Production of interleukin-12 and expression of its receptors by murine microglia

We examined the lower-limb electromyographic (EMG) activity from a patient with clinically complete spinal cord injury during orthotic gait. A newly developed gait orthosis was used to obtain bipedal locomotion. The surface EMG data during the gait together with the biomechanical variables were collected by way of a radio EMG system. A cyclic EMG activation pattern corresponding to the gait cycles were observed in each of the paralyzed lower-limb muscles during the orthotic gait. Although the EMG activation did not seem to contribute toward generating the gait, it showed some similarities to that of the infant stepping or immature gait. These results might be regarded as one of the indirect pieces of evidence that suggest the existence of a spinally originating motor mechanism underlying human locomotion.     

Is backward stepping over obstacles achieved through a simple temporal reversal of forward stepping?

The main purpose of the study was to examine whether backward stepping over obstacles was a simple temporal reversal of kinematic and muscle activation patterns found in forward obstacle avoidance. Obstacle avoidance was used as a probe to represent one aspect of walking over variable terrain. Kinematics, trajectories and muscle activation profiles for forward versus backward stepping over obstacles revealed that the simple reversal of locomotor patterns observed for level walking cannot be applied to obstacle avoidance. However, key kinematic data and limb trajectories for backward leading limb stepping were found to be similar to existing forward trailing limb data. Therefore, it appears that stepping over obstacles requires a complex upper level reorganization of the basic locomotor pattern based on biomechanical and sensory feedback.     

Human lumbosacral spinal cord interprets loading during stepping

Studies suggest that the human lumbosacral spinal cord can generate steplike oscillating electromyographic (EMG) patterns, but it remains unclear to what degree these efferent patterns depend on the phasic peripheral sensory information associated with bilateral limb movements and loading. We examined the role of sensory information related to lower-extremity weight bearing in modulating the efferent motor patterns of spinal-cord-injured (SCI) subjects during manually assisted stepping on a treadmill. Four nonambulatory subjects, each with a chronic thoracic spinal cord injury, and two nondisabled subjects were studied. The level of loading, EMG patterns, and kinematics of the lower limbs were studied during manually assisted or unassisted stepping on a treadmill with body weight support. The relationships among lumbosacral motor pool activity [soleus (SOL), medial gastrocnemius (MG), and tibialis anterior (TA)], limb load, muscle-tendon length, and velocity of muscle-tendon length change were examined. The EMG mean amplitude of the SOL, MG, and TA was directly related to the peak load per step on the lower limb during locomotion. The effects on the EMG amplitude were qualitatively similar in subjects with normal, partial, or no detectable supraspinal input. Responses were most consistent in the SOL and MG at load levels of < 50% of a subject's body weight. The modulation of the EMG amplitude from the SOL and MG, both across steps and within a step, was more closely associated with limb peak load than muscle-tendon stretch or the velocity of muscle-tendon stretch. Thus stretch reflexes were not the sole source of the phasic EMG activity in flexors and extensors during manually assisted stepping in SCI subjects. The EMG amplitude within a step was highly dependent on the phase of the step cycle regardless of level of load. These data suggest that level of loading on the lower limbs provides cues that enable the human lumbosacral spinal cord to modulate efferent output in a manner that may facilitate the generation of stepping. These data provide a rationale for gait rehabilitation strategies that utilize the level of load-bearing stepping to enhance the locomotor capability of SCI subjects.     

MyoD and Myf-5 differentially regulate the development of limb versus trunk skeletal muscle

The myogenic progenitors of epaxial (paraspinal and intercostal) and hypaxial (limb and abdominal wall) musculature are believed to originate in dorsal-medial and ventral-lateral domains, respectively, of the developing somite. To investigate the hypothesis that Myf-5 and MyoD have different roles in the development of epaxial and hypaxial musculature, we further characterized myogenesis in Myf-5- and MyoD-deficient embryos by several approaches. We examined expression of a MyoD-lacZ transgene in Myf-5 and MyoD mutant embryos to characterize the temporal-spatial patterns of myogenesis in mutant embryos. In addition, we performed immunohistochemistry on sectioned Myf-5 and MyoD mutant embryos with antibodies reactive with desmin, nestin, myosin heavy chain, sarcomeric actin, Myf-5, MyoD and myogenin. While MyoD(-/-) embryos displayed normal development of paraspinal and intercostal muscles in the body proper, muscle development in limb buds and brachial arches was delayed by about 2.5 days. By contrast, Myf-5(-/-) embryos displayed normal muscle development in limb buds and brachial arches, and markedly delayed development of paraspinal and intercostal muscles. Although MyoD mutant embryos exhibited delayed development of limb musculature, normal migration of Pax-3-expressing cells into the limb buds and normal subsequent induction of Myf-5 in myogenic precursors was observed. These results suggest that Myf-5 expression in the limb is insufficient for the normal progression of myogenic development. Taken together, these observations strongly support the hypothesis that Myf-5 and MyoD play unique roles in the development of epaxial and hypaxial muscle, respectively.     

Dorsoventral limb patterning based on anatomical analysis of muscles and nerve plexuses

The developing vertebrate limb is an excellent system to study the mechanisms that lead to skeletal, muscular and nervous patterns. Pattern formation in the limb occurs in relation to three axes: the antero-posterior axis, the proximo-distal axis and the dorso-ventral axis. Extensive classical embryological experiments on chick limb buds have identified some of the cell interactions related to these three axes. Recent works in developmental biology have begun to identify the molecular basis of these cell interactions which control patterns and forms of the limb. In this review, a possible model of dorsoventral limb patterning is proposed, based on an experiment using ectoderm/mesoderm recombinations in which the dorsoventral axis of the tissues is inverted. Based on comparative anatomical studies of the shoulder and pelvic regions, the anatomy of the transitional zone between limb and trunk regions is discussed. In addition, the problem of the nerve-muscle relationship in gross anatomy is also discussed from the viewpoint of the pattern formation.     

Motor patterns and kinematics during backward walking in the pacific giant salamander: evidence for novel motor output

Kinematic and motor patterns during forward and backward walking in the salamander Dicamptodon tenebrosus were compared to determine whether the differences seen in mammals also apply to a lower vertebrate with sprawling posture and to measure the flexibility of motor output by tetrapod central pattern generators. During treadmill locomotion, electromyograms (EMGs) were recorded from hindlimb muscles of Dicamptodon while simultaneous high-speed video records documented movement of the body, thigh, and crus and allowed EMGs to be synchronized to limb movements. In forward locomotion, the trunk was lifted above the treadmill surface. The pelvic girdle and trunk underwent smooth side-to-side oscillations throughout the stride. At the beginning of the stance phase, the femur was protracted and the knee joint extended. The knee joint initially flexed in early stance and then extended as the foot pushed off in late stance, reaching maximum extension just before foot lift-off. The femur retracted steadily throughout the stance. In the swing phase, the femur rapidly protracted, and the leg was brought forward in an "overhand crawl" motion. In backward walking, the body frequently remained in contact with the treadmill surface. The pelvic girdle, trunk, and femur remained relatively still during stance phase, and most motion occurred at the knee joint. The knee joint extended throughout most of stance, as the body moved back, away from the stationary foot. The knee flexed during swing. Four of five angles showed significantly smaller ranges in backward than in forward walking. EMGs of forward walking showed that ventral muscles were coactive, beginning activity just before foot touchdown and ceasing during the middle of stance phase. Dorsal muscles were active primarily during swing. Backward locomotion showed a different pattern; all muscles except one showed primary activity during the swing phase. This pattern of muscle synergy in backward walking never was seen in forward locomotion. Also, several muscles demonstrated lower burst rectified integrated areas (RIA) or durations during backward locomotion. Multivariate statistical analysis of EMG onset and RIA completely separated forward and backward walking along the first principal component, based on higher RIAs, longer durations of muscle activity, and greater synergy between ventral muscles during early stance in forward walking. Backward walking in Dicamptodon uses a novel motor pattern not seen during forward walking in salamanders or during any other locomotor activity in previously studied tetrapods. The central neuronal mechanisms mediating locomotion in this primitive tetrapod are thus capable of considerable plasticity.     

Induction of swimming in the high spinal stingray by L-DOPA

Stingrays with high spinal transections, which do not spontaneously locomote, can be induced to swim by intravenous injection of L-DOPA. The L-DOPA-induced swim of the spinal animal is associated with patterns of EMG activity that appear similar to those of the spontaneous swim of the decerebrate preparation. However, in contrast to the decerebrate condition, the L-DOPA-induced cycles of swimming are slower and less vigorous. Furthermore, secondary periodicites and altered intersegmental timing relationships are also evident.     

Organizing principles for voluntary movement: extending single-joint rules

1. Four subjects performed fast flexions of the elbow or shoulder over three different distances. Elbow flexions were performed both in a horizontal, single-degree-of-freedom manipulandum and in a sagittal plane with the limb unconstrained. Shoulder flexions were only performed in the sagittal plane by the unconstrained limb. We simultaneously recorded kinematic and electromyographic (EMG) patterns at the "focal" joint, that which the subject intentionally flexed, and at the other, "nonfocal" joint that the subject had been instructed to not flex. 2. Comparisons of the elbow EMG patterns across tasks show that agonist and antagonist muscles were similar in pattern but not size, reflecting the net muscle torque patterns. Comparisons at the shoulder also revealed similar EMG patterns across tasks that reflected net muscle torques. 3. Comparisons of EMG patterns across joints show that elbow and shoulder flexors behaved similarly. This was not true of the extensors. The triceps EMG burst was delayed for longer distances but the posterior deltoid had an early, distance-invariant onset. 4. Similarities in EMG reflect torque demands required at the focal joint to produce flexion and at the nonfocal joint to reduce extension induced by dynamic interactions with the focal, flexing joint. These similarities appear despite very different kinematic intentions and outcomes. This argues against a strong role for length-sensitive reflexes in their generation. 5. These results support the hypothesis that movements are controlled by muscle activation patterns that are planned for the expected torque requirements of the task. This general rule is true whether we are performing single-joint or multiple-joint movements, with or without external constraints. The similarities between single-joint and multijoint movement control may be a consequence of ontogenetic development of multijoint movement strategies that prove useful and are therefore also expressed under the constrained conditions of specialized tasks such as those performed in single-joint manipulanda.     

Segment-specific retention of a larval neuromuscular system and its role in a new, rhythmic, pupal motor pattern in Manduca sexta

At pupation in Manduca sexta, accessory planta retractor muscles and their motoneurons degenerate in segment-specific patterns. Accessory planta retractor muscles in abdominal segments 2 and 3 survive in reduced form through the pupal stage and degenerate after adult emergence. Electromyographic and electrophysiological recordings show that these accessory planta retractor muscles participate in a new, rhythmic 'pupal motor pattern' in which all four muscles contract synchronously at approximately 4 s intervals for extended bouts. Accessory planta retractor muscle contractions are driven by synaptic activation of accessory planta retractor motoneurons and are often accompanied by rhythmic activity in intersegmental muscles and spiracular closer muscles. The pupal motor pattern is influenced by descending neural input although isolated abdominal ganglia can produce a pupal motor pattern-like rhythm. The robust pupal motor pattern first seen after pupal ecdysis weakens during the second half of pupal life. Anemometric recordings indicate that the intersegmental muscle and spiracular closer muscle component of the pupal motor pattern produces ventilation. Accessory planta retractor muscle contractions lift the flexible abdominal floor, to which the developing wings and legs adhere tightly. We hypothesize that, by a bellows-like action, the accessory planta retractor muscle contractions circulate hemolymph in the appendages. Morphometric analysis shows that dendritic regression is similar in accessory planta retractor motoneurons with different pupal fates, and that accessory planta retractor motoneurons begin to participate in the pupal motor pattern while their dendrites are regressed.     

Environmental pollution and asthma

We studied the dynamical relationship between magnocellular red nucleus (RNm) discharge and electromyographic (EMG) activity of 10-15 limb muscles in two monkeys during voluntary limb movement. Recordings were made from 158 neurons during two different kinds of limb movement tasks. One was a tracking task in which the subjects were required to acquire targets displayed on an oscilloscope by rotating one of six different single degree of freedom manipulanda. During this task, we recorded the angular position of the manipulandum. The monkeys also were trained in several free-form food-retrieval tasks that were much less constrained mechanically. There was generally significantly greater neuronal discharge during the free-form tasks than during the tracking task. During both types of tasks, cross-correlation and impulse response functions calculated between RNm and EMG were predominantly pulse-shaped, indicating that the dynamics of the RNm discharge were very similar to those of the muscle activity. There was no evidence during either task for a substantial dynamical transformation (e.g., integration) between the two signals as had been previously suggested. In only 15% of the cases, did these correlations have step or pulse-step dynamics. There was a relatively broad, unimodal distribution of lag times between RNm and EMG, based on the time of occurrence of the peak correlation. During tracking, the mode of this distribution was approximately 50 ms, with 80% of the lags falling between -100 and 200 ms. During the free-form task, the mode was between 0 and 20 ms, with 65% of the lags between -100 and 200 ms. A positive lag indicates that RNm discharge preceded EMG. The shape and timing of both the cross-correlation and the impulse response functions were consistent with a model in which many RNm neurons contribute mutually correlated signals which are simply summed within the spinal cord to produce a muscle activation signal.     

Coordinated expression of Hoxa-11 and Hoxa-13 during limb muscle patterning

The limb muscle precursor cells migrate from the somites and congregate into the dorsal and ventral muscle masses in the limb bud. Complex muscle patterns are formed by successive splitting of the muscle masses and subsequent growth and differentiation in a region-specific manner. Hox genes, known as key regulator genes of cartilage pattern formation in the limb bud, were found to be expressed in the limb muscle precursor cells. We found that HOXA-11 protein was expressed in the premyoblasts in the limb bud, but not in the somitic cells or migrating premyogenic cells in the trunk at stage 18. By stage 24, HOXA-11 expression began to decrease from the posterior halves of the muscle masses. HOXA-13 was expressed strongly in the myoblasts of the posterior part in the dorsal/ventral muscle masses and weakly in a few myoblasts of the anterior part of the dorsal muscle mass. Transplantation of the lateral plate of the presumptive wing bud to the flank induced migration of premyoblasts from somites to the graft. Under these conditions, HOXA-11 expression was induced in the migrating premyoblasts in the ectopic limb buds. Application of retinoic acid at the anterior margin of the limb bud causes duplication of the autopodal cartilage and transformation of the radius to the ulna, and at the same time induces duplication of the muscle pattern along the anteroposterior axis. Under these conditions, HOXA-13 was also induced in the anterior region of the ventral muscles in the zeugopod. These results suggest that Hoxa-11 and Hoxa-13 expression in the migrating premyoblasts is under the control of the limb mesenchyme and the polarizing signal(s). In addition, these results indicate that these Hox genes are involved in muscle patterning in the limb buds.     

Characteristics of locomotor control in children with cerebral palsy

The typical features of electromyographical (EMG) recordings from children with cerebral palsy (CP) consist of a coactivation of antagonistic leg muscles during the stance phase, a low and tonic activation of extensor EMG, and enhanced stretch reflex excitability with short latency. This characteristic reflex pattern is suggested to reflect an arrested normal maturation. The strong similarity between the walking pattern of CP children (8-16 years of age) and the reflex pattern during the process of learning to walk (7-10 months of age) lets us draw the following conclusion. During normal maturation a close parallelism exists between the control of group I afferent inhibition with the suppression of mono/oligosynaptic stretch reflexes and group II afferent facilitation with the increase of polysynaptic (mainly extensor) EMG responses. This maturation depends on supraspinal control, and does not occur in CP children. In adult patients with a supraspinal lesion, a regression to this early reflex pattern takes place.     

EMG responses to maintain stance during multidirectional surface translations

To characterize muscle synergy organization underlying multidirectional control of stance posture, electromyographic activity was recorded from 11 lower limb and trunk muscles of 7 healthy subjects while they were subjected to horizontal surface translations in 12 different, randomly presented directions. The latency and amplitude of muscle responses were quantified for each perturbation direction. Tuning curves for each muscle were examined to relate the amplitude of the muscle response to the direction of surface translation. The latencies of responses for the shank and thigh muscles were constant, regardless of perturbation direction. In contrast, the latencies for another thigh [tensor fascia latae (TFL)] and two trunk muscles [rectus abdominis (RAB) and erector spinae (ESP)] were either early or late, depending on the perturbation direction. These three muscles with direction-specific latencies may play different roles in postural control as prime movers or as stabilizers for different translation directions, depending on the timing of recruitment. Most muscle tuning curves were within one quadrant, having one direction of maximal activity, generally in response to diagonal surface translations. Two trunk muscles (RAB and ESP) and two lower limb muscles (semimembranosus and peroneus longus) had bipolar tuning curves, with two different directions of maximal activity, suggesting that these muscle can play different roles as part of different synergies, depending on translation direction. Muscle tuning curves tended to group into one of three regions in response to 12 different directions of perturbations. Two muscles [rectus femoris (RFM) and TFL] were maximally active in response to lateral surface translations. The remaining muscles clustered into one of two diagonal regions. The diagonal regions corresponded to the two primary directions of active horizontal force vector responses. Two muscles (RFM and adductor longus) were maximally active orthogonal to their predicted direction of maximal activity based on anatomic orientation. Some of the muscles in each of the synergic regions were not anatomic synergists, suggesting a complex central organization for recruitment of muscles. The results suggest that neither a simple reflex mechanism nor a fixed muscle synergy organization is adequate to explain the muscle activation patterns observed in this postural control task. Our results are consistent with a centrally mediated pattern of muscle latencies combined with peripheral influence on muscle magnitude. We suggest that a flexible continuum of muscle synergies that are modifiable in a task-dependent manner be used for equilibrium control in stance.     

Trunk muscle activation and cocontraction while resisting applied moments in a twisted posture

Previous studies of twisting have revealed substantial cocontraction of agonist and antagonist muscles within the torso when torsional moments are generated. The objective of the current study was to quantify the activations and cocontraction of eight trunk muscles as subjects maintained an axially rotated trunk posture and resisted external applied bending moments. Ten subjects twisted their torsos 25 degrees to the right (clockwise) and resisted 20 and 40 Nm bending moments from 12 directions. The moment directions were in a transverse plane and labelled clockwise as viewed from above, ranging from 0 degrees (mid-saggital, anterior) to 330 degrees, in 30 degrees increments. RMS EMG amplitude data were collected using surface electrodes and normalized to maximal voluntary contractions. Significant changes were observed in the muscle responses due to the interaction of the moment direction and moment magnitude for six of the eight muscles tested. Comparison of the present data with that collected previously in neutral postures indicated: (1) a large increase in the activation levels of the right erector spinae and the left external oblique muscles; and (2) a counter-clockwise shift in the moment direction at which the peak activation of these same muscles occurs. Analysis of the relative activation levels (RALs), constructed from the NEMG data to quantify the cocontraction, indicated that the changes in cocontraction were more robust in response to changes in the bending moment's direction as opposed to changes in bending moment's magnitude.     

Inspiratory and expiratory patterns of the pectoralis major muscle during pulmonary defensive reflexes

Experiments were conducted to determine the discharge pattern of the pectoralis major muscle during pulmonary defensive reflexes in anesthetized cats (n = 15). Coughs and expiration reflexes were elicited by mechanical stimulation of the intrathoracic trachea or larynx. Augmented breaths occurred spontaneously or were evoked by the same mechanical stimuli. Electromyograms (EMGs) were recorded from the diaphragm, rectus abdominis, and pectoralis major muscles. During augmented breaths, the pectoralis major had inspiratory EMG activity similar to that of the diaphragm, but during expiration reflexes the pectoralis major also had purely expiratory EMG activity similar to the rectus abdominis. During tracheobronchial cough, the pectoralis major had an inspiratory pattern similar to that of the diaphragm in 10 animals, an expiratory pattern similar to that of the rectus abdominis in 3 animals, and a biphasic pattern in 2 animals. The pectoralis major was active during both the inspiratory and expiratory phases during laryngeal cough. We conclude that, in contrast to the diaphragm or rectus abdominis muscles, the pectoralis major is active during both inspiratory and expiratory pulmonary defensive reflexes.     

Ontogeny of feeding motor patterns in infant rats: An electromyographic analysis of suckling and chewing.

During mammalian ontogeny, there is a transition from suckling to the chewing of food. Is suckling a neuromuscular precursor to chewing, or are suckling and chewing independent systems? Electromyograms (EMGs) were recorded in rat pups of ages 6, 9, 12, 15, 18, and 21 days from the superficial masseter, anterior digastric, sternohyoideus, and genioglossus muscles during suckling and chewing. The EMG patterns of the 3 components of suckling behavior (nipple attachment, rhythmic sucking, and the stretch response) are distinctive from one another and reflect the musculoskeletal biomechanics of suckling. Chewing EMGs are present by 12 days of age and attain the adult pattern by 18–21 days of age. During nipple attachment, pups exhibit a motor pattern that is similar to that of adult chewing, but other aspects of suckling differ from chewing in some EMG features. Comparison of EMGs between behaviors and between ages allowed interpretation of the degree of continuity of muscular activity across the suckling-to-chewing transition. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Step-tracking movements of the wrist. IV. Muscle activity associated with movements in different directions

We examined the patterns of muscle activity associated with multiple directions of step-tracking movements of the wrist in humans and monkeys. Human subjects made wrist movements to 12 different targets that required varying amounts of flexion-extension and radial-ulnar deviation. Wrist muscles displayed two patterns of electromyographic (EMG) modulation as movement direction changed: amplitude graded and temporally shifted. The amplitude-graded pattern was characterized by modulation of the quantity of muscle activity that occurred during two distinct time periods, an agonist burst interval that began before movement onset and an antagonist burst interval that began just after movement onset. The timing of muscle activity over the two intervals showed little variation with changes in movement direction. For some directions of movement, EMG activity was present over both time intervals, resulting in "double bursts." Modulation of activity during the agonist burst interval was particularly systematic and was well fit by a cosine function. In contrast, the temporally shifted pattern was characterized by a gradual change in the timing of a single burst of muscle activity. The burst occurred at a time intermediate between the agonist and antagonist burst intervals. The temporally shifted pattern was seen less frequently than the amplitude-graded pattern and was present only in selected wrist muscles for specific directions of movement. Monkeys made wrist movements to 8-16 different targets that required varying amounts of flexion-extension and radial-ulnar deviation. These movements were performed more slowly than those of human subjects. The wrist muscles of the monkeys we examined displayed the amplitude-graded pattern of activity but not the temporally shifted pattern. Stimulation of individual wrist muscles in monkeys resulted in wrist movements that were markedly curved, particularly for the wrist extensors. These results indicate that step-tracking movements of the wrist are generated mainly by using the amplitude-graded pattern to modulate muscle activity. We propose that this pattern reflects a central process that decomposes an intended movement into an agonist, "propulsive" component and an antagonist, "braking" component. Separate bursts of muscle activity then are generated to control each component. On the other hand, we argue that the temporally shifted pattern may function to reduce the amount of movement curvature associated with the activation of wrist muscles.     

Identification of brain regions that are markedly activated by morphine in tolerant but not in naive rats

Thirty healthy subject's left and right lumber paraspinal (LP) EMG activity was recorded during a trunk flexion-return movement and the maximum integrated EMG amplitude (absolute EMG) during this movement in each side was compared. Twenty subjects showed less than 20% difference between the left and right side (symmetrical subjects-SS) and 10 subjects showed more than a 20% difference (asymmetrical subjects AS). As were administered acupuncture stimulation on LP muscles. Significant reduction in lumbar EMG asymmetry was observed after acupuncture stimulation (exact p=.049). No specific pattern of response in absolute EMG values was observed in the stimulate side. On the nonstimulated side, there was a significant reduction in absolute EMG values when the baseline value for that side was high (p=.037) and a significant increase when it was low (p=.0185). The results suggest that acupuncture may be beneficial for decreasing functional muscular distortion and improving synergistic coordination.     

Bilateral experimental muscle pain changes electromyographic activity of human jaw-closing muscles during mastication

The effects of bilateral experimental muscle pain on human masticatory patterns were studied. Jaw movements and electromyographic (EMG) recordings of the jaw-closing muscles were divided into multiple single masticatory cycles and analyzed on a cycle-by-cycle basis. In ten men simultaneous bilateral injections of hypertonic saline (5%) into the masseter muscles caused strong pain (mean+/-SE: 7.5+/-0.4 on a 0-10 scale), significantly reduced EMG activity of jaw-closing muscles in the agonist phase, and significantly increased EMG activity in the antagonist phase. Nine of the subjects reported a sensation of less intense mastication during pain. Injections of isotonic saline (0.9%) did not cause pain or significant changes in masticatory patterns. The influence of higher brain centers on conscious human mastication can not be discarded but the observed phase-dependent modulation could be controlled by local neural circuits and/or a central pattern generator in the brain stem which are capable of integrating bilateral nociceptive afferent activity.