LOWER MOTOR NEURONS

All lower motor neuron (LMN) groups except the facial nerve nucleus that supplies the muscles of facial expression consist of both alpha LMNs that supply the skeletal muscle fibers (extrafusal fibers) and gamma LMNs that supply the small contractile elements in the muscle spindles (intrafusal fibers). The muscles of facial expression do not have muscle spindles and are not supplied by gamma LMNs. The alpha LMNs regulate contraction of the skeletal muscles to produce movement. The gamma LMNs regulate the sensitivity of the muscle spindles for group Ia and group II afferent modulation of alpha LMN excitability.

CLINICAL POINT

An alpha LMN supplies motor axons to a variable number of skeletal muscle fibers (extrafusal fibers), ranging from just a few (e.g., extraocular muscles) to several thousand (large muscles such as the quadriceps). The LMN and its innervated skeletal muscle fibers are called a motor unit. Supporting cells (such as Schwann cells) and myocytes produce trophic factors to maintain the nerve-muscle association; when nerve injury occurs, growth factors help to attract motor axonal regrowth to reestablish the prior nerve-muscle association. When motor axons degenerate, the neuromuscular junctions (NMJs) disappear, and the nicotinic cholinergic receptors spread across the membrane of the denervated skeletal muscle fibers. This results in denervation hypersensitivity to nicotinic cholinergic stimulation, noted as random individual muscle fiber twitches (fibrillation), best observed by electromyography. If motor nerves are attracted back to the muscle fibers and NMJs are restored, the nicotinic cholinergic receptors are again restricted to the secondary folds of the NMJ. If the motor axon that was lost cannot regrow, neighboring motor axons of other motor units that supply adjacent skeletal muscle fibers may send sprouts to the denervated muscle fibers and incorporate them into the motor unit; the consequence is a larger motor unit and a greater demand on the LMN cell body that now supplies a greater than normal number of skeletal muscle fibers.

This mechanism may account for recovery of physiological function in some LMN diseases such as polio. If the alpha-LMN cell body itself is damaged or is in the process of dying (e.g., in amyotrophic lateral sclerosis), the axon may produce aberrant action potentials (agonal bursts of electrical activity) that result in muscle fiber contraction throughout the motor unit, called a fasciculation, which is visually observable. A denervated muscle fiber must be reinnervated within 1 year or so if it is to restore relatively normal function; a longer period leads to permanent changes that preclude proper reinnervation. Many experimental approaches are seeking to restore innervation or attract a more robust nerve supply to denervated muscle fibers by applying or inducing gene expression of growth factors and trophic factors. Denervated skeletal muscle fibers are flaccidly paralyzed, lack muscle tone, cannot be induced to contract with muscle stretch reflexes, and undergo atrophy; these are classic characteristics of LMN syndrome.

DISTRIBUTION OF LOWER MOTOR NEURONS IN THE SPINAL CORD

LMNs are found as clusters of neurons in the anterior (ventral) horn of the spinal cord, represented as lamina IX of Rexed. Distinct clusters of LMNs supply distinct skeletal muscles with motor innervation. These LMN groups are organized topographically; LMNs distributing to trunk and neck muscles are found medially, and LMNs distributing to muscles of distal extremities are found laterally. Within spinal cord segments, LMNs distributing to flexor muscle groups are found dorsally, and LMNs distributing to extensor muscle groups are found ventrally.

DISTRIBUTION OF LOWER MOTOR NEURONS IN THE BRAIN STEM

LMNs are found in medial and lateral columns in a longitudinal view of the brain stem. The medial column (LMNs of the oculomotor nucleus, trochlear nucleus, abducens nucleus, and hypoglossal nucleus) derives from the general somatic efferent system, and the lateral column (LMNs of motor nucleus V, facial nucleus, nucleus ambiguus, and spinal accessory nucleus) derives from the special visceral efferent system. LMNs in the spinal cord are found in a longitudinal column coursing through the anterior horn at all levels.

UPPER MOTOR NEURONS

CORTICAL EFFERENT PATHWAYS

Cortical neurons in the motor cortex (area 4) and the supplemental and premotor cortices (area 6) send axons to the basal ganglia (caudate nucleus and putamen), the thalamus (ventral anterior [VA], and ventral lateral [VL] nuclei), the red nucleus, the pontine nuclei, the cranial nerve (CN) motor nuclei on both sides, and the spinal cord ventral horn, mainly on the contralateral side. These axons form the corticospinal tract, corticobulbar tract, corticostriatal projections, corticopontine projections, corticothalamic projections, and cortical connections to the upper motor neurons (UMNs) of the brain stem (reticular formation [RF] motor areas, red nucleus, superior colliculus). Neurons of the sensory cortex (areas 3, 1, 2) send axons mainly to secondary sensory nuclei (corticonuclear fibers) to regulate incoming lemniscal sensory projections destined for conscious interpretation. Neurons in the frontal eye fields (area 8) project to the superior colliculus, the horizontal and vertical gaze centers of the brain stem, and the interstitial nucleus of Cajal to coordinate voluntary eye movements and associated head movements. Other regions of sensory cortex project axons to thalamic and brain stem structures that regulate incoming lemniscal sensory information. Some cortical efferent fibers project to limbic forebrain regions, such as the amygdaloid nuclei, hippocampal formation, and septal nuclei.

COLOR IMAGING OF CORTICAL EFFERENT PATHWAYS

This diffusion tensor image shows the cortical efferent pathways in a lateral oblique section. These pathways, shown in blue, channel from widespread areas of the cerebral cortex to structures in the forebrain, the thalamus, the brain stem, the cerebellum, and the spinal cord. Additional cortical association pathways are depicted in green (running in anterior-posterior direction) and commissural pathways are shown in red (running in left-right direction).

CORTICOBULBAR TRACT

The corticobulbar tract (CBT) arises mainly from the lateral portion of the primary motor cortex (area 4). CBT axons project through the genu of the internal capsule into the cerebral peduncle, the basis pontis, and the medullary pyramids on the ipsilateral side. The axons distribute to CN motor nuclei on the ipsilateral and contralateral sides except for the portion of the facial nerve nucleus (CN VII) that supplies the muscles of facial expression for the lower face, which receives exclusively contralateral projections. The CBT projections to the hypoglossal nucleus are mainly contralateral; CBT projections to the spinal accessory nucleus are mainly ipsilateral. CBT lesions result mainly in contralateral drooping lower face that is paretic to attempted movements from voluntary commands (central facial palsy), in contrast to Bell's palsy (CN VII palsy), in which the entire ipsilateral face is paralyzed.

CORTICOSPINAL TRACT

The motor portion of the corticospinal tract (CST) originates from neurons of many sizes, mainly from the primary motor cortex (area 4) and the supplemental and premotor cortices (area 6). The primary sensory cortex (areas 3, 1, 2) contributes axons into the CST, but these axons terminate mainly in secondary sensory nuclei to regulate the processing of incoming lemniscal sensory information. The CST travels through the posterior limb of the internal capsule, the middle region of the cerebral peduncle, numerous fascicles of axons in the basis pontis, and the medullary pyramid on the ipsilateral side. Most of the CST axons (approximately 80%, but variable from individual to individual) cross the midline in the decussation of the pyramids at the medullary-spinal cord junction. These crossed fibers descend in the lateral CST in the lateral funiculus of the spinal cord and synapse on alpha and gamma LMNs, both directly and indirectly through interneurons. CST axons that do not decussate continue as the anterior CST in the anterior funiculus of the spinal cord and then decussate at the appropriate level through the anterior white commissure to terminate directly and indirectly on alpha and gamma LMNs contralateral to the cortical cells of origin. Only a very small portion of the motor connections of the corticospinal tract terminate on LMNs on the ipsilateral side of the spinal cord.

CLINICAL POINT

The motor portion of the CST arises mainly from neurons in the primary motor cortex (area 4) and the supplemental and premotor cortices (area 6). The primary sensory cortex and superior parietal lobule contribute corticospinal axons (corticonuclear fibers) to secondary sensory nuclei in the lower brain stem and spinal cord. Approximately 80% of the CST axons cross in the decussation of the pyramids and terminate directly and indirectly with alpha and gamma LMNs that control movements of the distal extremities, especially the hands and fingers. At least 10% of the CST terminates monosynaptically on alpha LMNs, especially those associated with hand and finger musculature. A lesion in the internal capsule damages the CST, corticorubral fibers, and corticoreticular fibers, resulting in contralateral hemiplegia. Initially, the hemiplegia is flaccid, with loss of tone and reflexes. Within days to a week or so, the hemiplegia becomes spastic, with hyperreflexia and hypertonus. The affected musculature shows initial resistance to attempted passive movement, followed by a dissipation or "melting" of tone (the clasp-knife reflex), perhaps because of high threshold Ib Golgi tendon organ inhibitory influences on the homonymous LMNs. The initial suspected mechanism of classical UMN syndrome was disinhibition of dynamic gamma LMNs, which drives initial resistance to passive stretch, mediated via subsequent Ia afferent influences over alpha LMNs; this mechanism was reinforced by observations that dorsal root sectioning diminished spasticity in UMN syndromes. Further studies have revealed additional potential mechanisms, including diminished reciprocal inhibition, recurrent Renshaw inhibition, and presynaptic inhibition on Ia afferents, all suggestive of major changes in interneurons of the spinal cord following a classic UMN lesion. In UMN syndrome, the plantar reflexes are extensor (reverting to a developmentally early stage in the absence of the CST), and abdominal reflexes are absent on the affected side. Clonus (repetitive alternating flexor and extensor muscle stretch reflexes) also may occur and is possibly attributable to interneuronal changes such as diminished Renshaw inhibition.

CLINICAL POINT

The CBT arises mainly from the lateral portion of the primary motor cortex; it descends through the genu of the internal capsule and the cerebral peduncle (medial to the corticospinal tract fibers) ipsilaterally, and it distributes both bilaterally to the motor CN nuclei (CNN) of the brain stem, except to the facial nucleus for the lower face, which receives almost exclusively contralateral projections. The corticobulbar axons terminate mainly on interneurons that regulate LMN output. Originally, corticobulbar was a term reserved for cortical projections to LMNs of the medulla (bulb), but it now has been expanded to include CNN for V, VII, nucleus ambiguus, XII, and the spinal accessory (XI) nucleus. A lesion in the genu of the internal capsule (embolic or thrombotic stroke, or hemorrhage of the middle cerebral artery or its branches) or the cerebral peduncle (Weber's syndrome, compression of the peduncle against the free edge of the tentorium cerebelli with transtentorial herniation) results mainly in a drooping face (central facial palsy) on the contralateral side. The intact hemisphere can control voluntary movement of the LMNs in the CNN for all other brain stem motor nuclei. In some individuals, a predominance of contralateral fibers to LMNs for the soft palate or the tongue is noted, resulting in a temporary contralateral palsy; or a predominance of ipsilateral fibers to LMNs of XI may be noted, resulting in an ipsilateral palsy of the sternocleidomastoid and upper trapezius muscles. This central paresis occurs without atrophy. Bilateral corticobulbar lesions result in profound paralysis of voluntary movement in all muscles supplied by CNN, with preservation of muscle bulk, reflex responses, and some emotional responses using those LMNs. The LMNs in CNN III, IV, and VI receive cortical input from the frontal eye fields (area 8) and parietal eye fields of both sides.

CORTICOSPINAL TRACT TERMINATIONS IN THE SPINAL CORD

Crossed axons in the lateral CST, intermixed with axons of the rubrospinal tract, travel in the lateral funiculus. These CST axons terminate directly and indirectly mainly on LMNs associated with distal musculature, especially for skilled hand and finger movements. The uncrossed anterior CST axons decussate predominantly in the anterior white commissure and terminate directly and indirectly mainly on LMNs that supply medial musculature. A small number of anterior CST axons terminate ipsilateral to the cortical cells of origin. An isolated lesion in the CST in the medullary pyramids results in weakness of contralateral fine, dexterous hand and finger movements. All other lesions involving the CST, intermixed with other descending motor systems (internal capsule, cerebral peduncle, pons), produce contralateral spastic hemiplegia with hypertonus, hyperreflexia, and plantar extensor responses as long-term consequences. Lesions in the lateral CST produce similar symptoms ipsilateral to the damaged lateral funiculus below the level of the lesion.

RUBROSPINAL TRACT

The cortico-rubro-spinal system is an indirect corticospinal system that regulates spinal cord LMNs. The red nucleus in the midbrain receives topographically organized ipsilateral connections from the primary motor cortex (area 4). Axons of the rubrospinal tract (RST) decussate in the ventral tegmental decussation and descend in the lateral brain stem and the lateral funiculus of the spinal cord, where they are intermixed extensively with axons of the lateral CST. The RST terminates directly and indirectly on alpha and gamma LMNs in the spinal cord, particularly those associated with flexor movements of the extremities. The RST helps to drive flexor movements of the upper extremity and helps to hold in check flexor movements of the lower extremity. RST lesions usually occur in conjunction with the CST in the spinal cord; corticorubral lesions also occur in conjunction with the CST in the internal capsule and cerebral peduncle. These lesions result in contralateral spastic hemiplegia as long-term consequences. Brain stem lesions caudal to the red nucleus result in decerebration (extensor spasticity), reflecting the removal of the flexor drive of the rubrospinal tract to LMNs supplying the upper limbs.

VESTIBULOSPINAL TRACTS

The lateral vestibulospinal tract arises from the lateral vestibular nucleus and terminates directly and indirectly on ipsilateral alpha- and gamma-LMNs associated with extensor musculature, especially proximal musculature. If this powerful antigravity extensor system were not kept in check by descending connections from the red nucleus and by connections from the cerebellum, it would produce a constant state of extensor hypertonus. Removal of these influences can occur with lesions caudal to the red nucleus, producing decerebration with powerful extensor posturing. The medial vestibulospinal tract arises from the medial vestibular nucleus and provides inhibition of alpha- and gamma-LMNs controlling neck and axial musculature. The medial vestibulospinal tract terminates mainly on interneurons in the cervical spinal cord ventral horn. These two vestibulospinal tracts stabilize and coordinate the position of the head, neck, and body and provide important reflex and brain stem control over tone and posture. The vestibulospinal tracts work with the reticulospinal tracts to control tone and posture.

CLINICAL POINT

Primary vestibular input from both the maculae of the utricle and the cristae of the ampullae of the semicircular canals terminates in the vestibular nuclei of the medulla and pons, including the cells of origin of the vestibular UMN tracts, the lateral and medial vestibular nuclei. This allows influences from the direction of the gravitational field (linear acceleration) and head movement (angular acceleration) to affect the firing of neurons in the vestibular nuclei. The lateral vestibular nuclei give rise to a powerful vestibulospinal antigravity system that terminates mainly indirectly on alpha- and gamma-LMNs in the medial part of the ventral horn, which is associated with proximal extensor musculature. This system, if left unchecked and uninhibited, would drive the neck and body into marked extensor posturing, called decerebration (or decerebrate rigidity). The lateral vestibulospinal system is inhibited mainly by the red nucleus and the anterior cerebellum. In decerebrate posturing, sectioning of the dorsal roots (dorsal rhizotomy) abolishes the extraordinary "rigidity" (it is actually spasticity, not true rigidity), suggesting the decerebration results from the unregulated activity of the reticulospinal and lateral vestibulospinal tract driving the gamma-LMNs. This is consistent with the earlier hypothesis of the mechanism of spasticity, although additional spinal interneuronal inhibition is also most likely involved in decerebrate posturing. The medial vestibulospinal tract exerts inhibitory influences on LMNs that innervate neck muscles, permitting unconscious adjustments to move the head in response to vestibular stimuli. Thus, the vestibulospinal tracts help to promote body and head movements to maintain appropriate posture with vestibular activation, particularly during movement; these systems also coordinate with projections via the medial longitudinal fasciculus that synchronize eye movements.

RETICULOSPINAL AND CORTICORETICULAR PATHWAYS

The pontine reticulospinal tract (RetST) arises from neurons of the medial pontine RF (nuclei pontis caudalis and oralis). Axons descend as the pontine (medial) RetST, mainly ipsilaterally, and terminate directly and indirectly on alpha- and gamma-LMNs at all levels. This tract has a distinct extensor bias for axial musculature and reinforces the action of the lateral vestibulospinal tract. Although some cortical axons terminate in the nuclei of origin of the pontine RetST, the cortex provides minimal influence on the activity of this tract; the pontine RetST is driven primarily by polysensory input from trigeminal and somatosensory sources. The medullary RetST originates from the medial RF (nucleus gigantocellularis) and is heavily driven by cortical input, especially from the motor cortex and supplemental and premotor cortices. Axons of the medullary (lateral) RetST terminate bilaterally, directly and indirectly, on alpha- and gamma-LMNs at all levels. The medullary RetST exerts a flexor bias, reinforcing the CST and RST. The reticulospinal tracts are important regulators of basic tone and posture. They are not organized somatotopically.

TECTOSPINAL TRACT AND INTERSTITIOSPINAL TRACT

The tectospinal tract arises from neurons in deep layers of the superior colliculus, decussates in the dorsal tegmental decussation, descends contralaterally near the midline, and terminates directly and indirectly on alpha- and gamma-LMNs in the cervical spinal cord associated with head and neck movements. This pathway mediates reflex and visual tracking influences for positioning the head with regard to visual input. The interstitiospinal tract arises from the interstitial nucleus of Cajal, a region of the midbrain that helps to coordinate eye movements and gaze centers. The interstitiospinal tract descends ipsilaterally in the medial longitudinal fasciculus and terminates directly and indirectly on alpha- and gamma-LMNs associated with the axial musculature of the trunk that is involved in rotational movement of the body around its central axis.

CLINICAL POINT

The superior colliculus, neurons of origin of the tectospinal tract, is responsive to input from the retina, the visual cortex, and the frontal eye fields. Of particular note is the role of tectospinal and tectobulbar projections (especially to the reticular formation) that help to coordinate movements of both the head and the eyes. Part of the tectospinal pathway may receive indirect input from the inferior colliculus and help to mediate head movements in response to loud or conspicuous sounds.

SPINAL CORD TERMINATIONS OF MAJOR DESCENDING UPPER MOTOR NEURON TRACTS

The lateral corticospinal tract and the RST terminations are directed mainly toward LMNs associated with distal limb musculature. The anterior CST, the RSTs, and the vestibulospinal tracts are directed mainly toward LMNs associated with more proximal and axial musculature.

CENTRAL CONTROL OF EYE MOVEMENTS

Central control of eye movements is achieved through the coordination of extraocular motor nuclei for CNs III (oculomotor), IV (trochlear), and VI (abducens). This is achieved by the parapontine reticular formation (horizontal gaze center); it receives input from the vestibular nuclei; the deep layers of the superior colliculus (input from V1, V2, and V3); the cerebral cortex (frontal eye fields); and the interstitial nucleus of Cajal (which receives input from the vestibular nuclei and the frontal eye fields). The parapontine reticular formation supplies the ipsilateral VI nucleus for movement of the lateral rectus muscle and the contralateral III nucleus (via interneurons in VI nucleus) for movement of the medial rectus muscle, thus coordinating horizontal eye movements. The interstitial nucleus of Cajal helps to coordinate vertical and oblique eye movements. Secondary sensory vestibular projections also terminate in the extraocular motor CNN. Axons interconnecting the extraocular motor CNN travel through the medial longitudinal fasciculus.

CENTRAL CONTROL OF RESPIRATION

Inspiration and expiration are regulated by nuclei of the RF. The dorsal respiratory nucleus (lateral nucleus solitarius) sends crossed axons to terminate on cervical spinal cord LMNs of the phrenic nucleus and on thoracic spinal cord LMNs that supply intercostal muscles and accessory musculature associated with inspiration. The ventral respiratory nucleus (nucleus retroambiguus) sends crossed axons to terminate on thoracic spinal cord LMNs that supply accessory musculature associated with expiration. The dorsal respiratory nucleus receives input from the carotid body V (via CN IX); from the aortic body chemosensors (via CN X); and from central chemoreceptive zones of the lateral medulla. The dorsal respiratory nucleus and ventral respiratory nucleus mutually inhibit each other. The medial parabrachial nucleus acts as a respiratory pacemaker to regulate the dorsal respiratory nucleus and the ventral respiratory nucleus. The medial parabrachial nucleus receives input from higher centers, such as the amygdala and the cerebral cortex.

CLINICAL POINT

The dorsal respiratory nucleus (lateral nucleus solitarius) sends axonal projections to the contralateral cervical LMNs of the phrenic nucleus and thoracic LMNs of accessory respiratory muscles, regulating inspiration. The ventral respiratory nucleus (nucleus retroambiguus) sends axonal projections to contralateral thoracic LMNs that supply accessory musculature associated with expiration. The medial parabrachial nucleus functions as a pacemaker and receives input from higher levels of the central nervous system. Progressive damage to the forebrain and brain stem elicits relatively predictable changes in respiration. Progressive damage through the telencephalon and diencephalons elicits Cheyne-Stokes respiration (crescendo-decrescendo breathing; periods of hyperpnea alternating with brief periods of apnea). The hyperpnea phase is provoked by Pco₂ from the apneic phase and results in the lowering of Pco₂, again provoking apnea. If damage extends through the mesencephalon and upper pons, respiration becomes shallow, with hyperventilation, but the patient still is relatively hypoxic. If damage extends through the lower pons, respiration involves long inspiratory pauses prior to expiration, called apneustic breathing. Damage extending further into the medulla produces ataxic breathing with irregular patterns, including inspiratory gasps and periods of apnea. This pattern of breathing foreshadows total respiratory failure and death as the basic brain stem centers fail.

CEREBELLUM

FUNCTIONAL SUBDIVISIONS OF THE CEREBELLUM

The cerebellum is classically subdivided into anterior, middle (posterior), and flocculonodular (FN) lobes, each associated with ipsilateral syndromes, such as stiff-legged gait (anterior lobe); loss of coordination, with dysmetria, action tremor, hypotonus, ataxia, and decomposition of movement (middle lobe); and truncal ataxia (FN lobe). The cerebellum also is classified according to a longitudinal scheme that is based on cerebellar cortical regions that project to deep cerebellar nuclei, which in turn project to and coordinate the activity of specific UMN cell groups. This scheme includes the vermis and FN lobe (projecting to the fastigial nucleus and the lateral vestibular nucleus); the paravermis (projecting to the globose and emboliform nuclei); and the lateral hemispheres (projecting to the dentate nucleus). Each cerebellar subdivision is interlinked with circuitry related to specific UMN systems.

CEREBELLAR NEURONAL CIRCUITRY

The cerebellum is organized into four parts: an outer three-layered cortex, white matter, deep cerebellar nuclei, and cerebellar peduncles that connect with the spinal cord, brain stem, and thalamus. In the cortex, the Purkinje cells (the major output neurons) have their dendritic trees in the molecular layer (arranged in parallel "plates" adjacent to each other), their cell bodies in the Purkinje cell layer, and their axons in the granular layer and deeper white matter. Inputs into the cerebellar cortex arrive as climbing fibers (from inferior olivary nuclei); mossy fibers (all other inputs except monoaminergic); or fine, highly branched, varicose arborizations (noradrenergic and other monoaminergic inputs). The mossy fibers synapse on granule cells, whose axons form an array of parallel fibers that extend through the dendritic trees of several hundred Purkinje cells. Additional interneurons modulate interconnections in the molecular layer (outer stellate cells); at the Purkinje cell body (basket cells); and at granule cell-molecular layer associations (Golgi cells). Noradrenergic axons of locus coeruleus neurons terminate in all three layers and modulate the excitability of other cerebellar connectivities.

CLINICAL POINT

The cerebellum is a target for significant adverse effects of several types of drugs, sometimes in therapeutic dose ranges and sometimes in toxic dose ranges. Many pharmaceutical agents can exert both direct effects on the cerebellum and more global neurological effects, including ischemia or hypoxia. Cerebellar damage is usually manifested first as impairment of gait, followed later by limb ataxia. These cerebellar side effects often resolve after discontinuation of the medication, but some deficits may remain. Some antiseizure agents, including phenytoin, carbamazepine, and barbiturates, can lead to cerebellar symptoms; after prolonged treatment, particularly with phenytoin, some permanent deficits such as degeneration of Purkinje cells may occur. Valproate may provoke an intention tremor. Some cancer chemotherapeutic agents also can cause adverse cerebellar effects, occasionally permanently. Treatment of psychiatric disorders by multiple pharmaceutical agents, particularly neuroleptics, also can produce adverse cerebellar effects. Toxic damage resulting from exposure to dangerous environmental agents also may damage the cerebellum. Exposure to organophosphate agents and organic solvents may induce cerebellar symptomatology. Exposure to heavy metals, including methylmercury, lead, and thallium, can induce gait disturbance and ataxia.

CIRCUIT DIAGRAMS OF AFFERENT CONNECTIONS IN THE CEREBELLUM

Afferents to the cerebellum include mossy fibers, climbing fibers, and locus coeruleus noradrenergic fibers. The mossy fibers synapse in deep nuclei and on granule cells. The climbing fibers intertwine around a Purkinje cell dendritic tree. The noradrenergic locus coeruleus axons terminate on all cell types in the cerebellar cortex. The loops and circuits in parts C and D of the figure show interneuronal modulation of afferent connections and Purkinje cell outflow. The entire circuitry of the cerebellar cortex provides fine-tuning of the original processing in the deep cerebellar nuclei. The entire Purkinje cell output to the deep nuclei is mediated by inhibition, using gamma-aminobutyric acid (GABA) as the neurotransmitter.

AFFERENT PATHWAYS TO THE CEREBELLUM

Afferents to the cerebellum terminate in both the deep nuclei and the cerebellar cortex in topographically organized zones. The body is represented in the cerebellar cortex in at least three separate regions. Afferents traveling through the inferior cerebellar peduncle include spinocerebellar pathways (dorsal and rostral spinocerebellar tracts, cuneocerebellar tract); the inferior olivary input; RF input from the lateral reticular nucleus and other regions; vestibular input from the vestibular ganglion and vestibular nuclei; and some trigeminal input. The middle cerebellar peduncle conveys mainly pontocerebellar axons carrying crossed corticopontocerebellar inputs. Afferents traveling through the superior cerebellar peduncle include the ventral spinocerebellar tract, visual and auditory tectocerebellar input, some trigeminal input, and noradrenergic locus coeruleus input. The dorsal spinocerebellar tract and cuneocerebellar tract derive mainly from muscle spindle afferent information, whereas the ventral and rostral spinocerebellar tracts derive mainly from Golgi tendon organ afferent information.

CLINICAL POINT

Several forms of progressive neuronal degeneration involve cerebellar neurons and connections, including Friedreich's ataxia and olivopontocerebellar atrophy. Friedreich's ataxia is an autosomal recessive disorder that begins in late childhood and progresses over several decades. The disorder commonly starts with ataxia and gait dysfunction, dysmetria and decomposition of movement, and dysarthria. Spastic motor involvement and sensory losses also may occur. Neuropathological examination reveals degeneration of primary afferents and of axons in the spinal cord white matter, especially the dorsal and lateral funiculi, including the spinocerebellar tracts. Some axonal damage also may occur in both the peripheral nervous system and the central nervous system, but the cerebellum itself is usually not a focus of direct neuronal degeneration.

Olivopontocerebellar atrophy is a progressive, mainly autosomal dominant, neurodegenerative disorder that affects adults in midlife. This disorder commonly begins with gait abnormalities and progresses to full-blown cerebellar dysfunction with limb ataxia and dysarthria. Additional symptoms, such as chorea, dystonia, and rigidity, suggest some degenerative involvement of the basal ganglia as well. Neuropathological examination usually reveals neurodegeneration of the cerebellar cortex, the inferior olivary nuclei, and the pontine nuclei. As a consequence, the inferior and middle cerebellar peduncles are diminished. Additional degenerative changes in the cerebral cortex and descending UMN pathways and in the basal ganglia also are commonly present.

CEREBELLAR EFFERENT PATHWAYS

Efferents from the cerebellum derive from the deep nuclei. Projections from the fastigial nucleus exit mainly through the inferior cerebellar peduncle and terminate mainly ipsilaterally in the lateral vestibular nucleus and in other vestibular nuclei as well as in pontine and medullary reticular nuclei that give rise to the reticulospinal tracts; there, they primarily modulate the activity of the vestibulospinal and reticulospinal UMN pathways. Axons from neurons of the globose and emboliform nuclei project mainly contralaterally through the decussation of the superior cerebellar peduncle to the red nucleus, with a smaller contribution to the VL nucleus of the thalamus; primarily, they modulate activity of the RST. Axons from neurons in the dentate nucleus project mainly contralaterally through the decussation of the superior cerebellar peduncle to the VL and to a lesser extent to the VA nuclei of the thalamus; mainly, they modulate the activity of the corticospinal tract. A small projection from the dentate nucleus also distributes to the contralateral red nucleus and to brain stem reticular motor nuclei

CLINICAL POINT

Paraneoplastic syndrome is a relatively uncommon, progressive disorder that causes damage to the cerebellum and other neural structures as a secondary effect of cancer. Sometimes the onset of cerebellar symptomatology may precede the detection of the cancer. One major hypothesis about the cause of this disorder is the presence of an immune reaction in which antibodies generated by the immune system against some epitope associated with the cancer cross-react with neural targets. The Purkinje cells appear to be a major target of these immunoglobulin G antibodies. The syndrome often is triggered or exacerbated by chemotherapy or radiation therapy. The entire cerebellum may be targeted, and symptoms include gait disturbance, ataxia of the limbs with accompanying cerebellar symptoms, dysarthria, and oculomotor coordination problems. Other possible targets of paraneoplastic syndrome include the cerebral cortex and its UMN projections as well as peripheral nerves

CEREBELLOVESTIBULAR AND VESTIBULOCEREBELLAR PATHWAYS

Primary sensory vestibular inputs terminate in the four vestibular nuclei and in the fastigial nucleus and the cerebellar cortex of the vermis and FN lobe. The vestibular nuclei also project to the cerebellar cortex of the vermis and FN lobe. Purkinje cells in the vermis and FN lobe, in turn, project back to the vestibular nuclei and the fastigial nucleus. The fastigial nucleus projects to the vestibular nuclei and to the pontine and medullary medial reticular formation. Thus, primary and secondary vestibular neurons project to the fastigial nucleus and cerebellar cortex, and both the cerebellar cortex and deep nuclei project back to the vestibular nuclei. This extensive reciprocal vestibulocerebellar circuitry regulates basic spatial position and body tone and posture

CLINICAL POINT

Alcohol consumption may result in acute or chronic dysfunction of the cerebellum and its pathways. Acutely, alcohol intoxication can cause global cerebellar dysfunction, including staggering gait, limb ataxia, dysmetria, dysdiadochokinesia, dysarthria, and oculomotor dysfunction. Cerebellar testing for alcohol intoxication in the field involves tandem walking, finger-to-nose testing, speech patterns and coordination, and gait testing. These more global effects of alcohol on the cerebellum generally subside with catabolism of the alcohol. Chronic alcoholism results in more permanent damage to the cerebellum, with a particular initial predilection for the anterior lobe of the cerebellum and the vermis (paleocerebellum). The patient may show a staggering, broad-based gait with a stiff-legged movement. The mechanism of this unusual appearance of cerebellar damage (in contrast to the hypotonic, ataxic gait that occurs with global cerebellar damage, particularly in the lateral hemispheres) appears to be removal of the anterior cerebellar influence, via cerebellovestibular connections, on the lateral vestibular nucleus, disinhibiting this extensor-dominant system. This anterior cerebellar syndrome may diminish if the patient stops drinking. With further alcohol exposure, the entire cerebellum may become damaged, leading to the classic appearance of global cerebellar dysfunction, including gait disturbance, limb ataxia, dysarthria, and uncoordinated extraocular involvement. In addition to direct toxicity from alcohol, neural damage may also occur because of vitamin deficiencies, liver dysfunction, and other metabolic aspects of alcoholism. Other parts of the brain, including the cerebral cortex, also can be significantly damaged in chronic alcoholism.

SCHEMATIC DIAGRAMS OF EFFERENT PATHWAYS FROM THE CEREBELLUM TO UPPER MOTOR NEURON SYSTEMS

The lateral cerebellar hemisphere connects through the dentate nucleus with nuclei VA and VL of the thalamus; the major thalamic inputs to the cells of origin of the CST in the motor cortex, and with the supplemental and premotor cortices. The paravermal cerebellar cortex connects through the globose and emboliform nuclei with the red nucleus, cells of origin for the RST. The cerebellar connections to the cells of origin for the CST and RST are mainly crossed, and these UMN systems cross again before terminating on LMNs. Thus, the cerebellum is associated with the ipsilateral LMNs through two crossings. The vermis and FN lobe connect with the fastigial nucleus and lateral vestibular nuclei. The fastigial nucleus projects mainly ipsilaterally to cells of origin of the vestibulospinal and reticulospinal tracts, exerting mainly an ipsilateral influence on spinal cord LMNs through these UMN systems. The lateral vestibular nucleus is the source of the lateral vestibular tract, which exerts a marked extensor influence on ipsilateral LMNs of the spinal cord.

BASAL GANGLIA

CONNECTIONS OF THE BASAL GANGLIA

The basal ganglia consist of the striatum (caudate nucleus and putamen) and the globus pallidus. The substantia nigra (SN) and the subthalamic nucleus (STN), which are reciprocally connected with the basal ganglia, are often included as part of the basal ganglia. Inputs into the basal ganglia from the cerebral cortex, the thalamus (intralaminar nuclei), the SN pars compacta (dopaminergic input), the subthalamic nucleus, and rostral raphe nuclei (serotonergic input), are directed mainly toward the striatum. Inputs from the STN are directed mainly toward the globus pallidus. The striatum projects to the globus pallidus. The internal segment of the globus pallidus projects to the thalamus (VA, VL, and centromedian nuclei), and the external segment projects to the STN. The VA and VL thalamic nuclei provide input into the cells of origin of the corticospinal tract. Damage to basal ganglia components often results in movement disorders. Damage to the dopamine neurons in SN pars compacta results in Parkinson's disease (characterized by resting tremor, muscular rigidity, bradykinesia, and postural instability).

CLINICAL POINT

Disorders of the basal ganglia are frequently referred to as movement disorders and were previously called involuntary movement disorders. Despite the conspicuous presence of motor-related symptoms, the basal ganglia also are involved in cognitive and affective processing, particularly in assisting the cerebral cortex to select wanted subroutines of activity and to suppress unwanted patterns. The basal ganglia assist in providing a connection between motivation and emotional context on one hand and movement on the other. Observations of discrete infarcts of parts of the basal ganglia have revealed such abnormalities as abnormal positioning of parts of the body with the presence of increased tone (dystonia) and other movements such as athetosis (slow, writhing movements) or chorea (brisk, dancelike movements). With caudate nucleus damage, more cognitive and affective symptoms may occur, such as apathy and loss of initiative, slowed thinking, and blunted emotional reactivity (abulia), possibly related to the interconnections between the caudate nucleus and the prefrontal cortex. In the classic movement disorders, as in the progressive neurodegenerative diseases, there is a mixture of symptoms showing loss of action, such as bradykinesia (difficulty in initiating movements or diminished movements such as blinking), and symptoms showing an excess of action, such as rigidity, athetosis, chorea, or dystonia. As an example of excess movement, Tourette's syndrome involves tics and involuntary vocalizations, sometimes accompanied by echolalia, grunts and vocal spasms, explosive cursing, and hyperactive behavior, often starting in childhood. Treatment strategies have included use of D2 dopamine antagonists such as haloperidol.

BASIC BASAL GANGLIA CIRCUITRY AND NEUROTRANSMITTERS

Inputs from the cerebral cortex and thalamus to the striatum are excitatory (glutamate). The striatopallidal connection is inhibitory (GABA), and the pallidothalamic connection is inhibitory (GABA) too, resulting in a net drive over the thalamocortical (and resultant corticospinal) output. However, extensive inhibitory and excitatory circuitry also exists through the internal segment of the globus pallidus, the substantia nigra, and the subthalamic nucleus, producing complex modulation of basal ganglia output. The dopaminergic nigrostriatal connections can exert both inhibitory and excitatory effects on the striatum. Thus, with loss of nigrostriatal dopamine axons in Parkinson's disease, both negative symptoms (bradykinesia) and positive symptoms (resting tremor, muscular rigidity, postural instability) exist side by side. Additional interneurons are found in some basal ganglia structures such as the excitatory cholinergic interneurons in the striatum.

CLINICAL POINT

In Parkinson's disease, the pars compacta of the substantia nigra shows loss of pigmented (melanin-containing) neurons that use dopamine as their major neurotransmitter. Both the substantia nigra and the target of the axonal projections, the caudate nucleus and putamen, are severely depleted of their dopamine content. By the time symptoms of Parkinson's disease are clinically evident, at least 50% (and sometimes as much as 80%) of the dopamine neurons in the pars compacta of the substantia nigra have degenerated. Neurons in the substantia nigra sometimes demonstrate Lewy inclusion bodies or neurofibrillary tangles, further evidence of the degenerative process in Parkinson's disease. The neuropathology of Parkinson's disease sometimes also includes the degeneration of dopamine neurons in the ventral tegmental area of the midbrain, of serotonergic neurons in the raphe nuclei, of cholinergic neurons in nucleus basalis, and of other pigmented neurons in regions such as the dorsal (motor) nucleus of CN X. Although the dopamine deficit in the substantia nigra is the most conspicuous pathological hallmark of Parkinson's disease, these other degenerative processes may contribute to some of the symptoms.

PARALLEL LOOPS OF CIRCUITRY THROUGH THE BASAL GANGLIA

The corticostriatal, striatopallidal, and pallidothalamic connections form parallel loops for motor, limbic, cognitive, and oculomotor circuitry. The motor circuitry is processed through the putamen; the limbic circuitry through the ventral pallidum and nucleus accumbens; the cognitive circuitry through the head of the caudate nucleus; and the oculomotor circuitry through the body of the caudate nucleus. Connections through the globus pallidus and the pars reticulata of the substantia nigra or ventral tegmental area then project to appropriate regions of the thalamus to link back to the cortical neurons of origin for the initial corticostriatal projections. These parallel loops through the basal ganglia and the cortex serve to modulate specific subroutines of cortical activity distinct to the appropriate function. The pars compacta of the substantia nigra may act as the principal interconnections among these parallel loop

CONNECTIONS OF NUCLEUS ACCUMBENS

Nucleus accumbens is located at the anterior end of the striatum in the interior of the ventral and rostral forebrain (see Figure 13.12). Inputs are derived from limbic structures (amygdala, hippocampal formation, bed nucleus of the stria terminalis) and from the ventral tegmental area of the midbrain via a rich dopaminergic projection. Nucleus accumbens is central to motivational states and addictive behaviors. It also appears to be a principal region in brain reward circuits associated with joy, pleasure, and gratification. The involvement of nucleus accumbens with a specific limbic basal ganglia loop helps to provide motor expression of emotional responses and accompanying gestures and behaviors.

CLINICAL POINT

The varicella-zoster virus of childhood chickenpox can reside as a latent virus in dorsal root ganglia, the trigeminal ganglia, and other ganglia. During immunosuppression (medication, cancers, chronic stressors), the reactivation of this virus can cause painful eruptions in the distribution of a sensory nerve root or a division of the trigeminal nerve; this condition is commonly known as shingles or herpes zoster (postherpetic) neuralgia. The most common sites are the thoracic nerve roots or the ophthalmic division (V₁) of the trigeminal nerve. The skin erupts with vesicles and a sharp, radiating or burning pain is felt in the region of the eruptions. Sometimes the painful sensations (dysesthesias) occur several days before the eruptions appear. A particular risk related to the ophthalmic division of CN V is corneal ulcerations and subsequent opacities. The nerve, the ganglion, and sometimes the surrounding tissues show inflammatory reactivity. Usually, with combined antiviral therapy and analgesics, the eruptions can subside within a week or so. However, the postherpetic neuralgia, with burning pain, can last for weeks to months and may require the same type of treatment that other neuropathic pain syndromes (reflex sympathetic dystrophy or complex regional pain syndrome) require, including analgesics, tricyclic antidepressants to alter the pain threshold, membrane-stabilizing agents, anti-inflammatory medication, and other approaches

CLINICAL POINT

The rubrospinal tract, arising from magnocellular neurons of the red nucleus, is part of a cortico-rubro-spinal system that may represent an indirect corticospinal pathway. Rubrospinal tract connections are contralateral and have mainly indirect effects (through interneurons) on both alpha and gamma LMNs. Some authors believe that the rubrospinal tract has a minor role in humans, although observations of decorticate and decerebrate posturing suggest otherwise. In conditions of UMN pathology, the cortico-rubro-spinal system is usually damaged in conjunction with the corticospinal tract (posterior limb of the internal capsule, lateral funiculus of the spinal cord), resulting in a clinical picture of UMN syndrome. Bilateral damage to the forebrain and diencephalon, leaving only the rubrospinal tract, reticulospinal tracts, and vestibulospinal tracts intact, results in a classic UMN appearance bilaterally, with upper limbs in a flexed position and lower limbs in an extended posture (called decorticate posturing). If the lesion extends just below the red nucleus, further removing rubrospinal tract influences, the lateral vestibulospinal tracts are markedly disinhibited, resulting in decerebrate posturing with all four limbs extended. These observations suggest that the rubrospinal system particularly drives flexor activity in the upper extremities and has a lesser role in the lower extremities.

CLINICAL POINT

The reticulospinal tracts originate from isodendritic neurons in the medial portion of the pontine and medullary RF. The pontine RF gives rise to the pontine (medial) reticulospinal tract, which influences mainly proximal musculature. The medullary RF gives rise to the medullary (lateral) reticulospinal tract, which lies more laterally in the spinal cord and influences muscles of the extremities. The reticulospinal tracts help to regulate basic tone and postural responses, sometimes coordinating musculature supplied by LMNs at multiple spinal cord levels. These tracts also may help to direct stereotyped movements such as those involved in extending a limb toward an object. The reticulospinal tracts can selectively influence both alpha- and gamma-LMNs, thus providing a mechanism for activation of static or dynamic gamma-LMNs in conditions of damage to other descending systems, such as the corticospinal and cortico-rubro-spinal systems.

CLINICAL POINT

Vestibular nuclei receive input from the hair cells in the ampullae of the semicircular canals and are connected with extraocular CN motor nuclei, thereby permitting vestibular reflex control of eye movements. This circuitry establishes the connections of the vestibulo-ocular reflex. When the head is rotated in one direction, the lateral semicircular canal initiates a vestibulo-ocular reflex that moves the eyes in the opposite direction, thereby maintaining the position of the eyes. Stimulation of the hair cells on one side of the vestibular apparatus with cold water in the external auditory meatus (the caloric response) provides the brain stem on that side with the neural signaling of apparent movement, and elicits eye movements that would be appropriate to an actual movement, were one occurring. This elicited movement is called caloric nystagmus; it evokes a sense of apparent movement, a tendency to fall to one side, and past-pointing. A lesion or irritative stimulation of the vestibular nerve on one side also gives the neural perception of movement, eliciting pathological nystagmus. If a person rotates in one direction to a greater extent than a simple vestibulo-ocular reflex can easily correct through compensatory eye movements, the eyes will be directed sufficiently far to one side that a quick movement (saccade) will be necessary to refocus them straight ahead. This is called rotational nystagmus, with the slow phase opposite from the direction of movement and the saccade (fast phase) in the direction of the movement; the saccade is neurally directed from the occipital lobe visual cortices. After the rotation stops, the individual will feel as if she or he is still rotating, but in the opposite direction (post-rotational nystagmus), with the saccade in the direction opposite from the original movement, and past-pointing in the direction of apparent movement. If an individual is stationary and stimuli move past the visual field (telephone poles and a person in a moving car), tracking reflexes move the eyes, and a cortically-evoked saccade corrects the eye position with a quick movement of the eyes. This normal physiologic process is called optokinetic nystagmus.