Somatovesical and vesicovesical excitatory reflexes in urethane-anaesthetized rats

The effect of spinal cord transection on excitatory somato- and vesicovesical micturition reflexes have been investigated in urethane-anaesthetized rats. In adult rats, 3 distinct types of excitatory reflexes to the bladder may be observed: a somatovesical reflex organized at spinal level and two vesicovesical reflexes organized at spinal and supraspinal level, respectively. In agreement with results of lesion experiments (Neurosci. Lett., 8 (1978) 27-33), bladder voiding is abolished following spinal cord transection although both somato- and vesicovesical reflexes may be demonstrated in acute spinal rats. Occurrence of the spinal vesicovesical reflex during the collecting phase of the cystometrogram appears to be inhibited by a supraspinal inhibitory pathway.     

Serial recording of reflexes after feline spinal cord transection

Implanted nerve cuff and muscle electrodes were used to serially record reflexes after spinal cord transection in cat. Recording of reflexes, in response to both sensory nerve and to mixed motor and sensory nerve stimulation, was accomplished through 2 months after cord section. Serial recording of afferent and efferent nerve volleys was achieved as well. Serial reflex changes that follow cord transection are described. Reflex amplitude to sensory nerve stimulation increased in two phases. The first increase was noted between 1 and 4 days after cord transection; the second increase was recorded between 2 and 4 weeks. These observations suggest that at least two neuronal mechanisms with distinct temporal courses mediate the appearance of spinal hyperreflexia. The animal model described may be useful for further study of the neuronal mechanisms which underlie the hyperreflexia of spinal cord injury.     

Intraspinal stimulation for bladder voiding in cats before and after chronic spinal cord injury

The long-term objective of this study is to develop neural prostheses for people with spinal cord injuries who are unable to voluntarily control their bladder. This feasibility study was performed in 22 adult cats. We implanted an array of microelectrodes into locations in the sacral spinal cord that are involved in the control of micturition reflexes. The effect of microelectrode stimulation was studied under light Propofol anesthesia at monthly intervals for up to 14 months. We found that electrical stimulation in the sacral parasympathetic nucleus at S(2) level or in adjacent ventrolateral white matter produced bladder contractions insufficient for inducing voiding, while stimulation at or immediately dorsal to the dorsal gray commissure at S(1) level produced strong (at least 20 mmHg) bladder contractions as well as strong (at least 40 mm Hg) external urethral sphincter relaxation, resulting in bladder voiding in 14 animals. In a subset of three animals, spinal cord transection was performed. For several months after the transection, intraspinal stimulation continued to be similarly or even more effective in inducing the bladder voiding as before the transection. We speculate that in the absence of the supraspinal connections, the plasticity in the local spinal circuitry played a role in the improved responsiveness to intraspinal stimulation.     

Effect of spinal cord injury and of intrathecal baclofen on brainstem reflexes

Reorganization of neural circuits within the central nervous system following injury appears to be a means of compensatory mechanism for loss of function. Reorganization following spinal cord injury is known to evoke changes at the cortical and spinal cord levels. Recent studies, however, provide evidence of enhanced brainstem reflexes and alterations in excitatory and inhibitory interneuronal brainstem circuits, suggesting that reorganization following spinal cord injury occurs also at the brainstem level. Reversal of these changes by continuous intrathecal baclofen infusion to normal levels or beyond indicates strong GABAergic involvement. Rapid changes in the blink reflex and its prepulse inhibition following intrathecal baclofen bolus application that parallel clinical changes in muscle hypertonia suggest a muscle tone regulating effect of baclofen at the brainstem level. Enhanced brainstem reflexes in spinal cord injury patients may be the consequence of decreased GABA-mediated inhibition and/or strengthening of facilitatory connections due to either direct or indirect plastic changes occurring at the brainstem level. Modulation of brainstem reflexes by baclofen may foster the understanding of pathophysiological mechanisms underlying diseases with increased brainstem activity. Rehabilitation after central nervous system injury will always be a challenge, but understanding the mechanisms of reorganization of undamaged neural pathways may help to develop better strategies for enhancing neuronal plasticity and for implementing neuronal reorganization into carefully planned therapy.     

Plasticity of urinary bladder reflexes evoked by stimulation of pudendal afferent nerves after chronic spinal cord injury in cats

Bladder reflexes evoked by stimulation of pudendal afferent nerves (PudA-to-Bladder reflex) were studied in normal and chronic spinal cord injured (SCI) adult cats to examine the reflex plasticity. Physiological activation of pudendal afferent nerves by tactile stimulation of the perigenital skin elicits an inhibitory PudA-to-Bladder reflex in normal cats, but activates an excitatory reflex in chronic SCI cats. However, in both normal and chronic SCI cats electrical stimulation applied to the perigenital skin or directly to the pudendal nerve induces either inhibitory or excitatory PudA-to-Bladder reflexes depending on stimulation frequency. An inhibitory response occurs at 3–10 Hz stimulation, but becomes excitatory at 20–30 Hz. The inhibitory reflex activated by electrical stimulation significantly (P < 0.05) increases the bladder capacity to about 180% of control capacity in normal and chronic SCI cats. The excitatory reflex significantly (P < 0.05) reduces bladder capacity to about 40% of control capacity in chronic SCI cats, but does not change bladder capacity in normal cats. Electrical stimulation of pudendal afferent nerves during slow bladder filling elicits a large amplitude bladder contraction comparable to the contraction induced by distension alone. A bladder volume about 60% of bladder capacity was required to elicit this excitatory reflex in normal cats; however, in chronic SCI cats a volume less than 20% of bladder capacity was sufficient to unmask an excitatory response. This study revealed the co-existence of both inhibitory and excitatory PudA-to-Bladder reflex pathways in cats before and after chronic SCI. However our data combined with published electrophysiological data strongly indicates that the spinal circuitry for both the excitatory and inhibitory PudA-to-Bladder reflexes undergoes a marked reorganization after SCI.     

Plasticity of interneuronal networks of the functionally isolated human spinal cord

The loss of walking after human spinal cord injury has been attributed to the dominance of supraspinal over spinal mechanisms. The evidence for central pattern generation in humans is limited due to the inability to conclusively isolate the circuitry from descending and afferent input. However, studying individuals following spinal cord injury with no detectable influence on spinal networks from supraspinal centers can provide insight to their interaction with afferent input. The focus of this article is on the interaction of sensory input with human spinal networks in the generation of locomotor patterns. The functionally isolated human spinal cord has the capacity to generate locomotor patterns with appropriate afferent input. Locomotor Training is a rehabilitative strategy that has evolved from animal and humans studies focused on the neural plasticity of the spinal cord and has been successful for many people with acute and chronic incomplete spinal cord injury. However, even those individuals with clinically complete spinal cord injury that generate appropriate locomotor patterns during stepping with assistance on a treadmill with body weight support cannot sustain overground walking. This suggests that although a significant control of locomotion can occur at the level of spinal interneuronal networks the level of sustainable excitability of these circuits is still compromised. Future studies should focus on approaches to increase the central state of excitability and may include neural repair strategies, pharmacological interventions or epidural stimulation in combination with Locomotor Training.     

Role of peripheral afferents and spinal reflexes in normal and impaired human locomotion

For many years, electrophysiological investigations of locomotion were restricted to animals, largely the cat. They concentrated on and emphasized the role of spinal interneuronal networks responsible for the generation of the locomotor pattern. Following the introduction of perturbation impulses and electrical nerve stimulation during stance and gait, information became increasingly available concerning the role of the reflex systems involved in the regulation of gait, their afferent pathways and their control by supraspinal motor centres. During gait monosynaptic stretch reflexes are inhibited. From a knowledge of the behaviour of the cerebral potentials evoked during stance and gait, it can be deduced that during gait the signals of group I afferents are blocked at both segmental and supraspinal levels. Polysynaptic reflex responses are mainly responsible for the compensation of perturbations introduced during gait. They are most probably mediated by group II afferents via a spinal pathway closely connected with the spinal locomotor centres. The functioning of these responses depends on an intact supraspinal control. They are suggested to be incorporated in a more complex e.m.g. pattern mainly determined by central mechanisms. In contrast to the gait condition, segmental stretch reflex activity does contribute to activation of extensor muscles of the leg during fast movements, such as running and hopping. In children at an early stage in the development of gait (around 1 to 2 years of age), as well as in patients with spastic paresis, the polysynaptic reflex responses are reduced or absent, and isolated monosynaptic reflex potentials are present. This suggests a reciprocal modulation of mono- and polysynaptic reflex mechanisms, both being dependant on supraspinal control. When this control is either not yet matured (small children) or impaired (spastic paresis), inhibition of monosynaptic stretch reflexes is absent and associated with a reduced facilitation of polysynaptic spinal reflexes. In spastic muscle hypertonia, the tension developed at the Achilles tendon during gait cannot be explained by gastrocnemius activation alone. In patients with spastic hemiparesis gastrocnemius e.m.g. activity is reduced in the spastic leg as compared to the unaffected one. It can be concluded that the paretic muscle undergoes changes in its mechanical properties, secondary to the supraspinal lesion, which results in the development of spastic muscle hypertonia.(ABSTRACT TRUNCATED AT 400 WORDS)     

Changes in urinary bladder neurotrophic factor mRNA and NGF protein following urinary bladder dysfunction

Spinal cord injury and cyclophosphamide-induced cystitis dramatically alter lower urinary tract function and produce neurochemical, electrophysiological, and anatomical changes that may contribute to reorganization of the micturition reflex. Mechanisms underlying this neural plasticity may involve alterations in neurotrophic factors in the urinary bladder. These studies have determined neurotrophic factors in the urinary bladder that may contribute to reorganization of the micturition reflex following cystitis or spinal cord injury. A ribonuclease protection assay was used to measure changes in urinary bladder neurotrophic factor mRNA (betaNGF, BDNF, GDNF, CNTF, NT-3, and NT-4) following spinal cord injury (acute/chronic) or cyclophosphamide-induced cystitis (acute/chronic). The correlation between urinary bladder nerve growth factor mRNA and nerve growth factor protein expression was also determined. Each experimental paradigm resulted in significant (P 相似文献   

Neural organization of the viscero-cardiac reflexes

The reflex responses evoked in the postganglionic nerves to the heart were tested in chloralose-anaesthetized cats. Electrical stimulation of the A delta afferent fibres from the left inferior cardiac nerve evoked spinal and supraspinal reflex responses with the onset latencies of 36 ms and 77 ms respectively. The most effective stimulus was a train of 3-4 electrical pulses with the intratrain frequency of 200-300 Hz. Electrical stimulation of the high threshold afferent fibres (C-fibres) from the left inferior cardiac nerve evoked the reflex response with the onset latency of 200 ms. The C-reflex was present in intact animals and disappeared after spinalization. The most effective stimulus to evoke this reflex was a train of electrical pulses delivered at a frequency of 1-2 Hz with an intratrain frequency of 20-30 Hz. The most prominent property of the C-reflex was its marked increase after prolonged repeated electrical stimulation. We conclude that: (1) viscero-cardiac sympathetic reflexes may be organized at the spinal and supraspinal level; (2) viscero-cardiac sympathetic reflexes evoked by stimulation of the A delta and C afferent fibres from the left inferior cardiac nerve have different central organization.     

Transplants as a therapy after spinal cord injury

This review describes shortly phenomena that take place in different parts of central nervous system (CNS) after the spinal cord injury: 1/ due to axotomy many of neurones present outside the cavity of lesion (even those of supraspinal origin) can atrophy or die as an effect of necrosis or apoptosis; 2/ at the injury site itself, the primary and secondary effects lead to increased cell loss and the scar or cyst formation that are the mechanical barrier for regenerating axons; 3/ due to abolished conduction across the injury site the spinal cord circuitry below the lesion is deprived of supraspinal inputs. Then this review presents the new therapeutic strategies that were developed recently to obtain at least partial recovery of motor functions after spinal cord injury. The cell body can be rescued by applying various factors that increase intrinsic neural repair (e.g. neurotrophins or anti-apoptotic agents). To enhance the axonal regrowth through the lesion cavity, the scar and cyst formation can be reduced by constructing the bridges using e.g. the Schwann cells, fetal tissue, stem cells, olfactory ensheating glial cells, or by application of macrophages. To induce partial restoration of some functions that are controlled by neural circuitry below the lesion the various methods for enhancing the plasticity in segmental circuitry were developed (e.g. rehabilitation by locomotor training or intraspinal transplantation of monoaminergic cells). As a consequence of the great unpredictability of effects obtained after injury at different parts of the spinal cord the various strategies for repair need to be coordinated for optimal recovery.     

Targeting Lumbar Spinal Neural Circuitry by Epidural Stimulation to Restore Motor Function After Spinal Cord Injury

Epidural spinal cord stimulation has a long history of application for improving motor control in spinal cord injury. This review focuses on its resurgence following the progress made in understanding the underlying neurophysiological mechanisms and on recent reports of its augmentative effects upon otherwise subfunctional volitional motor control. Early work revealed that the spinal circuitry involved in lower-limb motor control can be accessed by stimulating through electrodes placed epidurally over the posterior aspect of the lumbar spinal cord below a paralyzing injury. Current understanding is that such stimulation activates large-to-medium-diameter sensory fibers within the posterior roots. Those fibers then trans-synaptically activate various spinal reflex circuits and plurisegmentally organized interneuronal networks that control more complex contraction and relaxation patterns involving multiple muscles. The induced change in responsiveness of this spinal motor circuitry to any residual supraspinal input via clinically silent translesional neural connections that have survived the injury may be a likely explanation for rudimentary volitional control enabled by epidural stimulation in otherwise paralyzed muscles. Technological developments that allow dynamic control of stimulation parameters and the potential for activity-dependent beneficial plasticity may further unveil the remarkable capacity of spinal motor processing that remains even after severe spinal cord injuries.     

Suppression of the micturition reflex in urethane-anesthetized rats by intracerebroventricular injection of WAY100635, a 5-HT(1A) receptor antagonist

The influence of supraspinal 5-HT_1A receptors on reflex bladder activity was evaluated in anesthetized rats by studying the effects of intracerebroventricular (i.c.v.) administration of WAY100635 (1–100 μg), a selective 5-HT_1A receptor antagonist. The drug dose-dependently decreased the frequency and/or amplitude of isovolumetric reflex bladder contractions. Low doses (1–10 μg) increased the interval between contractions but only slightly reduced the amplitude of the contractions. However, 100 μg of WAY100635 elicited an initial complete block of bladder reflexes followed by a recovery period lasting 10–15 min during which the frequency of reflex contractions was normal but the amplitude was markedly suppressed by 70–80%. Mesulergine (0.1 mg/kg, i.v.), a 5-HT_2C antagonist, which transiently eliminated bladder activity in some rats (five of 11), blocked the inhibitory effect of WAY100635 (10 or 100 μg, i.c.v.) in only two of six rats. Our data coupled with the results of previous studies suggest that spinal and supraspinal 5-HT_1A receptors are involved in multiple inhibitory mechanisms controlling the spinobulbospinal micturition reflex pathway. The regulation of the frequency of bladder reflexes is presumably mediated by a suppression of afferent input to the micturition switching circuitry in the pons, whereas the regulation of bladder contraction amplitude may be related to an inhibition of the output from the pons to the parasympathetic nucleus in the spinal cord.     

Stimulation of spinal serotonergic receptors facilitates seminal emission and suppresses penile erectile reflexes

Penile erection and ejaculation are produced by spinal reflexes subject to tonic control from the brain. This study examines the possible involvement of serotonergic transmission in the supraspinal modulation of such reflexes. The effects of two drugs which facilitate serotonergic transmission by different mechanisms, namely the direct receptor agonist, 5-methoxy-N,N'-dimethyltryptamine (5-MeODMT), and the reuptake inhibitor, zimelidine, were compared in intact and spinal rats. Results show that serotonergic stimulation in intact rats by either drug produces a dose-related increase in the incidence of seminal emission as well as a definite decrease of the display of erectile responses. In the spinal animals 5-MeODMT treatment reproduced both effects. By contrast, zimelidine, which needs functional nerve endings to exert its agonistic action, was ineffective in the spinal rats. This is interpreted to exclude a peripheral mechanism for the effects of the serotonin agonists on penile reflexes of intact animals and makes a strong case for a spinal site of action. We postulate the existence of serotonergic receptors located in the lower segments of the spinal cord which, when stimulated, trigger seminal emission and suppress erection.     

Autonomic dysreflexia: a cardiovascular disorder following spinal cord injury

Autonomic dysreflexia(AD) is a serious cardiovascular disorder in patients with spinal cord injury(SCI). The primary underlying cause of AD is loss of supraspinal control over sympathetic preganglionic neurons(SPNs) caudal to the injury, which renders the SPNs hyper-responsive to stimulation. Central maladaptive plasticity, including C-fiber sprouting and propriospinal fiber proliferation exaggerates noxious afferent transmission to the SPNs, causing them to release massive sympathetic discharges that result in severe hypertensive episodes. In parallel, upregulated peripheral vascular sensitivity following SCI exacerbates the hypertensive response by augmenting gastric and pelvic vasoconstriction. Currently, the majority of clinically employed treatments for AD involve anti-hypertensive medications and Botox injections to the bladder. Although these approaches mitigate the severity of AD, they only yield transient effects and target the effector organs, rather than addressing the primary issue of central sympathetic dysregulation. As such, strategies that aim to restore supraspinal reinnervation of SPNs to improve cardiovascular sympathetic regulation are likely more effective for AD. Recent pre-clinical investigations show that cell transplantation therapy is efficacious in reestablishing spinal sympathetic connections and improving hemodynamic performance, which holds promise as a potential therapeutic approach.     

Repetetive hindlimb movement using intermittent adaptive neuromuscular electrical stimulation in an incomplete spinal cord injury rodent model

The long-term objective of this work is to understand the mechanisms by which electrical stimulation based movement therapies may harness neural plasticity to accelerate and enhance sensorimotor recovery after incomplete spinal cord injury (iSCI). An adaptive neuromuscular electrical stimulation (aNMES) paradigm was implemented in adult Long Evans rats with thoracic contusion injury (T8 vertebral level, 155 ± 2 Kdyne). In lengthy sessions with lightly anesthetized animals, hip flexor and extensor muscles were stimulated using an aNMES control system in order to generate desired hip movements. The aNMES control system, which used a pattern generator/pattern shaper structure, adjusted pulse amplitude to modulate muscle force in order to control hip movement. An intermittent stimulation paradigm was used (5-cycles/set; 20-second rest between sets; 100 sets). In each cycle, hip rotation caused the foot plantar surface to contact a stationary brush for appropriately timed cutaneous input. Sessions were repeated over several days while the animals recovered from injury. Results indicated that aNMES automatically and reliably tracked the desired hip trajectory with low error and maintained range of motion with only gradual increase in stimulation during the long sessions. Intermittent aNMES thus accounted for the numerous factors that can influence the response to NMES: electrode stability, excitability of spinal neural circuitry, non-linear muscle recruitment, fatigue, spinal reflexes due to cutaneous input, and the endogenous recovery of the animals. This novel aNMES application in the iSCI rodent model can thus be used in chronic stimulation studies to investigate the mechanisms of neuroplasticity targeted by NMES-based repetitive movement therapy.     

Electrical stimulation for the treatment of bladder dysfunction: current status and future possibilities

Electrical stimulation of peripheral nerves can be used to cause muscle contraction, to activate reflexes, and to modulate some functions of the central nervous system (neuromodulation). If applied to the spinal cord or nerves controlling the lower urinary tract, electrical stimulation can produce bladder or sphincter contraction, produce micturition, and can be applied as a medical treatment in cases of incontinence and urinary retention. This article first reviews the history of electrical stimulation applied for treatment of bladder dysfunction and then focuses on the implantable Finetech-Brindley stimulator to produce bladder emptying, and on external and implantable neuromodulation systems for treatment of incontinence. We conclude by summarizing some recent research efforts including: (a) combined sacral posterior and anterior sacral root stimulator implant (SPARSI), (b) selective stimulation of nerve fibers for selective detrusor activation by sacral ventral root stimulation, (c) microstimulation of the spinal cord, and (d) a newly proposed closed-loop bladder neuroprosthesis to treat incontinence caused by bladder overactivity.     

Flexor reflexes in chronic spinal cord injury triggered by imposed ankle rotation

Hypersensitivity of the flexor reflexes to input from force-sensitive muscle afferents may contribute to the prevalence and severity of muscle spasms in patients with spinal cord injuries. In the present study, we triggered flexor reflexes with constant-velocity ankle movements into end-range dorsiflexion and plantarflexion positions in 8 individuals with spinal cord injuries. We found that all 8 subjects had coordinated increases in flexion torque at the hip and ankle following externally imposed plantarflexion movements at the ankle. In addition, end-range dorsiflexion movements also triggered flexor reflexes in 3 subjects, although greater loads were required to trigger such reflexes using dorsiflexion movements (compared to plantarflexion movements). These three-joint reflex torque patterns triggered by ankle movement were broadly comparable to flexion withdrawal responses elicited by electrocutaneous stimuli applied to a toe, although the amplitude of the torque response was generally lower. We conclude that excitation of muscle and joint-related afferents induced by end-range movements may be responsible for exaggerated flexion reflex responses in spinal cord injury.     

Descending modulation of monosynaptic reflexes after traumatic injury of the cat spinal cord

Studies of the descending modulation of monosynaptic reflex responses have revealed that electrical stimulation of dorsolateral, ventrolateral and ventral funiculi in C2 facilitated and suppressed test responses of intact animals, but evoked only suppression of spinal reflexes after injury of the spinal cord. The obtained data have shown that descending pathways which transmit facilitatory influences are more vulnerable to injury of the spinal cord.     

Getting the spinal cord to think for itself

Despite the interruption in communication between the brain and lower centers by spinal cord injury, many of the neurons engaged in generating locomotion survive. Several strategies have been used to activate spinal cord circuitry independent of the higher centers, including direct electrical stimulation, pharmacological agents, and training programs that involve moving the legs through the motions of walking. Ambulatory leg movements are achieved by these interventions, leading to substantial functional improvements in the subset of patients with incomplete spinal cord injury. The neurobiological basis for these phenomena likely involves activity-dependent reconfiguration of synaptic connections within the spinal cord. Fostering this process may lead to further benefits for individuals with spinal cord injury.     

Somato-vesical reflexes in chronic spinal cats

The effects of afferent volleys in hindlimb cutaneous and muscle nerves on vesical tone and contractility and on the discharges in pelvic nerves to the bladder were measured in anesthetized CNS-intact and 2-19 months chronic spinal cats. In chronic spinal cats volleys in group III and IV fibers increased the tone of the quiet, empty bladder (excitatory somato-vesical reflex). The same volleys inhibited the slow, large, rhythmic micturition contractions of the expanded bladder (inhibitory somato-vesical reflex). In CNS intact cats single or short tetanic volleys induced a reflex discharge in pelvic vesical nerve branches with 3 distinct components. These reflexes could be observed during micturition contractions, not markedly between the contractions or when the bladder was empty and quiet. The latencies of the 3 components were 90, 320 and 770 ms, respectively. The two early components (AI- and A2-reflex) were evoked by volleys in group II and III hindlimb afferents. The late component (C-reflex) was induced by group IV volleys. In chronic spinal cats a group II and III-induced A-reflex (latency 90 ms) and a group IV-induced C-reflex (latency 340 ms) were observed. The central pathways and the physiological significance of the various somato-vesical reflexes are discussed.