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Pediatric spinal cord injury (SCI) often leads to increased nociceptive input resulting in aberrant motor output like tremor and spasticity. Acute plasticity within spinal pain and motor networks following pediatric SCI may result in long-term sensorimotor disabilities. Despite this, pediatric SCI remains poorly understood. Part of the problem lies in the paucity of detailed studies aimed at defining sensorimotor control by nociceptors during development. This review provides an overview of work that highlights afferent control of sensorimotor networks by defined nociceptors in the developing spinal cord. Here, we focus on the well established and widely used neonatal sensorimotor model called sacrocaudal afferent (SCA) pathway. Until recently, the identity of specific subclasses of nociceptive afferents in the SCA pathway controlling developing sensorimotor networks was unknown. We highlight here the use of members of the Transient Receptor Potential (TRP) ion channels and mouse genetics to identify specific subsets of nociceptive afferents in the SCA pathway. In addition, we highlight the use of mouse genetics to map sensorimotor networks during development and potential future applications. A neonatal spinal cord model of central neuropathic pain via a defined set of nociceptors is presented as a probe into potential therapeutic avenues in neonatal SCI. Finally, knowledge translation from neonatal basic research to the pediatric population in the clinic is described. In conclusion, studies in neonatal models may lead to therapeutic strategies and pharmaceuticals for chronic pain and motor dysfunction after SCI during development. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Many of the general concepts regarding the control of walking were described years ago by: Sherrington (1906) Integrative Actions of the Nervous System. Yale University Press: New Haven, CT; Sherrington (1910a) Remarks on the reflex mechanism of the step, Brain 33, 1-25; Sherrington (1910b) Flexor-reflex of the limb, crossed extension reflex, and reflex stepping and standing (cat and dog), J. Physiol. (Lond.) 40, 28-121; Sherrington (1931) Quantitative management of contraction in lowest level coordination, Brain 54, 1-28; Graham-Brown (1912) The intrinsic factors in the act of progression in the mammal, Proc. R. Soc. Lond. 84, 308-319; Graham-Brown (1914) On the nature of the fundamental activity of the nervous centres; together with an analysis of the conditioning of rhythmic activity in progression, and a theory of the evolution of function in the nervous system, J. Physiol. 49, 18-46; Graham-Brown (1915) On the activities of the central nervous system of the unborn foetus of the cat, with a discussion of the question whether progression (walking, etc.) is a 'learnt' complex, J. Physiol. 49, 208-215; Graham-Brown (1922) The physiology of stepping, J. Neur. Psychopathol. 3, 112-116. Only in recent years, however, have the mechanisms been analyzed in detail. Quite a few of these mechanisms have been described using the decerebrate cat. Locomotion is initiated in decerebrate cats by activation of the mesencephalic locomotor region (MLR) that activates the medial medullary reticular formation (MRF) which in turn projects axons to the spinal cord which descend within the ventrolateral funiculus (VLF). The MRF region regulates as well as initiates the stepping pattern and is thought to be involved in interlimb coordination. Afferent feedback from proprioceptors and exteroceptors can modify the ongoing locomotor pattern. Recently, the types of afferents responsible for signaling the stance to swing transition have been identified. A general rule states that if the limb is unloaded and the leg is extended, then swing will occur. The afferents that detect unloading of the limb are the Golgi tendon organs and stimulation of these afferents (at group I strengths) prolongs the stance phase in walking cats. The afferents that detect the extension of the leg have been found to be the length- and velocity-sensitive muscle afferents located in flexor muscles. Plasticity of locomotor systems is discussed briefly in this article. Descerebrate animals can adapt locomotor behaviors to respond to new environmental conditions. Oligosynaptic reflex pathways that control locomotion can be recalibrated after injury in a manner that appears to be functionally related to the recovery of the animal.

Compared to proprioceptive afferent collateral projections, less is known about the anatomical, neurochemical, and functional basis of nociceptive collateral projections modulating lumbar central pattern generators (CPG). Quick response times are critical to ensure rapid escape from aversive stimuli. Furthermore, sensitization of nociceptive afferent pathways can contribute to a pathological activation of motor circuits. We investigated the extent and role of collaterals of capsaicin-sensitive nociceptive sacrocaudal afferent (nSCA) nerves that directly ascend several spinal segments in Lissauer's tract and the dorsal column and regulate motor activity. Anterograde tracing demonstrated direct multisegmental projections of the sacral dorsal root 4 (S4) afferent collaterals in Lissauer's tract and in the dorsal column. Subsets of the traced S4 afferent collaterals expressed transient receptor potential vanilloid 1 (TRPV1), which transduces a nociceptive response to capsaicin. Electrophysiological data revealed that S4 dorsal root stimulation could evoke regular rhythmic bursting activity, and our data suggested that capsaicin-sensitive collaterals contribute to CPG activation across multiple segments. Capsaicin's effect on S4-evoked locomotor activity was potent until the lumbar 5 (L5) segments, and diminished in rostral segments. Using calcium imaging we found elevated calcium transients within Lissauer's tract and dorsal column at L5 segments when compared to the calcium transients only within the dorsal column at the lumbar 2 (L2) segments, which were desensitized by capsaicin. We conclude that lumbar locomotor networks in the neonatal mouse spinal cord are targets for modulation by direct multisegmental nSCA, subsets of which express TRPV1 in Lissauer's tract and the dorsal column. J. Comp. Neurol. 521:2870-2887, 2013. © 2013 Wiley Periodicals, Inc.

Among the most nettlesome obstacles in the yearlong debate over increasing the accessibility and affordability of health insurance has been the question of what effect health care reform legislation would have on the incidence of abortion. The recent experience in Massachusetts suggests that universal health care coverage has been associated with a decrease in the number of abortions performed, despite public and private funding of abortion that is substantially more liberal than the provisions of the federal legislation currently under consideration by Congress. Parties on both sides of the national debate on this issue, including the U.S. Conference of Catholic . . .

Spinal cholinergic neurons are critical for motor function in both the autonomic and somatic nervous systems and are affected in spinal cord injury and in diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy. Using two screening approaches and in situ hybridization, we identified 159 genes expressed in typical cholinergic patterns in the spinal cord. These include two general cholinergic neuron markers, one gene exclusively expressed in motor neurons, and nine genes expressed in unknown sub-types of somatic motor neurons. Further, we present evidence that chondrolectin (Chodl) is expressed by fast motor neurons and that estrogen-related receptor beta (ERR beta) is a candidate marker for slow motor neurons. In addition, we suggest paired-like homeodomain transcription factor 2 (Pitx2) as a marker for cholinergic partition cells. J. Comp. Neurol. 518:2284-2304, 2010. (C) 2010 Wiley-Liss, Inc. (Less)

The early stages of spinal cord injury (SCI) start with excitotoxic damage caused by a massive release of glutamate. However, glutamate release is not the only factor to consider. Inflammatory molecules like tumor necrosis factor alpha (TNFalpha), belonging to a group of cytokines initially identified and named for their ability to kill tumor cells, is also a key factor in neuronal death and inflammation. TNFalpha is released from macrophages and activated microglia following a SCI, reaching a peak 1 h after the primary injury. Motoneurons whose survival is necessary for successful rehabilitation are especially vulnerable to the effects of TNFalpha release. While TNFalpha has been postulated to increase glutamatergic synaptic transmission, evidence for this has been indirect. Here, we show using whole-cell recording from lumbar motoneurons that AMPA and NMDA receptor-mediated excitatory postsynaptic currents are rapidly increased following bath application of TNFalpha. Concurrently, the single-channel open probability of AMPA and NMDA channels were also augmented by TNFalpha. Overall, our data lead us to propose the idea that motoneuronal vulnerability to excitotoxicity is not only due to the excessive release of glutamate, but may also be attributable to the increased sensitivity of AMPARs and NMDARs to the proinflammatory factor, TNFalpha, released after SCI.

Whenever we move, our brain tunes our postural reflexes so that our balance is maintained. This remarkable task is usually accomplished without any conscious thought on our part. Depending on the task at hand, the output of multiple muscles must be constantly tweaked to maintain balance. How this is accomplished is a mystery that is far from being understood. Part of the complexity of the problem is that posture is controlled by numerous interacting networks such as the spinal cord, cerebellum, cortex and brainstem (Jacobs & Horak, 2007; Deliagina et al. 2008). The control of posture can be divided into two systems. The first is the anticipatory mode, where postural corrections are made prior to movement, and the second is the feedback mode where corrections are made in response to perturbations (Deliagina et al. 2007). The focus of this perspectives article is on the feedback mode, which operates to maintain a dorsal side up orientation in quadrupeds, and an upright orientation in humans. Deliagina and colleagues suggest that the body of quadrupeds can be split into at least two independent postural systems: one that controls the head and neck, and another which controls the trunk. Vestibular and visual input are mainly used to stabilize the head while somatosensory inputs from the limbs are primarily used to correct trunk displacements. With regard to the trunk, local spinal reflexes and long-loop supraspinal pathways are thought to participate in correcting perturbations of the limb. Descending feedback to the spinal cord is attributed to the reticulospinal, vestibulospinal and corticospinal tracts and facilitates the final postural corrective response. The recent work by Karayannidou and colleagues published in this issue of The Journal of Physiology provides insight into how pyramidal tract neurons (PTNs) from the fore and hind limb projections in the primary motor cortex respond to postural changes during two distinct tasks (Karayannidou et al. 2009). PTNs are the main output neurons of the motor cortex and influence activity of motoneurons and interneurons in the ventral horn of the spinal cord. They receive somatosensory input from proprioceptors in the limbs and other areas, including the posterior parietal cortex which integrates several sensory modalities. Consequently, PTNs are well positioned to provide corrective inputs to pools of motoneurons and interneurons within the spinal cord. PTNs are not hard-wired to produce a given response in muscles. PTN discharge can vary between tasks even when the EMG output from the muscles is relatively similar. For example, when monkeys were trained to perform a precision or power grip task, PTNs discharged at a higher rate during the precision grip task (Muir & Lemon, 1983) even though the same muscle activation occurred in both tasks. Drew and colleagues found that PTNs recorded in walking cats increased their rate of firing when a compensatory movement of the forelimb was required to avoid an obstacle (Drew, 1993). Karayannidou and colleagues provide further evidence of the task-dependent nature of PTNs. They designed a task whereby cats were trained to walk on a treadmill that allowed them to tilt their bodies 15 deg to the left or to the right. They then compared this task with one that imposed a similar tilt but which required that the animal remain stationary. The behavioural response to the tilts was essentially identical in both tasks. After the tilt was imposed, there was a marked asymmetry in the hind and forelimbs; the legs on the tilt down side exhibited a longer length, accompanied by an increase in extensor tone. The authors examined whether the PTNs responded in a similar manner following a tilt imposed during walking compared to standing. They found that many PTNs would increase their rate of firing in response to a tilt regardless of the task, while others would only respond during one task and not another. A particularly interesting subgroup responded to tilts in one direction with an animal walking on a treadmill but only responded to tilts in the opposite direction with a stationary animal. Overall, the authors provide compelling data suggesting that PTNs modulate their output to postural perturbations, and that this modulation could depend on the task being performed. What exactly are these PTNs doing? We know that the motor cortex participates in some, but not all, aspects of postural control (Deliagina et al. 2007; Jacobs & Horak, 2007). While it is possible to say that PTNs respond differently depending on the task, their involvement in postural adjustment cannot be ascertained. How then can we make the leap from correlation to causality? This depends on the ability to selectively inactivate groups of PTNs. Certainly, approaches exist whereby genetically identified neurons can be reversibly inactivated (Gosgnach et al. 2006) and techniques are being developed to identify PTNs using genetic approaches (Molyneaux et al. 2005). Combined with calcium imaging of populations of cells in the cortex (Stosiek et al. 2003; Murayama et al. 2007), I expect the tracking and assigning of causality to PTNs will be tractable. While this is unlikely to occur overnight, the exciting discoveries of Karayannidou and colleagues encourage us to intensify our efforts.

The use of isolated in vitro spinal cord preparations to examine the underlying networks that control locomotion has become popular. It is also well known that afferent feedback can excite and modulate these networks. However, it is often difficult to selectively activate classes of afferents that subserve specific modalities using in vitro preparations. Here, we describe a technique where afferent receptors that detect temperature were selectively activated. To accomplish this we used an in vitro preparation of the mouse where the spinal cord was isolated (T5-cauda equina) with one hind limb left attached. We designed a special chamber allowing the hind paw to be placed in such a way that it remained attached to the spinal cord but received a separate supply of artificial cerebrospinal fluid (aCSF). This allowed us to alter the temperature of the hind limb compartment without affecting the temperature of the central compartment containing the spinal cord. We also demonstrate using this approach that agonists which activate receptors which detect noxious heat could be intradermally injected into the hind limb without it diffusing into the central compartment.

Dopamine can modulate and excite spinal locomotor networks, affect afferent transmission and increase motoneuronal excitability. One of the mechanisms whereby dopamine increases motoneuronal excitability is to potentiate AMPA channel-mediated glutamatergic transmission onto motoneurons. However, it is not known which dopaminergic receptor subtypes or the intracellular mechanisms contribute to these effects. In this study, we used whole-cell patch clamp techniques to record chemically evoked AMPA currents in neonatal mouse motoneurons. Bath application of D(1)-like receptor agonist (SKF 39383) increased the AMPA current amplitude and prolonged the decay time constant. In the presence of D(1) receptor antagonist LE300, the effects of DA on AMPA currents were blocked. In contrast, bath-application of the D(2)-like receptor agonist quinpirole did not modulate AMPA currents. In the presence of D(2) receptor antagonist L-741626, dopaminergic modulation of AMPA currents was unaffected. These results suggest that augmentation of AMPA transmission by dopamine is accomplished by D(1) receptor-based mechanisms. This short-term modulation does not appear to involve cycling of AMPA receptor into the membrane, since blocking insertion with botulinum toxin C did not affect the augmentation of AMPA currents after activating D(1) receptors. On the other hand, blocking protein kinase A (PKA) with H-89 completely abolished the effects of D(1) agonists. In addition, we used cell-attached single channel recording to demonstrate that stimulating D(1) receptors increased individual AMPA channel open probability and open duration. Our data demonstrate that dopamine increases the efficacy of glutamatergic transmission onto motoneurons by increasing AMPA conductances via a D(1) PKA-based signaling system.

It is well recognized that dopamine (DA) can modulate spinal networks and reflexes. DA fibers and receptors are present in the spinal cord, and evidence for DA release within the spinal cord has been published. A critical gap is the lack of data regarding dopaminergic modulation of intrinsic and synaptic properties of motoneurons and ventral interneurons in the mammalian spinal cord. In this paper, we address this issue by examining the cellular mechanisms underlying the excitatory effect of DA on motor systems. We examine the effects of DA on two classes of cells important for motor control, motoneurons and Hb9 interneurons, located in lamina VIII. We show that DA can boost excitability in spinal motoneurons by decreasing the first spike latency and the afterhyperpolarization. Collectively, this leads to an increase in the frequency–current slope likely attributable to modulation ofIAand SKCa(small-conductance calcium-activated K+channel) currents. We also demonstrate that DA increases glutamatergic transmission onto motoneurons. Our data also suggest that DA stabilizes the rhythmic output of conditionally bursting interneurons. Collectively, these data indicate that DA has widespread actions on intrinsic and synaptic properties of ventral spinal neurons.

During the 1960s, as oncology research was rapidly expanding, MacFarlane Burnett’s idea that cancer resulted from a failure of tumor surveillance by the aging immune system was broadly acknowledged. The development of cancer genetics focused the field on mutational causes of tumorigenesis. However, a new appreciation for the role that a well-functioning immune system plays in protecting against virally induced tumors was brought to light in the 1980s with the acquired immunodeficiency syndrome (AIDS) epidemic. The phenomenon of the human immunodeficiency virus (HIV)-associated cancer epidemic within defined populations, particularly due to the recent dramatic responses to treatment of the underlying immunodeficiency, has given insight into other etiologic factors for a variety of tumors.

Over the last five years, rapid advances have been made in our understanding of the location, function, and recently, organization of the central pattern generator (CPG) for locomotion. In the mammal, the use of the neonatal rat has largely contributed to these advances. Additionally, the use of the in vitro mouse spinal cord preparation is becoming more common, catalysed in part by the potential for the use of genetic approaches to study locomotor function. Although tempting, it is necessary to resist the a priori assumption that the organization of the spinal CPG is identical in the rat and mouse. This review will describe the development of locomotor-like behaviour in the mouse from embryonic day 12 to postnatal day 14. While there are still many gaps in our knowledge, compared with the rat, the in vitro mouse appears to follow a qualitatively similar course of locomotor development. The emphasis in this review is the use or potential use of the mouse as a complement to existing data using the neonatal rat preparation.

This report describes locomotor-like activity generated by the neonatal mouse spinal cord in vitro. We demonstrate that locomotor-like activity can be produced either spontaneously or by a train of stimuli applied to the dorsal roots or in the presence of bath-applied drugs. Calcium imaging of the motoneuron activity generated by a train of dorsal root stimuli revealed a rostrocaudally propagating component of the optical signal in the anterior lumbar (L1-L3) and in the caudal segments (S1-S4). We hypothesize that this spatio-temporal pattern arises from a rostrocaudal gradient of excitability in the relevant segments. Our experiments suggest that left/right reciprocal inhibition and NMDA-mediated oscillations are not essential mechanisms underlying rhythmogenesis in the neonatal mouse cord. Finally, our data are discussed in the context of other models of locomotion in lower and higher vertebrates.

The purpose of this study was to determine the test-retest reliability of 4 single-leg horizontal hop tests (i.e., single hop for distance, triple hop for distance, crossover hop for distance, and 6-m hop for time), with a time interval of approximately 4 weeks separating the 2 testing sessions. Eighteen healthy, young, adult men, all cadets enrolled at the U.S. Air Force Academy, Colorado, performed the single hop for distance, the triple hop for distance, the crossover hop for distance, and the 6-m hop for time during 2 testing sessions separated by 31.2 +/- 0.4 days. Reliability data for each of the single-leg hop tests were studied through a repeated measures analysis of variance, intraclass correlation coefficients (ICCs), and standard errors of measurement (SEMs). The ICCs ranged from 0.92 to 0.97 for the 4 single-leg hop tests. The SEMs for the single-leg hop tests that assessed the distance hopped ranged from 4.61 to 17.74 cm. The SEM for the 6-m hop for time test was 0.06 seconds. No significant differences were noted when the mean scores of the 2 test trials were compared by a repeated measures analysis of variance for any of the single-leg hop tests. These results indicate that the single-leg hop tests examined in this study offer strength and conditioning professionals a reliable method to assess the single-leg horizontal hopping capabilities of healthy, young, adult men, with intervals of approximately 4 weeks between testing sessions.

After lateral gastrocnemius–soleus (LGS) nerve section in intact cats, a rapid locomotor compensation involving synergistic muscles occurs and is accompanied by spinal reflex changes. Only some of these changes are maintained after acute spinalization, indicating the involvement of descending pathways in functional recovery. Here, we address whether the development of these adaptive changes is dependent on descending pathways. The left LGS nerve was cut in three chronic spinal cats. Combined kinematics and electromyographic (EMG) recordings were obtained before and for 8 d after the neurectomy. An increased yield at the ankle was present early after neurectomy and, as in nonspinal cats, was gradually reduced within 8 d. Compensation involved transient changes in step cycle structure and a longer term increase in postcontact medial gastrocnemius (MG) EMG activity. Precontact MG EMG only increased in one of three cats. In a terminal experiment, the influence of group I afferents from MG and LGS on stance duration was measured in two cats. LGS effectiveness at increasing stance duration was largely decreased in both cats. MG effectiveness was only slightly changed: increased in one cat and decreased in another. In cat 3, the plantaris nerve was cut after LGS recovery. The recovery time courses from both neurectomies were similar (p> 0.8), suggesting that this spinal compensation is likely a generalizable adaptive strategy. From a functional perspective, the spinal cord therefore must be considered capable of adaptive locomotor plasticity after motor nerve lesions. This finding is of prime importance to the understanding of functional plasticity after spinal injury.

To investigate the origin of spontaneous activity in developing spinal networks, we examined the activity patterns and synaptic organization of ventrally located lumbosacral interneurons, including those whose axons project into the ventrolateral funiculus (VLF), in embryonic day 9 (E9)–E12 chick embryos. During spontaneous episodes, rhythmic synaptic potentials were recorded from the VLF and from spinal interneurons that were synchronized, cycle by cycle, with rhythmic ventral root potentials. At the beginning of an episode, ventral root potentials started before the VLF discharge and the firing of individual interneurons. However, pharmacological blockade of recurrent motoneuron collaterals did not prevent or substantially delay interneuron recruitment during spontaneous episodes. The synaptic connections of interneurons were examined by stimulating the VLF and recording the potentials evoked in the ventral roots, in the VLF, or in individual interneurons. Low-intensity stimulation of the VLF evoked a short-latency depolarizing potential in the ventral roots, or in interneurons, that was probably mediated mono- or disynaptically. At higher intensities, long-latency responses were recruited in a highly nonlinear manner, eventually culminating in the activation of an episode. VLF-evoked potentials were reversibly blocked by extracellular Co2+, indicating that they were mediated by chemical synaptic transmission. Collectively, these findings indicate that ventral interneurons are rhythmically active, project to motoneurons, and are likely to be interconnected by recurrent excitatory synaptic connections. This pattern of organization may explain the synchronous activation of spinal neurons and the regenerative activation of spinal networks when provided with a suprathreshold stimulus.

We examined the effects of spontaneous or evoked episodes of rhythmic activity on synaptic transmission in several spinal pathways of embryonic day 9–12 chick embryos. We compared the amplitude of synaptic potentials evoked by stimulation of the ventrolateral funiculus (VLF), the dorsal or ventral roots, before and after episodes of activity. With the exception of the short-latency responses evoked by dorsal root stimulation, the potentials were briefly potentiated and then reduced for several minutes after an episode of rhythmic activity. Their amplitude progressively recovered in the interval between successive episodes. The lack of post-episode depression in the short-latency component of the dorsal root evoked responses is probably attributable to the absence of firing in cut muscle afferents during an episode of activity.The post-episode depression of VLF-evoked potentials was mimicked by prolonged stimulation of the VLF, subthreshold for an episode of activity. By contrast, antidromically induced motoneuron firing and the accompanying calcium entry did not depress VLF-evoked potentials recorded from the stimulated ventral root. In addition, post-episode depression of VLF-evoked synaptic currents was observed in voltage-clamped spinal neurons. Collectively, these findings suggest that somatic postsynaptic activity and calcium entry are not required for the depression. We propose instead that the mechanism may involve a form of long-lasting activity-induced synaptic depression, possibly a combination of transmitter depletion and ligand-induced changes in the postsynaptic current accompanying transmitter release. This activity-dependent depression appears to be an important mechanism underlying the occurrence of spontaneous activity in developing spinal networks.

Whelan, P. J. and K. G. Pearson. Plasticity in reflex pathways controlling stepping in the cat. J. Neurophysiol. 78: 1643–1650, 1997. Previous studies have shown that stimulation of group ‘I’ afferents from ankle extensor muscles can prolong the cycle period in decerebrate walking cats and that the magnitude of these effects can be altered after chronic axotomy of the lateral-gastrocnemius/soleus (LGS) nerve. The effectiveness of LGS group I afferents in prolonging the cycle period decreases after axotomy, whereas the effectiveness of the uncut medial-gastrocnemius (MG) group I afferents is increased. The objectives of this investigation were to establish the time course of these changes in effectiveness and to determine whether these changes persist after transection of the spinal cord. The effects of stimulating the LGS and/or MG group I afferents on the cycle period were examined in 22 walking decerebrate animals in which one LGS nerve had been cut for 2 to 31 days. The effectiveness of LGS group I afferents declined progressively in the postaxotomy period, beginning with significant decreases at 3 days and ending close to zero effectiveness at 31 days. Large increases in the effectiveness of MG group I afferents occurred 5 days after axotomy, but there was no progressive change from 5 to 31 days. To test whether these changes in effectiveness were localized to sites within the spinal cord, the cord was transected in some decerebrate animals and stepping induced by theadministration of L-DOPA L-3-4 dihydroxyphenylalanine (LDOPA) and Nialamide. The effects of stimulating the MG and/or the LGS group I afferents on the cycle period were reexamined. In all four animals tested, stimulating the axotomized LGS group I afferents had a reduced effectiveness during locomotor activity in both the decerebrate and spinal states, whereas the increased effectiveness of the MG group I afferents was retained after transection of the spinal cord in two of five animals. Different mechanisms may be responsible for the changes in strength of the LGS and MG group I afferent pathways that project onto the rhythm generating sites in the spinal cord. This possibility follows from our observations of a linear relationship between the time after axotomy and decreased effectiveness of LGS group I afferents but no significant relationship between time postaxotomy and increased effectiveness of MG group I afferents; no significant relationship between the decreased effectiveness of LGS group I afferents and the increased effectiveness of MG group I afferents; and, after spinalization, consistent (4/4 cases) preservation of decreased LGS effectiveness but frequent (3/5 cases) loss of increased MG effectiveness.

Group I afferents in nerves innervating the lateral gastrocnemius-soleus (LG-Sol), plantaris (Pl), and vastus lateralis/intermedius (VL/VI) muscles were stimulated during walking in decerebrate cats. The stimulus trains were triggered at a fixed delay following the onset of bursts in the medial gastrocnemius muscle. Stimulation of all three nerves with long stimulus trains (600 ms) prolonged the extensor bursts and delayed the onset of flexor burst activity. LG-Sol nerve stimulation had the strongest effect; often delaying the onset of flex- or burst activity until the stimulus train was ended. By contrast, flexor bursts were usually initiated before the end of the stimulus train to the Pl and VL/VI nerves. The minimum stimulus strength required to increase the cycle period was between 1.3 x threshold and 1.6 x threshold for all three nerves. Simultaneous stimulation of the Pl and VL/VI nerves produced a larger effect on the cycle period than stimulation of either nerve alone. The spatial summation of inputs from knee and ankle muscles suggests that the excitatory action of the group I afferents during the stance phase is distributed to all leg extensor muscles. Stimulation of the group I afferents in extensor nerves generally produced an increase in the amplitude of the heteronymous extensor EMG towards the end of the stance phase. This increase in amplitude occurred even though there were only weak monosynaptic connections between the stimulated afferents and the motoneurones that innervated these heteronymous muscles. This suggests that the excitation was produced via oligosynaptic projections onto the extensor motoneuronal pool. Stimulation with 300 ms trains during the early part of flexion resulted in abrupt termination of the swing phase and reinitiation of the stance phase of the step cycle. The swing phase resumed coincidently with the stimulus offset. Usually, stimulation of two extensor nerves at group I strengths was required to elicit this effect. We were unable to establish the relative contributions of input from the group Ia and group Ib afferents to prolonging the stance phase. However, we consider it likely that group Ib afferents contribute significantly, since their activation has been shown to prolong extensor burst activity in reduced spinal preparations. Thus, our results add support to the hypothesis that unloading of the hindlimb during late stance is a necessary condition for the initiation of the swing phase in walking animals.

1. When a hind leg of a walking cat fails to contact the ground at the end of swing, the limb is rapidly lifted and replaced in an attempt to seek support. In this investigation we tested the hypothesis that one factor in the initiation of this corrective response is the absence of signals from the group I afferents of extensor muscles. 2. Experiments were performed on decerebrate cats walking on a treadmill. The corrective response to loss of ground support occurred when one hind leg stepped into a hole cut into the treadmill belt. Group I afferents in various extensor nerves were stimulated via implanted cuff electrodes when the foot entered the hole. 3. Stimulation of extensor group I afferents suppressed the corrective flexion response. Instead of a flexor burst being generated soon after the foot entered the hole, extensor activity was maintained for a period exceeding the duration of the stimulus trains. The onset of the corrective response occurred at a relatively fixed latency of 70 ms after the end of the short stimulus trains (200-400 ms) provided that the contralateral limb was still in stance phase. For longer stimulus trains (500-1,000 ms) that terminated during or just prior to the swing phase of the contralateral leg, the onset of ipsilateral flexor activity occurred only after the contralateral leg had regained support. 4. We conclude that the absence of signals from group I afferents when a foot fails to contact the ground allows the locomotor rhythm generator to re-initiate a flexor burst to produce the corrective response.(ABSTRACT TRUNCATED AT 250 WORDS)

The amplitude of the Hoffmann reflex (H-reflex) of the human soleus muscle is modulated in a cyclical way during walking. This paper addresses two questions associated with the neural mechanisms that might generate this modulation: (1) Does the amplitude of the H-reflex simply rise and fall as a function of the background excitability of the soleus motoneuron pool? (2) Is the modulation of the H-reflex dependent on events associated with activation of the antagonist muscle? The amplitude of the soleus H-reflex was compared under three conditions: natural walking, walking without activating the tibialis anterior muscle, and walking with activation of the soleus muscle in the swing phase. Human subjects were able to perform these three tasks with minimal training. The results indicated that the soleus H-reflex remained very depressed in the swing phase of walking, even when a voluntary contraction of the soleus muscle was superimposed during this time. Moreover, the presence of tibialis anterior activity had a very minor effect on the amplitude of the soleus H-reflex during walking. It is concluded that modulation of the soleus H-reflex is not simply a reflection of the background excitability of the motoneuron pool, and the modulation is not dependent on activation of the antagonist muscle. Other more powerful mechanisms are acting to modulate the reflex, most likely presynaptic inhibition of the primary afferents.

We used calcium imaging to visualize the spatiotemporal pattern of motoneuron activity during dorsal root-evoked locomotor-like bursting in the lumbosacral spinal cord of the neonatal mouse. Dorsal root stimuli elicited a tonic discharge in motoneurons on which alternating left-right rhythmic discharges were superimposed. Both the tonic and the rhythmic components could be recorded optically from populations of motoneurons labeled with calcium-green dextran. Optical and electrical recordings revealed that rhythmic signals from different parts of the lumbar (L1, L2) and sacral (S1-S3) segments rose, peaked, and decayed in a rostrocaudal sequence. This pattern gave rise to a rostrocaudal "wave" in the activation of motoneurons during each cycle of locomotor-like activity. A similar rostrocaudal delay was observed during episodes of alternation that occurred in the absence of stimulation, suggesting that this delay was not caused by the train of dorsal root stimuli. It is hypothesized that this behavior may simplify the appropriate sequencing of motoneurons during locomotion.

To evaluate magnetic resonance imaging (MRI) in the preoperative localization of abnormal parathyroid glands, we examined 16 patients with primary hyperparathyroidism at initial presentation with MRI and ultrasound of the neck. These studies were analyzed prospectively and compared with the findings at bilateral neck exploration. The surgeon was intentionally blinded to the imaging studies. MRI was accurate in the lateralizing of an abnormal gland in 21 of 32 sides (66 percent). Sensitivity was 65 percent and specificity was 66 percent. Ultrasound was accurate in 19 of 32 sides (59 percent). Sensitivity was 50 percent and specificity was 75 percent. The difference was not statistically significant. We do not believe that MRI is indicated prior to initial exploration in patients with primary hyperparathyroidism.

1. This study examines whether the efficacy of polysynaptic group I excitatory pathways to extensor motoneurons are modified after axotomy of a synergistic nerve. Previously, it has been shown that stimulation of extensor nerves at group I strength can extend the stance phase and delay swing. Stimulation of the lateral gastrocnemius and soleus (LG/S) nerve prolongs stance for the duration of the stimulus train, whereas stimulation of the medial gastrocnemius (MG) nerve moderately increases stance. Our hypothesis was that after axotomy of the LG/S nerve the efficacy of the MG group I input would increase. 2. This idea was tested in 10 adult cats that had their left LG/S nerves axotomized for 3-28 days. On the experimental day the cats were decerebrated and the left (experimental) and right (control) LG/S and MG nerves were stimulated during late stance as the animals were walking on a motorized treadmill. A significant increase in the efficacy of the left MG nerve occurred 5 days after axotomy of the LG/S nerve when compared with the control response. By contrast, the previously cut LG/S nerve showed a reduction in efficacy after 3 days compared with the control limb. 3. Functionally, this plasticity may be an important mechanism by which the strength of the group I pathway is calibrated to different loads on the extensor muscles.

1. In this investigation, we tested the hypothesis that muscle spindle afferents signaling the length of hind-leg flexor muscles are involved in terminating extensor activity and initiating flexion during walking. The hip flexor muscle iliopsoas (IP) and the ankle flexors tibialis anterior (TA) and extensor digitorum longus (EDL) were stretched or vibrated at various phases of the step cycle in spontaneously walking decerebrate cats. Changes in electromyogram amplitude, duration, and timing were then examined. The effects of electrically stimulating group I and II afferents in the nerves to TA and EDL also were examined. 2. Stretch of the individual flexor muscles (IP, TA, or EDL) during the stance phase reduced the duration of extensor activity and promoted the onset of flexor burst activity. The contralateral step cycle also was affected by the stretch, the duration of flexor activity being shortened and extensor activity occurring earlier. Therefore, stretch of the flexor muscles during the stance phase reset the locomotor rhythm to flexion ipsilaterally and extension contralaterally. 3. Results of electrically stimulating the afferents from the TA and EDL muscles suggested that different groups of afferents were responsible for the resetting of the step cycle. Stimulation of the TA nerve reset the locomotor step cycle when the stimulus intensity was in the group II range (2-5 xT). By contrast, stimulation of the EDL nerve generated strong resetting of the step cycle in the range of 1.2-1.4 xT, where primarily the group Ia afferents from the muscle spindles would be activated. 4. Vibration of IP or EDL during stance reduced the duration of the extensor activity by similar amounts to that produced by muscle stretch or by electrical stimulation of EDL at group Ia strengths. This suggests that the group Ia afferents from IP and EDL are capable of resetting the locomotor pattern generator. Vibration of TA did not affect the locomotor rhythm. 5. Stretch of IP or electrical stimulation of TA afferents (5 xT) during the flexion phase did not change the duration of the flexor activity. Stimulation of the EDL nerve at 1.8-5 xT during flexion increased the duration of the flexor activity. In none of our preparations did we observe resetting to extension when the flexor afferents were activated during flexion. 6. We conclude that as the flexor muscles lengthen during the stance phase of gait, their spindle afferents (group Ia afferents for EDL and IP, group II afferents for TA) act to inhibit the spinal center generating extensor activity thus facilitating the initiation of swing.