To understand neuroanatomy, it is useful to study structures as parts of functional systems.
Large alpha motor neurons of the spinal cord ventral horns and brainstem motor nuclei (facial nucleus, trigeminal motor nucleus, nucleus ambiguus, hypoglossal nucleus) extend axons into spinal and cranial nerves to innervate skeletal muscles. Damage to these lower motor neurons results in loss of all voluntary and reflex movement because they comprise the output of the motor system. Neurons in the precentral gyrus and neighboring cortical regions (upper motor neurons) send axons to synapse with lower motor neurons. Axons from these upper motor neurons comprise the corticospinal and corticobulbar tracts. The motor cortex and spinal cord are connected with other deep cerebral and brainstem motor nuclei, including the caudate nucleus, putamen, globus pallidus, red nuclei, subthalamic nuclei, substantia nigra, reticular nuclei, and neurons of the cerebellum. Neurons in these structures are distinct from cortical motor (pyramidal) neurons and are referred to as extrapyramidal neurons. Many parts of the cerebral cortex are connected by fiber tracts to the primary motor cortex. These connections are important for complex patterns of movement and for coordinating motor responses to sensory stimuli.
Lower Motor Neurons & Skeletal Muscles
Each alpha motor neuron axon contacts up to about 200 muscle fibers, and together they constitute the motor unit (Figure 7–6). Axons of the motor neurons intermingle to form spinal ventral roots, plexuses, and peripheral nerves. Muscles are innervated from specific segments of the spinal cord, and each muscle is supplied by at least two roots. Motor fibers are rearranged in the plexuses so that most muscles are supplied by one peripheral nerve. Thus, the distribution of muscle weakness differs in spinal root and peripheral nerve lesions.
Anatomic components of the motor unit. (Redrawn, with permission, from Greenberg DA et al, eds. Clinical Neurology, 8th ed. McGraw-Hill, 2012.)
The lower motor neurons are the final common pathway for all voluntary movement. Therefore, damage to lower motor neurons or their axons causes flaccid weakness of innervated muscles. In addition, muscle tone or resistance to passive movement is reduced, and deep tendon reflexes are impaired or lost. Tendon reflexes and muscle tone depend on the activity of alpha motor neurons (Figure 7–7), specialized sensory receptors known as muscle spindles, and smaller gamma motor neurons whose axons innervate the spindles. Some gamma motor neurons are active at rest, making the spindle fibers taut and sensitive to stretch. Tapping on the tendon stretches the spindles, which causes them to send impulses that activate alpha motor neurons. These in turn fire, producing the brief muscle contraction observed during the myotactic stretch reflex. Alpha motor neurons of antagonist muscles are simultaneously inhibited. Both alpha and gamma motor neurons are influenced by descending fiber systems, and their state of activity determines the level of tone and activity of the stretch reflex.
Diagram illustrating the pathways responsible for the stretch reflex and the inverse stretch reflex. Stretch stimulates the muscle spindle, and impulses pass up the Ia fiber to excite the motor neuron. It also stimulates the Golgi tendon organ, and impulses passing up the Ib fiber activate the interneuron to release the inhibitory mediator glycine. With strong stretch, the resulting hyperpolarization of the motor neuron is so great that it stops discharging. (Redrawn, with permission, from Barnett KE et al, eds. Ganong’s Review of Medical Physiology, 24th ed. McGraw-Hill, 2012.)
Each point of contact between nerve terminal and skeletal muscle forms a specialized synapse known as a neuromuscular junction composed of the presynaptic motor nerve terminal and a postsynaptic motor end plate (Figure 7–8). Presynaptic terminals store synaptic vesicles that contain the neurotransmitter acetylcholine. The amount of neurotransmitter within a vesicle constitutes a quantum of neurotransmitter. Action potentials depolarize the motor nerve terminal, opening voltage-gated calcium channels and stimulating calcium-dependent release of neurotransmitter from the terminal. Released acetylcholine traverses the synaptic cleft to the postsynaptic (end plate) membrane, where it binds to nicotinic cholinergic receptors. These receptors are ligand-gated cation channels, and, on binding to acetylcholine, they allow entry of extracellular sodium into the motor end plate. This depolarizes the motor end plate, which in turn depolarizes the muscle fiber. After activation, cholinergic receptors are rapidly inactivated, reducing sodium entry. They remain inactive until acetylcholine dissociates from the receptor. This is facilitated by the enzyme acetylcholinesterase, which hydrolyzes acetylcholine and is present in the postsynaptic zone.
Sites of involvement in disorders of neuromuscular transmission. Left: Normal transmission involves depolarization-induced influx of calcium (Ca2+) through voltage-gated channels. This stimulates release of acetylcholine (ACh) from synaptic vesicles at the active zone and into the synaptic cleft. ACh binds to ACh receptors and depolarizes the postsynaptic muscle membrane. Right: Disorders of neuromuscular transmission result from blockage of Ca2+ channels (Lambert-Eaton syndrome or aminoglycoside antibiotics), impairment of Ca2+-mediated ACh release (botulinum toxin), or antibody-induced internalization and degradation of ACh receptors (myasthenia gravis). (Redrawn, with permission, from Greenberg DA et al, eds. Clinical Neurology, 8th ed. McGraw-Hill, 2012.)
Neuromuscular transmission may be disturbed in several ways (Figure 7–8). In the Lambert-Eaton myasthenic syndrome, antibodies to calcium channels inhibit calcium entry into the nerve terminal and reduce neurotransmitter release. In these cases, repetitive nerve stimulation facilitates accumulation of calcium in the nerve terminal and increases acetylcholine release. Clinically, limb muscles are weak, but if contraction is maintained, power increases. Electrophysiologically, there is an increase in the amplitude of the muscle response to repetitive nerve stimulation. Aminoglycoside antibiotics also impair calcium channel function and cause a similar syndrome. Proteolytic toxins produced by Clostridium botulinum cleave specific presynaptic proteins, preventing neurotransmitter release at both neuromuscular and parasympathetic cholinergic synapses. As a result, patients with botulism develop weakness, blurred vision, diplopia, ptosis, and large unreactive pupils. In myasthenia gravis, autoantibodies to the nicotinic acetylcholine receptor (AChR) block neurotransmission by inhibiting receptor function and activating complement-mediated lysis of the postsynaptic membrane. Myasthenia gravis is discussed in greater detail later in this chapter.
Motor nerves exert trophic influences on the muscles they innervate. Denervated muscles undergo marked atrophy, losing more than half of their original bulk in 2–3 months. Nerve fibers are also required for organization of the muscle end plate and for the clustering of cholinergic receptors to that region. Receptors in denervated fibers fail to cluster and become spread across the muscle membrane. Muscle fibers within a denervated motor unit may then discharge spontaneously, giving rise to a visible twitch (fasciculation) within a portion of a muscle. Individual fibers may also contract spontaneously, giving rise to fibrillations, which are not visible to the examiner but can be detected by electromyography. Fibrillations usually appear 7–21 days after damage to lower motor neurons or their axons.
5. From where do lower motor neurons emanate, and to where do they send axons?
6. Describe four mechanisms that can disturb the function of the neuromuscular junction.
The motor cortex is the region from which movements can be elicited by electrical stimuli (Figure 7–9). This includes the primary motor area (Brodmann area 4), premotor cortex (area 6), supplementary motor cortex (medial portions of 6), and primary sensory cortex (areas 3, 1, and 2). In the motor cortex, groups of neurons are organized in vertical columns, and discrete groups control contraction of individual muscles. Planned movements and those guided by sensory, visual, or auditory stimuli are preceded by discharges from prefrontal, somatosensory, visual, or auditory cortices, which are then followed by motor cortex pyramidal cell discharges that occur several milliseconds before the onset of movement.
Lateral aspect of the cerebrum. The cortical areas are shown according to Brodmann, with functional localizations. (Redrawn, with permission, from Waxman SG. Clinical Neuroanatomy, 26th ed. McGraw-Hill, 2010.)
Cortical motor neurons contribute axons that converge in the corona radiata and descend in the posterior limb of the internal capsule, cerebral peduncles, ventral pons, and medulla. These fibers constitute the corticospinal and corticobulbar tracts and together are known as upper motor neuron fibers (Figure 7–10). As they descend through the diencephalon and brainstem, fibers separate to innervate extrapyramidal and cranial nerve motor nuclei. The lower brainstem motor neurons receive input from crossed and uncrossed corticobulbar fibers, although neurons that innervate lower facial muscles receive primarily crossed fibers.
Schematic illustration of upper motor neuron pathways. (Redrawn, with permission, from Ropper AH et al, eds. Adams and Victor’s Principles of Neurology, 9th ed. McGraw-Hill, 2009.)
In the ventral medulla, the remaining corticospinal fibers course in a tract that is pyramidal in shape in cross section—thus, the name pyramidal tract. At the lower end of the medulla, most fibers decussate, although the proportion of crossed and uncrossed fibers varies somewhat between individuals. The bulk of these fibers descend as the lateral corticospinal tract of the spinal cord.
Different groups of neurons in the cortex control muscle groups of the contralateral face, arm, and leg. Neurons near the ventral end of the central sulcus control muscles of the face, whereas neurons on the medial surface of the hemisphere control leg muscles (Figure 7–10). Because the movements of the face, tongue, and hand are complex in humans, a large share of the motor cortex is devoted to their control. A somatotopic organization is also apparent in the lateral corticospinal tract of the cervical cord, where fibers to motor neurons that control leg muscles lie laterally and fibers to cervical motor neurons lie medially.
Upper motor neurons are the final common pathway between cortical and subcortical structures, such as the basal ganglia, in the planning, initiation, sequencing, and modulation of all voluntary movement. Much has been learned about the normal function of upper motor neurons through the study of animals and humans with focal brain lesions. Upper motor neuron pathways can be interrupted in the cortex, subcortical white matter, internal capsule, brainstem, or spinal cord. Unilateral upper motor neuron lesions spare muscles innervated by lower motor neurons that receive bilateral cortical input, such as muscles of the eyes, jaw, upper face, pharynx, larynx, neck, thorax, and abdomen. Unlike paralysis resulting from lower motor neuron lesions, paralysis from upper motor neuron lesions is rarely complete for a prolonged period of time. Acute lesions, particularly of the spinal cord, often cause flaccid paralysis and absence of spinal reflexes at all segments below the lesion. With spinal cord lesions, this state is known as spinal shock. After a few days to weeks, a state known as spasticity appears, which is characterized by increased tone and hyperactive stretch reflexes. A similar but less striking sequence of events can occur with acute cerebral lesions.
Upper motor neuron lesions cause a characteristic pattern of limb weakness and change in tone. Antigravity muscles of the limbs become more active relative to other muscles. The arms tend to assume a flexed, pronated posture, and the legs become extended. In contrast, muscles that move the limbs out of this posture (extensors of the arms and flexors of the legs) are preferentially weakened. Tone is increased in antigravity muscles (flexors of the arms and extensors of the legs), and if these muscles are stretched rapidly, they respond with an abrupt catch, followed by a rapid increase and then a decline in resistance as passive movement continues. This sequence constitutes the “clasp knife” phenomenon. Clonus—a series of involuntary muscle contractions in response to passive stretch—may be present, especially with spinal cord lesions.
Pure pyramidal tract lesions in animals cause temporary weakness without spasticity. In humans, lesions of the cerebral peduncles also cause mild paralysis without spasticity. It appears that control of tone is mediated by other tracts, particularly corticorubrospinal and corticoreticulospinal pathways. This may explain why the degrees of weakness and spasticity often do not correspond in patients with upper motor neuron lesions.
The distribution of paralysis resulting from upper motor neuron lesions varies with the location of the lesion. Lesions above the pons impair movements of the contralateral lower face, arm, and leg. Lesions below the pons spare the face. Lesions of the internal capsule often impair movements of the contralateral face, arm, and leg equally, because motor fibers are packed closely together in this region. In contrast, lesions of the cortex or subcortical white matter tend to differentially affect the limbs and face because the motor fibers are spread over a larger area of brain. Bilateral cerebral lesions cause weakness and spasticity of cranial, trunk, and limb muscles, which leads to dysarthria, dysphonia, dysphagia, bifacial paresis, and sometimes reflexive crying and laughing (pseudobulbar palsy).
7. Define the motor cortex and describe its organization.
8. Fibers from which nuclei and in which tracts constitute upper motor neurons? What is their path?
9. Describe the somatotopic organization of motor neurons in the cortex.
10. What are the characteristics of weakness and tone in upper motor neuron lesions?
11. How is the distribution of paralysis and spasticity affected by the location of an upper motor neuron lesion?
The cerebellar cortex can be divided into three anatomic regions (Figure 7–11B). The flocculonodular lobe, composed of the flocculus and the nodulus of the vermis, has connections to vestibular nuclei and is important for the control of posture and eye movement. The anterior lobe (Figure 7–11A) lies rostral to the primary fissure and includes the remainder of the vermis. It receives proprioceptive input from muscles and tendons via the dorsal and ventral spinocerebellar tracts and influences posture, muscle tone, and gait. The posterior lobe, which comprises the remainder of the cerebellar hemispheres, receives major input from the cerebral cortex via the pontine nuclei and middle cerebellar peduncles and is important for the coordination and planning of voluntary skilled movements initiated from the cerebral cortex.
Anatomic divisions of the cerebellum in midsagittal view: (A) unfolded (arrows) and (B) viewed from behind. (Redrawn, with permission, from Greenberg DA et al, eds. Clinical Neurology, 5th ed. McGraw-Hill, 2002.)
Efferent fibers from these lobes project to deep cerebellar nuclei, which in turn project to the cerebrum and brainstem through two main pathways (Figure 7–12). The fastigial nucleus receives input from the vermis and sends fibers to bilateral vestibular nuclei and reticular nuclei of the pons and medulla via the inferior cerebellar peduncles. Other regions of the cerebellar cortex send fibers to the dentate, emboliform, and globose nuclei, whose efferents form the superior cerebellar peduncles, enter the upper pons, decussate completely in the lower midbrain, and travel to the contralateral red nucleus. At the red nucleus, some fibers terminate, whereas others ascend to the ventrolateral nucleus of the thalamus, whence thalamic neurons send ascending efferent fibers to the motor cortex of the same side. A smaller group of fibers descend after decussation in the midbrain and terminate in reticular nuclei of the lower brainstem. Thus, the cerebellum controls movement through connections with cerebral motor cortex and brainstem nuclei.
Cerebellar connections in the superior, middle, and inferior cerebellar peduncles. The peduncles are indicated by gray shading and the areas to and from which they project by blue shading. (Redrawn, with permission, from Greenberg DA et al, eds. Clinical Neurology, 8th ed. McGraw-Hill, 2012.)
The cerebellum is responsible for the coordination of muscle groups, control of stance and gait, and regulation of muscle tone. Rather than causing paralysis, damage to the cerebellum interferes with the performance of motor tasks. The major manifestation of cerebellar disease is ataxia, in which simple movements are delayed in onset and their rates of acceleration and deceleration are decreased, resulting in intention tremor and dysmetria (“overshooting”). Lesions of the cerebellar hemispheres affect the limbs, producing limb ataxia, whereas midline lesions affect axial muscles, causing truncal and gait ataxia and disorders of eye movement. Cerebellar lesions are often associated with hypotonia as a result of depression of activity of alpha and gamma motor neurons. If a lesion of the cerebellum or cerebellar peduncles is unilateral, the signs of limb ataxia appear on the same side as the lesion. However, if the lesion lies beyond the decussation of efferent cerebellar fibers in the midbrain, the clinical signs are on the side opposite the lesion.
12. What is the overall role of the cerebellum?
13. What are the anatomic regions of the cerebellum, what do they control, and through which other regions of the brain do they make connections?
14. What are the consequences of damage to the cerebellum, and what symptoms and signs are seen in patients with cerebellar lesions?
15. Below what point do unilateral cerebellar lesions manifest on the opposite side?
Several subcortical, thalamic, and brainstem nuclei are critical for regulating voluntary movement and maintaining posture. These include the basal ganglia (ie, the caudate nucleus and putamen [corpus striatum]), globus pallidus, substantia nigra, and subthalamic nuclei. They also include the red nuclei and the mesencephalic reticular nuclei. The major pathways that involve the basal ganglia form three neuronal circuits (Figure 7–13). The first is the cortical-basal ganglionic-thalamic-cortical loop. Inputs mainly from premotor, primary motor, and primary sensory cortices (areas 1, 2, 3, 4, and 6) project to the corpus striatum, which sends fibers to the medial and lateral portions of the globus pallidus. Fibers from the globus pallidus form the ansa and fasciculus lenticularis, which sweep through the internal capsule and project onto ventral and intralaminar thalamic nuclei. Axons from these nuclei project to the premotor and primary motor cortices (areas 4 and 6), completing the loop. In the second loop, the substantia nigra sends dopaminergic fibers to the corpus striatum, which has reciprocal connections with the substantia nigra. The substantia nigra also projects to the ventromedial thalamus. The third loop is composed of reciprocal connections between the globus pallidus and the subthalamic nucleus. The subthalamic nucleus also sends efferents to the substantia nigra and corpus striatum.
Diagrammatic representation of the principal connections of the basal ganglia. Solid lines indicate excitatory pathways; dashed lines indicate inhibitory pathways. The transmitters are indicated in the pathways, where they are known. Glu, glutamate; DA, dopamine. Acetylcholine is the transmitter produced by interneurons in the striatum (ie, the putamen and the caudate nucleus, which have similar connections). SNPR, substantia nigra, pars reticulata; SNPC, substantia nigra, pars compacta; ES, external segment; IS, internal segment. The subthalamic nucleus also projects to the pars compacta of the substantia nigra; this pathway has been omitted for clarity. (Redrawn, with permission, from Barnett KE et al, eds. Ganong’s Review of Medical Physiology, 24th ed. McGraw-Hill, 2012.)
Basal ganglia circuits regulate the initiation, amplitude, and speed of movements. Diseases of the basal ganglia cause abnormalities of movement and are collectively known as movement disorders. They are characterized by motor deficits (bradykinesia, akinesia, loss of postural reflexes) or abnormal activation of the motor system, resulting in rigidity, tremor, and involuntary movements (chorea, athetosis, ballismus, and dystonia).
Several neurotransmitters are found within the basal ganglia, but their role in disease states is only partly understood. Acetylcholine is present in high concentrations within the corpus striatum, where it is synthesized and released by large Golgi type 2 neurons (Figure 7–14). Acetylcholine acts as an excitatory transmitter at medium-sized spiny striatal neurons that synthesize and release the inhibitory neurotransmitter GABA and project to the globus pallidus. Dopamine is synthesized by neurons of the substantia nigra, whose axons form the nigrostriatal pathway that terminates in the corpus striatum. Dopamine released by these fibers inhibits striatal GABAergic neurons. In Parkinson disease, degeneration of nigral neurons leads to loss of dopaminergic inhibition and a relative excess of cholinergic activity. This increases GABAergic output from the striatum and contributes to the paucity of movement that is a cardinal manifestation of the disease. Anticholinergics and dopamine agonists tend to restore the normal balance of striatal cholinergic and dopaminergic inputs and are effective in treatment. The pathogenesis of Parkinson disease is discussed later in this chapter.
Simplified neurochemical anatomy of the basal ganglia. Dopamine (DA) neurons exert a net inhibitory effect and acetylcholine (ACh) neurons a net excitatory effect on the GABAergic output from the striatum. In Parkinson disease, DA neurons degenerate. The net effect is to increase GABAergic output from the striatum. (Redrawn, with permission, from Greenberg DA et al, eds. Clinical Neurology, 5th ed. McGraw-Hill, 2002.)
Huntington disease is inherited as an autosomal dominant disorder. When disease onset occurs later in life, patients develop involuntary, rapid, jerky movements (chorea) and slow writhing movements of the proximal limbs and trunk (athetosis). When disease onset occurs earlier in life, patients develop signs of parkinsonism with tremor (cogwheeling) and stiffness. The spiny GABAergic neurons of the striatum preferentially degenerate, resulting in a net decrease in GABAergic output from the striatum. This contributes to the development of chorea and athetosis. Dopamine antagonists, which block inhibition of remaining striatal neurons by dopaminergic striatal fibers, reduce the involuntary movements. Neurons in deep layers of the cerebral cortex also degenerate early in the disease, and later this extends to other brain regions, including the hippocampus and hypothalamus. Thus, the disease is characterized by cognitive defects and psychiatric disturbances in addition to the movement disorder.
The gene for the disease is located on chromosome 4p and encodes for a 3144-amino acid protein, huntingtin, which is widely expressed and interacts with several proteins involved in intracellular trafficking and endocytosis, gene transcription, and intracellular signaling. The protein contains a trinucleotide (CAG) repeat of 11–34 copies that encodes a polyglutamine domain and is expanded in patients with the disease. Deletion of the gene in mice causes embryonic death, whereas heterozygous animals are healthy. Transgenic mice with an expanded repeat develop a neurodegenerative disorder, suggesting that the disease results from the toxic effect of a gain of function mutation.
The mechanisms by which mutant huntingtin causes disease are not certain. The mutant protein is degraded, and the resulting fragments that contain the glutamine repeats form aggregates, which are deposited in nuclear and cytoplasmic inclusions. These fragments may bind abnormally to other proteins and interfere with normal protein processing or disrupt mitochondrial function. Nuclear fragments may interfere with nuclear functions such as gene expression. For example, in the cerebral cortex, mutant huntingtin reduces the production of brain-derived neurotrophic factor by suppressing its transcription. In addition, normal huntingtin is protective for cortical and striatal neurons and blocks the processing of procaspase 9, thereby reducing apoptosis (programmed cell death). Therefore, both loss of neurotrophic support and enhanced caspase activity could promote striatal cell loss in Huntington disease.
16. Which are the component nuclei of the basal ganglia, and what is their functional role?
17. What are the clinical consequences of lesions in the basal ganglia?
18. What are some of the neurotransmitters within the basal ganglia, and what is their role in disorders of basal ganglia function?
Somatosensory pathways confer information about touch, pressure, temperature, pain, vibration, and the position and movement of body parts. This information is relayed to thalamic nuclei and integrated in the sensory cortex of the parietal lobes to provide conscious awareness of sensation. Information is also relayed to cortical motor neurons to adjust fine movements and maintain posture. Some ascending sensory fibers, particularly pain fibers, enter the midbrain and project to the amygdala and limbic cortex, where they contribute to emotional responses to pain. In the spinal cord, painful stimuli activate local pathways that induce the firing of lower motor neurons and cause a reflex withdrawal. Thus, somatosensory pathways provide tactile information, guide movement, and serve protective functions.
A variety of specialized end organs and free nerve endings transduce sensory stimuli into neural signals and initiate the firing of sensory nerve fibers. Fibers that mediate cutaneous sensation from the trunk and limbs travel in sensory or mixed sensorimotor nerves to the spinal cord (Figure 7–15). Cutaneous sensory nerves contain small myelinated Aδ fibers that transmit information about pain and temperature, larger myelinated fibers that mediate touch and pressure sensation, and more numerous unmyelinated pain and autonomic C fibers. Myelinated proprioceptive fibers and afferent and efferent muscle spindle fibers are carried in the larger sensorimotor nerves. The cell bodies of the sensory neurons are in the dorsal root ganglia, and their central projections enter the spinal cord via the dorsal spinal roots. Innervation of the skin, muscles, and surrounding connective tissue is segmental, and each root innervates a region of skin known as a dermatome (Figure 7–16). Cell bodies of the sensory neurons that innervate the face reside in the trigeminal ganglion and send their central projections in the trigeminal nerve to the brainstem. The trigeminal innervation of the face is subdivided into three regions, each innervated by one of the three divisions of the trigeminal nerve.
Schematic illustration of a spinal cord segment with its dorsal root, ganglion cells, and sensory organs. Sensory organs shown (from top to bottom) are the pacinian corpuscle, muscle spindle, tendon organ, encapsulated ending, and free nerve endings. The somatotopic arrangement of fibers in the dorsal columns, spinothalamic tract, and corticospinal tract is also shown. (Redrawn, with permission, from Waxman SG. Clinical Neuroanatomy, 26th ed. McGraw-Hill, 2010.)
Segmental distribution of the body viewed in the approximate quadruped position, including sensory distribution of the trigeminal (V) cranial nerve. (Redrawn, with permission, from Waxman SG. Clinical Neuroanatomy, 26th ed. McGraw-Hill, 2010.)
The dorsal roots enter the dorsal horn of the spinal cord (Figure 7–15). Large myelinated fibers divide into ascending and descending branches and either synapse with dorsal gray neurons within a few cord segments or travel in the dorsal columns, terminating in the gracile or cuneate nuclei of the lower medulla on the same side. Secondary neurons of the dorsal horn also send axons up the dorsal columns. Fibers in the dorsal columns are displaced medially as new fibers are added, so that in the cervical cord, leg fibers are located medially and arm fibers laterally (Figure 7–15). The gracile and cuneate nuclei send fibers that cross the midline in the medulla and ascend to the thalamus as the medial lemniscus (Figure 7–17). The dorsal column-lemniscal system carries information about pressure, limb position, vibration, direction of movement, recognition of texture and shape, and two-point discrimination.
Sensory pathways conveying touch, pressure, vibration, joint position, pain, and temperature sensation. (Redrawn, with permission, from Greenberg DA et al, eds. Clinical Neurology, 5th ed. McGraw-Hill, 2002.)
Thinly myelinated and unmyelinated fibers enter the lateral portion of the dorsal horn and synapse with dorsal spinal neurons within one or two segments. The majority of secondary fibers from these cells cross in the anterior spinal commissure and ascend in the anterolateral spinal cord as the lateral spinothalamic tracts. Crossing fibers are added to the inner side of the tract, so that in the cervical cord the leg fibers are located superficially and arm fibers are deeper. These fibers carry information about pain, temperature, and touch sensation.
Sensation from the face is carried by trigeminal sensory fibers that enter the pons and descend to the medulla and upper cervical cord (Figure 7–18). Fibers carrying information about pain and temperature sensation terminate in the nucleus of the spinal tract of cranial nerve V, which is continuous with the dorsal horn of the cervical cord. Touch, pressure, and postural information is conveyed by fibers that terminate in the main sensory and mesencephalic nuclei of the trigeminal nerve. Axons arising from trigeminal nuclei cross the midline and ascend as the trigeminal lemniscus just medial to the spinothalamic tract. Fibers from the spinothalamic tract, medial lemniscus, and trigeminal lemniscus merge in the midbrain and terminate along with sensory fibers ascending from the spinal cord in the posterior thalamic nuclei, mainly in the nucleus ventralis posterolateralis. These thalamic nuclei project to the primary somatosensory cortex (Brodmann areas 3, 1, and 2) and to a second somatosensory area on the upper bank of the sylvian fissure (lateral cerebral sulcus). The primary somatosensory region is organized somatotopically like the primary motor cortex.
Schematic drawing of the trigeminal system. (Redrawn, with permission, from Waxman SG. Clinical Neuroanatomy, 26th ed. McGraw-Hill, 2010.)
Free nerve endings of unmyelinated C fibers and small-diameter myelinated Aδ fibers in the skin convey sensory information in response to chemical, thermal, and mechanical stimuli. Intense stimulation of these nerve endings evokes the sensation of pain. In contrast to skin, most deep tissues are relatively insensitive to chemical or noxious stimuli. However, inflammatory conditions can sensitize sensory afferents from deep tissues to evoke pain on mechanical stimulation. This sensitization appears to be mediated by bradykinin, prostaglandins, and leukotrienes released during the inflammatory response. Information from primary afferent fibers is relayed via sensory ganglia to the dorsal horn of the spinal cord and then to the contralateral spinothalamic tract, which connects to thalamic neurons that project to the somatosensory cortex.
Damage to these pathways produces a deficit in pain and temperature discrimination and may also produce abnormal painful sensations (dysesthesias) usually in the area of sensory loss. Such pain is termed neuropathic pain and often has a strange burning, tingling, or electric shocklike quality. It may arise from several mechanisms. Damaged peripheral nerve fibers become highly mechanosensitive and may fire spontaneously without known stimulation. They also develop sensitivity to norepinephrine released from sympathetic postganglionic neurons. Electrical impulses may spread abnormally from one fiber to another (ephaptic conduction), enhancing the spontaneous firing of multiple fibers. Neuropeptides released by injured nerves may recruit an inflammatory reaction that stimulates pain. In the dorsal horn, denervated spinal neurons may become spontaneously active. In the brain and spinal cord, synaptic reorganization occurs in response to injury and may lower the threshold for pain. In addition, inhibition of pathways that modulate transmission of sensory information in the spinal cord and brainstem may promote neuropathic pain.
Pain-modulating circuits exert a major influence on the perceived intensity of pain. One such pathway (Figure 7–19) is composed of cells in the periaqueductal gray matter of the midbrain that receive afferents from frontal cortex and hypothalamus and project to rostroventral medullary neurons. These in turn project in the dorsolateral white matter of the spinal cord and terminate on dorsal horn neurons. Additional descending pathways arise from other brainstem nuclei (locus ceruleus, dorsal raphe nucleus, and nucleus reticularis gigantocellularis). Major neurotransmitters utilized by these systems include endorphins, serotonin, and norepinephrine, providing the rationale for the use of opioids, serotonin agonists, and serotonin and norepinephrine reuptake inhibitors in the treatment of pain.
Schematic illustration of the pathways involved in pain control. (Courtesy A Basbaum.)
Proprioception and Vibratory Sense
Receptors in the muscles, tendons, and joints provide information about deep pressure and the position and movement of body parts. This allows one to determine an object’s size, weight, shape, and texture. Information is relayed to the spinal cord via large Aα and Aβ myelinated fibers and to the thalamus by the dorsal column-lemniscal system. Detecting vibration requires sensing touch and rapid changes in deep pressure. This depends on multiple cutaneous and deep sensory fibers and is impaired by lesions of multiple peripheral nerves, the dorsal columns, medial lemniscus, or thalamus but rarely by lesions of single nerves. Vibratory sense is often impaired together with proprioception.
Primary sensory cortex provides awareness of somatosensory information and the ability to make sensory discriminations. Touch, pain, temperature, and vibration sense are considered the primary modalities of sensation and are relatively preserved in patients with damage to sensory cortex or its projections from the thalamus. In contrast, complex tasks that require integration of multiple somatosensory stimuli and of somatosensory stimuli with auditory or visual information are impaired. These include the ability to distinguish two points from one when touched on the skin (two-point discrimination), localize tactile stimuli, perceive the position of body parts in space, recognize letters or numbers drawn on the skin (graphesthesia), and identify objects by their shape, size, and texture (stereognosis).
The patterns of sensory loss often indicate the level of nervous system involvement. Symmetric distal sensory loss in the limbs, affecting the legs more than the arms, usually signifies a generalized disorder of multiple peripheral nerves (polyneuropathy). Sensory symptoms and deficits may be restricted to the distribution of a single peripheral nerve (mononeuropathy) or two or more peripheral nerves (mononeuropathy multiplex). Symptoms limited to a dermatome indicate a spinal root lesion (radiculopathy).
In the spinal cord, segregation of fiber tracts and the somatotopic arrangement of fibers give rise to distinct patterns of sensory loss. Loss of pain and temperature sensation on one side of the body and of proprioception on the opposite side occurs with lesions that involve one half of the cord on the side of the proprioceptive deficit (Brown-Séquard syndrome; Figure 7–20). Compression of the upper spinal cord causes loss of pain, temperature, and touch sensation first in the legs, because the leg spinothalamic fibers are most superficial. More severe cord compression compromises fibers from the trunk. In patients with spinal cord compression, the lesion is often above the highest dermatome involved in the deficit. Thus, radiographic studies should be tailored to visualize the cord at and above the level of the sensory deficit detected on examination. Intrinsic cord lesions that involve the central portions of the cord often impair pain and temperature sensation at the level of the lesion because the fibers crossing the anterior commissure and entering the spinothalamic tracts are most centrally situated. Thus, enlargement of the central cervical canal in syringomyelia typically causes loss of pain and temperature sensation across the shoulders and upper arms (Figure 7–21).
Brown-Séquard syndrome with lesion at left tenth thoracic level (motor deficits not shown). (Redrawn, with permission, from Waxman SG. Neuroanatomy with Clinical Correlations, 25th ed. McGraw-Hill, 2003.)
Syringomyelia (the presence of a cavity in the spinal cord resulting from breakdown of gliomatous new formations, presenting clinically with pain and paresthesias followed by muscular atrophy of the hands) involving the cervicothoracic portion of the cord. (Redrawn, with permission, from Waxman SG. Clinical Neuroanatomy, 26th ed. McGraw-Hill, 2010.)
Brainstem lesions involving the spinothalamic tract cause loss of pain and temperature sensation on the opposite side of the body. In the medulla, such lesions can involve the neighboring spinal trigeminal nucleus, resulting in a “crossed” sensory deficit involving the ipsilateral face and contralateral limbs. Above the medulla, the spinothalamic and trigeminothalamic tracts lie close together, and lesions there cause contralateral sensory loss of the face and limbs. In the midbrain and thalamus, medial lemniscal fibers run together with pain and temperature fibers, and lesions are more likely to impair all primary sensation contralateral to the lesion. Because sensory fibers converge at the thalamus, lesions there tend to cause fairly equal loss of pain, temperature, and proprioceptive sensation on the contralateral half of the face and body. Lesions of the sensory cortex in the parietal lobe impair discriminative sensation on the opposite side of the body, whereas detection of the primary modalities of sensation may remain relatively intact.
19. What fibers carry pain, and how are they segregated from fibers that carry proprioception information in the spinal cord?
20. What are the differences in characteristics of sensory loss at different levels of the nervous system?
21. What is the function of the sensory cortex in the parietal lobe, and what are the clinical features of damage to this region?
Vision & Control of Eye Movements
The visual system provides our most important source of sensory information about the environment. The visual system and pathways for the control of eye movements are among the best characterized pathways in the nervous system. Familiarity with these neuroanatomic features is often extremely valuable in localization of neurologic disease.
The cornea and lens of the eye refract and focus images on the photosensitive posterior portion of the retina. The posterior retina contains two classes of specialized photoreceptor cells, rods and cones, which transduce photons into electrical signals. At the retina, the image is reversed in the horizontal and vertical planes so that the inferior visual field falls on the superior portions of the retina and the lateral field is detected by the nasal half of the retina.
Fibers from the nasal half of the retina traverse the medial portion of the optic nerve and cross to the other side at the optic chiasm (Figure 7–22). Each optic tract contains fibers from the same half of the visual field of both eyes. The optic tracts terminate in the lateral geniculate nuclei of the thalamus. Lateral geniculate neurons send fibers to the primary visual cortex in the occipital lobe (area 17, calcarine cortex; see Figure 7–9). These fibers form the optic radiations, which extend through the white matter of the temporal lobes and the inferior portion of the parietal lobes.
Common visual field defects and their anatomic bases. (1) Central scotoma caused by inflammation of the left optic disk (optic neuritis) or optic nerve (retrobulbar neuritis). (2) Total blindness of the right eye from a complete lesion of the right optic nerve. (3) Bitemporal hemianopia caused by pressure exerted on the optic chiasm by a pituitary tumor. (4) Right nasal hemianopia caused by a perichiasmal lesion (eg, calcified internal carotid artery). (5) Right homonymous hemianopia from a lesion of the left optic tract. (6) Right homonymous superior quadrantanopia caused by partial involvement of the optic radiation by a lesion in the left temporal lobe (Meyer loop). (7) Right homonymous inferior quadrantanopia caused by partial involvement of the optic radiation by a lesion in the left parietal lobe. (8) Right homonymous hemianopia from a complete lesion of the left optic radiation. A similar defect may also result from lesion. (9) Right homonymous hemianopia (with macular sparing) resulting from posterior cerebral artery occlusion. (Redrawn, with permission, from Greenberg DA et al, eds. Clinical Neurology, 8th ed. McGraw-Hill, 2012.)
Eye movements are produced by the extraocular muscles, which function in pairs to move the eyes along three axes (Figure 7–23). These muscles are innervated by the oculomotor (III), trochlear (IV), and abducens (VI) nerves. The oculomotor nerve innervates the ipsilateral medial, superior, and inferior rectus muscles and the inferior oblique muscles. It also supplies the ipsilateral levator palpebrae, which elevates the eyelid. The oculomotor nerve also carries parasympathetic fibers that mediate pupillary constriction (see later discussion). Trochlear nerve fibers decussate before leaving the brainstem, and each trochlear nerve supplies the contralateral superior oblique muscle. The abducens nerve innervates the lateral rectus muscle of the same side.
Extraocular muscles subserving the six cardinal positions of gaze. The eye is adducted by the medial rectus and abducted by the lateral rectus. The adducted eye is elevated by the inferior oblique and depressed by the superior oblique; the abducted eye is elevated by the superior rectus and depressed by the inferior rectus. (Redrawn, with permission, from Greenberg DA et al, eds. Clinical Neurology, 8th ed. McGraw-Hill, 2012.)
Cortical and brainstem gaze centers innervate the extraocular motor nuclei and provide for supranuclear control of gaze. A vertical gaze center is located in the midbrain tegmentum, and lateral gaze centers are present in the pontine paramedian reticular formation. Each lateral gaze center sends fibers to the neighboring ipsilateral abducens nucleus and, via the medial longitudinal fasciculus, to the contralateral oculomotor nucleus. Therefore, activation of the right lateral gaze center stimulates conjugate deviation of the eyes to the right. Rapid saccadic eye movements are initiated by the frontal eye fields in the premotor cortex that stimulate conjugate movement of the eyes to the opposite side. Slower eye movements involved in pursuit of moving objects are controlled by parieto-occipital gaze centers, which stimulate conjugate gaze to the side of the gaze center. These cortical areas control eye movements through their connections with the brainstem gaze centers.
The size of the pupils is determined by the balance between parasympathetic and sympathetic discharge to the pupillary muscles. The parasympathetic oculomotor nuclei of Edinger-Westphal send fibers in the oculomotor nerves that synapse in the ciliary ganglia within the orbits and innervate the pupillary constrictor muscles.
The motor portion of pupillary dilation is controlled by a three-neuron system (Figure 7–24). It is composed of axons from neurons in the posterolateral hypothalamus that descend through the lateral brainstem tegmentum and the intermediolateral column of the cervical spinal cord to the level of T1. There they terminate on preganglionic sympathetic neurons within the lateral gray matter of the thoracic cord. These neurons send axons that synapse with postganglionic neurons in the superior cervical ganglion. Postganglionic neurons send fibers that travel with the internal carotid artery and the first division of the trigeminal nerve to innervate the iris. The fibers also innervate the tarsal muscles of the eyelids. Damage to these pathways causes Horner syndrome, which consists of miosis, ptosis, and sometimes impaired sweating ipsilateral to the lesion.
Oculosympathetic pathways. This three-neuron pathway projects from the hypothalamus to the intermediolateral column of the spinal cord, then to the superior cervical (sympathetic) ganglion, and finally to the pupil, the smooth muscle of the eyelids, and the sweat glands of the forehead and face. Interruption of these pathways results in Horner syndrome. (Redrawn, with permission, from Greenberg DA et al, eds. Clinical Neurology, 5th ed. McGraw-Hill, 2002.)
The rods are sensitive to low levels of light and are most numerous in the peripheral regions of the retina. In retinitis pigmentosa, there is degeneration of the retina that begins in the periphery. Poor twilight vision is thus an early symptom of this disorder. Cones are responsible for perception of stimuli in bright light and for discrimination of color. They are concentrated in the macular region, which is crucial for visual acuity. In disorders of the retina or optic nerve that impair acuity, diminished color discrimination is often an early sign.
Visual processing begins in the retina, where information gathered from rods and cones is modified by interactions among bipolar, amacrine, and horizontal cells. Amacrine and bipolar cells send their output to ganglion cells, whose axons comprise the optic nerve. Photoreceptors convey information about the absolute level of illumination. Retinal processing renders ganglion cells sensitive to simultaneous differences in contrast for detection of edges of objects.
Ganglion cell axons terminate in a highly ordered fashion in well-defined layers of the lateral geniculate nuclei. Because of the separation of fibers in the optic chiasm, the receptive fields of cells in the lateral geniculate lie in the contralateral visual field. Geniculate neurons are arranged in six layers, and ganglion cell axons from each eye terminate in separate layers. Cells in different layers are in register, so that the receptive fields of cells in the same part of each layer are in corresponding regions of the two retinas. A greater proportion of cells are devoted to the macular region of both retinas. This reflects use of the central retina for high acuity and color vision. Some visual processing occurs in the geniculate, particularly for contrast and edge perception and detection of movement.
In the primary visual cortex, visual fields from the eyes are also represented in a topographic projection. Cortical neurons are functionally organized in columns perpendicular to the cortical surface. Geniculate fibers terminate within layer IV of the visual cortex, and cells within a column above and below layer IV show the same eye preference and similar receptive fields. Narrow alternating columns of cells supplied by one eye or the other lie next to each other (ocular dominance columns). A tremendous amount of visual processing occurs in primary visual cortex, including the synthesis of complex receptive fields and determination of axis orientation, position, and color. The retina is not simply represented as a map on the cortex; rather, each area of the retina is represented in multiple columns and analyzed with respect to position, color, and orientation of objects. As in the geniculate, a major portion of the primary visual cortex is devoted to analysis of information derived from the macular regions of both retinas. Cortical areas 18 and 19 (and many other areas) provide higher levels of visual processing.
The anatomic organization of the visual system is useful for localizing neurologic disease (Figure 7–22). Lesions of the retina or optic nerves (prechiasmal lesions) impair vision from the ipsilateral eye. Lesions that compress the central portion of the chiasm, such as pituitary tumors, disrupt crossing fibers from the nasal halves of both retinas, causing bitemporal hemianopia. Lesions involving structures behind the chiasm (retrochiasmal lesions) cause visual loss in the contralateral field of both eyes. Lesions that completely destroy the optic tract, lateral geniculate nucleus, or optic radiations on one side produce a contralateral homonymous hemianopia. Selective destruction of temporal lobe optic radiations causes superior quadrantanopia, and lesions of the parietal optic radiations cause inferior quadrantanopia. The posterior portions of the optic radiations and the calcarine cortex are supplied mainly by the posterior cerebral artery, although the macular region of the visual cortex receives some collateral supply from the middle cerebral artery. Therefore, a lesion of primary visual cortex generally causes contralateral homonymous hemianopia, but if it is due to posterior cerebral artery occlusion it may spare macular vision.
Conjugate eye movements are regulated by proprioceptive information from neck structures and information about head movement and position from the vestibular system. This information is used to maintain fixation on a stationary point when moving the head. In a comatose patient, the integrity of these oculovestibular and oculocephalic pathways can be assessed by the “doll’s eye” maneuver. This is elicited by briskly turning the head, which normally results in conjugate movement of the eyes in the opposite direction in a comatose patient. Irrigation of the ear with 10–20 mL of cold water reduces the activity of the labyrinth on that side and elicits jerk nystagmus, with the fast component away from the irrigated ear in a conscious individual. In coma, the fast saccadic component is lost, and the vestibular influence on eye movements dominates. Cold-water irrigation then results in deviation of the eyes toward the irrigated ear. These caloric responses are lost with midbrain or pontine lesions, with damage to the labyrinths, or with drugs that inhibit vestibular function.
The size of the pupils is controlled by the amount of ambient light sensed by the retina (Figure 7–25). Fibers from each retina terminate within midbrain pretectal nuclei that send fibers to both Edinger-Westphal nuclei. The fibers mediate pupillary constriction in bright light. In dim light, this reflex is inhibited and the influence of sympathetic fibers predominates, causing pupillary dilatation. The pupillary constrictor fibers release acetylcholine, which activates muscarinic AChRs and thus stimulates contraction of the pupillary sphincter muscle of the iris. Sympathetic pupillary fibers release norepinephrine, which activates α1-adrenergic receptors, causing contraction of the radial muscle of the iris. Drugs that inhibit muscarinic receptors, such as atropine, or that stimulate α1-adrenergic receptors, such as epinephrine, dilate the pupils, whereas drugs that stimulate muscarinic receptors or block α1-adrenergic receptors cause pupillary constriction.
Anatomic basis of the pupillary light reflex. The afferent visual pathways from the retina to the pretectal nuclei of the midbrain are represented by dashed lines, the efferent pupilloconstrictor pathways from the midbrain to the retinas by solid lines. Note that illumination of one eye results in bilateral pupillary constriction. (Redrawn, with permission, from Greenberg DA et al, eds. Clinical Neurology, 8th ed. McGraw-Hill, 2012.)
22. What is the pathway of fibers from the retina to the visual cortex?
23. What is the innervation of the extraocular muscles?
24. Describe how lesions in various parts of the visual pathways produce characteristic visual field defects.
Structures of the middle ear serve to amplify and transmit sounds to the cochlea, where specialized sensory cells (hair cells) are organized to detect ranges in amplitude and frequency of sound. The semicircular canals contain specialized hair cells that detect movement of endolymphatic fluid contained within the canals. Similar hair cells in the saccule and utricle detect movement of the otolithic membrane, which is composed of calcium carbonate crystals embedded in a matrix. The semicircular canal hair cells detect angular acceleration, whereas the hair cells of the utricle and saccule detect linear acceleration. Axons from auditory and vestibular neurons comprise the eighth cranial nerve, which traverses the petrous bone, is joined by the facial nerve, and enters the posterior fossa through the auditory canal. Auditory fibers terminate in the cochlear nuclei of the pons, and vestibular fibers terminate in the vestibular nuclear complex.
Cochlear neurons send fibers bilaterally to a network of auditory nuclei in the midbrain, and impulses are finally relayed through the medial geniculate thalamic nuclei to the auditory cortex in the superior temporal gyri. Vestibular nuclei have connections with the cerebellum, red nuclei, brainstem gaze centers, and brainstem reticular formation. The vestibular nuclei exert considerable control over posture through descending vestibulospinal, rubrospinal, and reticulospinal pathways.
There are three types of hearing loss: (1) conductive deafness, which is due to diseases of the external or middle ear that impair conduction and amplification of sound from the air to the cochlea; (2) sensorineural deafness, resulting from diseases of the cochlea or eighth cranial nerve; and (3) central deafness, resulting from diseases affecting the cochlear nuclei or auditory pathways in the CNS. Because of the redundancy of central pathways, almost all cases of hearing loss are due to conductive or sensorineural deafness. Besides hearing loss, auditory diseases may cause tinnitus, the subjective sensation of noise in the ear. Tinnitus resulting from disorders of the cochlea or eighth cranial nerve sounds like a constant nonmusical tone and may be described as ringing, whistling, hissing, humming, or roaring. Transient episodes of tinnitus occur in most individuals and are not associated with disease. When persistent, tinnitus is often associated with hearing loss.
Conductive and sensorineural deafness may be distinguished by examining hearing with a vibrating 512-Hz tuning fork. In the Rinne test, the tuning fork is held on the mastoid process behind the ear and then is placed at the auditory meatus. If the sound is louder at the meatus, the test is positive. Normally the test is positive because sound transmitted through air is amplified by middle-ear structures. In sensorineural deafness, although sound perception is reduced, the Rinne test is still positive because middle-ear structures are intact. In conductive deafness, sounds are heard less well through air and the test is negative. In the Weber test, the tuning fork is applied to the forehead at the midline. In conductive deafness, the sound is heard best in the abnormal ear, whereas with sensorineural deafness the sound is heard best in the normal ear. Audiometry can distinguish types of hearing loss. In general, sensorineural deafness causes greater loss of high-pitched sounds, whereas conductive deafness causes more loss of low-pitched sounds.
In contrast to hearing, vestibular function is commonly disturbed by small brainstem lesions. The vestibular nuclei occupy a large portion of the lateral brainstem, extending from medulla to midbrain. Although there are extensive bilateral connections between vestibular nuclei and other motor pathways, these connections are not redundant but are highly lateralized and act in concert to control posture, balance, and conjugate eye movement.
Patients with diseases of the vestibular system complain of disequilibrium and dizziness. Cerebellar disease also causes disequilibrium, but this is often described as a problem with coordination rather than a feeling of dizziness in the head. Interpretation of the complaint of dizziness can often be difficult. Many patients use the term loosely to describe sensations of light-headedness, weakness, or malaise. Directed questioning is often required to establish whether there is truly an abnormal sensation of movement (vertigo).
Vertigo may be due to disease of the labyrinth or vestibular nerve (peripheral vertigo) or to dysfunction of brainstem and CNS pathways (central vertigo). In general, peripheral vertigo is more severe and associated with nausea and vomiting, especially if the onset is acute. Diseases of the semicircular canal neurons or their fibers frequently cause rotational vertigo, whereas diseases involving the utricle or saccule cause sensations of tilting or listing, as on a boat. Traumatic and ischemic lesions may cause associated hearing loss. Dysfunction of one labyrinth often causes horizontal and rotatory jerk nystagmus. The slow phase of the nystagmus is caused by the unopposed action of the normal labyrinth, which drives the eyes to the side of the lesion. The fast-jerk phase is due to a rapid saccade, which maintains fixation.
Vertigo resulting from lesions of the CNS is usually less severe than peripheral vertigo and is often associated with other findings of brainstem dysfunction. In addition, nystagmus associated with central lesions may be present in vertical or multiple directions of gaze. Common causes of central vertigo include brainstem ischemia, brainstem tumors, and multiple sclerosis.
Consciousness, Arousal, & Cognition
Consciousness is awareness of self and the environment. It has two aspects: arousal, which is the state of wakefulness, and cognition, which is the sum of mental activities. This distinction is useful because neurologic disorders can affect arousal and cognition differently. Arousal is generated by activity of the ascending reticular activating system (Figure 7–26), which is composed of neurons within the central mesencephalic brainstem, the lateral hypothalamus, and the medial, intralaminar, and reticular nuclei of the thalamus. Widespread projections from these nuclei synapse on distal dendritic fields of large pyramidal neurons in the cerebral cortex and generate an arousal response. Cognition is the chief function of the cerebral cortex, particularly of prefrontal cortex and cortical association areas of the occipital, temporal, and parietal lobes. Some specialized mental functions are localized to specific cortical regions. Several subcortical nuclei in the basal ganglia and thalamus are intimately linked with cortical association areas, and damage to these nuclei or their interconnections with cortex may give rise to cognitive deficits similar to those observed with cortical lesions.
Brainstem reticular activating system and its ascending projections to the thalamus and cerebral hemispheres. (Redrawn, with permission, from Greenberg DA et al, eds. Clinical Neurology, 8th ed. McGraw-Hill, 2012.)
The reticular activating system is excited by a wide variety of stimuli, especially somatosensory stimuli. It is most compact in the midbrain and can be damaged by central midbrain lesions, resulting in failure of arousal, or coma. Higher nuclei and projections are less localized, and lesions rostrad to the midbrain, therefore, must be bilateral to cause coma.
Less severe dysfunction causes confusional states in which consciousness is clouded and the patient is sleepy, inattentive, and disoriented. Alertness is reduced, and the patient appears drowsy or falls asleep easily without frequent stimulation. More awake patients perceive stimuli slowly but are distractible, assigning important and irrelevant stimuli equal value. Perceptions may be distorted, leading to hallucinations, and the patient may be unable to organize and interpret a complex set of stimuli. The inability to perceive properly interferes with learning and memory and with problem solving. Thoughts become disorganized and tangential, and the confused patient may maintain false beliefs even in the face of evidence of their falsity (delusions). In some cases, the confusional state presents as delirium, which is characterized by heightened alertness, disordered perception, agitation, delusions, hallucinations, convulsions, and autonomic hyperactivity (sweating, tachycardia, hypertension).
Coma may result from structural or metabolic causes. Some structural lesions of the cerebral hemispheres, such as hemorrhages, large areas of ischemic infarction, abscesses, or tumors can expand over minutes or a few hours and cause brain tissue to herniate into the posterior fossa (Figure 7–27). If lateral within the temporal lobe, the expanding mass may drive the uncus of the temporal lobe into the ambient cistern surrounding the midbrain, compressing the ipsilateral third cranial nerve (uncal herniation). This causes pupillary dilation and impaired function of eye muscles innervated by that nerve. Continued pressure distorts the midbrain, and the patient lapses into coma with posturing of the limbs. With continued herniation, pontine function is impaired, causing loss of oculovestibular responses. Eventually, medullary function is lost and breathing ceases. Hemispheric lesions closer to the midline compress the thalamic reticular formation structures and can cause coma before eye findings develop (central herniation). With continued pressure, midbrain function is affected, causing the pupils to dilate and the limbs to posture. With progressive herniation, pontine vestibular and then medullary respiratory functions are lost.
Anatomic basis of herniation syndromes. An expanding supratentorial mass lesion may cause brain tissue to be displaced into an adjacent intracranial compartment, resulting in (1) cingulate herniation under the falx cerebri, (2) downward transtentorial (central) herniation, (3) uncal herniation over the edge of the tentorium, or (4) cerebellar tonsillar herniation into the foramen magnum. Coma and ultimately death result when (2), (3), or (4) produces brainstem compression. (Redrawn, with permission, from Greenberg DA et al, eds. Clinical Neurology, 5th ed. McGraw-Hill, 2002.)
Several nonstructural disorders that diffusely disturb brain function can produce a confusional state or, if severe, coma (Table 7–1). Most of these disorders are acute, and many, particularly those caused by drugs and metabolic toxins, are reversible. Clues to the cause of these “metabolic” encephalopathies are provided by general physical examination, drug screens, and certain blood studies. When these disorders cause coma, pupillary light responses are usually preserved despite impaired oculovestibular or respiratory function. This finding is of great help in distinguishing metabolic from structural causes of coma.
Table 7–1Nonstructural causes of confusional states and coma. ||Download (.pdf) Table 7–1 Nonstructural causes of confusional states and coma.
Drugs (sedative-hypnotics, ethanol, opioids)
Global cerebral ischemia
Meningitis and encephalitis
Seizure or prolonged postictal state
Neurons in the dorsal midbrain and especially nuclei within the pontine reticular formation are important for sleep. Thus, lesions involving the pons may preserve consciousness but disturb sleep. In contrast, diffuse lesions of the neocortex, such as those resulting from global cerebral ischemia, may preserve the reticular activating system and brainstem sleep centers, resulting in a patient with preserved sleep-wake cycles who cannot interact in any meaningful way with the environment (coma vigil or apallic state).
Several disorders disturb cognition rather than the level of consciousness. Specific cortical regions generally mediate different cognitive functions, although there is considerable overlap and interconnection between cortical and subcortical structures in all mental tasks. When several of these abilities are impaired, the patient is said to suffer from dementia. Dementia is discussed in more detail later in this chapter.
The prefrontal cortex (Figure 7–9) generally refers to areas 9, 10, 11, 12, 45, 46, and 47 of Brodmann on the superior and lateral surfaces of the frontal lobes and the anterior cingulate, parolfactory, and orbitofrontal cortex inferiorly and mesially. These regions are essential for orderly planning and sequencing of complex behaviors, attending to several stimuli or ideas simultaneously, concentrating and flexibly altering the focus of concentration, grasping the context and meaning of information, and controlling impulses, emotions, and thought sequences. Damage to the frontal lobes or connections to the caudate and dorsal medial nuclei of the thalamus causes the frontal lobe syndrome. Patients may suffer dramatic alterations in personality and behavior, whereas most sensorimotor functions remain intact. Some patients become vulgar in speech, slovenly, grandiose, and irascible, whereas others lose interest, spontaneity, curiosity, and initiative. The affect may become apathetic and blunted (abulia). Some patients lose the capacity for creativity and abstract reasoning and the ability to solve problems while becoming excessively concrete in their thinking. Often they are distractible and unable to focus attention when presented with multiple stimuli. The most dramatic manifestations are seen after bilateral frontal lobe damage; unilateral damage can lead to subtle alterations in behavior that may be difficult to detect. Involvement of premotor areas may lead to incontinence, inability to perform learned motor tasks (apraxia), variable increases in muscle tone (paratonia), and appearance of primitive grasp and oral reflexes (sucking, snouting, and rooting).
In about 90% of people, language is a function of the left hemisphere. Whereas 99% of right-handed people are left hemisphere dominant, about 40% of left-handed people are right hemisphere dominant for language. In most left-handed people, hemispheric dominance for language is incomplete, and damage to the dominant hemisphere tends to disturb language less severely than in right-handed individuals. The cortical regions most critical for language include Broca area (area 44), Wernicke area (area 22), the primary auditory cortex (areas 41 and 42), and neighboring frontal and temporoparietal association areas (Figure 7–9). Injury to these areas or their connections to other cortical regions result in aphasia. Lesions in the frontal speech areas cause nonfluent, dysarthric, halting speech, whereas lesions of the temporal speech area cause fluent speech that contains many errors or may be totally devoid of understandable words. Patients with damage to temporal speech areas also lack comprehension of spoken words. Isolation of the temporal speech area from the occipital lobes causes an inability to read (alexia). Portions of the parietal lobe adjacent to the temporal lobe are important for retrieval of previously learned words, and damage here may result in anomia. The inferior parietal region is important for the translation of linguistic messages generated in the temporal language areas into visual symbols. Damage to this region may result in an inability to write (agraphia).
Memory requires that information be registered by the primary somatosensory, auditory, or visual cortex. Posterior cortical areas involved in comprehension of language are needed for immediate processing of spoken or written events and recalling them immediately. The hippocampi and their connections to the dorsal medial nuclei of the thalamus and the mammillary nuclei of the hypothalamus constitute a limbic system network crucial for learning and processing of events for long-term storage. When these areas are damaged, the patient is unable to learn new material or retrieve memories from the recent past. The most severe symptoms occur with bilateral lesions; unilateral disease causes more subtle learning deficits. Memories that remain with a person for years are considered remote memories and are stored in corresponding association cortex areas (eg, visual cortex for scenes). Remote memories remain intact in patients with damage to limbic structures required for learning. However, they may be lost by damage to cortical association areas. Understanding the mechanisms by which recent memories are transferred from the limbic memory network to association cortex for long-term storage is a major goal of current research.
The parietal association cortex is the region principally involved in visuomotor integration of constructional tasks. The visual cortex is required for observation, whereas the auditory cortex and the temporal language cortex are necessary for drawing objects on command. The inferior parietal cortex (areas 39 and 40) integrates visual and auditory information, and the output from this region is translated into motor patterns by motor cortex. Thus, lesions to the parietal lobes commonly cause constructional impairment. Damage to either hemisphere may result in constructional errors. Drawings may show rotation of objects, disorientation of objects on the background, fragmentation of design, inability to draw angles properly, or omission of parts of a figure presented for copying. It is often difficult to determine which side is damaged, although if language is preserved, a nondominant parietal deficit is more likely.
Calculation ability, abstract reasoning, problem solving, and several other aspects of intelligence are difficult to localize because they require integration of several cortical regions. They are frequently disturbed by diseases that cause widespread cortical dysfunction, such as those that cause dementia.
25. What is the network of neurons that maintain normal arousal and consciousness?
26. What are the symptoms and signs of cerebral herniation caused by focal brain lesions?
27. Which cognitive functions are controlled by the frontal lobes and by the parietal association cortex?
28. What regions of the cortex are important for language and memory?