Lippincott Illustrated Reviews: Physiology (Lippincott Illustrated Reviews Series)

Motor Control Systems

11

I. OVERVIEW

The neural pathways that control muscle activity in humans were developed during early evolutionary history to facilitate directed locomotion. Coordination of muscle groups that move the limbs was accomplished initially using simple neural feedback loops, but, as body complexity and the difficulty of the tasks that it was required to perform increased, so too the muscle control systems evolved. The human body devotes a large percentage of the nervous system to motor control. The simple neural feedback loops were retained during evolution and now function as muscle reflexes, but these pathways have been supplemented with successively higher layers of control (Figure 11.1). Motor regions of the cerebral cortex decide when movements are necessary. Basal ganglia compile motor sequences based on learned experience and then relay these sequences through the thalamus for execution by the primary motor cortex. Control sequences ensure that pairs of muscle groups whose actions typically oppose one another (e.g., extensors and flexorsabductors and adductors, and external and internal rotators) contract and relax in a coordinated fashion to effect smooth limb movements. Motor commands are refined even as they are being executed by the cerebellum, which receives streams of sensory data from muscles, joints, skin, eyes, and the vestibular system. The cerebellum allows the cortex to compensate for unexpected changes in terrain, posture, and limb position.

II. MUSCLE SENSORY SYSTEMS

Complex motor behaviors (such as walking) require closely coordinated sequences of muscular contractions whose timing and strength is modified constantly during changes in body position and weight distribution. Such coordination is not possible unless the central nervous system (CNS) is informed about limb movements relative to the torso, made possible by the sense of kinesthesia. Kinesthesia is a form of proprioception and one of the somatic senses. Kinesthesia relies primarily on two sensory systems that sense muscle length (muscle spindles) and tension (Golgi tendon organs [GTOs]).

A. Muscle spindles

Skeletal muscle comprises two fiber types. Extrafusal fibers (derived from the Latin fusus for “spindle”) generate the force needed to move bones. Intrafusal fibers are sensory, monitoring muscle length and changes in length. Intrafusal fibers are contained within discrete sensory structures (spindles) that are distributed randomly throughout the muscle body (Figure 11.2).

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Figure 11.1

Layering of motor control pathways.

1. Structure: Muscle spindles contain up to 12 intrafusal fibers enclosed within a connective tissue capsule. Each intrafusal fiber comprises a noncontractile portion centered between two weakly contractile regions. The spindles nestle between contractile fibers and are anchored at either end so that contractile and sensory fibers move as one unit. Spindles contain two types of intrafusal fiber: nuclear bag fibersand nuclear chain fibers (see Figure 11.2). Nuclear bag fibers swell centrally to form a “bag” containing numerous clustered nuclei. Nuclear chain fibers are thinner and more numerous than nuclear bag fibers. Their nuclei form a chain down the fiber's length.

2. Sensory transduction: Muscle spindles signal via two types of sensory nerve afferents (group Ia and group II). Both classes have wide, myelinated axons to maximize signal conduction velocity (Table 11.1; also see 5·III·B). When a muscle is stretched (e.g., by limb extension), the intrafusal fibers are stretched also, causing distortion of the nerves that wrap around them. Stretching activates mechanosensitive cation channels, resulting in depolarization and increased afferent nerve firing frequency.

a. Group Ia: Group Ia fibers coil around the central (equatorial) regions of both nuclear bag and nuclear chain fibers to form primary muscle spindle receptors. They yield a dynamic response to stretching (Figure 11.3). Type Ia afferents show maximal firing rates when the muscle fibers (and nerve endings) are being stretched actively. Firing rate decreases when the muscle reaches and maintains a new length.

b. Group II: Group II fiber endings are located at the ends of nuclear chain fibers and some nuclear bag fibers (see Figure 11.2). They form secondary muscle spindle receptors that yield a static response to stretching. Their output is proportional to muscle length, and the nerve fibers continue firing at increased rates if the muscle is held at the new length (see Figure 11.3).

3. Regulation: Intrafusal fibers are contractile, but they do not contribute significantly to muscle force development. Instead, the contractile portions serve only to shorten the fiber during muscle excitation and keep the central, sensory portion taut even as the muscle contracts. Maintaining tension allows the intrafusal fibers to continue functioning as stretch sensors throughout the contraction. Intrafusal fibers are innervated by γ-motor neurons, which conduct more slowly than the α- motor neurons that stimulate extrafusal muscle contraction (see Table 11.1). The α- and γ-motor neurons fire simultaneously, so that the spindle shortens in parallel with the body of the muscle when the muscle contracts. The combination of muscle spindles and their associated γ-motor neurons constitutes a fusimotor system.

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Figure 11.2

Muscle spindles.

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Figure 11.3

Intrafusal fiber responses to stretch.

B. Golgi tendon organs

Each end of a skeletal muscle is attached to a tendon that typically tethers it to a bone. The musculotendinous junction contains GTOs, which are sensory organs that monitor the amount of tension that develops in a muscle when stretched passively or when it contracts (Figure 11.4).

1. Structure: GTOs are situated at the junction between a skeletal muscle and a tendon. GTOs comprise a connective tissue capsule filled with collagen fibers that are interwoven with group Ib sensory nerve endings. Type Ib nerve afferents are myelinated to increase signal conduction rates (see Table 11.1).

2. Sensory transduction: When a muscle is stretched or contracts, the associated GTO is stretched also. The collagen fibers within the GTO tighten and compress the nerve endings that weave between them. Compression opens mechanosensitive channels in the nerve endings, causing depolarization and increasing nerve-firing rates.

C. Joints and skin sensors

Although joints between bones would intuitively seem to be ideal sites for locating receptors that report on limb position, in practice, the role of joint receptors in kinesthesia is minimal. Slow-adapting Ruffini endings in skin do have an important role, however (see 16·VII·A). Skin that covers joints is stretched whenever a limb or digit is retracted, causing Ruffini endings to fire. The importance of sensory data from Ruffini endings is increased in the fingers, where layering of the various muscles and tendons required for execution of fine movements may impede acquisition of sensory information from spindles and GTOs.

III. SPINAL CORD REFLEXES

Walking with an upright gait is, quite literally, a delicate balancing act. A misplaced foot or slight irregularity of terrain can easily upset the balance and precipitate a fall. Avoiding such mishaps requires that a fall be anticipated and an appropriate correction to gait be made with minimal delay. Motor sensory and control neurons are specialized to conduct signals at up to 120 m/s, representing some of the fastest nerve cells in the body (see Table 11.1). This ensures that sensory information is relayed to the CNS and compensatory commands executed in the shortest time possible. Reaction times are enhanced further by using local reflexes mediated by the spinal cord to make many routine adjustments to gait. The neurons involved are relatively short so as to further minimize signal transmission and processing times.

A. Reflex arcs

Reflex arcs are simple neuronal circuits in which a sensory stimulus initiates a motor response directly. Classic examples include withdrawal reflexes triggered by touching a hot stove or stepping on a sharp object. Such arcs are often mediated by the spinal cord, where a sensory neuron synapses with and activates a motor neuron. More complex arcs involve synapses with multiple neurons, at least one of which may be inhibitory. The spinal cord mediates a number of important reflex arcs, including the myotatic reflex, the inverse myotatic reflex, and the flexion reflex.

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Figure 11.4

Golgi tendon organ.

B. Myotatic

A myotatic reflex (also known as a stretch reflex or deep-tendon reflex) is initiated by stretching a muscle and causes contraction of the same (“homonymous”) muscle. Reflex contraction of the thigh (quadriceps) muscles caused by tapping the patellar ligament is a familiar example (Figure 11.5).

1. Response: Tapping the patellar ligament stretches the quadriceps and activates spindles buried within. Sensory signals are carried by Ia nerve afferents to the spinal cord, where they synapse with and excite α-motor neurons innervating the same muscle. The muscle contracts reflexively, the leg extends, and the foot jerks forward. The myotatic reflex is designed to resist inappropriate changes in muscle length and is important for maintaining posture.

2. Reciprocal innervation: Forward foot movement stretches the hamstring muscles at the back of the thigh and stimulates their spindles also. This might be expected to initiate a second reflex that opposes the actions of the first, but the arc is interrupted by a Ia inhibitory spinal interneuron. The Ia interneuron is activated by the same Ia afferent signal that caused the quadriceps to contract. The interneuron synapses with and inhibits the α-motor neurons that innervate the hamstring muscles (e.g., semitendinosus) and, thereby, allows the leg to extend without resistance. This circuitry is referred to as reciprocal innervation and is used commonly in situations in which two or more sets of muscles oppose each other around a joint (e.g., flexors and extensors).

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Figure 11.5

Myotatic reflex.

C. Inverse myotatic

The inverse myotatic reflex, also known as a Golgi tendon reflex, activates whenever a muscle contracts and GTOs are stretched (Figure 11.6). Type Ib afferents from GTOs synapse with Ib inhibitory interneurons upon entering the spinal cord. When activated, they inhibit α-motor output to the homonymous muscle. Excitatory interneurons simultaneously activate α-motor output to the heteronymous muscle. The Golgi tendon reflex is believed to be important for fine motor control and for maintaining posture, acting synergistically with the myotatic reflex above.

D. Flexion and crossed-extension

Stepping on a thorn or other injurious object precipitates two urgent actions. The first withdraws the foot from the source of pain (leg flexion). The second braces the opposing limb so that weight can be transferred while still maintaining balance. This complex motion is mediated by flexion and crossed-extension reflexes (Figure 11.7). Similar reflexes can be induced in the upper limbs. The action sequence can be broken down into three stages: stimulus sensation, wounded (ipsilateral) limb flexion, and then extension of the opposing (contralateral) limb.

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Figure 11.6

Inverse myotatic reflex (Golgi tendon reflex).

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Figure 11.7

Flexion and crossed-extension reflexes.

1. Sensation: Flexion and crossed-extension reflexes are usually initiated as a response to a noxious, painful stimulus. Pain fibers project to and synapse with interneurons in the spinal cord.

2. Flexion: The sensory afferents synapse on the ipsilateral side with excitatory motor neurons that innervate flexor muscles. Extensor muscles are inhibited simultaneously, and the limb retracts from the pain source.

3. Crossed-extension: Sensory fibers also cross the spinal cord's anterior fissure and synapse with motor neurons controlling contralateral limb movement. Extensors are excited and contract, whereas flexors are inhibited and relax. This is known as a cross-extension reflex and braces the contralateral limb for the sudden weight transfer caused by raising the wounded limb.

E. Renshaw cells

Intensely painful stimuli trigger a volley of spikes in the pain afferents that potentially could cause dependent flexor muscles to become tetanic if the reflex circuit were unregulated. Regulation comes in the form of Renshaw cells, which are a special class of spinal inhibitory interneuron that are excited by α-motor neuron collaterals (Figure 11.8). Renshaw cells fire whenever a muscle receives a command to contract, but they project back to and inhibit the same α-motor neuron that excited them. Renshaw cells can cause inhibition lasting tens of seconds. Their activity level is tied to that of the motor neuron, so the more intense the command to contract, the greater the degree of α-motor neuron inhibition. Renshaw cells also receive modulating inputs from higher motor control centers that allow for sustained voluntary contractions. They also project to motor neurons innervating opposing and associated muscle groups. These relationships enhance fluidity of limb movement.

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Figure 11.8

Renshaw cells.

F. Central pattern generators

Motor systems execute many repetitive behaviors, such as those associated with locomotion (walking, running, swimming), grooming, bladder control, ejaculation, eating (chewing, swallowing), and breathing (movement of the chest wall and diaphragm). These behaviors do not require conscious thought, although they can be modified by higher control centers. The rhythmic behaviors are established by neuronal circuits known as central pattern generators (CPGs). CPGs are found in many CNS areas, including the spinal cord. The only requirement is an excitable cell or cell cluster with intrinsic pacemaker activity (e.g., two neurons that sequentially excite each other) and dependent circuits of interconnected neurons that control motor neurons. Walking, for example, involves a repetitive set of motor commands that move one leg forward, shift weight, and then extend the opposite leg. The motor commands and movements are sequential and predictable. Speeding or slowing the pace requires simple adjustments to CPG timing.

IV. HIGHER CONTROL CENTERS

Spinal cord reflexes and CPGs establish stereotyped behaviors, but planning and recalling learned movements requires higher levels of control. These are added in layers, with each successive layer providing for more sophisticated and finer degrees of motor control (see Figure 11.1).1 As is the case for most organ systems, the greatest insights into function come from observing what happens when these pathways are damaged.

Clinical Application 11.1: Spinal Cord Injury

Tens of thousands of individuals in the United States suffer traumatic spinal cord injury (SCI) every year, most often as a result of a motor vehicle accident, a fall, or violence. Injuries to the spinal cord proper are usually caused by damage to the vertebral column or supporting ligaments, including fractures, dislocation, or disruption or herniation of an intervertebral disk. Acute SCI is often followed by a period of spinal shock that lasts 2–6 weeks, characterized by a complete loss of physiologic function caudal to the level of injury. This includes flaccid paralysis of all muscles, absence of tendon reflexes, and loss of bladder and bowel control. Males may often develop priapism. The mechanisms underlying shock are still under investigation.

The extent of SCI injury is described as being complete or incomplete. Cord transection causes complete SCI, characterized by a complete loss of sensory and motor function caudal to the trauma site. Incomplete SCI describes injuries in which some degree of sensory or motor function is preserved.

Even in cases of complete SCI, some reflex pathways may recover in time. Because these pathways are now disconnected from higher motor control centers, they can cause inappropriate movements. For example, sudden flexing of the ankle or wrist may trigger prolonged rhythmic contractions caused by unregulated Golgi tendon organ–mediated reflex loops (clonus).

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Spinal cord compression (white arrow) and hemorrhage (black arrowhead) caused by L1 vertebral body fracture and dislocation.

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Figure 11.9

Motor cortex organization.

A. Cerebral cortex

The cerebral cortex is responsible for planning voluntary motor commands. Many different cortical regions are involved in coordinating motor activities, but the most important are in area 4, the primary motor cortex, and area 6, which contains the premotor cortex and the supplementary motor area (Figure 11.9).

1. Primary motor cortex: The primary motor cortex sends motor fibers via the corticospinal tract to the spinal interneurons that ultimately cause muscle contraction. Commands are executed only after extensive processing by the cerebellum and basal ganglia. Their execution also takes into account information being received simultaneously from various skin and muscle proprioceptors.

2. Premotor cortex: The premotor cortex may be responsible for planning movements based on visual and other sensory cues.

3. Supplementary motor area: The supplementary motor area retrieves and coordinates memorized motor sequences such as those required for playing the piano.

B. Basal ganglia

The cortex makes decisions about when to move and what tasks need to be accomplished, but execution requires careful planning about the timing of contractile events, the distance that limbs and digits need to move, and the force that needs to be applied. Thus, the sequence of movements required to apply fine paint strokes to a watercolor portrait are very different from those required to apply exterior paint in broad strokes to the side of a house. The task of planning and executing motor commands falls on the basal ganglia. These areas are not absolutely required for motor function, but movements become grossly distorted and erratic if they are damaged.

1. Structure: The basal ganglia comprise a group of large nuclei that are located at the base of the cortex in close proximity to the thalamus (Figure 11.10). They work together as a functional unit. The nuclei receive motor commands from the cortex, pass them through a series of feedback loops, and then relay them to the thalamus for return to, and execution by, the primary motor cortex.

a. Striatum: The striatum (or neostriatum) comprises two nuclei: the putamen and the caudate nucleus. The striatum is the gateway through which commands from the cortex enter the nuclear complex. The striatum is dominated by GABAergic neurons, and its output is largely inhibitory.

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Figure 11.10

Basal ganglia.

image 1A comprehensive description of the anatomical pathways, structures, and mechanisms involved is beyond the purview of this text but are considered in greater detail in LIR Neuroscience.

b. Globus pallidus: The globus pallidus ([GP] also known as the palladium) can be divided into two regions (internal [IGP] and external [EGP]) based on function. The palladium is composed of inhibitory GABAergic neurons.

c. Substantia nigra: The substantia nigra (Latin for “black substance”) is filled with melanin, a dark pigment that serves as a substrate for dopamine formation. Functionally, it can be divided into two areas: the pars reticulata and the pars compacta. Both regions contain inhibitory neurons. The pars reticulata is primarily GABAergic, whereas the pars compacta contains dopaminergic neurons. Because the pars reticulata and IGP often function together and have a similar anatomical structure, they are often considered as a single functional unit.

d. Subthalamic nucleus: The subthalamic nucleus is a part of the subthalamus. It is a key link in a basal-nuclei feedback circuit and is the only primarily excitatory (glutamatergic) center within the basal ganglia.

2. Feedback circuits: The motor cortex communicates its intent to the striatum. There are two pathways for information flow from the striatum through the basal nuclei: a direct path and an indirect path. Both end at the thalamus, which is tonically active and stimulates cortical areas that ultimately control the musculature (Figure 11.11).

a. Direct path: When the striatum is activated, it inhibits IGP–pars reticulata complex output. These two nuclei are tonically active normally, and their output suppresses the thalamus’ tonic output to the motor cortex. Thus, activating the striatum allows the thalamus to stimulate the motor cortex. In practice, the direct path increases motor activity.

b. Indirect path: A second pathway involves the EGP and the subthalamic nucleus. Exciting the striatum prevents the EGP from signaling. The EGP normally inhibits the subthalamic nucleus, which would otherwise be tonically active and, therefore, increasing the activity of the IGP. The IGP inhibits the thalamus and prevents it from exciting the motor cortex. In practice, the indirect pathway decreases motor activity.

c. Biasing output: When the striatum receives a motor command, the direct and indirect pathways are activated simultaneously, and their effects on the IGP are conflicting and balanced. Any influence that changes this balance might be used to regulate motor output. The substantia nigra pars compacta can potentially have a major influence over motor output because it sends dopaminergic axons back to two areas of the striatum. When active, these neurons increase the activity of the direct pathway via an excitatory dopaminergic (D1) receptor while simultaneously suppressing the indirect pathway via a dopamine D2 receptor (see Table 5.2). Both effects favor increased motor activity.

3. Diseases affecting the basal ganglia: The balance that exists between the direct and indirect pathways is delicate. Disrupting even a single circuit component can thus have devastating motor consequences. These can include a slowing of movement (bradykinesia) or a complete loss of motor control (akinesia), rigidity due to increased muscle tone (hypertonia), and involuntary writhing movements at rest (dyskinesia). The best-studied motor disorders are Parkinson disease (PD) and Huntington disease (HD).

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Figure 11.11

Motor function relationships between the basal ganglia. GABA = γ-aminobutyric acid.

a. Parkinson disease: The motor disturbances associated with PD result from death of large numbers of dopaminergic neurons within the pars compacta (Figure 11.12). Loss of these neurons causes resting arm and hand tremors; increased muscle tone and limb rigidity; bradykinesia; and, in the later stages, postural instability. Patients also have a slow, shuffling gait. These symptoms all reflect the consequences of losing the dopaminergic feedback loop between the pars compacta and striatum. Directed movement becomes difficult, and the inherent conflicts between direct and indirect pathways become evident. Treatment options currently include drugs that raise dopamine levels, either by providing a substrate for dopamine formation (L-dopa) or by inhibiting its breakdown (monoamine oxidase inhibitors1; see Figure 5.7 and Table 5.3).

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Figure 11.12

Parkinson disease. Dashed red lines indicate pathways with diminished influence.

Tremors are the most common form of movement disorder. A tremor is a rhythmic body movement reflecting an imbalance between the actions of two antagonistic muscle groups. All individuals show physiologic tremors that may be exaggerated by physical stress; hunger; caffeine; and many classes of drugs affecting dopaminergic, adrenergic, and cholinergic neurotransmission.

b. Huntington disease: HD is a hereditary disorder affecting huntingtin, a ubiquitous protein whose normal function is still not understood fully. Striatal neurons that normally inhibit motor output via the indirect pathway are destroyed due to abnormal protein accumulations, removing the normal constraints on the direct pathway (Figure 11.13). Early disease symptoms include chorea (from the Greek word for “dance”), characterized by involuntary limb muscle contractions that produce abrupt jerking and writhing motions. HD ultimately involves most brain regions, causing severe psychiatric disturbances and dementia. There is no treatment option, and death usually follows diagnosis by ~20 years.

C. Cerebellum

The cerebellum is not essential for locomotion, but it is intimately involved in motor control. It verifies that instructions issued by the cortex are executed as intended and makes corrections as necessary.

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Figure 11.13

Huntington disease. Dashed red lines indicate pathways with diminished influence.

image 1For more information on drugs used to treat Parkinson and other neurodegenerative diseases, see LIR Pharmacology, 5e, p. 99.

1. Function: The full extent of cerebellar involvement in motor control is not known, but principal functions include fine-tuning and smooth execution of movements.

a. Fine-tuning: The cerebellum receives extensive sensory information about body and head position, muscle contractility and length, and tactile information from the skin. It then compares this information with the motor commands that were issued by the higher centers and makes fine motor adjustments as necessary. This prevents a finger from overshooting its target when reaching out to flip a light switch, for example.

b. Sequencing: Activities such as playing the piano involve finger movements that are executed so fast that there is insufficient time for sensory information to be relayed back to the CNS for processing and feedback. Such activities are only possible because the cerebellum anticipates when a particular movement should end and then executes a command that arrests it at a precise moment in time. It simultaneously anticipates and executes a command that ensures a smooth transition to the next motion.

c. Motor learning: The cerebellum is able to anticipate and execute motor commands because it stores and constantly updates information about the correct timing of commands required for complex motor sequences.

2. Cerebellar dysfunction: The cerebellum finesses motor commands but is not absolutely required for locomotion. Cerebellar lesions cause varying degrees of coordination loss, depending on the lesion's site and severity.

a. AtaxiaAtaxia refers to a general lack of muscular coordination. Gait may become slow, wide, and swaying. The conscious brain is now forced to think about body position, but the time lag between receipt of proprioceptive information and execution of motor commands means that limbs usually overreach and miss their intended targets. The brain then executes a poorly controlled compensatory movement, resulting in a behavior pattern known as dysmetria.

b. Intention tremors: Because the conscious brain has to guide and continually update movements, simple tasks, such as reaching for an object, become slow, and the path taken to the target meanders from side to side (an intention tremor). Intention tremors are readily discerned using a simple finger-to-nose test (Figure 11.14).

D. Brainstem

Simple neuronal circuits in the spinal cord produce stereotypical behaviors that facilitate walking and other rhythmic movements. The brainstem sets these pathways in motion and coordinates them with reference to sensory information received from the eyes and vestibular system. It also controls eye movement to stabilize visual images during head and body movement. The brainstem contains four important motor control areas: the superior colliculus (tectum), the red nucleus, the vestibular nuclei, and the reticular formation (Figure 11.15).

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Figure 11.14

Intention tremor.

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Figure 11.15

Brainstem motor control centers.

1. Superior colliculus: The superior colliculus controls head and neck movements with reference to visual information. Fibers from this area project to the cervical spine via the tectospinal tract.

2. Red nucleus: The red nucleus is located in the midbrain. The red nucleus controls flexor muscles in the upper limbs via the rubrospinal tract.

3. Vestibular nuclei: There are four vestibular nuclei: one in the pons (superior vestibular nucleus) and three in the medulla (the mediallateral, and inferior vestibular nuclei). They receive and integrate information from the inner ear about head and body motion. Output from these regions controls eye movement via the oculomotor nerve (cranial nerve III). They also help coordinate head, neck, and body movements via the vestibulospinal tracts. The medial vestibulospinal tract arises in the medial vestibular nucleus, which helps stabilize the head during body movements. The lateral vestibulospinal tract projects to all levels of the spinal cord, where it stimulates extensor muscle contraction and inhibits flexors to help control posture during body movements.

4. Reticular formation: The reticular formation is also involved in many complex motor behaviors. Fibers arising from this area project via the reticulospinal tract to all levels of the spinal cord. They influence the activity of both α- and γ-motor neurons to facilitate voluntary body movements originating in the cortex and initiated via the corticospinal tract.

Chapter Summary

• Skeletal muscles facilitate locomotion and manipulation of the external environment. Executing complex movements, such as walking, requires multiple levels of coordination, involving the spinal cordbrainstemcerebellumbasal ganglia, and motor areas of the cerebral cortex.

• Motor control centers receive sensory data from specialized myofibrils contained within skeletal muscles (intrafusal fibers) and from tendons (Golgi tendon organs [GTOs]). Intrafusal fibers relay information about muscle length and changes in length. GTOs are tension sensors.

• The spinal cord contains central pattern generators that sustain rhythmic limb movements during walking, for example. Simple spinal circuits allow for rapid reflex responses to noxious stimuli and unanticipated changes in muscle length.

• The myotatic reflex causes muscles to contract when stretched while simultaneously inhibiting opposing muscles to allow free limb movement. The inverse myotatic reflex limits muscle contraction and simultaneously activates an opposing muscle. Flexion and crossed-extension reflexes prepare opposing limbs to brace for transfer of weight when stepping on a sharp or otherwise injurious object, for example.

• Decisions about how and when to move begin in the cortex. Principal motor areas of the cortex include the primary motor cortex, the premotor cortex, and the supplementary motor area.

• Timing and sequencing motor commands is the responsibility of the basal ganglia. Motor commands are subjected to a series of feedback loops that hone the sequences and ensure accurate and smooth movements.

• The cerebellum fine-tunes movements during execution, referencing information being received from proprioceptors and other sensory systems.

• The brainstem executes motor commands and helps coordinate movements with reference to sensory data being relayed from the eyes and vestibular system.

Study Questions

Choose the ONE best answer.

II.1 Autoimmune diseases such as multiple sclerosis cause neurological impairment by affecting axon conduction velocity. Which of the following would slow axonal signal propagation to the greatest extent?

A. Increasing axon diameter

B. Increasing axon length

C. Increasing myelin thickness

D. Decreasing leak-channel density

E. Decreasing depolarization rate

Best answer = E. Axonal conduction velocity is dependent on the rate of membrane depolarization during an action potential, which, in turn, is a function of channel gating kinetics (5·III·B). Conduction velocity would also be reduced by decreasing (not increasing) axon diameter or by demyelination, which would increase current loss via leak channels. Increasing leak-channel density might also be expected to slow axonal conduction velocity. Conduction velocity is independent of axonal length.

II.2 Epilepsy is a common neurologic disorder characterized by spontaneous episodic neuronal firing and seizures. Research indicates that a glial spatial buffering dysfunction may be involved. Spatial buffering's role includes which of the following?

A. Limiting K+ buildup and nerve hyperexcitability

B. Preventing acidification of brain extracellular fluid

C. Increasing axonal conduction velocity

D. Synaptic neurotransmitter recycling

E. Transferring nutrients from blood to neurons

Best answer = A. Glia take up K+ from the neuronal interstitium and transfer it via gap junctions to adjacent cells for disposal at a remote site (or to the circulation; 5·V·B). Neural function is highly sensitive to local K+concentrations, and buildup could cause hyperexcitability and inappropriate spiking activity. Spatial buffering does not normally play a major role in pH balance. Axonal conduction velocity is enhanced by myelination, which is also a glial function (5·V·A). Glia also participate in neurotransmitter recycling by synaptic uptake and return to neurons (5·V·C), but this is not a spatial buffering function. Nutrient transfer via glial cells is referred to as the “lactate shuttle” which is unrelated to spatial buffering (5·V·D).

II.3 Cerebrospinal fluid (CSF) loss reduces buoyancy, allowing the brain to sag and triggering a “low CSF pressure headache” through loss of buoyancy. In addition to buoyancy, what other protective feature does CSF provide?

A. It contains mucin to lubricate the brain.

B. Cerebrospinal fluid volume? 15 mL that forms a cohesive film between brain and cranium.

C. It is enriched in HCO3 to buffer pH changes.

D. It is K+ free to enhance neuronal K+ efflux.

E. It drains along the olfactory nerve to moisturize the olfactory epithelium.

Best answer = C. Unlike most other body fluids, cerebro-spinal fluid (CSF) is protein free (i.e., it contains no mucins). Proteins normally provide a significant defense against pH changes, and, thus, CSF is enriched in HCO3 to compensate (6·VII·D). About 120 mL of CSF bathes the central nervous system, floating the brain to prevent compression of cerebral blood vessels and forming a protective cushion between brain and bone (6·VII·B). CSF contains ~3 mmol/L K+, slightly less than that of plasma. CSF drains into the venous system via an intracranial sinus.

II.4 A 45-year-old woman complains of pain in her fingertips and toes during cold exposure or emotional stress. This “Raynaud phenomenon” is caused by exaggerated sympathetic vasoconstriction in the extremities, producing ischemic pain. Which of the following statements best applies to her condition?

A. Sympathetic ganglia serving the fingers are located in the hand.

B. The sympathetic postganglionic nerve is myelinated.

C. The patient may gain relief from an α-adrenergic inhibitor.

D. Pain may be relieved by an acetylcholinesterase inhibitor.

E. The vascular neuromuscular junction contains nicotinic acetylcholine receptors.

Best answer = C. Vasoconstriction is mediated by norepinephrine release from sympathetic nerve terminals. Norepinephrine binds to α-adrenergic receptors on vascular smooth muscle cells, so the patient's vasospasm may be relieved by an α-adrenergic inhibitor (7·IV). Vascular neuromuscular signaling does not involve nicotinic acetylcholine receptors. Sympathetic ganglia are located close to the vertebral column, not peripherally, and postganglionic neurons are unmyelinated. Synaptic transmission within sympathetic ganglia is cholinergic, and, thus, an acetylcholinesterase inhibitor would augment sympathetic efferent activity thereby worsening the symptoms.

II.5 A 38-year-old woman is nauseated after receiving cytoxan, an anticancer drug administered to treat breast cancer. Drug-induced nausea is mediated by the area postrema, a sensory circumventricular organ (CVO).

Which of the following best describes CVOs’ function?

A. Aldosterone and thyroxine are released via circumventricular organs.

B. The hypothalamus monitors plasma composition via circumventricular organs.

C. Circumventricular organs allow blood and cerebro-spinal fluid to mix.

D. Circumventricular organ sensory processes extend across the blood–brain barrier.

E. The central chemoreceptor that monitors PCO2 is a circumventricular organ.

Best answer = B. The hypothalamus uses sensory circumventricular organs (CVOs) to monitor plasma composition, which facilitates homeostatic control of Na+, water, and other body parameters (7·VII·C). A blood–brain barrier (BBB) is interrupted in CVOs, and the capillaries are leaky, allowing fluid to filter from blood for sensing by CVO neurons. CVO sensory neurons do not penetrate the capillary wall and extend across the BBB. Aldosterone and thyroxine are released from the adrenal and thyroid glands, respectively, and they do not contain CVOs. Central chemoreceptors are located behind the BBB. Although CVO capillaries are leaky, blood remains contained in the vasculature by the capillary walls, which prevents blood and brain extracellular fluid or cerebrospinal fluid from mixing.

II.6 A 32-year-old male presents to the emergency department with head trauma after falling from a ladder. An attendant physician shines a flashlight in each eye and observes normal pupillary reflexes. Which of the following best describes such reflexes?

A. They are an example of a vagovagal reflex.

B. Light causes cone receptor depolarization.

C. Reflexive miosis involves ciliary muscle.

D. Miosis results from increased sympathetic stimulation of smooth muscle.

E. Pupillary reflexes are mediated by retinal ganglion cells.

Best answer = E. The pupillary light reflex is triggered by light falling on photosensitive retinal ganglion cells (8·II·C). The pupil constricts reflexively through parasympathetic stimulation of iris sphincter muscles. Light falling on cones hyperpolarizes the receptor cells through a decrease in Na+ influx through cyclic nucleotide–activated channels. The pupillary light reflex is mediated by the optic nerve and oculomotor nerve, not by the vagus nerve.

II.7 A driver traveling a dark rural road at night is temporarily blinded by the high beams of an oncoming vehicle. Which of the following observations best describes the blinded driver's retinal function?

A. Vision recovery involves rhodopsin dephosphorylation.

B. The channel that mediates night vision also transduces olfaction.

C. The high beams cause blindness through rod depolarization.

D. Light inhibits guanylyl cyclase–activating proteins in rods.

E. Temporary blindness is caused by Na+ channel internalization.

Best answer = A. Rhodopsin activation by light initiates a signal cascade that causes rod signaling, but it also initiates pathways that limit signaling (8·V·C). These include rhodopsin phosphorylation by rhodopsin kinase, so recovery necessarily involves rhodopsin dephosphorylation. Rod cell stimulation and desensitization involves membrane hyperpolarization, mediated by a cyclic guanosine monophosphate–dependent Na+ channel, which is different from the olfactory cyclic nucleotide–gated channel (10·III·C). Na+ channel internalization is not part of the desensitization process. Guanylyl cyclase–activating proteins are stimulated by light.

II.8 A 62-year-old woman with a history of temporal arteritis suffers sudden monocular vision loss caused by retinal artery occlusion and subsequent ganglion cell ischemia. Which of the following statements best describes how these retinal ganglion cells function?

A. They are dedicated to single rods.

B. Light always causes cell depolarization.

C. They signal via the oculomotor nerve.

D. They generate action potentials.

E. They assist photoreceptor recycling.

Best answer = D. Ganglion cells transmit visual information to the brain using action potentials, their axons forming the ocular nerve (the oculomotor nerve controls eye movement). Most other cells in the retina respond to light with graded potentials rather than action potentials (8·VII). Ganglion cells collate data from groups of photoreceptors (not single rods), which gives them a wide receptive field. Ganglion cells activate when light is turned on or off, depending upon where light falls on the retina relative to their receptive field. Pigment cells, not ganglion cells, aid photoreceptor recycling.

II.9 A child with congenital hearing loss is diagnosed with round window atresia (absence of a round window) following computed tomography imaging studies. Atresia impairs hearing by which of the following mechanisms?

A. Pressure across the eardrum cannot equalize.

B. It prevents ossicular chain movement.

C. It impairs impedance matching.

D. It prevents perilymph movement.

E. It stiffens the basilar membrane base.

Best answer = D. The round window allows perilymph to move within the cochlear chambers when the oval window is displaced by the stapes (9·IV). The cochlea is encased in bone, which prevents chamber expansion when the oval window is displaced. Therefore, in the absence of a round window, perilymph movement and basilar membrane flexion cannot occur. Impedance matching is a function of the ossicular chain, and air pressure equalization relies on the eustachian tube, neither of which should be affected by atresia. Basilar membrane stiffening would affect frequency discrimination but should not cause hearing loss.

II.10 A rare inherited disorder that prevents synthesis of tip-link proteins has been observed in animal models. Gene expression might be expected to have which of the following effects on auditory transduction?

A. Endocochlear potential would collapse.

B. Hair cells would lose sensory function.

C. K+ recycling would be inhibited.

D. Stereocilia would not be displaced by sound.

E. Only vestibular function would be impaired.

Best answer = B. Sounds are transduced by hair cells, which are excited when tip links between adjacent stereocilia tense, and a K+-permeant mechanoelectrical transduction (MET) channel opens (9·IV·C). The tip links tense when stereocilia are displaced by sound waves passing through the cochlea. If the tip links were missing, the stereocilia would still be displaced by sound, but the hair cells would be unable to generate a receptor potential. Auditory and vestibular hairs cells would be affected similarly. The endocochlear potential and K+ recycling relies on the stria vascularis to concentrate K+ within endolymph, which should not be affected by a tip-link disorder.

II.11 Which of the following best describes the properties of the organ of Corti?

A. The apex is attuned to high frequency sounds.

B. The basilar membrane is wider at the apex.

C. The scala media is filled with perilymph.

D. Inner hair cells are sound amplifiers.

E. Stereocilia do not bend toward the kinocilium.

Best answer = B. The basilar membrane resonates at different frequencies along its length (9·IV·D). The membrane is wider at the apex and resonates at low frequencies. The basilar membrane base and the hair cells it supports are attuned to high frequencies. Auditory nerve signals are dominated by output from inner hair cells, which signal when stereocilia bend toward the kinocilium. The outer hair cells are believed to help amplify these signals. The scala media is filled with endolymph, not perilymph.

II.12 The right ear of a comatose patient is irrigated with cold water to assess vestibuloocular reflex (VOR) function. Which of the following statements best describes the VOR or its components?

A. The horizontal semicircular canal detects vertical motion.

B. The vestibuloocular reflex is initiated by otolith displacement.

C. Ear cooling causes receptor-mediated K+ influx.

D. The vestibuloocular reflex is mediated by thermosensory nerves.

E. Vestibuloocular reflex vestibular nuclei are located in the thalamus.

Best answer = C. The temperature gradient created by irrigating the ear canal with cold water causes endolymph to move within the horizontal semicircular canal (9·V·E). Movement is transduced by mechanosensory channels on sensory hair cells, which open to allow K+ influx and depolarization. The vestibuloocular reflex does not involve thermoreceptors. The horizontal canal normally detects rotational head movements in a horizontal plane, which relays sensory information to vestibular nuclei in the brainstem, not the thalamus. Otoliths are normally found in the otolith organs, not the semicircular canals.

II.13 A 23-year-old woman with monosodium glutamate (MSG) syndrome complex experiences nausea, palpitations, and diaphoresis after eating food containing MSG. MSG is a food additive that enhances umami taste. Which of the following best describes the MSG sensory transduction mechanism?

A. It is sensed by type I taste receptor cells.

B. The monosodium glutamate receptor is a Na+ channel.

C. Umami cells release adenosine triphosphate.

D. Monosodium glutamate binds to a domain on “sweet” receptors.

E. Monosodium glutamate activates type III receptor cells.

Best answer = C. Monosodium glutamate (MSG) binds to a G protein–coupled receptor (not a Na+ channel) on umami-specific type II cells (10·II·C). Receptor binding initiates Ca2+ release from intracellular stores, which causes membrane depolarization and opening of pannexin hemichannels. Pannexins allow adenosine triphosphate to diffuse out of the cell and stimulate a gustatory nerve. MSG may have lesser, indirect effects on type I cells (salt) and type III cells (acid) but is detected primarily by type II cells.

II.14 A 32-year-old male presents with anosmia (loss of sense of smell) following accidental inhalation of a volatile chemical at work. Which of the following statements best describes olfactory neuron function?

A. They do not regenerate, so anosmia is permanent.

B. They do not generate action potentials.

C. Olfaction is mediated by guanylyl cyclase.

D. Their axons form cranial nerve II.

E. The patient's sense of taste is probably intact.

Best answer = E. Taste and smell are mediated by two different types of sensory cell. Taste receptors are epithelial cells, whereas olfactory receptors are primary sensory neurons (10·III·B). Olfactory neurons are turned over and replaced every ~48 days, so the sensory deficit is probably temporary. Olfactory receptor binding causes a change in adenylyl cyclase activity rather than guanylyl cyclase activity. If sufficiently intense, a stimulus will cause the neuron to fire an action potential, which is transmitted to the brain via cranial nerve (CN) I, the olfactory nerve (CN II is the optic nerve).

II.15 An 83-year-old man with myasthenia gravis is unable to eat foods such as steak because of bulbar muscle fatigue. Studies of the man's bulbar muscles during contraction might have revealed which of the following compared with normal?

A. Decreased α-motoneuron activity

B. Decreased γ-motoneuron activity

C. Decreased Ia sensory afferent activity

D. Decreased Ib sensory afferent activity

E. Decreased II sensory afferent activity

Best answer = D. The antibodies that are produced in patients with myasthenia gravis destroy the nicotinic acetylcholine receptor, interfering with normal excitation and force development (Clinical Application 12.2). Muscle tension development during contraction is sensed by Golgi tendon organs, which signal via group Ib sensory afferents (11·II·A). Contraction is initiated by α-motoneurons, which might be expected to signal normally, as would the γ-motoneurons that initiate intrafusal fiber contraction. Group Ia and group II afferents relay sensory information from muscle spindles when a muscle is stretched.

II.16 A distracted cook picks up and immediately drops a metal spatula that had become painfully hot to the touch. Which of the following statements best describes such reflexes?

A. They are mediated by local spinal circuits.

B. Pain stimuli are transduced by Ruffini endings.

C. Pain stimuli are transmitted via α-motoneurons.

D. They would be unaffected by demyelination.

E. They are mediated by central pattern generators.

Best answer = A. Reflexive movements triggered by painful stimuli are mediated by spinal reflex circuits (or “arcs”; 11·III·A). Painful stimuli are mediated by pain receptors and transmitted via myelinated sensory afferent fibers to the spinal cord. The short signal path and fibers adapted for high conduction velocity decrease reaction time. The motoneurons are also myelinated, which makes both arms susceptible to demyelinating disease. Ruffini endings sense mechanical stimulation of the skin (16·VII·A; 11·II·C), whereas central pattern generators are involved in establishing rhythmic movements (11·III·F).



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