Utilizing a complete transection spinal cord injury (SCI) model at the fourth thoracic vertebral level in adult rats, we evaluated whether blocking noxious stimuli below the injury diminishes abnormal somatic and autonomic motor reflexes, manifested in muscular spasticity and hypertensive autonomic dysreflexia, respectively. Gabapentin (GBP) is well-tolerated and currently used to manage neuropathic pain in the SCI population; evidence suggests it acts to decrease presynaptic glutamate release. Since clinical evidence indicates that GBP may suppress muscular spasticity in the chronic SCI population, we hypothesized that preventing neurotransmission of noxious stimuli with GBP eliminates a critical physiological link to these distinct, debilitating SCI-induced secondary impairments.
Behavioural assessments of tail muscle spasticity and mean arterial blood pressure responses to noxious somatic and/or visceral stimulation were used to test the effects of GBP on these abnormal reflexes.
We employed femoral artery catheterization and radio-telemetric approaches to monitor blood pressure alterations in response to noxious colorectal distension (CRD) weeks after complete SCI.
At 2-3 weeks post-SCI, acute GBP administration (50 mg/kg, i.p.) significantly attenuated both autonomic dysreflexia and tail spasticity induced by noxious stimuli compared to saline-treated cohorts.
These results demonstrate, for the first time, that a single pharmacological intervention, GBP, can effectively attenuate the manifestation of both muscular spasticity and autonomic dysreflexia in response to noxious stimuli.
blood pressure; hypertension; pain; spasms; hyper-reflexia; Neurontin; spinal reflex
Complete thoracic (T) spinal cord injury (SCI) above the T6 level typically results in autonomic dysreflexia, an abnormal hypertensive condition commonly triggered by nociceptive stimuli below the level of SCI. Over-expression of nerve growth factor in the lumbosacral spinal cord induces profuse sprouting of nociceptive pelvic visceral afferent fibers that correlates with increased hypertension in response to noxious colorectal distension. After complete T4 SCI, we evaluated the plasticity of propriospinal neurons conveying visceral input rostrally to thoracic sympathetic preganglionic neurons. The anterograde tracer biotinylated dextran amine (BDA) was injected into the lumbosacral dorsal gray commissure (DGC) of injured/non-transected rats immediately after injury (acute) or 2 weeks later (delayed). At 1 or 2 weeks after delayed or acute injections, respectively, a higher density (p<0.05) of BDA+ fibers was found in thoracic dorsal gray matter of injured versus non-transected spinal cords. For corroboration, fast blue (FB) or cholera toxin subunit beta (CTb) was injected into the T9 dorsal horns 2 weeks post-injury/non-transection. After 1 week transport, more retrogradely-labeled (p<0.05) DGC propriospinal neurons (T13-S1) were quantified in injured versus non-transected cords. We also monitored immediate early gene, c-fos, expression following colorectal distension and found increased (p<0.01) c-Fos+ cell numbers throughout the DGC after injury. Collectively, these results imply that, in conjunction with local primary afferent fiber plasticity, injury-induced sprouting of DGC neurons may be a key constituent in relaying visceral sensory input to sympathetic preganglionic neurons that elicit autonomic dysreflexia after high thoracic SCI.
dorsal gray commissure; dorsal commissural nucleus; neuronal tracers; c-Fos; hypertension; stereology; colorectal distension
Spinal cord injuries above mid-thoracic levels can lead to a potentially life-threatening hypertensive condition termed autonomic dysreflexia that is often triggered by distension of pelvic viscera (bladder or bowel). This syndrome is characterized by episodic hypertension due to sudden, massive discharge of sympathetic preganglionic neurons in the thoracolumbar spinal cord. This hypertension is usually accompanied by bradycardia, particularly if the injury is caudal to the 2nd to 4th thoracic spinal segments. The development of autonomic dysreflexia is correlated with aberrant sprouting of peptidergic afferent fibers into the spinal cord below the injury. In particular, sprouting of nerve growth factor-responsive afferent fibers has been shown to have a major influence on dysreflexia, perhaps by amplifying the activation of disinhibited sympathetic neurons. Using a model of noxious bowel distension after complete thoracic spinal transection at the 4th thoracic segment in rats, we selectively altered C-fiber sprouting, at specified spinal levels caudal to the injury, with microinjections of adenovirus encoding the growth-promoting nerve growth factor or the growth-inhibitory semaphorin 3A. This was followed by assessment of physiological responses to colorectal distension and subsequent histology. Additionally, anterograde tract tracers were injected into the lumbosacral region to compare the extent of labeled propriospinal rostral projections in uninjured cords to those incords after complete 4th thoracic transection. In summary, over-expression of chemorepulsive semaphorin 3A impeded C-fiber sprouting in lumbosacral segments and mitigated hypertensive autonomic dysreflexia, whereas the opposite results were obtained with nerve growth factor over-expression. Furthermore, compared to naïve rats there were significantly more labeled lumbosacral propriospinal projections rostrally after thoracic injury. Collectively, our findings suggest that distension of pelvic viscera increases the excitation of expanded afferent terminals in the disinhibited lumbosacral spinal cord. This, in turn, triggers excitation and sprouting of local propriospinal neurons to relay visceral sensory stimuli and amplify the activation of sympathetic preganglionic neurons in the thoracolumbar cord, to enhance transmission in the spinal viscero-sympathetic reflex pathway. These responses are manifested as autonomic dysreflexia.
nerve growth factor; semaphorin3A; sprouting; sympathetic; neurotrophin; propriospinal; gene therapy
OBJECTIVES AND METHODS: To assess the impairment of supraspinal control over spinal sympathetic centres and the occurrence of autonomic dysreflexia in patients with spinal cord injury. Autonomic dysreflexia is caused by the disconnection of spinal sympathetic centres from supraspinal control and is characterised by paroxysmal hypertensive episodes caused by non-specific stimuli below the level of the lesion. Therefore, patients with spinal cord injury were examined clinically and by different techniques to assess the occurrence of autonomic dysreflexia and to relate disturbances of the sympathetic nervous system to episodes of autonomic dysreflexia. RESULTS: None of the paraplegic patients, but 59% (13/22) of tetraplegic patients (91% of the complete, 27% of the incomplete patients) presented signs of autonomic dysreflexia during urodynamic examination. Only 62% of the tetraplegic patients complained about symptoms of autonomic dysreflexia. Pathological sympathetic skin responses (SSRs) of the hands were related to signs of autonomic dysreflexia in 93% of cases. No patient with preserved SSR potentials of the hands and feet showed signs of autonomic dysreflexia, either clinically or during urodynamic examination. Ambulatory blood pressure measurements (ABPMs) indicated a loss of circadian blood pressure rhythm (sympathetic control) but preserved heart rate rhythm (parasympathetic regulation) only in patients with complete tetraplegia. Pathological ABPM recordings were seen in 70% of patients with symptoms of autonomic dysreflexia. CONCLUSIONS: The urodynamic examination was more sensitive in indicating signs of autonomic dysreflexia in patients with spinal cord injury, whereas SSR allowed the assessment of the degree of disconnection of the sympathetic spinal centres from supraspinal control. Using ABPM recordings the occurrence of episodes of autonomic dysreflexia over 24 hours and the effectiveness of therapeutical treatment can be assessed.
Autonomic dysreflexia is a potentially life-threatening hypertensive syndrome following high thoracic (T) spinal cord injury (SCI). It is commonly triggered by noxious pelvic stimuli below the injury site that correlates with increased sprouting of primary afferent C-fibers into the lumbosacral spinal cord. We have recently demonstrated that injury-induced plasticity of lumbosacral propriospinal neurons, which relay pelvic visceral sensations to thoracolumbar sympathetic preganglionic neurons, is also correlated with the development of this syndrome. To determine the phenotype of pelvic afferent fiber sprouts after SCI, cholera toxin subunit beta (CTb) was injected into the distal colon 2 weeks post T4 transection/sham to label colonic visceral afferents. After 1 week transport, the lumbosacral spinal cords were cryosectioned and immunohistochemically stained for CTb, the nociceptive-specific marker calcitonin gene-related peptide (CGRP), and the myelinated fiber marker RT97. Quantitative analysis showed that the density of CGRP+ afferent fibers was significantly increased in the L6/S1 dorsal horns of T4-transected versus sham rats, whereas RT97+ afferent fiber density showed no change. Importantly, CTb-labeled pelvic afferent fibers were co-localized with CGRP+ fibers, but not with RT97+ fibers. These results suggest that the sprouting of unmyelinated nociceptive pelvic afferents following high thoracic SCI, but not myelinated fibers, contributes to hypertensive autonomic dysreflexia induced by pelvic visceral pain.
distal colon; cholera toxin subunit beta; pelvic primary afferent; neuronal plasticity
Autonomic dysreflexia (AD), a potentially dangerous complication of high-level spinal cord injury (SCI) characterized by exaggerated activation of spinal autonomic (sympathetic) reflexes, can cause pulmonary embolism, stroke, and, in severe cases, death. People with high-level SCI also are immune compromised, rendering them more susceptible to infectious morbidity and mortality. The mechanisms underlying postinjury immune suppression are not known. Data presented herein indicate that AD causes immune suppression. Using in vivo telemetry, we show that AD develops spontaneously in SCI mice with the frequency of dysreflexic episodes increasing as a function of time postinjury. As the frequency of AD increases, there is a corresponding increase in splenic leucopenia and immune suppression. Experimental activation of spinal sympathetic reflexes in SCI mice (e.g., via colorectal distension) elicits AD and exacerbates immune suppression via a mechanism that involves aberrant accumulation of norepinephrine and glucocorticoids. Reversal of postinjury immune suppression in SCI mice can be achieved by pharmacological inhibition of receptors for norepinephrine and glucocorticoids during the onset and progression of AD. In a human subject with C5 SCI, stimulating the micturition reflex caused AD with exaggerated catecholamine release and impaired immune function, thus confirming the relevance of the mouse data. These data implicate AD as a cause of secondary immune deficiency after SCI and reveal novel therapeutic targets for overcoming infectious complications that arise due to deficits in immune function.
Severe spinal cord injuries above mid-thoracic levels can lead to a potentially life-threatening hypertensive condition termed autonomic dysreflexia that is often triggered by painful distension of pelvic viscera (bladder or bowel) and consequent sensory fiber activation, including nociceptive C-fibers. Interruption of tonically active medullo-spinal pathways after injury causes disinhibition of thoracolumbar sympathetic preganglionic neurons, and intraspinal sprouting of nerve growth factor (NGF)-responsive primary afferent fibers is thought to contribute to their hyperactivity. We investigated spinal levels that are critical for eliciting autonomic dysreflexia using a model of noxious colorectal distension (CRD) after complete spinal transection at the 4th thoracic segment in rats. Post-traumatic sprouting of calcitonin gene-related peptide (CGRP)-immunoreactive primary afferent fibers was selectively altered at specific spinal levels caudal to the injury with bilateral microinjections of adenovirus encoding the growth-promoting NGF or growth-inhibitory semaphorin 3A (Sema3a) compared to control green fluorescent protein (GFP). Two weeks later, cardio-physiological responses to CRD were assessed among treatment groups prior to histological analysis of afferent fiber density at the injection sites. Dysreflexic hypertension was significantly higher with NGF over-expression in lumboscral segments compared to GFP, whereas similar over-expression of Sema3a significantly reduced noxious CRD-evoked hypertension. Quantitative analysis of CGRP immunostaining in the spinal dorsal horns showed a significant correlation between the extent of fiber sprouting into the spinal segments injected and the severity of autonomic dysreflexia. These results demonstrate that site-directed genetic manipulation of axon guidance molecules after complete spinal cord injury can alter endogenous circuitry in order to modulate plasticity-induced autonomic pathophysiology.
nerve growth factor; semaphorin 3A; sprouting; sympathetic; neurotrophin
The aim of this article is to analyze the vascular dysfunctions occurring after spinal cord injury (SCI). Vascular dysfunctions are common complications of SCI. Cardiovascular disturbances are the leading causes of morbidity and mortality in both acute and chronic stages of SCI.
Neuroanatomy and physiology of autonomic nervous system, sympathetic and parasympathetic, is reviewed.
SCI implies disruption of descendent pathways from central centers to spinal sympathetic neurons, originating in intermediolateral nuclei of T1–L2 cord segments. Loss of supraspinal control over sympathetic nervous system results in reduced overall sympathetic activity below the level of injury and unopposed parasympathetic outflow through intact vagal nerve.
SCI associates significant vascular dysfunction. Spinal shock occurs during the acute phase following SCI and it is a transitory suspension of function and reflexes below the level of the injury. Neurogenic shock, part of spinal shock, consists of severe arterial hypotension and bradycardia. Autonomic dysreflexia appears during the chronic phase, after spinal shock resolution, and it is a life–threatening syndrome of massive imbalanced reflex sympathetic discharge occurring in patients with SCI above the splanchnic sympathetic outflow (T5–T6). Arterial hypotension with orthostatic hypotension occurs in both acute and chronic phases. The etiology is multifactorial. We described a few factors influencing the orthostatic hypotension occurrence in SCI: sympathetic nervous system dysfunction, low plasma catecholamine levels, rennin–angiotensin–aldosterone activity, peripheral alpha–adrenoceptor hyperresponsiveness, impaired function of baroreceptors, hyponatremia and low plasmatic volume, cardiovascular deconditioning, morphologic changes in sympathetic neurons, plasticity within spinal circuits, and motor deficit leading to loss of skeletal muscle pumping activity. Additional associated cardiovascular concerns in SCI, such as deep vein thrombosis and long–term risk for coronary heart disease and systemic atherosclerosis are also described.
Proper prophylaxis, including non–pharmacologic and pharmacological strategies, diminishes the occurrence of the vascular dysfunction following SCI. Each vascular disturbance requires a specific treatment.
spinal shock; neurogenic shock; orthostatic hypotension; autonomic dysreflexia; deep vein thrombosis; coronary heart disease
Objectives: The sympathetic skin response (SSR) is a technique to assess the sympathetic cholinergic pathways, and it can be used to study the central sympathetic pathways in spinal cord injury (SCI). This study investigated the capacity of the isolated spinal cord to generate an SSR, and determined the relation between SSR, levels of spinal cord lesion, and supraspinal connections.
Methods: Palmar and plantar SSR to peripheral nerve electrical stimulation (median or supraorbital nerve above the lesion, and peroneal nerve below the lesion) were recorded in 29 patients with SCI at various neurological levels and in 10 healthy control subjects.
Results: In complete SCI at any neurological level, SSR was absent below the lesion. Palmar SSR to median nerve stimuli was absent in complete SCI with level of lesion above T6. Plantar SSR was absent in all patients with complete SCI at the cervical and thoracic level. In incomplete SCI, the occurrence of SSR was dependent on the preservation of supraspinal connections. For all stimulated nerves, there was no difference between recording from ipsilateral and contralateral limbs.
Conclusions: No evidence was found to support the hypothesis that the spinal cord isolated from the brain stem could generate an SSR. The results indicate that supraspinal connections are necessary for the SSR, together with integrity of central sympathetic pathways of the upper thoracic segments for palmar SSR, and possibly all thoracic segments for plantar SSR.
Two of the most prevalent secondary complications following spinal cord injury (SCI), besides loss of function and/or sensation below the level of injury, are uncontrolled muscle spasticity and hypertensive autonomic dysreflexia. Despite the desires of the SCI community, there have been few advances in the treatment and/or management of these fundamental impediments to the quality of life associated with chronic SCI. Therefore, the purpose of this review is to focus on current drug treatment strategies that alleviate symptoms of spasticity and autonomic dysfunction. Subsequently, looking ahead, we discuss whether individuals suffering from autonomic dysreflexia and/or muscle spasms can take certain compounds that specifically and rapidly block the neurotransmission of pain into the injured spinal cord to get rapid relief for both aberrant reflexes for which painful stimuli below the level of SCI are common precipitants.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-011-0025-5) contains supplementary material, which is available to authorized users.
Spasms; hypertension; bradycardia; pharmacological; spinal cord injury; clinical interventions
The baroreceptor reflex buffers autonomic changes by decreasing sympathetic activity and increasing vagal activity in response to blood pressure elevations, and by the reverse actions when the blood pressure falls. Because of the many bidirectional interactions of pain and autonomic function, we investigated the effect of painful nerve injury by spinal nerve ligation (SNL) on heart rate (HR), blood pressure (BP) and their regulation by the baroreceptor reflex. Rats receiving SNL were separated into either a hyperalgesic group that developed sustained lifting, shaking and grooming of the foot after plantar punctate nociceptive stimulation by pin touch, or into a group of animals that failed to show this hyperalgesic behavior after SNL. SNL produced no effect on resting BP recorded telemetrically in unrestrained rats compared to control rats receiving either skin incision or sham SNL. However, two tests of baroreceptor gain showed depression only in animals that developed sustained hyperalgesia after SNL. Animals that failed to develop hyperalgesia after SNL were found to have elevations in HR both before and for the first 4 days after SNL, and HR variability analysis gave indications of decreased vagal control of resting HR and elevated sympatho-vagal balance at these same time intervals. In human patients, other research has shown that blunted baroreceptor reflex sensitivity predicts poor outcome during conditions such as hypertension, congestive heart failure, myocardial infarction, and stroke. If baroreceptor reflex suppression is also found in human subjects during chronic neuropathic pain, this may adversely affect survival.
We recently reported that the neuropathic pain medication, gabapentin (GBP; Neurontin), significantly attenuated both noxious colorectal distension (CRD)-induced autonomic dysreflexia (AD) and tail pinch-induced spasticity compared to saline-treated cohorts 2–3 weeks after complete high thoracic (T4) spinal cord injury (SCI). Here we employed long-term blood pressure telemetry to test, firstly, the efficacy of daily versus acute GBP treatment in modulating AD and tail spasticity in response to noxious stimuli at 2 and 3 weeks post-injury. Secondly, we determined whether daily GBP alters baseline cardiovascular parameters, as well as spontaneous AD events detected using a novel algorithm based on blood pressure telemetry data. At both 14 and 21 days after SCI, irrespective of daily treatment, acute GBP given 1 h prior to stimulus significantly attenuated CRD-induced AD and pinch-evoked tail spasticity; conversely, acute saline had no such effects. Moreover, daily GBP did not alter 24 h mean arterial pressure (MAP) or heart rate (HR) values compared to saline treatment, nor did it reduce the incidence of spontaneous AD events compared to saline over the three week assessment period. Power spectral density (PSD) analysis of the MAP signals demonstrated relative power losses in mid frequency ranges (0.2–0.8 Hz) for all injured animals relative to low frequency MAP power (0.02–0.08 Hz). However, there was no significant difference between groups over time post-injury; hence, GBP had no effect on the persistent loss of MAP fluctuations in the mid frequency range after injury. In summary, the mechanism(s) by which acute GBP treatment mitigate aberrant somatosensory and cardiophysiological responses to noxious stimuli after SCI remain unclear. Nevertheless, with further refinements in defining the dynamics associated with AD events, such as eliminating requisite concomitant bradycardia, the objective repeatability of automatic detection of hypertensive crises provides a potentially useful tool for assessing autonomic function pre- and post-SCI, in conjunction with experimental pharmacotherapeutics for neuropathic pain, such as GBP.
neuropathic pain; colorectal distension; power spectral density; telemetry; blood pressure; heart rate
To determine the incidence of symptomatic autonomic dysreflexia (AD) and asymptomatic autonomic dysreflexia (silent AD) in men with spinal cord injury (SCI) undergoing sperm retrieval procedures.
Thirteen men underwent cardiovascular monitoring during vibrostimulation (or self-stimulation) to the point of ejaculation. Cardiovascular results were compared with objective and subjective signs of AD to determine the incidence of symptomatic and silent AD. Past history and knowledge of AD were correlated to participants' experience of AD in the clinical setting.
Change in diastolic and systolic blood pressure is the primary outcome data that will be compared to AD history and data from each participant's questionnaire.
Twelve of the 13 men experienced a rise in blood pressure consistent with AD (defined as an increase in blood pressure > 20 mmHg). Men with incomplete tetraplegia were able to identify symptoms associated with AD, and those with complete tetraplegia did not experience symptoms. Eleven of the 13 men knew that sexual activity could cause AD; however, only 2 of the 13 men acknowledged a history of AD with sexual activity and/or ejaculation.
Symptomatic and silent AD occur frequently during sperm retrieval in men with SCI above T6. Knowledge and past history of AD are not accurate indicators of who will experience AD with sexual activity and/or ejaculation.
Autonomic dysreflexia; Sexuality; Spinal cord injuries; Tetraplegia; Infertility; Blood pressure; Ejaculation; Sperm retrieval
The aim of this article is to analyze cardiac dysfunctions occurring after spinal cord injury (SCI). Cardiac dysfunctions are common
complications following SCI. Cardiovascular disturbances are the leading causes of morbidity and mortality in both acute and chronic
stages of SCI.
We reviewed epidemiology of cardiac disturbances after SCI, and neuroanatomy and pathophysiology of autonomic nervous system,
sympathetic and parasympathetic.
SCI causes disruption of descendent pathways from central control centers to spinal sympathetic neurons, originating into
intermediolateral nuclei of T1–L2 spinal cord segments. Loss of supraspinal control over sympathetic nervous system results in
reduced overall sympathetic activity below the level of injury and unopposed parasympathetic outflow through intact vagal nerve.
SCI associates significant cardiac dysfunction. Impairment of autonomic nervous control system, mostly in patients with cervical or
high thoracic SCI, causes cardiac dysrrhythmias, especially bradycardia and, rarely, cardiac arrest, or tachyarrhytmias and hypotension.
Specific complication dependent on the period of time after trauma like spinal shock and autonomic dysreflexia are also reviewed. Spinal
shock occurs during the acute phase following SCI and is a transitory suspension of function and reflexes below the level of the injury.
Neurogenic shock, part of spinal shock, consists of severe bradycardia and hypotension. Autonomic dysreflexia appears during the chronic
phase, after spinal shock resolution, and it is a life–threatening syndrome of massive imbalanced reflex sympathetic discharge
occurring in patients with SCI above the splanchnic sympathetic outflow (T5–T6). Besides all this, additional cardiac
complications, such as cardiac deconditioning and coronary heart disease may also occur.
Proper prophylaxis, including nonpharmacologic and pharmacological strategies and cardiac rehabilitation diminish occurrence of the
cardiac dysfunction following SCI. Each type of cardiac disturbance requires specific treatment.
spinal shock; neurogenic shock; cardiac dysrrhythmias; bradycardia; tachyarrhytmias; autonomic dysreflexia; cardiac deconditionting; coronary heart disease
The flexion reflex can be elicited via stimulation of skin, muscle, and high-threshold afferents inducing a generalized flexion of the limb. In spinalized animal models this reflex is quite prominent and is strongly modulated by actions of hip proprioceptors. However, analogous actions on the flexion reflex in spinal cord injured (SCI) humans have not yet been examined. In this study, we investigated the effects of imposed static hip angle changes on the flexion reflex in ten motor incomplete SCI subjects when input from plantar cutaneous mechanoreceptors was also present. Flexion reflexes were elicited by low-intensity stimulation of the sural nerve at the lateral malleolus, and were recorded from the ipsilateral tibialis anterior (TA) muscle. Plantar skin stimulation was delivered through two surface electrodes placed on the metatarsals, and was initiated at different delays ranging from 3 to 90 ms. We found that non-noxious sural nerve stimulation induced two types of flexion reflexes in the TA muscle, an early, and a late response. The first was observed only in three subjects and even in these subjects, it appeared irregularly. In contrast, the second (late) flexion reflex was present uniformly in all ten subjects and was significantly modulated during hip angle changes. Flexion reflexes recorded with hip positioned at different angles were compared to the associated control reflexes recorded with hip flexed at 10°. Hip flexion (30°, 40°) depressed the late flexion reflex, while no significant effects were observed with the hip set in neutral angle (0°). Strong facilitatory effects on the late flexion reflex were observed with the hip extended to 10°. Moreover, the effects of plantar skin stimulation on the flexion reflex were also found to depend on the hip angle. The results suggest that hip proprioceptors and plantar cutaneous mechanoreceptors strongly modulate flexion reflex pathways in chronic human SCI, verifying that this type of sensory afferent feedback interact with spinal interneuronal circuits that have been considered as forerunners of stepping and locomotion. The sensory consequences of this afferent input should be considered in rehabilitation programs aimed to restore movement and sensorimotor function in these patients.
Cutaneous afferents; Flexion reflex; Hip proprioceptors; Rehabilitation; Sensorimotor integration
As humans age, the tonic level of activity in sympathetic vasoconstrictor nerves increases and may contribute to age-related increases in blood pressure. In previous studies in normotensive young men with varying levels of resting sympathetic nerve activity, we observed a balance among factors contributing to blood pressure regulation, such that higher sympathetic activity was associated with lower cardiac output and lesser vascular responsiveness to α-adrenergic agonists, which limited the impact of high sympathetic activity on blood pressure. In the present study, we tested the hypothesis that older normotensive men would exhibit a similar balance among these variables (sympathetic nerve activity, cardiac output, and α-adrenergic responsiveness) but that this balance would be shifted toward higher sympathetic nerve activity values. We measured muscle sympathetic nerve activity, cardiac output, arterial pressure, and forearm vasoconstrictor responses in 17 older men and compared these with previous data collected in 14 younger men. Muscle sympathetic activity (burst incidence) was positively related to diastolic blood pressure in the older men (r=0.49; P=0.05); this relationship was not observed in young men. In addition, there was no relationship between cardiac output and muscle sympathetic activity (r=0.29; P>0.05) or between muscle sympathetic activity and vasoconstrictor responses in the older men (eg, norepinephrine: r=−0.21; P>0.05). Although our older subjects were normotensive, the relationship between muscle sympathetic nerve activity and diastolic blood pressure and the lack of “balance” among the other variables suggest that these changes with aging may contribute to the risk of sympathetically mediated hypertension in older humans.
age; cardiac output; sympathetic vasoconstriction; total peripheral resistance; hypertension
AUTONOMIC DYSREFLEXIA IS AN ACUTE SYNDROME OF EXCESSIVE, UNCONTROLLED SYMPATHETIC OUTPUT that can occur in patients who have had an injury to the spinal cord (generally at or above the sixth thoracic neurologic level). It is caused by spinal reflex mechanisms that remain intact despite the patient's injury, leading to hypertension. This review describes the clinical features of autonomic dysreflexia, its common causes (most frequently stimulation of the lower urinary tract) and a recommended approach to treatment. The condition can nearly always be managed successfully, but prompt recognition is essential — without treatment there may be dire consequences, including death.
Sympathetic skin response (SSR) is a test for evaluation of the sympathetic sweat gland pathways, and it has been used to study the central sympathetic pathways in spinal cord injury (SCI). This study aimed to assess the autonomic pathways according to normal or abnormal SSR in urinary incontinence patients due to incomplete spinal cord injury.
Materials and Methods:
Suprapubic, palmar, and plantar SSR to the peripheral nerve electrical stimulation were recorded in 16 urinary incontinence patients with incomplete spinal cord injury at various neurological levels and in 30 healthy control subjects.
All the recordings of SSR from the incomplete SCI patients with urinary incontinence as compared with their counterparts in the control group showed significantly reduced amplitudes with more prominent reduction in the suprapubic area recording site (P value < 0.0004). SSR with significantly prolonged latencies were recorded from palm and plantar areas in response to suprapubic area and tibial N stimuli, respectively (P value < 0.02). In this study, a significantly higher stimulus intensity (P value < 0.01) was needed to elicit SSR in the cases compared with the control group.
This study showed abnormal SSR in urinary incontinence patients due to incomplete SCI. In addition, for the first time we have described recording of abnormal SSR from the suprapubic area as another way to show bladder sympathetic system involvement.
Spinal cord injury; sympathetic skin response; urinary incontinence
Static muscle contraction activates metabolically sensitive muscle afferents that reflexively increase sympathetic nerve activity and arterial pressure. To determine if this contraction-induced reflex is modulated by the sinoaortic baroreflex, we performed microelectrode recordings of sympathetic nerve activity to resting leg muscle during static handgrip in humans while attempting to clamp the level of baroreflex stimulation by controlling the exercise-induced rise in blood pressure with pharmacologic agents. The principal new finding is that partial pharmacologic suppression of the rise in blood pressure during static handgrip (nitroprusside infusion) augmented the exercise-induced increases in heart rate and sympathetic activity by greater than 300%. Pharmacologic accentuation of the exercise-induced rise in blood pressure (phenylephrine infusion) attenuated these reflex increases by greater than 50%. In contrast, these pharmacologic manipulations in arterial pressure had little or no effect on: (a) forearm muscle cell pH, an index of the metabolic stimulus to skeletal muscle afferents; or (b) central venous pressure, an index of the mechanical stimulus to cardiopulmonary afferents. We conclude that in humans the sinoaortic baroreflex is much more effective than previously thought in buffering the reflex sympathetic activation caused by static muscle contraction.
Spinal reflex excitability study in sensory–motor incomplete spinal cord-injured (SCI) and spinal intact subjects.
To investigate the effects of plantar cutaneous afferent excitation on the soleus H-reflex and flexion reflex in both subject groups while seated.
Rehabilitation Institute of Chicago and City University of New York, USA.
The flexion reflex in SCI subjects was elicited by non-nociceptive stimulation of the sural nerve. In normal subjects, it was also elicited via innocuous medial arch foot stimulation. In both cases, reflex responses were recorded from the ipsilateral tibialis anterior muscle. Soleus H-reflexes were elicited and recorded via conventional methods. Both reflexes were conditioned by plantar cutaneous afferent stimulation at conditioning test intervals ranging from 3 to 90 ms.
Excitation of plantar cutaneous afferents resulted in facilitation of the soleus H-reflex and late flexion reflex in SCI subjects. In normal subjects, the soleus H-reflex was depressed while the late flexion reflex was absent. The early flexion reflex was irregularly observed in SCI patients, while in normal subjects a bimodal reflex modulation pattern was observed.
The effects of plantar cutaneous afferents change following a lesion to the spinal cord leading to exaggerated activity in both flexors and extensors. This suggests impaired modulation of the spinal inhibitory mechanisms involved in the reflex modulation. Our findings should be considered in programs aimed to restore sensorimotor function and promote recovery in these patients.
foot sole; flexion reflex; soleus H-reflex; rehabilitation; sensorimotor integration; SCI
Autonomic dysreflexia (AD) is a potentially life-threatening complication of spinal cord injury (SCI) characterized by episodic paroxysmal hypertension and bradycardia in response to a noxious stimulus below the level of injury. Recognition of AD is crucial for individuals with SCI and their family members to facilitate timely and appropriate management. The objectives of this study were to (a) evaluate knowledge of AD among SCI consumers and their family members and (b) identify the preferred format and timing of education regarding AD recognition and management for these stakeholders.
Cross-sectional descriptive study on a cohort of community-dwelling individuals with chronic SCI (N = 100) and their family members (N = 16) by self-report mail survey. Frequency distributions were used to tabulate survey responses on AD knowledge level and to characterize learning preferences and 2 × 2 χ2 analyses were conducted to determine whether there were factors (ie, impairment) associated with AD knowledge (ie, how to treat AD).
Individuals with SCI and their family members have gaps in their knowledge of AD. Traumatic SCI etiology (vs nontrauma) was associated with greater knowledge about treating AD. Although the SCI sample was a high-risk group, 41% had not heard of AD. More concerning was that 22% of individuals with SCI reported symptoms consistent with unrecognized AD. Respondents indicated that AD education would be best delivered during rehabilitation by a healthcare professional.
Further work is needed to promote knowledge about recognizing and managing AD. This may help reduce risk of cardiac and cerebrovascular disease in the SCI population.
Spinal cord injuries; Tetraplegia; Paraplegia; Autonomic dysreflexia; Patient education
Descending serotonergic, noradrenergic, and dopaminergic systems project diffusely to sensory, motor and autonomic spinal cord regions. Using neonatal mice, this study examined monoaminergic modulation of visceral sensory input and sympathetic preganglionic output. Whole-cell recordings from sympathetic preganglionic neurons (SPNs) in spinal cord slice demonstrated that serotonin, noradrenaline, and dopamine modulated SPN excitability. Serotonin depolarized all, while noradrenaline and dopamine depolarized most SPNs. Serotonin and noradrenaline also increased SPN current-evoked firing frequency, while both increases and decreases were seen with dopamine. In an in vitro thoracolumbar spinal cord/sympathetic chain preparation, stimulation of splanchnic nerve visceral afferents evoked reflexes and subthreshold population synaptic potentials in thoracic ventral roots that were dose-dependently depressed by the monoamines. Visceral afferent stimulation also evoked bicuculline-sensitive dorsal root potentials thought to reflect presynaptic inhibition via primary afferent depolarization. These dorsal root potentials were likewise dose-dependently depressed by the monoamines. Concomitant monoaminergic depression of population afferent synaptic transmission recorded as dorsal horn field potentials was also seen. Collectively, serotonin, norepinephrine and dopamine were shown to exert broad and comparable modulatory regulation of viscero-sympathetic function. The general facilitation of SPN efferent excitability with simultaneous depression of visceral afferent-evoked motor output suggests that descending monoaminergic systems reconfigure spinal cord autonomic function away from visceral sensory influence. Coincident monoaminergic reductions in dorsal horn responses support a multifaceted modulatory shift in the encoding of spinal visceral afferent activity. Similar monoamine-induced changes have been observed for somatic sensorimotor function, suggesting an integrative modulatory response on spinal autonomic and somatic function.
The flexion reflex in human spinal cord injury (SCI) is believed to incorporate interneuronal circuits that consist elements of the stepping generator while ample evidence suggest that hip proprioceptive input is a controlling signal of locomotor output. In this study, we examined the expression of the non-nociceptive flexion reflex in response to imposed sinusoidal passive movements of the ipsilateral hip in human SCI. The flexion reflex was elicited by low-intensity stimulation (300 Hz, 30 ms pulse train) of the right sural nerve at the lateral malleolus, and recorded from the tibialis anterior (TA) muscle. Sinusoidal hip movements were imposed to the right hip joint at 0.2 Hz by a Biodex system while subjects were supine. The effects of leg movement on five leg muscles along with hip, knee, and ankle joint torques were established simultaneously with the modulation pattern of the flexion reflex during hip oscillations. Phase-dependent modulation of the flexion reflex was present during hip movement, with the reflex to be significantly facilitated during hip extension and suppressed during hip flexion. The phase-dependent flexion reflex modulation coincided with no changes in TA pre- and post-stimulus background ongoing activity during hip extension and flexion. Reflexive muscle and joint torque responses, induced by the hip movement and substantiated by excitation of flexion reflex afferents, were entrained to specific phases of hip movement. Joint torque responses were consistent with multi-joint spasmodic muscle activity, which was present mostly during the transition phase of the hip from flexion to extension and from mid- to peak extension. Our findings provide further evidence on the interaction of hip proprioceptors with spinal interneuronal circuits engaged in locomotor pathways, and such interaction should be considered in rehabilitation protocols employed to restore sensorimotor function in people with SCI.
EMG; Interneurons; Locomotion; Paraplegia; Reflex circuits; Rehabilitation; Spasms
Different findings indicate that rostral ventrolateral reticular nucleus (RVL) is neuronal substrate of integration and regulation of the cardiovascular functions. Some efferent RVL neurons project to the thoraco-lumbar spinal cord and excite preganglionic sympathetic neurons, to the spinal phrenic motor neurons involved in inspiratory function and increase the activity of vasoconstrictor fibres innervating blood vessels in the skin and skeletal muscle. Our study was aimed at revealing presence of neurons within RVL supplying branching collateral input to the medial preoptic area (MPA) and to the lumbo-sacral spinal cord (SC-L) in the rat. All animal experiments were carried out in accordance with current institutional guidelines for the care and use of experimental animals. We have employed double fluorescent-labelling procedure: the projections were defined by injections of two retrograde tracers: Rhodamine Labelled Bead (RBL) and Fluoro Gold (FG) in the MPA and SC-L, respectively. Our results showed the presence of few single FG neurons and single RBL neurons in the RVL. The size of FG-neurons and RBL-neurons was medium (25–30 μm) and large (50 μm).
Few double-projecting neurons were distributed in the middle third of RVL nucleus, their size was 30–40 μm. The results demonstrate that pools of neurons in the RVL have collateral projections to the MPA and SC-L and they are involved in ascending and descending pathway. These data suggest that these neurons could play a role in maintaining activity of central and peripheral blood flow.
ventrolateral reticular nucleus (RVL); retrograde fluorescent tracer; medial preoptic area; spinal cord; rat.
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.
urinary bladder; spinal cord injury; plasticity; cat; electrical stimulation