V). Fibers from nucleus proprius and fibers from cells of the intermediate gray (lamina VII), to which nucleus proprius cells project, cross the midline in the anterior white commissure and ascend in the spinal cord in the anterolateral funiculus as the spinothalamic-spinoreticular tracts. The cells of origin of those systems are the targets of considerable convergence and divergence in the spinal cord. The true spinothalamic tract projects to the ventral posterolateral nucleus of the thalamus, but most of the fibers in the anterolateral funiculus system, particularly the spinoreticular fibers, never reach the thalamus directly. Instead, they end in the reticular formation.

After many synapses with interneurons of the spinal cord, which tend to diffuse the stimulus, the fibers eventually enter the spinoreticular portion of the spinothalamic-spinoreticular system and ascend toward the reticular formation. In the reticular formation, many collaterals are given off, further diffusing the signals. From the reticular formation, the information is carried to the inferior colliculus, periaqueductal gray, other mesencephalic "pain-processing" regions, and to nonspecific nuclei of the thalamus. The pain information may be transmitted to the cortex directly via the diffuse projections from the nonspecific nuclei, and also may reach the cortex indirectly through intrathalamic connections with direct projection nuclei of the thalamus. The cortex then interprets activation of the reticular formation as excruciating, persistent, sometimes poorly localized, long-term pain. In addition to the crossed spinoreticular fibers that synapse in the reticular formation, ipsilateral fibers also enter the reticular formation. C-fibers enter the spinal cord and synapse in substantia gelatinosa. Polysynaptic channels carry the information diffusely into the ipsilateral reticular information. Thus, the reticular formation receives diffuse input from both ipsilateral and contralateral projections that derive from a variety of spinal cord neuronal pools. This account for the futility and ineffectiveness of tractotomies and lesions induced to alleviate chronic pain in humans in all but terminal patients. Despite severing of the anterolateral white matter of the cord to alleviate contralateral intractable pain, the pain usually returns in several months. Pain has perhaps the most widespread and diffuse ascending channels to the forebrain of any sensory modality. A system that evolved for quick, adaptive responses to noxious stimuli has carried forward such a strong evolutionary legacy that it often defies even the best efforts of medical technology today.

A final comment about the spinothalamic-spinoreticular system is warranted. Some textbooks describe a separate lateral spinothalamic tract carrying pain, and a ventral spinothalamic tract carrying light moving touch and temperature. This subdivision is somewhat artificial and results from a partial separation of both modalities and somatotopic levels. It is therefore best to think of the protopathic channel in the anterolateral funiculus as the combined spinothalamic-spinoreticular system. This system conveys the direct fast pain fibers (spinothalamic), some of the diffuse slow pain fibers (spinoreticular), fibers conveying temperature, and fibers conveying light moving touch. This last modality was noted in patients with lesions of the dorsal funiculus. When this epicritic system was destroyed, patients could still detect touch from a light wisp of cotton moved across the body.

 2. Trigeminal Sensory System

The trigeminal sensory system (Fig. 1-37) is a rostral continuation of the somatosensory system. All trigeminal primary sensory cell bodies, except those innervating muscle spindles, are located in the trigeminal, or semilunar, ganglion, outside the brain stem. Reflexes mediated through this system are both monosynaptic and polysynaptic. The monosynaptic reflexes travel via Ia muscle spindle afferents of cranial nerve V (for example, for the jaw jerk reflex), and are conveyed through the mesencephalic nucleus of V. Polysynaptic reflexes include those mediated through other cranial nerve motor nuclei, such as the blink reflex mediated through afferents of cranial nerve V and through LMNs of the facial nerve (VII) nucleus. There is also a cerebellar channel for the trigeminal system. Primary afferents from the semilunar ganglion synapse in the main sensory nucleus and the descending nucleus of V whose projections then enter the cerebellum, mainly through the inferior peduncle. A few trigeminocerebellar fibers also enter through the superior cerebellar peduncle.

The primary sensory afferent fibers conveying epicritic information for conscious interpretation have their cell bodies in the semilunar ganglion just outside the mid pons. The primary sensory axons project to a secondary sensory nucleus, the main sensory nucleus of V. Fibers from the main sensory nucleus ascend as the dorsal trigeminal thalamic tract (DTTT), probably to the contralateral ventral posteromedial nucleus of the thalamus (VPM). The fibers of nucleus VPM then project to the most lateral aspect of the postcentral gyrus of the parietal lobe just lateral to the region of postcentral gyrus receiving fibers from the upper extremity through nucleus VPL of the thalamus.

Primary sensory afferent fibers projecting protopathic information for conscious interpretation also have their cell bodies in the semilunar ganglion. They project mainly to the descending nucleus of V, especially the most caudal portion of it. This nucleus extends from the mid-pons caudally to the upper few levels of spinal cord. Cells of this nucleus send fibers carrying sensations of fast pain, temperature, and some cutaneous information to nucleus VPM of the thalamus in the crossed ventral trigeminothalamic tract (VTTT). Some additional crossed projections from cells of the main sensory nucleus of V convey epicritic trigeminal information to nucleus VPM via the VTTT. Many axonal projections of neurons in the descending nucleus of V terminate in the reticular formation and never reach the thalamus directly, and, like the spinothalamic-spinoreticular system, send diffuse information into the lateral reticular formation, where it is joined by sensory input from all other sensory systems. The somatosensory system and the trigeminal sensory system are therefore similar in the projection of fibers for conscious interpretation of cutaneous sensation to the thalamus via direct lemniscal channels and to the reticular formation via polysynaptic connections for the processing of slow pain.

The modalities that travel in the trigeminal system arise from receptors found in the face, the oral cavity, the anterior two thirds of the tongue (general sensation, not taste), the teeth, the nasal cavity, the paranasal sinuses, and part of the meninges. General sensation from the pharynx and posterior 1/3rd of the tongue also distributes with nerve IX to the descending nucleus of V.

3. Visual System

The retina, in the inner posterior curve of the eye, contains the photoreceptors, the rods and cones, that process visual information. The cones transduce color vision and the rods transduce black and white images. Light enters the eye by passing through the transparent cornea, then continues through the anterior chamber of the eye, which contains aqueous humor, passes through the lens, where it is further refracted and passes through the vitreous body, which contains a gelatinous but transparent fluid. The light passes through all the layers of the retina and strikes the visual pigments in the photoreceptors, which are protected by a melanin-pigmented layer to avoid dispersion and backscatter. The cone’s cluster in the central region of the retina, the macula (the fovea centralis in the center of the macula, in which only cones are found), the region struck by light from an object fixed by the eye. These cones are responsible for color images for daylight vision (photopic vision). The rods are particularly abundant in the peripheral zones of the retina and are responsible for night vision (scotopic vision). When light strikes a photoreceptor, it alters the conformational structure of the visual pigment in the outer segment of the photoreceptor, resulting in a change in ionic conductance in the photoreceptor. In the case of rods, the 11-cis retinal portion of the pigment rhodopsin is transformed to all transretinal, which alters the Ca⁺⁺ conductance in the rod. This in turn alters the Na⁺ conductance, setting up a receptor potential. The photoreceptor actually hyperpolarizes when light transduction occurs, resulting in a decrease in neurotransmission compared to the constant transmitter release apparently occurring in the dark. The pigments are located in stacked discs in the outer segment of the photoreceptor.

In the retina, the visual message is sent through a vertical arrangement of cells. The photoreceptors communicate with bipolar cells, which in turn project to the ganglion cells in the innermost layer of the retina. An additional horizontal organization of horizontal cells and amacrine cells adds local processing of visual information in the retina. Many of the retinal elements communicate with graded potentials rather than action potentials and can produce either depolarization or hyperpolarization in the next neuron in line. Only in ganglion cell axons, the main outflow of retina, are action potentials consistently seen. The ganglion cells give rise to the optic nerve, optic chiasm, and optic tract, successively (Figs. 1-38 and 1-39). Optic tract fibers project directly to the lateral geniculate body (LGB) of the thalamus. The patterns of crossed and uncrossed fibers depend on the area of the retina in which the ganglion cell is located. Ganglion cells on the temporal (outside) half of the retina project uncrossed fibers to the ipsilateral lateral geniculate body (Fig. 1-38). Ganglion cells on the nasal (inside) half of the retina project crossed fibers to the contralateral lateral geniculate body. The area of crossing fibers is a prominent landmark on the ventral surface of the hypothalamus, called the optic chiasm. The tracts leaving the chiasm are called the optic tracts. The optic tract therefore contains projections carrying visual information from the contralateral half of the visual world (visual field) (Fig. 1-39). The LGB then projects to the primary visual cortex (area 17) in the occipital lobe on the banks of the calcarine fissure through the optic radiation’s in the posterior-most portion of the posterior limb of the internal capsule. The optic radiation’s spread out through the parietal and temporal lobes as they pass around the lateral walls of the occipital pole of the lateral ventricles. Fibers carrying information from the upper retina (lower visual fields) project through the parietal lobe to the upper bank of the calcarine fissure, while fibers carrying information from the lower retina (upper visual fields) project through the temporal lobe in Myer's loop to the lower bank of the calcarine fissure. Each of these zones of upper or lower visual information in the cortex can be selectively damaged, producing a contralateral visual quadrant deficit (called quadrantanopsia).

The optic tract also projects fibers to the superior colliculus, which is primarily responsible for visual reflex responses by sending information to the cervical spinal cord via the tectospinal system in the descending limb of the medial longitudinal fasciculus. The superior colliculus also sends tectocerebellar fibers through the superior peduncle to the cerebellar cortex. In addition, the superior colliculus sends fibers to the pulvinar of the thalamus, which in turn projects to associative areas of visual cortex in the occipital lobe, areas of 18 and 19. These projections are thought to tell where an object is in the visual field, while the lateral geniculate body projections are thought to tell what that object is, and to provide for a fine-grain analysis of the outside visual world. The optic tract also projects to the pretectum, which conveys fibers bilaterally to the nucleus of Edinger-Westphal, resulting in the pupillary light reflex through the efferent III nerve projections to the ciliary ganglion and the ciliary ganglion projections to the pupillary constrictor muscle. Additional optic tract input synapses in the suprachiasmatic nucleus of the hypothalamus, where circadian light-dark rhythms may be influenced via supraspinal projections to the sympathetic TI-T2 intermediolateral cell column. The superior cervical ganglion in turn influences the output of the hormone melatonin from the pineal gland, influencing gonadal maturation.

The auditory system transduce mechanical energy of sound waves into electrical signals, which are then analyzed by the CNS not only for tone, loudness, and mechanical phenomena but for content related to speech and complex interpretation of the outside world. The peripheral apparatus for transduction of mechanical energy (Fig. 1-40) is a system of membranes, small bones called ossicles, fluid-filled ducts, and sensitive hair cells. The outer ear funnels the sound waves to the tympanic membrane, which vibrates at a specific frequency according to the energy of the sound wave striking it. This tympanic membrane separates the outer ear from the middle ear.

The middle ear contains a chain of three small bones, the ossicles, which connects the tympanic membrane with the oval window of the inner ear. The malleus is attached to the tympanic membrane and is moved by vibration of that membrane. The malleus in turn attaches to the incus, which moves the stapes. The stapes inserts on the oval window and transfers the energy conducted to it through the other ossicles to the oval window. This ossicular chain amplifies the original vibration of the tympanic membrane and provides a distinct and interpretable movement of the oval window in response to a given frequency of sound waves. Two muscles, the tensor tympani and the stapedius, insert on the malleus and the stapes, respectively. These muscles, innervated by the V and VII nerves, respectively, are controlled through auditory reflex mechanisms that contract the muscles in response to loud noises. These muscles dampen the movement through the ossicular chain and prevent physical damage to the peripheral auditory apparatus.

Movement of the oval window sets up a fluid wave in the scala vestibuli, a cavity at the base of the cochlea filled with perilymph. The cochlea is a coiled structure in the inner ear, supported by the bony modiolus, with fluid-filled canals running through it; the hair cells, the true auditory transducing cells, are located in a special region of this cochlea called the organ of Corti. The fluid wave through the perilymph starts at the base of the scala vestibuli, travels to the apex (called the helicotrema) and at this point is directly continuous with the second perilymph-filled cavity, the scala tympani. At the base of the cochlea, the scala tympani end at the round window. Thus the perilymph wave moves to the helicotrema and back to the base. Between these two perilymph-filled channels, in cross section, runs the cochlear duct, called the scala media. This duct is filled with endolymph, a fluid high in potassium. The basilar membrane of the cochlear duct separates this from the scala vestibuli; on the basilar membrane sits the organ of Corti. Another membrane, Reissner's membrane, separates the scala tympani from the cochlear duct. On the basement membrane sits the organ of Corti, which contains rows of hair cells. There is an inner row of inner hair cells and three to five outer rows of outer hair cells. Attached to the body part of the cochlea is an additional membrane, the tectorial membrane, whose distal portion moves with endolymph fluid waves. The perilymph fluid wave results in movement of the basilar membrane and sets up a fluid wave through the endolymph.

The basilar membrane widens toward the helicotrema. Each specific portion of the basilar membrane, from the base to the helicotrema, responds best, with maximal displacement, to a specific frequency of sound. The base responds best to high-frequency sounds, while regions toward the helicotrema respond best to low-frequency sounds. This specific differential sensitivity to sound of specific frequencies reflects tonotopic organization. As a specific region of the basilar membrane is displaced, the hair cells of the organ of Corti move with the basilar membrane according to mechanical forces that are different from those acting on the tectorial membrane. The hairs of the cells extend away from the direction of the basilar membrane into the tectorial membrane. The tectorial membrane movement in response to the endolymph fluid waves exerts a sheering force against the hairs, bending them. The tectorial membrane contacts the hairs either directly or sets up fluid movement that displaces the hairs. The deflection of the hairs sets up a charge in electrical conductance in the hair cell. This change in conductance, producing a graded electrical potential, releases a neurotransmitter from the base, which excites the primary sensory endings (corresponding to dendrites) of the primary sensory ganglion cells.

The ganglion cells are found in the spiral of the cochlea and are called the spiral or auditory ganglion. These cells are bipolar neurons, with the peripheral process innervating the hair cells and the central process entering the CNS through the auditory or cochlear division of the VIII nerve. See Figure 1-41 for a schematic diagram of the auditory system. These primary afferent fibers of the VIII nerve project ipsilaterally to the dorsal and ventral cochlear nuclei in the pons through the cochlear portion of the VIII cranial nerve. The dorsal cochlear nucleus gives rise to fibers that cross the midline in the dorsal and intermediate acoustic stria and ascend in the lateral lemniscus. The ventral cochlear nucleus projects fibers that cross in the ventral acoustic stria through the trapezoid body and ascending the lateral lemniscus. The cochlear nuclei also send uncrossed fibers, which either synapse with the superior olivary nucleus or ascend into the lateral lemniscus. The lateral lemniscus fibers synapse in the inferior colliculus. The inferior colliculus projects through the brachium of the inferior colliculus to the medial geniculate body of the thalamus, which in turn projects to the primary auditory cortex in the temporal lobe on the transverse gyrus of Heschl. Other brain stem nuclei, such as the nuclei of the lateral lemniscus and nuclei of the trapezoid body, are interposed in the projection system of the lateral lemniscus.

One nucleus of particular importance is the superior olivary nucleus in the pons. The medial portion of this nucleus has "rabbit-ear cells" that receive information from both sides of the cochlear apparatus and act to integrate the temporal sequence of sound striking each ear at a slightly different time. Nuclei of the lateral lemniscus and nuclei of the trapezoid body also receive indirect auditory projections and send fibers into both the ipsilateral and contralateral lateral lemniscus. Therefore the auditory lemniscal channel is both crossed and uncrossed and shows repeated re-crossing at each level of auditory connections. This explains why a unilateral lesion in the ascending auditory pathway does not produce contralateral deafness but only decreased hearing in general. However, auditory nerve damage or cochlear damage will produce unequivocal one-sided deafness ipsilateral to the lesion.

At each step of the auditory pathway, reciprocal descending projections are found. One particularly prominent connection runs from the superior olivary nucleus to contact the hair cells or primary afferent endings on the hair cells. This system, the olivocochlear bundle, can modulate the transmission of auditory information that enters the CNS.

The vestibular system consists of two sets of receptors in the inner ear that communicates information about angular acceleration and linear acceleration into the CNS. This information aids the brain in the interpretation of the direction of gravitation and the direction of movements through space. One set of receptors is found in the cristae ampullares of the semicircular canals (or ducts), while the other set is found in the maculae of the utricle and saccule (Fig. 1-42). There are three semicircular canals on either side of the body in the inner ear: a lateral canal, a posterior canal, and an anterior canal. These canals are all at right angles to each other, like the X, Y, and Z planes in solid geometry. If a patient's head is tilted forward 30 degrees, the lateral canals are parallel to the ground. This pair of lateral canals works together. The anterior canal of one side works in conjunction with, and is parallel to, the posterior canal of the other side. The canals are filled with endolymph and are in continuity with the endolymph of the cochlear duct through a thin ductus reuniens. Each canal has an enlarged region called the ampulla. Hair cells sit in the base of the ampulla and are collectively called the crista. The hairs of the hair cells protrude upward into a gelatinous wedge, called the cupula. The cupula extends approximately one third of the way into the ampulla. As the head moves, the endolymph drags behind as the canal moves (much like a driver is pushed back into the car set during acceleration and is thrown forward with braking). As the endolymph moves differentially with regard to the canal, the cupula is bent and the hairs are moved. This movement produces a change in hair cell conductance, which is communicated to the primary sensory nerve endings through use of a neurotransmitter. This information reported by the canals is angular acceleration and is transient. During a slow banking of a plane, a pilot has differential endolymph movement only for approximately 20 seconds. After this period, the endolymph and canals are rotating at the same velocity, interpreted by the CNS as a stationary position. Therefore the canals report changes in the position of the head and are transient sensory receptors. All six canals must operate properly for correct interpretation of head movements; one side balances, and works together with, the other side. Damage to the canals or the vestibular nerve reporting this information on one side will produce a vestibular imbalance. The patient often will feel as if he or his environment is moving abnormally or inappropriately, usually in a spinning motion (called vertigo).

The second type of vestibular receptor is found in two enlarged sac-like structure, the utricle and the saccule. These sacs are filled with endolymph, also connected with the endolymph in the semicircular canals. In the base of these sacs are maculae, containing hair cells. Sitting on these hairs are calcium carbonate structures, similar to small pebbles, called statoliths, or otoconia. These statoliths produce pressure on the hairs, with resultant alterations ionic conduction in the hair cells, which in turn is transmitted to the primary sensory nerve endings. The utricle is oriented so that maximal stimulation occurs with upright posture. In addition, some investigators believe that the saccule responds to low-frequency vibrations. These stimuli report the direction of the gravitational field (linear acceleration) through statolith stimulation of the hair cells. These hair cells do not adapt to statolith stimulation and are therefore different from the transient and adaptable hair cells in the cristae ampullares of the semicircular canals. The utricle and saccule report linear acceleration continuously (are non-adapting), as long as the statoliths stimulate the hairs of the hair cells.

The primary sensory information concerning angular acceleration from the semicircular ducts, and linear acceleration from the utricle and saccule, travels through cranial nerve VIII, the vestibular portion. See Figure 1-43 for a schematic diagram of the vestibular system. The cell bodies of these bipolar primary sensory afferents are located in Scarpa's ganglion (vestibular ganglion). These ganglion cells send peripheral processes to innervate the hair cells in the cristae ampullares of the semicircular canals and the maculae of the utricle and saccula; they also send central axonal processes to the four vestibular nuclei and directly to the flocculonodular lobe of the cerebellum. The vestibular nuclei send projections to the cerebellum through the medial portion of the inferior cerebellar peduncle, the juxtarestiform body. These projections coordinate the position of the body in space with the state of contraction and tension on the muscles. Other secondary sensory vestibular projections ascend in the medial longitudinal fasciculus to the motor nuclei of cranial nerves III, IV, and VI, for coordination control of eye movements during changes in head position. Distortion of one side of the vestibular input results in an imbalance in the MLF system, producing a rhythmic oscillatory movement in the eyes, called nystagmus. It also is possible that conscious sense of vestibular stimulation can be detected through projections from the vestibular nuclei to the medial geniculate body and subsequent MGB projections to regions of temporal cortex. The vestibular nuclei also send fibers into the reticular formation, where reflex responses related to nausea, vomiting, and other characteristics of vestibular malfunction are initiated.

Two of the vestibular nuclei also send UMN projections to the spinal cord. The lateral vestibular nucleus conveys ipsilateral control over extensor muscles of the body via the lateral vestibulospinal tract. The medial vestibular nucleus conveys control over muscles of the neck that maintain the head in space through the medial vestibulospinal tract projections to LMNs in the upper cervical spinal cord.

The primary sensory afferents carrying taste information (Fig. 1-44A) from taste buds (which contain chemoreceptors responsive to molecular stimulation) and travel through the following cranial nerves: (1) nerve VII through projections of the geniculate ganglion from the anterior two thirds of the tongue, (2) nerve IX through projections of the petrosal ganglion from the posterior one third of the tongue, and (3) nerve X through projections of the nodose ganglion from the epiglottis. This information is conveyed through the solitary tract in the medulla into the nucleus of the solitary tract, a secondary sensory nucleus. This nucleus in turn projects crossed fibers to nucleus VPM of the thalamus through the solitariothalamic tract. Nucleus VPM of the thalamus projects to the lateral aspect of the postcentral gyrus of the parietal lobe, overlapping the trigeminal system projections through this same thalamic nucleus. As a result, taste information from the tongue and epiglottis overlaps the cortical zone of projections of facial and oral cavity sensation. The nucleus solitarius also sends projections to the parabrachial nuclei of the pons; nuclei that are interconnected with the hypothalamus (nucleus PVN), central amygdaloid nucleus, and other visceral processing regions. This system of projections may permit the affective interpretation of taste to be integrated into the hypothalamic mechanisms that in turn regulate visceral behavior. Some reflex visceral information (Fig. 1-44B) is also sent to the nucleus of the solitary tract, particularly through the IX and X nerves. For example chemoreceptive information from the carotid body and baroreceptive information from the carotid sinus travel via the IX nerve and the solitary tract in the medulla to the synapse in the nucleus of the solitary tract. The nucleus of the solitary tract in turn conveys this reflex information to preganglionic autonomic neurons of the vagal complex for reflex regulation of cardiovascular and respiratory responses.

Visceral pain information (Fig. 1-44C) is not associated with the nucleus of the solitary tract. It enters the spinal cord and is processed in the same way as other pain sensation, through both crossed and uncrossed spinoreticular projections. It also should be noted that general sensation of the pharynx and posterior palate is conveyed to the descending nucleus of V and not to the nucleus of the solitary tract.

The olfactory system is sometimes considered to be a visceral sensory system. However, this system has intimate association with the limbic system, is not processed through the brain stem and thalamus, and is most appropriately discussed in the section on the limbic system.

LMNs of the spinal cord send axons through the ventral roots and peripheral nerves directly to striated muscles, where the release of acetylcholine regulates the contraction of the muscle. These neurons depend upon two kinds of input to maintain their activity and subsequent muscle tone: (1) sensory input via reflex connections; (2) UMN supraspinal regulation of tone, posture, and voluntary movements. LMNs innervating muscles of the body are located in the ventral horn of the spinal cord and are subdivided into two categories. The large alpha-motor neurons directly innervate extrafusal striated muscle fibers and are under control of both sensory input and supraspinal systems. The smaller gamma-motor neurons innervate intrafusal fibers of the muscle spindles and are mainly under control of supraspinal system. LMNs innervating skeletal muscles of the head and neck are located in the motor cranial nerve nuclei. These nuclei are the motor nuclei of III, IV and VI for extraocular muscles, V for muscles of mastication, VII for muscles of facial expression, nucleus ambiguus for palatopharyngeal and laryngeal muscles, XI for trapezius and sternocleidomastoid muscles, and XII for muscles of the tongue.

UMNs communicate with LMNs either directly through monosynaptic connections or indirectly through interneurons located near the LMNs (Fig. 1-45). These upper motor neurons direct and control the lower motor neurons, individually or as groups, and achieve behavioral responses through an integrated activity.

The cortex is the source of the two UMN systems. The first is the corticospinal tract (Fig. 1-46). It originates in the cerebral cortex from premotor cortex of the frontal lobe (30 percent), from the motor strip of the precentral gyrus (30 percent), and from the sensory cortex of the postcentral gyrus of the parietal lobe (40 percent). Cells of these cortical areas send fibers through the corona radiata, a fan-like array of fibers, into the posterior limb of the internal capsule in the forebrain, and through the middle three fifths of the cerebral peduncles of the mesencephalon. In the basis pontis, these fibers are broken up into numerous small bundles. They recondense in the pyramids of the medulla. At the caudal-most end of the medulla, 80 to 90 percent of the fibers cross the midline as the decussation of the pyramids. The crossed fibers continue as the lateral corticospinal tract in the lateral funiculus of the spinal cord. The uncrossed portions of the fibers descend in the anterior corticospinal tract in the anterior (ventral) funiculus down to all levels of the spinal cord. A majority of these anterior corticospinal fibers then cross through the anterior white commissure and synapse contralateral to the cortical cells of origin. Perhaps it is the small percentage of corticospinal tract fibers that remain ipsilateral all the way to their terminations that therapeutic intervention utilizes in rehabilitation of some stroke patients and some recovery from forebrain injuries. The corticospinal tract terminates heavily in cervical spinal cord segments (about 55 percent), corresponding to control of LMNs that innervate hands and finger musculature. The corticospinal control heavily influences fine flexor movements associated with skilled hand and finger movements. The thoracic, lumbar, and sacral spinal cord levels receive the other 45 percent of the corticospinal connections. In the human, 90 percent of the corticospinal fibers synapse indirectly on interneurons while the other 10 percent synapse directly on LMNs. In non-primates, the corticospinal tract synapses entirely with interneurons. Direct corticospinal connections with LMNs are a recent evolutionary development seen in primates only, and appear to confer a greater control over finger and thumb musculature. These movements are essential for tool use and fine dexterous motor acts.

The corticobulbar system (Fig. 1-47) arises from the lateral regions of the same cortical areas as the corticospinal system and travels along with the corticospinal system to the brain stem. However, corticobulbar fibers pass through the genu of the internal capsule rather than the posterior limb. This tract distributes crossed fibers to the lower part of the facial nucleus supplying muscles of the lower face, both crossed and uncrossed fibers to nuclei of cranial nerves V and XII, both crossed and uncrossed fibers to the upper half of the facial nucleus supplying muscles of the upper face, and to the other motor cranial nerve nuclei. The result is bilateral cortical control of most of these motor nuclei. Therefore, damage to descending corticobulbar fibers on one side of the brain (genu of internal capsule) usually results in a palsy of only the lower facial muscles, because the other LMNs of the cranial nerve nuclei still can be controlled by connections from the undamaged side. In some individuals, the V and XII nerve nuclei also receive mainly crossed corticobulbar fibers; damage to corticobulbar fibers on one side will result in deviation of the tongue or the jaw, when protruded, to the side opposite the lesion. Only bilateral corticobulbar damage will leave all of the motor cranial nerve nuclei with loss of UMN control (called pseudobulbar palsy).

A major flexor UMN system originates in the brain stem. The rubrospinal tract (Fig. 1-48) arises from the red nucleus in the ventral tegmentum of the midbrain. The rubrospinal fibers cross the midline in the ventral tegmental decussation, at the level of emergence from the red nucleus, and synapse mainly indirectly through interneurons with LMNs throughout the spinal cord. The rubrospinal tract exerts a bias toward LMNs to flexor skeletal muscles. In this way, it reinforces and augments the flexor bias of the corticospinal tract, particularly in movements of the extremities. The motor cortex also innervates the red nucleus in a topographic manner, thus exerting control over its flexor counterpart, the rubrospinal system. So to some extent, the rubrospinal system and its cortical control can be thought of as an "indirect" corticospinal tract.

The vestibulospinal system (Fig. 1-49) consists of two tracts. The first tract is the lateral vestibulospinal tract (Fig. 1-49A) that originates in the lateral vestibular nucleus. It synapse’s both directly and indirectly with ipsilateral LMNs throughout the cord and exerts a powerful extensor bias. This tract is important in the maintenance of antigravity tone and upright posture. The second tract is the medial vestibulospinal tract (Fig. 1-49B). It originates in the medial vestibular nucleus and synapses directly with ipsilateral LMNs of the cervical region of the spinal cord, which innervates muscles of the neck.

Two reticulospinal tracts (Fig. 1-50) originate in the rhombencephalon. Cells of origin of the pontine reticulospinal tract (Fig. 1-50A) reside in the reticular formation in the caudal and rostral pontine reticular nuclei. This tract projects to interneurons in the spinal cord mainly on the ipsilateral side and aids the lateral vestibulospinal system in maintaining extensor tone. The medullary reticulospinal tract (Fig. 1-50B) originates in the reticular formation of the medulla in nucleus reticularis gigantocellularis, synapses with interneurons of the spinal cord mainly on the ipsilateral side, and aids in the maintenance of flexor tone, thus augmenting the effects of the rubrospinal and corticospinal tracts. Both of the reticulospinal tracts are mainly ipsilateral; they are the only UMN tracts that are not specifically somatotopically organized.

The bulbospinal systems are important in maintaining basic muscle tone and posture through the LMNs. In the pons, the fibers come principally from locus coeruleus and in the medulla, a lesser number of fibers arise from the lateral and dorsal tegmentum. These fibers use norepinephrine as a transmitter. Additional pontine and medullary fibers come from the raphe nuclei (nucleus raphe magnus, obscurus, and pallidus) and use serotonin as a transmitter. The exact role of these noradrenergic and serotonergic fibers in maintaining the activity of LMNs has not yet been worked out. However, they do seem to be important for the proper functioning of the LMNs in maintenance of tone, perhaps acting as neuromodulators, augmenting or dampening the effects of other neurotransmitters.

All of the brain stem UMN systems receive either direct (rubrospinal, reticulospinal) or indirect (vestibulospinal, bulbospinal) input from the cerebral cortex, with the possible exception of the pontine reticulospinal system. The red nucleus may mediate influences from higher structures on the lateral vestibular nucleus. Thus the cerebral cortex influences LMNs not only through the corticospinal and corticobulbar tracts, but also through corticorubrospinal, corticoreticulospinal, and corticobulbospinal connections.

The cerebellum functions by comparing existing motor behavior with newly initiated behavior and smoothes and coordinates the resulting movement through connections with the cells of origin of the UMN systems (Fig. 1-51). The cerebellum receives its sensory input mostly through the inferior peduncle; these enter from the dorsal, rostral, and cuneocerebellar tracts, from the inferior olive and the lateral reticular nuclei, and from the vestibular and reticular nuclei. Cortical input synapses first in the pontine nuclei, which send projections to the contralateral cerebellar cortex through the midline cerebellar peduncle. A few inputs from the ventral spinocerebellar tract and from trigeminocerebellar and tectocerebellar projections enter the cerebellum through the superior cerebellar peduncle. The cerebellum integrates this sensory and motor input to smooth and coordinate muscle activity through communication with upper motor neurons.

Purkinje cells in the vermis of the cerebellum project to the fastigial nucleus and also directly project to the lateral vestibular nucleus at the medullopontine junction through the juxtarestiform body to the vestibular and reticular nuclei that send upper motor neuronal projections to the spinal cord lower motor neurons.

Purkinje cells in the paravermis project to the globose and emboliform nuclei, which in lower animals are merged into a single interpositus nucleus. These nuclei send projections through the superior peduncle principally to the red nucleus, and also to the ventrolateral nucleus of the thalamus and reticular nuclei of the brain stem.

Purkinje cells in the cerebellar hemisphere’s project to the dentate nucleus, which sends its outflow through the superior peduncle to the ventrolateral nucleus of the thalamus. Additional dentate fibers terminate in the red nucleus. Nucleus VL of the thalamus then directly regulates the cortical cells, which give rise to some of the cells of origin of the corticospinal. and corticobulbar systems, as well as the corticorubrospinal, corticoreticulospinal, and corticobulbospinal systems. Thus, the outflow of the entire cerebellum is heavily directed toward the UMNs through the outflow of the deep nuclei. The cerebellum achieves control of movement through regulation of these brain stem and cortical systems, which have direct control over the LMNs. The cerebellar outflow is not directed exclusively towards motor regulation. The fastigial nucleus exerts a prominent effect on blood pressure, and probably acts through the reticular formation to regulate some visceral functions. The integrated circuitry for this regulation is not understood well.

The basal ganglia are composed of the caudate nucleus, the putamen, and the globus pallidus (the pallidum). The caudate nucleus and putamen together make up the striatum. These nuclei are developmentally, anatomically, and neurochemically quite similar. The striatum (see Fig. 1-52 for a schematic diagram) receives input from all lobes of the cerebral cortex, from the centromedian nucleus of the thalamus, from the pars compacta of the substantia nigra via the nigrostriatal pathway, a dopamine pathway, and from the raphe nuclei of the midbrain via an ascending serotonergic pathway. The striatum has reciprocal connections with the substantia nigra via a striatonigral pathway that uses GABA and perhaps Substance P as its transmitters, terminating in pars reticulata of substantia nigra. The main output of the striatum terminates in the globus pallidus. Some of these striatal projections use enkephalins as their transmitters. The globus pallidus also receives input from the subthalamus via the subthalamic fasciculus and communicates back to the subthalamus via the pallido-subthalamic pathway. Thus, two caudally placed nuclei have reciprocal interactions with the basal ganglia, the substantia nigra with the striatum and the subthalamic nucleus with the pallidum. These connections are apparently important in suppressing unwanted activities of the basal ganglia. When substantia nigra is damaged in humans, Parkinson's disease results, with muscular rigidity, a resting tremor, and bradykinesia (a slowness of initiating voluntary movements). When the subthalamic nucleus is damaged in humans, hemiballismus (wild uncontrolled flailing movements of the limbs) results.

The major output of the basal ganglia is directed through the pallidum. The globus pallidus projects to the ventrolateral and ventral anterior nuclei of the thalamus, as well as to the nonspecific centromedian nucleus of the thalamus. These pallidothalamic projections travel via the ansa lenticularis (looping under the internal capsule) and the lenticular fasciculus (traveling through the internal capsule), which then join the thalamic fasciculus to terminate in the thalamus. The globus pallidus also sends polysynaptic descending projections into the brain stem through the pallidotegmental tract.

The activity of the basal ganglia is integrated with the thalamus, cerebellum, and cortex to regulate motor movements. The thalamus, particularly the ventrolateral nucleus, receives communication from the globus pallidus, the dentate nucleus of the cerebellum, and the red nucleus, although probably to separate fields of neurons in this nucleus. The thalamus then sends information to UMNs of the cortex, which modulate the outflow of the vital cortical motor neurons. Therefore both the cerebellum and the basal ganglia influence motor outflow through connections with UMNs. The basal ganglia are reported to participate in the initiation and control of stereotyped, repetitive movements. However, the function of the basal ganglia is best considered as an adjunct to the cortex, through which they can maintain a focus on desired voluntary movements and can suppress superfluous unwanted movements. The basal ganglia are so thoroughly integrated with other motor components of the CNS that it is easier to explain dysfunction than function. Damage to the cerebellum or the basal ganglia and its associated nuclei result in involuntary motor disorders such as tremor, rigidity, incoordination, and involuntary movements. These motor phenomena result from altered activity in the affected structure, which in turn alters the activity of the UMNs to which it projects, and the subsequent LMNs under the regulation of those altered UMN systems. Pathology of the cerebellum and basal ganglia clearly illustrate the point that neuronal damage often can be reflected in a patient's actions or activities only through subsequent altered activity or dysfunction of long chains of neurons. For example, substantia nigra damage results in motor problems of the limbs through the dysfunction of a chain of at least six neurons, out to the peripheral motor apparatus.

The pituitary gland is composed of two major lobes, the anterior lobe (adenohypophysis) and the posterior lobe (neurohypophysis). The posterior pituitary contains the terminals of neurosecretory cells from the supraoptic and paraventricular nuclei, which release vasopressin and oxytocin directly into the blood. The anterior pituitary has few direct neuronal connections from the hypothalamus; instead, the median eminence of the hypothalamus acts as a zone (hypophyseotrophic zone) in which releasing and inhibitory factors are secreted into primary capillaries of the hypophyseal-portal system, which transports these factors to the anterior pituitary where they activate or inhibit the release of hormones into the blood.

The median eminence and the releasing factor neurons are controlled by hypothalamic inputs that influence the release of these factors and by other brain stem and forebrain systems whose projections influence the outflow of the releasing or inhibitory factors. The other regulatory systems influencing the median eminence include peptide systems, catecholamine systems, and serotonin systems.

The nuclei and areas of the hypothalamus can be divided into two functional but overlapping groups, the neuroendocrine centers and the visceral regulatory centers. The neuroendocrine centers include parts of the supraoptic and paraventricular nuclei, which release vasopressin and oxytocin from terminals in the posterior pituitary. The arcuate and periventricular nuclei, which send dopaminergic fibers to the contact zone of the median eminence to influence the release of releasing or inhibitory factors, and many neurons that produce releasing or inhibitory factors that are released from axonal projections to the contact zone of the median eminence. Some of these releasing and inhibitory factor neurons have their cell bodies outside the hypothalamus.

The visceral regulatory nuclei of the hypothalamus include the posterior hypothalamic area, the anterior hypothalamic area, the mammillary nuclei, the dorsomedial and ventromedial nuclei, the lateral hypothalamic area, the preoptic nuclei, and the suprachiasmatic nucleus. The posterior hypothalamic area regulates some sympathetic activities through the descending projections of the medial forebrain bundle. The anterior hypothalamic area regulates some parasympathetic activities via projections to the midbrain through the dorsal longitudinal fasciculus. Both of these autonomic regulatory areas of the hypothalamus are regulated by input from the limbic forebrain. In addition, some zones of PVN, the dorsal, lateral, and posterior hypothalamus send direct fiber projections to the spinal cord intermediolateral cell column, and the vagal complex to regulate preganglionic autonomic outflow directly.

The mammillary nuclei of the hypothalamus form a major connection in the limbic system. They receive input from the hippocampus via the fornix. These nuclei also receive input from the mesencephalic tegmentum through the mammillary peduncle. The mammillary nuclei send projections to the anterior nucleus of the thalamus via the mammillthalamic tract, forming part of Papez's circuit of limbic activity. The mammillary nuclei also send outflow to the mesencephalic tegmentum through the mammilotegmental tract, which it is integrated with other descending hypothalamic influences that terminate in the mesencephalic tegmentum and exert control over the autonomic nervous system and motor nuclei.

The dorsomedial and ventromedial nuclei have been implicated in feeding behavior. The input to this area comes from the limbic forebrain. Output goes through both the medial forebrain bundle and the dorsal longitudinal fasciculus to autonomic and motor nuclei in the brain stem. There are also numerous intrahypothalamic projections interconnecting the dorsomedial and ventromedial nuclei with areas such as the lateral hypothalamic area.

The lateral hypothalamic area is associated with feeding and drinking behavior. It is also the main interconnecting zone between the limbic forebrain and the limbic midbrain areas. Major input from the mesencephalic tegmentum and from brain stem monoamine nuclei arrives via the medial forebrain bundle. The lateral hypothalamic area also receives input from olfactory structures, orbitofrontal cortex, and septal nuclei via descending projections of the medial forebrain bundle.

The preoptic area receives input from the amygdala via the stria terminalis, from the orbitofrontal cortex via the medial forebrain bundle, and from other hypothalamic nuclei. The preoptic: output projects mainly to other hypothalamic nuclei, where it is thought to regulate circadian and cyclic rhythms, particularly in association with sex hormones. Both the suprachiasmatic: and the preoptic: nuclei have been implicated in control of circadian rhythms, the former nucleus via direct retino-hypothalamic input carrying light-dark information. The preoptic area also contains many thermo-sensitive neurons.

Some areas of the hypothalamus respond to interleukin-1 and other cytokines, and respond to immunization with altered neuronal electrical activity and monoamine metabolism, particularly of norepinephrine. These areas may be receiving "molecular sensory" information from the immune system, and may be interposed in typical hypothalamic circuitry influencing the periphery, with the novel target of mobile cells of the immune system. Areas that participate in this neural-immune communication include the preoptic area, dorsomedial nucleus, and paraventricular nucleus.

It also is clear that the hypothalamus, as both a neuroendocrine and visceral regulatory system, is an important region of influence from the limbic: system and its connections. This relationship is further discussed below.

The limbic: system controls emotional responsiveness and affective behavior through the utilization of the visceral and neuroendocrine systems of the hypothalamus. The limbic: system consists of a midbrain portion situated in the midbrain tegmentum. The limbic midbrain (also some areas of pons) includes the dorsal and ventral tegmental nuclei, the interpeduncular nucleus, and the noradrenergic: locus coeruleus, the serotonergic central superior and dorsal raphe nuclei, the ventrolateral periaqueductal gray, and the dopaminergic ventral tegmental area. These areas receive integrated sensory and visceral information from the reticular formation. The limbic midbrain conveys the actual state of the body, both internally and externally, to the hypothalamus and to the limbic forebrain. The limbic forebrain projects back to the limbic midbrain, placing the hypothalamus in a strategic position for integrating information going in both directions. The lateral hypothalamus subserves this major integrative position within the hypothalamus. In addition, the limbic midbrain structures project to many limbic forebrain areas, including the septum, amygdala, olfactory tubercle, nucleus accumbens, cingulate and frontal cortex, and hippocampus.

The limbic forebrain consists of both cortical and subcortical structures. The subcortical structures include the septum, amygdala, and basal olfactory nuclei such as the olfactory tubercle (anterior perforated substance), nucleus accumbens, nucleus basalis of Meynert (cholinergic) and anterior olfactory nucleus. The cortical structures include the hippocampus, the cingulate cortex, entorhinal cortex (including parahippocampal and periamygdaloid cortex), and prefrontal cortex. Most of the limbic forebrain connections channel into the hypothalamus, where they influence both visceral hypothalamic and neuroendocrine outflow. The individual structures making up the limbic forebrain are difficult to describe functionally because they act as an integrated whole. The entire limbic forebrain must act together to achieve the regulation of affective behavior that is normally seen. However, a few pathways are of particular importance. The hippocampus sends information to the mammillary bodies, the septum, and the preoptic hypothalamus via the fornix. The nucleus basalis sends cholinergic axonal projections to wide ranges of cerebral cortex. The amygdala interconnects with many visceral and neuroendocrine centers of the hypothalamus via the stria terminalis and the direct amygdalofugal pathway (diagonal band of Broca). The septum has a major output to the hippocampus through the fornix and also interconnects with the hypothalamus. The cingulate cortex also has a major influence over the hippocampus through polysynaptic connections. Prefrontal cortex sends projections to the anterior and preoptic hypothalamus via the descending portion of the medial forebrain bundle. The anterior thalamic nuclei receive input from the mammillary nuclei (mammillthalamic tract), a major receiving zone of the fornix. Both cerebral neocortex and the olfactory system play a major controlling role over limbic forebrain structures.

The thalamus is the major relay center to the cortex for all sensory systems except the olfactory system for motor systems, particularly the cerebellum and basal ganglia, and for autonomic-visceral system through the anterior nuclei. A discussion of the thalamic nuclei and the portions of cortex to which they project were presented in the section on regional neuroanatomy. Since the thalamus and cortex have reciprocal connections and act in concert to maintain the overall activity of the cerebral cortex, only a few functional aspects of the cortex will be further discussed in this section.

The cerebral cortex receives information from specific projection nuclei of the thalamus, from a few fibers of nonspecific thalamic nuclei, from the olfactory system, from brain stem noradrenergic, dopaminergic, and serotonergic nuclei, and from the cholinergic nucleus basalis. The output of the cortex includes projection fibers. The projection fibers have been partially discussed with motor systems. The major projection fibers of the cerebral cortex include the following systems:

1. Corticospinal tract

2. Corticobulbar tract

3. Corticorubrospinal system

4. Corticoreticulospinal system

5. Corticobulbospinal system (polysynaptic)

6. Corticotectal fibers regulating visual reflex responses

7. Corticopontine fibers

8. Corticostriate fibers

9. Corticonuclear fibers to secondary nuclei for regulation of sensory input

10. Corticothalamic connections with all projection nuclei and with nonspecific thalamic nuclei

11. Cortical connections to other brain stem nuclei such as the inferior olivary nucleus

12. Cortical connections to autonomic preganglionic neurons in the spinal cord and brain stem, and associated control nuclei (nucleus solitarius)

From the list above, it is clear that the neocortex. has a connection with virtually all major subdivisions of the CNS. In addition to projection fibers, the cortex has much cortical intercommunication. These connections are of two types: commissural bundles that cross the midline, and association or arcuate fibers that interconnect cortical areas of a single hemisphere. The commissural bundles (see Fig. 1-30) are the corpus callosum and the anterior commissure. The corpus callosum interconnects the frontal lobes (through the rostrum and genu), the parietal lobes (through the body) and the temporal and occipital lobes (through the body and splenium). The anterior commissure mainly interconnects limbic forebrain structures of the temporal lobes. Arcuate fibers are either short arcuate fibers, interconnecting adjacent gyri, or long arcuate fibers, interconnecting more distant areas of cortex.

One particularly interesting feature of the cortex is lateralization of function. The two hemispheres are not identical. One of the hemispheres, the dominant hemisphere, controls both the understanding and the interpretation of language and the motor initiation of speech. In 98 percent of humans, the dominant hemisphere is the left hemisphere. Broca's area in the frontal lobe is the area of motor control, or expressive control of speech. Also, on the parietotemporal border of the dominant hemisphere is Wernicke's area, the receptive area for speech. Loss of these areas renders a person unable to initiate speech or to understand speech, respectively (called expressive and receptive aphasia, respectively). Although Broca's area and Wernicke's area are described as separate regions, they really represent a continuum of cortex involved in language function. Control of writing and reading of language is also under principal control of the dominant hemisphere, in more posterior areas of parietotemporal cortex. Damage here may result in dyslexia or dysgraphia. The non-dominant hemisphere processes geometric and spatial relationships. Recent data also suggest that the dominant auditory cortex play a major role in musical interpretation and appreciation. Thus, both the dominant and non-dominant (or the conversant and non-conversant) hemispheres must work together to achieve a final interpretation of the outside world and to achieve a full complement of human skills and behavior.