Control of Posture & Movement It is the integrated activity of multiple inputs from spinal, medullary, midbrain, and cortical

al levels that regulates the posture of the body and makes coordinated movement possible. The inputs converging on the motor neurons subserve three semidistinct functions: 1. They bring about voluntary activity; 2. They adjust body posture to provide a stable background for movement; and 3. They coordinate the action of the various muscles to make movements smooth and precise. The patterns of voluntary activity are planned within the brain, and the commands are sent to the muscles primarily via the corticospinal and corticobulbar systems. Posture is continually adjusted not only before but also during movement by postureregulating systems. Movement is smoothed and coordinated by the medial and intermediate portions of the cerebellum (spinocerebellum) and its connections. The basal ganglia and the lateral portions of the cerebellum (neocerebellum) are part of a feedback circuit to the premotor and motor cortex that is concerned with planning and organizing voluntary movement.

GENERAL PRINCIPLES Organization Motor output is of two types: reflexive, or involuntary, and voluntary. To move a limb, for example, the brain must plan a movement, arrange appropriate motion at many different joints at the same time, and adjust the motion by comparing plan with performance. The motor system "learns by doing," and performance improves with repetition. This involves synaptic plasticity. Commands for voluntary movement originate in cortical association areas. The movements are planned in the cortex as well as in the basal ganglia and the lateral portions of the cerebellar hemispheres, as indicated by increased electrical activity before the movement. The basal ganglia and cerebellum both funnel information to the premotor and motor cortex by way of the thalamus. Motor commands from the motor cortex are relayed in large part via the corticospinal tracts to the spinal cord and the corresponding corticobulbar tracts to motor neurons in the brain stem. Collaterals from these pathways and a few direct connections from the motor cortex end on brain stem nuclei, which also project to motor neurons in the brain stem and spinal cord, and these pathways, can also mediate voluntary movement. Movement sets up alterations in sensory input from the special senses and from muscles, tendons, joints, and the skin. This feedback information, which adjusts and smoothes movement, is relayed directly to the motor cortex and to the spinocerebellum. The spinocerebellum projects in turn to the brain stem. The main brain stem pathways that are concerned with posture and coordination are the rubrospinal, reticulospinal, tectospinal, and vestibulospinal tracts and corresponding projections to motor neurons in the brain stem. Control of Axial & Distal Muscles The brain stem and spinal cord, medial or ventral pathways and neurons are concerned with the control of muscles of the trunk and proximal portions of the limbs, whereas lateral pathways are concerned with the control of muscles in the distal portions of the limbs. The axial muscles are concerned with postural adjustments and gross movements, whereas the distal limb muscles are those that mediate fine, skilled movements. The ventral corticospinal tract and the medial descending paths from the brain stem (the tectospinal, reticulospinal, and vestibulospinal tracts) are concerned with adjustments of proximal muscles and posture, whereas the lateral corticospinal tract and the rubrospinal

tract are concerned with distal limb muscles and, particularly in the case of the lateral corticospinal tract, with skilled voluntary movements. Phylogenetically, the medial pathways are old, whereas the lateral pathways are new. Other Terms Because the fibers of the lateral corticospinal tract form the pyramids in the medulla, the corticospinal pathways have often been referred to as the pyramidal system. The rest of the descending brain stem and spinal pathways that do not pass through the pyramids and are concerned with postural control have been called the extrapyramidal system. In addition, the motor system has often been divided into upper and lower motor neurons. Lesions of the lower motor neurons-the spinal and cranial motor neurons that directly innervate the muscles-are associated with flaccid paralysis, muscular atrophy, and absence of reflex responses. The syndrome of spastic paralysis and hyperactive stretch reflexes in the absence of muscle atrophy is said to be due to destruction of the "upper motor neurons," the neurons in the brain and spinal cord that activate the motor neurons. However, there are three types of "upper motor neurons" to consider. Lesions in many of the posture-regulating pathways cause spastic paralysis, but lesions limited to the corticospinal and corticobulbar tracts produce weakness (paresis) rather than paralysis, and the affected musculature is generally hypotonic. Cerebellar lesions produce incoordination. CORTICOSPINAL & CORTICOBULBAR SYSTEM ANATOMY & FUNCTION Tracts The nerve fibers that pass from the motor cortex to the cranial nerve nuclei form the corticobulbar tract. The nerve fibers that cross the midline in the medullary pyramids and form the lateral corticospinal tract make up about 80% of the fibers in the corticospinal pathway. The remaining 20% make up the anterior or ventral corticospinal tract which does not cross the midline until the level at which it synapses with motor neurons. In addition, this tract contains axons of corticospinal neurons that never do cross the midline and end on the same side of the body. The ventral pathway, which is the oldest phylogenetically, ends primarily on interneurons. These interneurons synapse on neurons in the medial portion of the ventral horn that control axial and proximal limb muscles. Conversely, the lateral corticospinal pathway innervates lateral neurons in the ventral horn that are concerned with distal limb muscles and hence with skilled movements. In humans, the fibers of this phylogenetically new system end directly on the lateral motor neurons. Cortical Motor Areas The cortical areas from which the corticospinal and corticobulbar system originates are generally held to be those where stimulation produces prompt discrete movement. The best known is the motor cortex (M1) in the precentral gyrus. However, there is a supplementary motor area on and above the superior bank of the cingulate sulcus on the medial side of the hemisphere that reaches to the premotor cortex on the lateral surface of the brain Motor responses are also produced by stimulation of somatic sensory area I in the postcentral gyrus and by stimulation of somatic sensory area II in the wall of the sylvian fissure.

 These observations fit with the fact that 30% of the fibers making up the corticospinal and corticobulbar tracts come from the motor cortex but 30% come from the premotor cortex and 40% from the parietal lobe, especially the somatic sensory area. The various parts of the body are represented in the precentral gyrus, with the feet at the top of the gyrus and the face at the bottom. The facial area is represented bilaterally, but the rest of the representation is unilateral, the cortical motor area controlling the musculature on the opposite side of the body. The cortical representation of each body part is proportionate in size to the skill with which the part is used in fine, voluntary movement. The areas involved in speech and hand movements are especially large in the cortex; use of the pharynx, lips, and tongue to form words and of the fingers and apposable thumbs to manipulate the environment are activities in which humans are especially skilled. There is a regular representation of the body, with the axial musculature and the proximal portions of the limbs represented along the anterior edge of the precentral gyrus and the distal part of the limbs along the posterior edge. The cells in the cortical motor areas are arranged in columns. The cells in each column receive fairly extensive sensory input from the peripheral area in which they produce movement, providing the basis for feedback control of movement. Some of this input may be direct, and some is relayed from somatic sensory area I in the postcentral gyrus. Cerebral dominance, which is discussed in detail in also, affects the motor cortex in humans. Moving the fingers of the left hand is associated mainly with activation of the right motor cortex and vice versa. However, moving the fingers of the left hand also activates the left motor cortex, particularly in individuals who are right-handed. This correlates with the fact that lesions of the left motor cortex cause motor dysfunction in the left hand as well as the right hand, whereas lesions of the right motor cortex have little effect on the right hand. Plasticity In intact experimental animals and humans, the motor cortex shows the same kind of plasticity as the sensory cortex. Thus, for example, the finger areas of the contralateral motor cortex enlarge as a pattern of rapid finger movement is learned with the fingers of one hand; this change is detectable at 1 week and maximal at 4 weeks. Cortical areas of output to other muscles also increase in size when motor learning involves these muscles. When a small focal ischemic lesion is produced in the hand area of the motor cortex of monkeys, the hand area may reappear, with return of motor function, in an adjacent undamaged part of the cortex. Thus, the maps of the motor cortex are not immutable, and they change with experience. Supplementary Motor Area For the most part, the supplementary motor area projects to the motor cortex. It appears to be involved primarily in programming motor sequences. Lesions of this area in monkeys produce awkwardness in performing complex activities and difficulty with bimanual coordination. When human subjects count to themselves without speaking, the motor cortex is quiescent, but when they speak the numbers aloud as they count, blood flow increases in the motor cortex and the supplementary motor area. Thus, the supplementary motor area as well as the motor cortex is involved in voluntary movement when the movements being performed are complex and involve planning. Blood flow increases whether or not a planned movement is carried out. The increase occurs whether the movement is performed by the contralateral or the ipsilateral hand.

Premotor Cortex The premotor cortex projects to the brain stem areas concerned with postural control and to the motor cortex as well as providing part of the corticospinal and corticobulbar output. Its function is still incompletely understood, but it may be concerned with setting posture at the start of a planned movement and with getting the individual ready to perform. Posterior Parietal Cortex In addition to providing fibers that run in the corticospinal and corticobulbar tracts, the somatic sensory area and related portions of the posterior parietal lobe project to the premotor area. Lesions of the somatic sensory area cause defects in motor performance that are characterized by inability to execute learned sequences of movements such as eating with a knife and fork. Some of the neurons in area 5 are concerned with aiming the hands toward an object and manipulating it, whereas some of the neurons in area 7 are concerned with hand-eye coordination. Role in Movement The corticospinal and corticobulbar system is the primary pathway for the initiation of skilled voluntary movement. Careful section of the pyramids producing highly selective destruction of the lateral corticospinal tract in laboratory primates produces prompt and sustained loss of the ability to grasp small objects between two fingers and to make isolated movements of the wrists. However, the animal can still use the hand in a gross fashion and can stand and walk. These deficits are consistent with loss of control of the distal musculature of the limbs, which is concerned with fine skilled movements. On the other hand, lesions of the ventral corticospinal tract produce axial muscle deficits that cause difficulty with balance, walking, and climbing. Effects on Stretch Reflexes Section of the pyramids in monkeys produces prolonged hypotonia and flaccidity rather than spasticity. The anatomic arrangements in humans are such that disease processes rarely, if ever, damage the corticospinal and corticobulbar tracts without also destroying posture-regulating pathways. When spasticity is present, it is probably caused by damage to these latter pathways rather than to the corticospinal and corticobulbar tracts. Damage to the lateral corticospinal tract in humans produces the Babinski sign: dorsiflexion of the great toe and fanning of the other toes when the lateral aspect of the sole of the foot is scratched. Except in infancy, the normal response to this stimulation is plantar flexion in all the toes. The Babinski sign is believed to be a flexor withdrawal reflex that is normally held in check by the lateral corticospinal system. It is of value in the localization of disease processes, but its physiologic significance is unknown. POSTURE-REGULATING SYSTEMS Integration At the spinal cord level, afferent impulses produce simple reflex responses. At higher levels in the nervous system, neural connections of increasing complexity mediate increasingly complicated motor responses. In the intact animal, the individual motor responses are fitted into or "submerged" in the total pattern of motor activity. When the neural axis is transected, the activities integrated below the section are cut off or released from the "control of higher brain centers" and often appear to be accentuated. Release of this type, long a cardinal principle in neurology, may be due in some situations to removal of an inhibitory control by higher neural centers.

A more important cause of the apparent hyperactivity is loss of differentiation of the reaction, so that it no longer fits into the broader pattern of motor activity. An additional factor may be denervation hypersensitivity of the centers below the transection, but the role of this component remains to be determined.

Postural Control It is impossible to separate postural adjustments from voluntary movement in any rigid way, but it is possible to differentiate a series of postural reflexes that not only maintain the body in an upright, balanced position but also provide the constant adjustments necessary to maintain a stable postural background for voluntary activity. These adjustments include maintained static reflexes and dynamic, short-term phasic reflexes. The former involve sustained contraction of the musculature, whereas the latter involve transient movements. Both are integrated at various levels in the CNS from the spinal cord to the cerebral cortex and are effected largely through various motor pathways. A major factor in postural control is variation in the threshold of the spinal stretch reflexes, which is caused in turn by changes in the excitability of motor neurons and, indirectly, by changes in the rate of discharge in the efferent neurons to muscle spindles.

SPINAL INTEGRATION Spinal Shock In all vertebrates, transection of the spinal cord is followed by a period of spinal shock during which all spinal reflex responses are profoundly depressed. During this period the resting membrane potential of the spinal motor neurons is 2-6 mV greater than normal. Subsequently, reflex responses return and become relatively hyperactive. The duration of spinal shock is proportionate to the degree of encephalization of motor function in the various species. In frogs and rats it lasts for minutes; in dogs and cats it lasts for 1-2 hours; in monkeys it lasts for days; and in humans it usually lasts for a minimum of 2 weeks. The cause of spinal shock is uncertain. Cessation of tonic bombardment of spinal neurons by excitatory impulses in descending pathways undoubtedly plays a role, but the subsequent return of reflexes and their eventual hyperactivity also have to be explained. The recovery of reflex excitability may be due to the development of denervation hypersensitivity to the mediators released by the remaining spinal excitatory endings. Another possibility for which there is some evidence is the sprouting of collaterals from existing neurons, with the formation of additional excitatory endings on interneurons and motor neurons. The first reflex response to appear as spinal shock wears off in humans is frequently a slight contraction of the leg flexors and adductors in response to a noxious stimulus. In some patients, the knee jerks come back first. The interval between cord transection and the beginning return of reflex activity is about 2 weeks in the absence of any complications, but if complications are present it is much longer. It is not known why infection, malnutrition, and other complications of cord transection inhibit spinal reflex activity. Complications of Cord Transection Like all immobilized patients, they develop a negative nitrogen balance and catabolize large amounts of body protein. The weight of the body compresses the circulation to the skin over bony prominences, so that unless the patient is moved frequently the skin breaks down at these points and decubitus ulcers form.

The ulcers heal poorly and are prone to infection because of body protein depletion. The tissues that are broken down include the protein matrix of bone, and this plus the immobilization cause Ca2+ to be released in large amounts. This leads to hypercalcemia and hypercalciuria, and calcium stones often form in the urinary tract. The stones and the paralysis of bladder function both cause urinary stasis, which predisposes to urinary tract infection, the most common complication of spinal cord injury. Responses in Chronic Spinal Animals & Humans Once the spinal reflexes begin to reappear after spinal shock, their threshold steadily drops. In chronically quadriplegic humans, the threshold of the withdrawal reflex is especially low. Even minor noxious stimuli may cause not only prolonged withdrawal of one extremity but marked flexion-extension patterns in the other three limbs. Repeated flexion movements may occur for prolonged periods, and contractures of the flexor muscles develop. Stretch reflexes are also hyperactive, as are more complex reactions based on this reflex. For example, if a finger is placed on the sole of the foot of an animal after the spinal cord has been transected (spinal animal), the limb usually extends, following the finger as it is withdrawn. This magnet reaction (positive supporting reaction) involves proprioceptive as well as tactile afferents and transforms the limb into a rigid pillar to resist gravity and support the animal. Its disappearance is also in part an active phenomenon (negative supporting reaction) initiated by stretch of the extensor muscles. If the cord section is incomplete, the flexor spasms initiated by noxious stimuli can be associated with bursts of pain that are particularly bothersome. Locomotion Generator Not only can spinal cats and dogs be made to stand, but circuits intrinsic to the spinal cord produce walking movements when stimulated in a suitable fashion. There are two pattern generators for locomotion in the spinal cord, one in the cervical and one in the lumbar region. However, this does not mean that spinal animals or humans can walk without stimulation; the pattern generator has to be turned on by tonic discharge of a discrete area in the midbrain, the mesencephalic locomotor region, and of course this is only possible in patients with incomplete spinal cord transection. The generators can also be turned on in experimental animals by administration of the norepinephrine precursor L-dopa (levodopa) or the -adrenergic receptor agonist clonidine after complete section of the spinal cord. Autonomic Reflexes Reflex contractions of the full bladder and rectum occur in spinal animals and humans, although the bladder is rarely emptied completely. Hyperactive bladder reflexes can keep the bladder in a shrunken state long enough for hypertrophy and fibrosis of its wall to occur. Blood pressure is generally normal at rest, but the precise feedback regulation normally supplied by the baroreceptor reflexes is absent and wide swings in pressure are common. Bouts of sweating and blanching of the skin also occur. Sexual Reflexes Other reflex responses are present in the spinal animal, but in general they are only fragments of patterns that are integrated in the normal animal into purposeful sequences. The sexual reflexes are an example. Coordinated sexual activity depends upon a series of reflexes integrated at many neural levels and is absent after cord transection.

However, genital manipulation in male spinal animals and humans produces erection and even ejaculation. In female spinal dogs, vaginal stimulation causes tail deviation and movement of the pelvis into the copulatory position.

Mass Reflex In chronic spinal animals, afferent stimuli irradiate from one reflex center to another. When even a relatively minor noxious stimulus is applied to the skin, it may irradiate to autonomic centers and produce evacuation of the bladder and rectum, sweating, pallor, and blood pressure swings in addition to the withdrawal response. This distressing mass reflex can sometimes be used to give paraplegic patients a degree of bladder and bowel control. They can be trained to initiate urination and defecation by stroking or pinching their thighs, thus producing an intentional mass reflex.

MEDULLARY COMPONENTS Introduction In experimental animals in which the hindbrain and spinal cord are isolated from the rest of the brain by transection of the brain stem at the superior border of the pons, the most prominent finding is marked spasticity of the body musculature. The operative procedure is called decerebration, and the resulting pattern of spasticity is called decerebrate rigidity. Decerebration produces no phenomenon akin to spinal shock, and the rigidity develops as soon as the brain stem is transected. Mechanism of Decerebrate Rigidity On analysis, decerebrate rigidity is found to be spasticity due to diffuse facilitation of stretch reflexes. The facilitation is due to two factors: 1) Increased general excitability of the motor neuron pool and 2) Increase in the rate of discharge in the efferent neurons. Supraspinal Regulation of Stretch Reflexes The brain areas that facilitate and inhibit stretch reflexes generally act by increasing or decreasing spindle sensitivity. The large facilitatory area in the brain stem reticular formation discharges spontaneously, possibly in response to afferent input like the RAS. However, the smaller brain stem area that inhibits efferent discharge does not discharge spontaneously but is driven instead by fibers from the cerebral cortex and the cerebellum. The smaller brain stem area that inhibits efferent discharge does not discharge spontaneously but is driven instead by fibers from the cerebral cortex and the cerebellum. The net effect of destruction of the cerebellum in humans is hypotonia rather than spasticity. The vestibulospinal and some related descending pathways are also facilitatory to stretch reflexes and promote rigidity. Significance of Decerebrate Rigidity "A caricature of the normal standing position." What has been uncovered by decerebration, then, are the tonic, static postural reflex mechanisms that support the animal against gravity. The more common pattern of extensor rigidity in the legs and moderate flexion in the arms is actually decorticate rigidity due to lesions of the cerebral cortex, with most of the brain stem intact Tonic Labyrinthine Reflexes a. In the decerebrate animal, the pattern of rigidity in the limbs varies with the position. No righting responses are present, and the animal stays in the position in which it is put.

b. If the animal is placed on its back, the extension of all four limbs is maximal. As the animal is turned to side, the rigidity decreases, and when it is prone, the rigidity is minimal though still present. c. These changes in rigidity, the tonic labyrinthine reflexes, are initiated by the action of gravity on the otolithic organs and are effected via the vestibulospinal tracts. Tonic Neck Reflexes If the head of a decerebrate animal is moved relative to the body, changes in the pattern of rigidity occur. If the head is turned to one side, the limbs on that side ("jaw limbs") become more rigidly extended while the contralateral limbs become less so. This is the position often assumed by a normal animal looking to one side. Flexion of the head causes flexion of the forelimbs and continued extension of the hind limbs, the posture of an animal looking into a hole in the ground. Extension of the head causes flexion of the hind limbs and extension of the forelimbs, the posture of an animal looking over an obstacle. These responses are the tonic neck reflexes. They are initiated by stretch of the proprioceptors in the upper part of the neck, and they can be sustained for long periods. MIDBRAIN COMPONENTS Introduction After section of the neural axis at the superior border of the midbrain (midbrain animal), extensor rigidity like that seen in the decerebrate animal is present only when the animal lies quietly on its back. In the decerebrate animal, the rigidity, which is a static postural reflex, is prominent because there are no modifying phasic postural reflexes. Chronic midbrain animals can rise to the standing position, walk, and right themselves. While the animals are engaged in these phasic activities, the static phenomenon of rigidity is not seen. Righting Reflexes Righting reflexes operate to maintain the normal standing position and keep an animal's head upright. These reflexes are a series of responses integrated for the most part in the nuclei of the midbrain. CORTICAL COMPONENTS Effects of Decortication Removal of the cerebral cortex (decortication) produces little motor deficit in many species of mammals.

BASAL GANGLIA
Anatomic Considerations The term basal ganglia is generally applied to five structures on each side of the brain: 1. Caudate nucleus, 2. Putamen, and 3. Globus pallidus, three large nuclear masses underlying the cortical mantle, and the functionally related 4. Subthalamic nucleus (body of Luys) and 5. Substantia nigra. The globus pallidus is divided into an external and an internal segment. The substantia nigra is divided into a pars compacta and a pars reticulata. Parts of the thalamus are intimately related to the basal ganglia. The caudate nucleus and the putamen are frequently called the striatum; the putamen and the globus pallidus are sometimes called the lenticular nucleus

 The main afferent connections to the basal ganglia terminate in the striatum. They include the corticostriate projection from all parts of the cerebral cortex. There is also a projection from the centromedian nucleus of the thalamus to the striatum. The principal output from the basal ganglia is from the internal segment of the globus pallidus via the thalamic fasciculus to the ventral lateral, ventral anterior, and centromedian nuclei of the thalamus. Disorders of the basal ganglia (extrapyramidal disorders) do not cause weakness or reflex changes. Their hallmark is involuntary movement (dyskinesia), causing increased movement (hyperkinesia) or decreased movement (hypokinesia) and changes in muscle tone and posture.

CEREBELLUM
Anatomic Divisions The cerebellum sits astride the main sensory and motor systems in the brain stem. It is connected to the brain stem on each side by a superior peduncle (brachium conjunctivum), middle peduncle (brachium pontis), and inferior peduncle (restiform body). The medial vermis and lateral cerebellar hemispheres are more extensively folded and fissured than the cerebral cortex; the cerebellum weighs only 10% as much as the cerebral cortex, but its surface area is about 75% of that of the cerebral cortex. Anatomically, the cerebellum is divided into three parts by two transverse fissures. The posterolateral fissure separates the medial nodulus and the lateral flocculus on either side from the rest of the cerebellum, and the primary fissure divides the remainder into an anterior and a posterior lobe. Lesser fissures divide the vermis into smaller sections, so that it contains ten primary lobules numbered I-X from superior to inferior. Functional Divisions From a functional point of view, the cerebellum is also divided into three parts, but in a different way. The nodulus in the vermis and the flanking flocculus in the hemisphere on each side form the flocculonodular lobe or vestibulocerebellum. This lobe, which is phylogenetically the oldest part of the cerebellum, has vestibular connections and is concerned with equilibrium and learning- induced changes in the VOR. The rest of the vermis and the adjacent medial portions of the hemispheres form the spinocerebellum, the region that receives proprioceptive input from the body as well as a copy of the "motor plan" from the motor cortex. By comparing plan with performance, it smoothes and coordinates movements that are ongoing. The vermis projects to the brain stem area concerned with control of axial and proximal limb muscles, whereas the hemispheres project the brain stem areas concerned with control of distal limb muscles. The lateral portions of the cerebellar hemispheres are called the neocerebellum. They are the newest from a phylogenetic point of view, reaching their greatest development in humans. They interact with the motor cortex in planning and programming movements. The archicerebellum (vestibulocerebellum) comprises the flocculonodular lobe, helps maintain equilibrium and coordinate eye-head-neck movements, and is closely interconnected with the vestibular nuclei. The midline vermis (paleocerebellum) helps coordinate movement of the trunk and legs. Vermis lesions result in abnormalities of stance and gait. The lateral hemispheres, which make up the neocerebellum, control ballistic and finely coordinated limb movements, predominantly of the arms. It appears to be important for the initial learning of motor tasks, acquisition of cognitive information, and the efficient execution of previously learned sensorimotor responses

 cerebellum also may act in concert with the frontal lobes to facilitate efficient processing and retrieval of cognitive information Flocculonodular Lobe Animals in which the flocculonodular lobe has been destroyed walk in a staggering fashion on a broad base. They tend to fall and are reluctant to move without support. Similar defects are seen in children as the earliest signs of a midline cerebellar tumor that arises from cell rests in the nodule. Early in its course, it produces damage that is generally localized to the flocculonodular lobe. Selective ablation of the flocculonodular lobe in dogs abolishes the syndrome of motion sickness, whereas extensive lesions in other parts of the cerebellum and the rest of the brain fail to affect it.

Effects on Stretch Reflexes Stimulation of the cerebellar areas that receive proprioceptive input sometimes inhibits and sometimes facilitates movements evoked by stimulation of the cerebral cortex. Lesions in folia I-VI and the paramedian areas in experimental animals cause spasticity localized to the part of the body that is represented in the part of the cerebellum destroyed. However, hypotonia is characteristic of cerebellar destruction in humans. Anatomy and Physiology of CSF Circulation and Pathways The CSF is formed within the cerebral ventricular system, mainly by the choroid plexus. Each of the four ventricles contains choroid plexus tissue, consisting of villous folds lined by epithelium and a central core of highly vascularized connective tissue. The fluid is formed by active secretion and diffusion. Nonchoroidal sources of CSF exist The net direction of CSF flow is from the lateral ventricles to the third ventricle and hence to the fourth ventricle and then through the basal cisterns, tentorium, and subarachnoid space over the cerebral convexities to the area of the sagittal sinus, from where absorption into the systemic circulation takes place. The net flow of fluid in the spinal subarachnoid space is cephalad. Most CSF absorption takes place across the arachnoid villi into the venous channels of the sagittal sinus, but fluid is also absorbed across the ependymal lining of the ventricular system and from the spinal subarachnoid space. In the normal adult, the total volume of CSF is approximately 150 mL, of which 25% is within the ventricular system. CSF is formed at the rate of approximately 20 mL/hour, thereby indicating that CSF turns over three or four times per day. CSF formation continues when the intracranial pressure rises, unless extremely high levels are reached. Thus, there must be some absorption of fluid to accommodate the volume of CSF being formed each day. Tight junctions characteristically surround the apical margins of the cells in epithelia such as the intestinal mucosa, the walls of the renal tubules, and the choroid plexus. The tight junctions between capillary endothelial cells in the brain and between the epithelial cells in the choroid plexus effectively prevent proteins from entering the brain in adults and slow the penetration of smaller molecules.