Physiology C26 - Locomotion PDF

PHYSIO C26 – Locomotion The contribution of local circuitry to motor control is not, of course, limited to reflexive responses to sensory inputs. Studies of rhythmic movements, such as locomotion and swimming in animal models (Box 16B), have demonstrated that local circuits in the spinal cord, call...

PHYSIO C26 – Locomotion The contribution of local circuitry to motor control is not, of course, limited to reflexive responses to sensory inputs. Studies of rhythmic movements, such as locomotion and swimming in animal models (Box 16B), have demonstrated that local circuits in the spinal cord, called central pattern generators, are fully capable of controlling the timing and coordination of such complex patterns of movement, and of adjusting them in response to altered circumstances. In quadrupeds and bipeds alike, the movement of a single limb during locomotion can be thought of as a cycle consisting of two phases: -​ a stance phase, during which the limb is extended and placed in contact with the ground to propel the animal forward; -​ a swing phase, during which the limb is flexed to leave the ground and then brought forward to begin the next stance phase (Figure 16.15A). Increases in the speed of locomotion result from decreases in the amount of time it takes to complete a cycle, and most of the reduction in the cycle time is due to shortening of the stance phase. The swing phase remains relatively constant over a wide range of locomotor speeds. 1.​ Locomotion For the purpose of examining the patterns of muscle contraction during locomotion the step cycle in cats and humans can be divided into four distinct phases: -​ flexion (F), -​ first extension (E1), -​ second extension (E2), -​ third extension (E3) The F and E1 phases occur during the time the foot is off the ground (swing), while E2 and E3 occur when the foot is in contact with the ground (stance). F: Swing commences with flexion at the hip, knee, and ankle (the F phase). E1: Approximately midway through swing the knee and ankle begin to extend while the hip continues to flex (the E1 phase). Extension at the knee and ankle during E1 moves the foot ahead of the body and prepares the leg to accept weight, in anticipation of foot contact at the onset of stance. E2: During early stance (the E2 phase) the knee and ankle joints flex, even though extensor muscles are contracting strongly. The lengthening of the contracting ankle and knee extensor muscles is due to weight being transferred to the leg. The yielding of these muscles as weight is accepted allows the body to move smoothly over the foot and is essential for establishing an efficient gait. E3: During late stance (the E3 phase) the hip, knee, and ankle all extend to provide a propulsive force to move the body forward. The rhythmic movements of the legs during stepping are produced by contractions of a​ large number of muscles. In general, contractions of flexor muscles occur during the F phase, and contractions of extensor muscles occur during one or more of the E phases. However, the timing and level of activity in different muscles vary widely (Figure 37-2B). For example, the flexor muscle (semitendinosus) contracts briefly at the beginning of each of these phases. An additional complexity is that some muscles contract during both swing and stance. The complex sequence of muscle contractions is the motor pattern for stepping.  2.​ Preparations a.​ Spinal model In spinal preparations the spinal cord is transected at the lower thoracic level, thus isolating the spinal segments that control the hind limb musculature from the rest of the central nervous system. This allows investigations on the role of spinal circuits in generating rhythmic locomotor patterns. In chronic spinal preparations animals are studied for weeks or months after transection. Locomotor activity without drug treatment can return within a few weeks of cord transection. b.​ Decerebrate model In decerebrate preparations the brain stem is completely transected at the level of the midbrain, preventing more rostral brain centers, especially the cerebral cortex, from influencing the locomotor pattern. These preparations allow investigation of the role of the cerebellum and structures in the brain stem in controlling locomotion. Two decerebrate preparations are commonly used. In one, the locomotor rhythm is generated spontaneously, while in the other it is evoked by electrical stimulation of the mesencephalic locomotor region. This difference depends on the level of decerebration. -​ In sections rostral to the mamillary bodies, spontaneous walking occurs in premammillary preparations -​ In sections caudal to the mammillary bodies, spontaneous stepping does not occur: electrical stimulation of the mesencephalic locomotor region is required to evoke walking In both sections, a coordination of the fpur limbs is observed and the rate of stepping can be adjusted.  c.​ Deafferented preparations Rhythmic locomotor patterns can be generated even after complete removal of all sensory input from the moving limbs. Deafferentation is accomplished by transection of all the dorsal roots that innervate the limbs. Since the dorsal roots carry only sensory axons, motor innervation of the muscles remains intact. The loss of all tonic sensory input drastically reduces the excitability of interneurons and motor neurons in the spinal cord. Thus, changes in the locomotor pattern after deafferentation might result from the artificial reduction in excitability of neurons rather than from the loss of specific sensory inputs. d.​ Immobilized preparation The role of specific sensory input from the limbs can be more systematically investigated by preventing the motor neurons from actually causing any movement. This is typically accomplished by paralyzing the muscles with curare, a competitive inhibitor of acetylcholine that blocks synaptic transmission at the neuromuscular junction. When locomotion is initiated in such an immobilized preparation, often referred to as fictive locomotion, the motor nerves to flexor and extensor muscles fire alternately but no actual movement takes place. Thus, the effect of proprioceptive reflexes is removed while tonic sensory input is preserved. Because immobilized preparations allow intracellular and extracellular recording from neurons in the spinal cord, they are used to examine the synaptic events associated e.​ Neonatal rats When the spinal cord is removed from neonatal rats (0-5 days after birth) and placed in a saline bath, it will generate coordinated bursts of activity in leg motor neurons when exposed to NMDA and serotonin. This promising new preparation allows more detailed analysis of the locations and roles of the specific neurons involved in rhythm generation, as well as pharmacological studies on the rhythm-generating network. RECAP In general, the locomotor patterns generated in deafferented or immobilized spinal preparations are much simpler than normal stepping patterns: they usually consist of alternating bursts of activity in flexor and extensor motor neurons. However, more complex locomotor patterns can be generated in immobilized spinal animals with the application of additional drugs or after a period of training. Moreover, in decerebrate preparations elaborate locomotor patterns can be generated in hind limb motor neurons after deafferentation. These patterns resemble those recorded in the same animals before deafferentation. Finally, a variety of patterns can be generated in immobilized decerebrate preparations, and these patterns can be altered significantly by changing the level of tonic sensory input. f.​ Conclusions ​ Supraspinal structures are not necessary for producing the basic motor pattern for stepping. ​ The basic rhythmicity of stepping is produced by neuronal circuits contained entirely within the spinal cord. ​ The spinal circuits can be activated by tonic descending signals from the brain. ​ The spinal pattern-generating networks do not require sensory input but nevertheless are strongly regulated by input from limb proprioceptors.  3.​ Neural networks in the spinal cord The isolated spinal cord can generate rhythmic bursts of reciprocal activity in flexor and extensor motor neurons of the hind legs even in the absence of sensory input. The contractions in the flexor and extensor muscles are controlled by two systems of neurons, half-centers, that mutually inhibit each other: the switching of activity from one half-center to the other depended on fatigue in the inhibitory connections. The half-center hypothesis was supported by studies of the effects of the drug L-dihydroxyphenylalanine (L-DOPA, a precursor for the monoamine transmitters dopamine and norepinephrine) in spinal cats. After the cats were treated with L-DOPA, brief trains of electrical stimuli were applied to small-diameter cutaneous and muscle afferents. These evoked long-lasting bursts of activity in either flexor or extensor motor neurons depending on whether ipsilateral or contralateral nerves were stimulated. Collectively the group of small-diameter afferents producing these effects are referred to as flexor reflex afferents (FRA). The system of interneurons generating the flexor bursts was found to inhibit the system of interneurons generating the extensor bursts, and vice versa. This organizational feature is consistent with Graham Brown's notion that mutually inhibiting half-centers produce the alternating burst activity in flexor and extensor motor neurons. The interneurons mediating the reflexes from the flexor reflex afferents have not yet been fully identified, but they may include interneurons in the intermediate region of the gray matter in the sixth lumbar segment. Interneurons in this region of the cord produce prolonged bursts of activity in response to brief stimuli to either ipsilateral or contralateral FRA in spinal cats treated with L-DOPA (Figure 37-4C). The neuronal networks capable of generating rhythmic motor activity in the absence of sensory feedback are termed central pattern generators. 4.​ CPG A central pattern generator (CPG) is a neuronal network capable of generating a rhythmic pattern of motor activity in the absence of phasic sensory input from peripheral receptors. CPGs have been identified and analyzed in more than 50 rhythmic motor systems, including those controlling such diverse behaviors as walking, swimming, feeding, respiration. The basic pattern produced by a CPG is usually modified by sensory information from peripheral receptors and signals from other regions of the central nervous system. The generation of rhythmic motor activity by CPGs depends on three factors: (1)​ the cellular properties of individual nerve cells within the network (2)​ the properties of the synaptic junctions between neurons, (3)​ the pattern of interconnections between neurons. Modulatory substances, usually amines or peptides, can alter cellular and synaptic properties, thereby enabling a CPG to generate a variety of motor patterns. The simplest CPGs contain neurons that are able to burst spontaneously. Such endogenous bursters can drive motor neurons, and some motor neurons are themselves endogenous bursters. Bursters are common in CPGs producing continuous rhythms such as those for respiration. They are also found in locomotor systems. Locomotion is an episodic behavior bursters in locomotor systems must be regulated. Bursting is often induced by neuromodulators. Neuromodulators can also alter the cellular properties of neurons so that brief depolarizations lead to maintained depolarizations (plateau potentials) that far outlast the initial depolarization. Neurons with the capacity to generate plateau potentials have been found in many CPGs, and in some cases the ability of neurons to generate plateau potentials is essential for rhythm generation. Rhythmicity in CPGs does not always depend on bursting or plateau potential properties of neurons in the network. A simple network can generate rhythmic activity if it includes some time-dependent process that enhances or reduces activity within some of the neurons. -​ Post-inhibitory rebound, a transient increase in excitability of a neuron after the termination of inhibitory input. Two neurons that mutually inhibit each other can oscillate in an alternating fashion if each neuron has the property of post-inhibitory rebound. -​ Synaptic depression: delayed onset of activity after a depolarization (delayed excitation), and differences in the time course of synaptic actions via parallel pathways connecting two neurons. The sequencing of motor patterns is regulated by a number of mechanisms. The simplest mechanism is mutual inhibition: interneurons that fire out of phase with each other are usually reciprocally coupled by inhibitory connections. 5.​ Sensory input Although normal walking is automatic, it is not necessarily stereotyped. Three important types of sensory information are used to regulate stepping: -​ somatosensory input from the receptors of muscle and skin, -​ input from the vestibular apparatus (for controlling balance), -​ visual input. a.​ Proprioception elaborates the timing and amplitude of stepping patterns One of the clearest indications that somatosensory afferents from the limbs regulate the step cycle is that the rate of stepping in spinal and decerebrate cats matches the speed of the motorized treadmill belt on which they are stepping. Specifically, afferent input regulates the duration of the stance phase. As the stepping rate increases, stance duration decreases, while the duration of the swing phase remains relatively constant. This observation suggests that some form of sensory input signals the end of stance and thus leads to the initiation of swing. Stretching hip flexor muscles in decerebrate animals to mimic the lengthening that occurs at the end of the stance phase inhibits the extensor half-center and thus facilitates the initiation of burst activity in flexor motor neurons during walking. Proprioceptors in muscles acting at the hip were primarily responsible. He noticed that rapid extension at the hip joint led to contractions in the flexor muscles of chronic spinal cats. More recent studies have shown that preventing hip extension in a limb suppresses stepping in that limb, whereas rhythmically moving the hip can entrain locomotor rhythm. During entrainment burst activity in flexor motor neurons is initiated in synchrony with hip extension. The afferents responsible for signaling hip angle for swing initiation arise from the muscle spindles in hip flexor muscles. Stimulation of the GTO and muscle spindles of extensor muscles prolonges the stance phase Other important signals for regulating the step cycle arise from the Golgi tendon organs and muscle spindles of extensor muscles. Stimulation of the afferents from these receptors prolongs the stance phase, often delaying the onset of swing until the stimulus has terminated. Both groups of afferents are active during stance, with the GTO providing a measure of the load carried by the leg. The functional consequence of this reflex reversal is that the swing phase will not be initiated until the leg is unloaded and the forces exerted by extensor muscles are low. Limb unloading normally occurs near the end of leg extension, when the animal's weight is being borne by the other legs and the extensor muscles are shortened and thus unable to produce optimal forces. In addition to regulating the transition from stance to swing, proprioceptive feedback from muscle spindles and Golgi tendon organs contributes significantly to the generation of burst activity in extensor motor neurons. At least three excitatory pathways transmit information from extensor sensory fibers to extensor motor neurons: -​ a monosynaptic pathway from Ia fibers, -​ a disynaptic pathway from Ia and Ib fibers, and -​ a polysynaptic pathway from Ia and Ib fibers. The polysynaptic pathway includes the extensor half-center of the central rhythm generator, so in addition to regulating the level of extensor activity this pathway also controls the stance (possibly by excitatory input to the interneurons in this pathway from the extensor half-center). The continuous regulation of the level of extensor activity by proprioceptive feedback presumably allows automatic adjustment of force and length in extensor muscles to unexpected unloading and loading of the leg. b.​ Reflexes of exteroceptive afferents Exteroceptors in the skin have a powerful influence on the central pattern generator for walking. One important function for these receptors is to detect external obstacles and adjust the stepping movements to avoid them. A well-studied example is the stumbling-corrective reaction in cats. Placing reflex: A mechanical stimulus applied to the dorsal part of the paw during the swing phase produces excitation of flexor motor neurons and inhibition of extensor motor neurons, leading to rapid flexion of the paw away from the stimulus and elevation of the leg in an attempt to step over the object. ​ Flexor-extensor reflex An identical stimulus applied during the stance phase produces an opposite response: -​ excitation of extensor muscles that reinforces the ongoing extensor activity. -​ If a flexion reflex were produced, the animal might collapse because its weight is being supported by the limb. This is an example of a phase-dependent reflex reversal: the same stimulus will excite one group of motor neurons during one phase of locomotion and excite the antagonist motor neurons during another phase. 6.​ Descending pathways Although the basic motor pattern for stepping is generated in the spinal cord, fine control of stepping movements involves numerous regions of the brain, including the motor cortex, cerebellum, and various sites within the brain stem. Recordings from neurons in all these regions have shown that many are rhythmically active during locomotor activity and hence involved in some way with the production of the normal motor pattern. Each region, however, appears to play a different role in the regulation of locomotor function. Supraspinal regulation of stepping can, in broad terms, be divided into three functional systems. -​ activates the spinal locomotor system -​ controls the overall speed of locomotion, -​ controls limb movement in response to visual input a.​ Descending pathways from the brainstem initiate locomotion The tonic electrical stimulation of the mesencephalic locomotor region initiates stepping when animals are placed on a freely moving treadmill. The rhythm of the locomotor pattern is not related to the pattern of electrical stimulation but depends only on its intensity. Weak stimulation produces a walking gait that increases in speed as the intensity​ increases; progressively stronger stimulation produces trotting and finally galloping (Figure 37- 11A). Thus, a relatively simple control signal from the brain stem, modulated only in intensity, not only initiates locomotion but also controls the overall speed of walking. b.​ MLR projects to the Medullary Reticular formation The descending noradrenergic pathway from the locus ceruleus or the descending serotonergic pathway from the raphe nucleus are not essential for locomotion. These pathways regulate the magnitude and timing of motor neuron activity in the locomotor networks in the spinal cord. Thus, while adrenergic drugs can initiate stepping movements in the spinal preparation, aminergic systems may not serve this function in intact animals. These observations suggest that descending glutaminergic pathways are involved in initiating locomotor activity. The axons of neurons in the nuclei near the mesencephalic locomotor region do do not directly activate central pattern generators. They excite neurons in the medullary reticular formation, whose axons descend in the ventrolateral region of the spinal cord. Thus, the current evidence indicates that the signals that activate locomotion and control its speed are transmitted to the spinal cord by glutaminergic neurons whose axons travel in the reticulospinal pathway. c.​ The Motor Cortex Is Involved in the Control of Precise Stepping Movements in Visually Guided Walking During normal walking we often must guide our walking using visual cues. The motor cortex is essential in such visuomotor coordination. Experimental lesions of the motor cortex do not prevent animals from walking on a smooth floor or even on smooth inclines. However, they do severely impair tasks requiring a high degree of visuomotor coordination, such as walking on the rungs of horizontal ladders, stepping over a series of barriers, and stepping over single objects placed on a treadmill belt. Such “skilled walking” is associated with considerable modulation in the activity of a large number of neurons in the motor cortex (Figure 37-12). Since many of these neurons project directly into the spinal cord, they may regulate the activity of interneurons that form part of, or are influenced by, the central pattern generator for locomotion. d.​ The Cerebellum Fine-Tunes the Locomotor Pattern by Regulating the Timing and Intensity of Descending Signals Damage to the cerebellum results in marked abnormalities in locomotor movements, including abnormal variations in the speed and range of movements at different joints in single limbs and abnormal coupling between stepping in different limbs. These symptoms are collectively referred to as ataxia. Since ataxic gait is apparent in patients with cerebellar lesions even when they are walking on a flat, smooth surface, we can conclude that the cerebellum is involved in the regulation of all stepping movements. The cerebellum receives information about both the actual stepping movements and the state of the spinal rhythm-generating network via two ascending pathways. -​ For the hind legs of the cat these are the dorsal and ventral spinocerebellar tracts. o​ Neurons in the dorsal tract are strongly activated by numerous leg proprioceptors and thus provide the cerebellum with detailed information about the biomechanical state of the hind legs. o​ In contrast, neurons in the ventral tract are activated primarily by interneurons in the central pattern generator,thus providing the cerebellum with information about the state of the spinal locomotor network. It is thought that the cerebellum compares the actual movements of the legs (proprioceptive signals in the dorsal spinocerebellar tract) with the intended movements (information on the central pattern generator carried by the ventral spinocerebellar tract) and computes corrective signals that are then sent to various brain stem nuclei (see Figure 37-10). Thus the cerebellum may adjust the locomotor pattern when stepping movements unexpectedly deviate from the intended movements. The brain stem nuclei influenced by the cerebellum during walking include the vestibular nuclei, red nucleus, and nuclei in the medullary reticular formation. Cerebellar output to the vestibular nuclei may be involved in integrating proprioceptive information from the legs with vestibular signals for the control of balance. 7.​ Conclusion Locomotion in mammals typically involves rhythmic movements of the body and one or​ more appendages. These movements depend on the precise regulation of the timing and​ the strength of contractions in numerous muscles. Centrally located neuronal circuits, known​ as central pattern generators, can generate the basic motor pattern for locomotion even without afferent feedback from peripheral receptors. Numerous central pattern generators have now been analyzed at the cellular level, and it is clear that a wide variety of cellular, synaptic, and network properties are involved in these local networks. Central pattern generators are extremely flexible. Their cellular and synaptic properties can be modified by chemical signals, and their functioning depends on how they are activated and the pattern of afferent input they receive. Contemporary research on mammalian locomotion dates from the 1960s, when two important experimental animal preparations were introduced. In the decerebrate animal stepping can be initiated by electrical stimulation of a site in the brain stem (the mesencephalic locomotor region). In the spinal preparation centrally generated locomotor activity can be evoked after the administration of L-DOPA and nialamide. Investigations using these preparations have confirmed and extended fundamental observations made near the turn of the century, namely that the basic rhythm for locomotion is generated centrally in spinal networks, that the transition from stance to swing is regulated by afferent signals from leg flexor and extensor muscles, and that descending signals from the brain regulate the intensity of locomotion and modify stepping movements according to the terrain on which the animal is walking.