<p>  </p> <p>Persons with a spinal cord injury (SCI) above the sixth thoracic vertebrae commonly experience autonomic dysreflexia (AD), 90 percent of individuals with this level of injury are susceptible to AD which is associated with an increase in sympathetic nerve activity. Left untreated AD causes a paroxysmal rise in blood pressure that may result in seizures, heart attack, or even death. This project investigates how AD affects QT interval, RR interval, P wave height, heart rate, and QRS width both during an event and long term to help identify potential cardiac risks for individuals with SCI who experience chronic AD. Sympathetic tone has been shown to influence QT interval changes that can be indicative of an increased risk of arrhythmia, which can be exacerbated by recurring episodes of AD.</p> <p>A rat spinal cord injury model at the T3 level undergoing colorectal distention (CRD) was used to induce AD. Electrophysiological recordings from an implanted ECG sensor and noninvasive skin nerve activity (SKNA) sensor array during normal baseline and three trials of CRD were collected on days 5, 7, 9, 11, 14, 16, 19, and 21 post-SCI. Custom MATLAB algorithms were used to identify the QRS complex and T-peaks from the implant ECG signal. QT interval measurements were taken for 2 minutes of baseline and for 2 minutes after the initiation of each CRD trial. Corrected QT interval (QTc) was calculated using normalized Bazett’s formula to account for the impact of heart rate on QT interval. </p> <p>It was found that the rats’ susceptibility and reaction to AD events varied between subacute (5-14 days) and chronic phases of SCI. During the chronic phase the incidence of AD events increased during regular occurrences of CRD as indicated by above-threshold (≥15 mmHg) blood pressure spikes. AD events also resulted in increased QT interval short term variability marking an increased risk of arrythmias. Baseline P-wave height and QTc interval were also increased while QRS complex width decreased resulting in potentially detrimental cardiac effects. This rat model showed that humans who experience recurrent AD during the chronic phase of SCI may be at increased risk for arrythmia. </p>

Following spinal cord injury (SCI), up to 70% of patients develop a condition known as autonomic dysreflexia (AD). This study investigates the use of Pregabalin as a preemptive treatment to mitigate the development of AD following SCI in an animal model. Saline-treated and dPGB rats (first Pregabalin treatment 7 days post-SCI) demonstrated typical signs of AD, with mean arterial pressure (MAP) increases of 23.5% and 27.4% respectively, following colon distension. In contrast, iPGB animals (first Pregabalin treatment 1 hour post-SCI) had MAP increases of 14.6%; significantly lower than saline-treated animals. Additionally, iPGB animals had significantly lower urine volumes than saline-treated animals on days 9 and 10 post-SCI, indicating a more rapid return of spontaneous bladder voiding. It was concluded that only treatment with Pregabalin immediately following SCI can alleviate large increases in blood pressure that accompany AD episodes. Immunostaining for substance P revealed a significantly higher density in both the dorsal horn and central autonomic area in iPGB animals when compared to saline-treated and uninjured animals, indicating a possible mechanism of sympathetic inhibition following iPGB treatment.

Spinal cord injury can result in partial or complete loss of supraspinal control of sympathetic outflow below the lesion. Despite the importance of the sympathetic nervous system in autonomic dysreflexia and orthostatic hypotension, its integrity is not currently assessed in the clinical determination of lesion level - only motor and sensory pathways are examined. The aim of this thesis was to develop non-invasive means of assessing the integrity of sympathetic pathways following human spinal cord injury. Brief innocuous electrical stimuli applied to the forehead evoked cutaneous vasoconstrictor and sudomotor responses in the fingers and toes of able-bodied subjects, which were abolished by complete spinal lesions. Application of these same stimuli to the abdominal wall (below lesion) generated long-lasting cutaneous vasoconstriction (but not sweat release) and significant increases in blood pressure that accumulated with repeated stimuli. Moreover, the magnitude and duration of these spinal somatosympathetic reflexes did not depend on the number of impulses or duration of the sensory input, suggesting that only the initial part of the sensory barrage elicits reflex responses. This work has shown that cutaneous vascoconstriction provides a more robust measure of the integrity of sympathetic pathways than does sweat release. This was confirmed during natural stimulation of somatic afferents during vibroejaculation, which caused marked increases in blood pressure and marked cutaneous vasoconstriction but negligible sweat release below lesion. Muscle vasoconstrictor function below lesion was assessed by asking subjects to perform a maximal inspiratory breath-hold, which is known to cause a sustained activation of muscle vasoconstrictor neurones that counteracts the fall in blood pressure in able-bodied subjects. Blood pressure remained low in paraplegics and, especially, quadriplegics during this manouevre; importantly, heart rate showed a linear increase only in the spinal patients. In the absence of blood pressure measurements, the latter infers an interruption of descending muscle vasoconstrictor pathways. In conclusion, this thesis has demonstrated simple, non-invasive techniques that can be utilised to assess the function of the sympathetic nervous system in spinal cord injury, and highlighted the need to assess the injury in terms of the integrity of the sympathetic nervous system below the lesion level.

Spinal cord injury can result in partial or complete loss of supraspinal control of sympathetic outflow below the lesion. Despite the importance of the sympathetic nervous system in autonomic dysreflexia and orthostatic hypotension, its integrity is not currently assessed in the clinical determination of lesion level - only motor and sensory pathways are examined. The aim of this thesis was to develop non-invasive means of assessing the integrity of sympathetic pathways following human spinal cord injury. Brief innocuous electrical stimuli applied to the forehead evoked cutaneous vasoconstrictor and sudomotor responses in the fingers and toes of able-bodied subjects, which were abolished by complete spinal lesions. Application of these same stimuli to the abdominal wall (below lesion) generated long-lasting cutaneous vasoconstriction (but not sweat release) and significant increases in blood pressure that accumulated with repeated stimuli. Moreover, the magnitude and duration of these spinal somatosympathetic reflexes did not depend on the number of impulses or duration of the sensory input, suggesting that only the initial part of the sensory barrage elicits reflex responses. This work has shown that cutaneous vascoconstriction provides a more robust measure of the integrity of sympathetic pathways than does sweat release. This was confirmed during natural stimulation of somatic afferents during vibroejaculation, which caused marked increases in blood pressure and marked cutaneous vasoconstriction but negligible sweat release below lesion. Muscle vasoconstrictor function below lesion was assessed by asking subjects to perform a maximal inspiratory breath-hold, which is known to cause a sustained activation of muscle vasoconstrictor neurones that counteracts the fall in blood pressure in able-bodied subjects. Blood pressure remained low in paraplegics and, especially, quadriplegics during this manouevre; importantly, heart rate showed a linear increase only in the spinal patients. In the absence of blood pressure measurements, the latter infers an interruption of descending muscle vasoconstrictor pathways. In conclusion, this thesis has demonstrated simple, non-invasive techniques that can be utilised to assess the function of the sympathetic nervous system in spinal cord injury, and highlighted the need to assess the injury in terms of the integrity of the sympathetic nervous system below the lesion level.

<p>  </p> <p>Persons with a spinal cord injury (SCI) often suffer from secondary complications including the dysfunction of the autonomic nervous system below the level of injury. For persons with a SCI at or above T6, autonomic dysreflexia (AD) may be triggered by noxious stimulation below the level of injury causing rapid sympathetic hyperactivation, leading to paroxysmal hypertension. If AD is not recognized and managed promptly, this increase in blood pressure can lead to stroke, organ damage, and/or death. Currently, AD is only detected in clinical settings through continuous blood pressure monitoring. Recent studies have revealed that rapid detection of AD is possible by using extracted features from electrocardiogram (ECG) data collected non-invasively and applying a five-layer neural network.</p> <p>This project focuses on further characterization of physiological responses before and during AD to detect the overreaction of sympathetic nerve activity prior to the detrimental increase in hypertension. Using a rat model with implanted telemetry and noninvasive sensors, an acclimation protocol was developed to minimize noise and motion artifacts during data collection. We induced AD in a controlled manner using colorectal distention (CRD). We analyzed skin nerve activity (SKNA) and heart rate variability parameters in the time and frequency domain to improve the non-invasive detection of AD. A four-week acclimation protocol exposed a minimal increase in sympathetic activity during experimentation despite long periods of restraint. Results indicated an increase in SKNA features occurred about 18 seconds before the gold standard increase in blood pressure. Additionally, integrated SKNA features in the frequency domain quantified nerve activity and low frequency components were found to be dominant during AD, providing another parameter that could be included in an AD detection system to improve accuracy. In humans, SKNA may be used to alert patients of the onset of AD, allowing caretakers to respond quickly and make necessary changes to decrease the severe effects of AD.</p>

Relatively few studies have examined the effects of nociception pe se on sympathetic nerve activity in awake healthy human subjects. Painful stimuli can produce differential responses from cutaneous and muscle postganglionic sympathetic neurones in the anaesthetised cat, and some animal and human studies suggest that nociceptive stimuli originating in different tissues may produce differential sympathetic effects- deep nociception causing vasodepressive and superficial nociception triggering an excitatory effect on cardiovascular state. It is important to understand how the sympathetic nervous system responds to nociception in healthy subjects in order to make more meaningful comparisons with the behaviour which occurs following damage to sympathetic pathways, e.g. nerve lesions (chronic regional pain syndromes) and spinal cord injury (autonomic dysreflexia (AD)). Additionally, it has been suggested that muscle spindles afferents may play a role in chronic pain, most notably the 'vicious cycle' of pain. While this has been investigated in animal studies, it has not been thoroughly investigated in healthy human subjects. Muscle spindle and sympathetic nerve activity from muscle and skin postganglionic neurones were directly recorded in healthy awake human subjects using microneurography; effector organ responses (blood pressure, heartrate, skin blood flow and sweat release) were recorded in both healthy and spinal cord injured subjects. Deep and superficial nociception was induced by intramuscular and subdermal injections of hypertonic saline given at unexpected times and in quasi-random order. Regardless of the origin of nociception (deep or superficial), general responses tended to be excitatory with increases seen in muscle and skin sympathetic nerve activity, heartrate, blood pressure and sweat release. A gender effect was noted regarding skin blood flow, with males largely showing decreases and females increases. No changes were noted in spindle firing rates and painful stimuli did not significantly increase effector organ responses in spinal cord injured subjects. Contrasting with previous studies, we did not see a differential sympathetic response or change in spindle firing rate to painful stimuli originating in different tissues. While it is believed that noxious stimuli trigger AD, we did not see exaggerated sympathetic responses in spinal cord injured subjects. More investigation is required regarding innocuous triggers of AD.

Relatively few studies have examined the effects of nociception pe se on sympathetic nerve activity in awake healthy human subjects. Painful stimuli can produce differential responses from cutaneous and muscle postganglionic sympathetic neurones in the anaesthetised cat, and some animal and human studies suggest that nociceptive stimuli originating in different tissues may produce differential sympathetic effects- deep nociception causing vasodepressive and superficial nociception triggering an excitatory effect on cardiovascular state. It is important to understand how the sympathetic nervous system responds to nociception in healthy subjects in order to make more meaningful comparisons with the behaviour which occurs following damage to sympathetic pathways, e.g. nerve lesions (chronic regional pain syndromes) and spinal cord injury (autonomic dysreflexia (AD)). Additionally, it has been suggested that muscle spindles afferents may play a role in chronic pain, most notably the 'vicious cycle' of pain. While this has been investigated in animal studies, it has not been thoroughly investigated in healthy human subjects. Muscle spindle and sympathetic nerve activity from muscle and skin postganglionic neurones were directly recorded in healthy awake human subjects using microneurography; effector organ responses (blood pressure, heartrate, skin blood flow and sweat release) were recorded in both healthy and spinal cord injured subjects. Deep and superficial nociception was induced by intramuscular and subdermal injections of hypertonic saline given at unexpected times and in quasi-random order. Regardless of the origin of nociception (deep or superficial), general responses tended to be excitatory with increases seen in muscle and skin sympathetic nerve activity, heartrate, blood pressure and sweat release. A gender effect was noted regarding skin blood flow, with males largely showing decreases and females increases. No changes were noted in spindle firing rates and painful stimuli did not significantly increase effector organ responses in spinal cord injured subjects. Contrasting with previous studies, we did not see a differential sympathetic response or change in spindle firing rate to painful stimuli originating in different tissues. While it is believed that noxious stimuli trigger AD, we did not see exaggerated sympathetic responses in spinal cord injured subjects. More investigation is required regarding innocuous triggers of AD.

Disorders of the autonomic nervous system constitute serious complications of spinal cord injury (SCI) and their treatment is usually highly prioritised by spinal patients. Among these, autonomic dysreflexia and impaired thermoregulation are potentially life threatening conditions and require effective management. Olfactory ensheathing cells (OECs), progenitor cells and polymeric scaffolds have been tested in animal models of SCI and some of them have been considered for clinical trials. However, evaluation of the effect of such interventions on autonomic functions has received only rudimentary attention and would require a more thorough experimental assessment before the methods are utilised in human patients. This thesis tested two potential therapeutic strategies for autonomic dysreflexia and examined disorders of thermoregulatory functions in a rat model of spinal cord transection. Magnitude and duration of autonomic dysreflexia were evaluated with radio telemetry in spinalised animals treated with (i) implants of OECs and olfactory neurosphere-derived cells seeded in poly(lactic co glycolic) porous scaffolds or with (ii) transplants of OECs alone. (iii) Effects of SCI and of OECs on the morphology of sympathetic preganglionic neurons (SPNs; which are involved in pathogenesis of autonomic dysreflexia) stained for NADPH diaphorase were examined. (iv) Doppler ultrasonography and infrared thermography were used to assess responses of tail blood flow and surface temperature to cold. Transplants of OECs alone, but not in combination with olfactory neurosphere-derived cells and polymeric scaffolds, resulted in significantly shortened episodes of autonomic dysreflexia. This may be attributed to the alterations to the morphology of SPNs adjacent to the lesion: a transient increase in the morphometric features of the SPNs was evoked by spinal cord transection and this was further altered by transplantation of OECs. The thesis also showed that local responses of tail blood flow and temperature to cold were not abolished by complete SCI suggesting that temperature homeostasis could still be maintained in response to cold. It is hypothesised that OECs facilitate improved recovery from autonomic dysreflexia through alteration of the morphology of SPNs. Furthermore, it is suggested that the role of the tail in heat conservation can be regulated by mechanisms that are independent of the descendent neural control from supraspinal centres.

Spinal cord injury (SCI) remains a significant cause for morbidity and mortality in North America. Bladder dysfunction following SCI is very common and could lead to severe complications including renal failure and autonomic dysreflexia (AD). AD involves life threatening episodes of hypertension in patients with SCI above T6 level. Current management protocols for AD are symptomatic and usually ineffective. Botulinum toxin-A (BTX-A), has been successfully used recently in SCI patients because it reduces the detrusor contractility via inhibiting acetylcholine release from efferent nerve endings. Recent evidence, however, suggests a sensory involvement via modulation of sensory neuropeptides, neurotransmitters, and receptors. It is still, however, unclear whether BTX-A can affect putative spinal neurons involved in AD. In this study we demonstrated that intravesical BTX-A treatment has blocked AD in rats with T4-SCI, and also provided a novel mechanism for the control of autonomic dysreflexia via a minimally invasive treatment modality.

Spinal cord injury (SCI) remains a significant cause for morbidity and mortality in North America. Bladder dysfunction following SCI is very common and could lead to severe complications including renal failure and autonomic dysreflexia (AD). AD involves life threatening episodes of hypertension in patients with SCI above T6 level. Current management protocols for AD are symptomatic and usually ineffective. Botulinum toxin-A (BTX-A), has been successfully used recently in SCI patients because it reduces the detrusor contractility via inhibiting acetylcholine release from efferent nerve endings. Recent evidence, however, suggests a sensory involvement via modulation of sensory neuropeptides, neurotransmitters, and receptors. It is still, however, unclear whether BTX-A can affect putative spinal neurons involved in AD. In this study we demonstrated that intravesical BTX-A treatment has blocked AD in rats with T4-SCI, and also provided a novel mechanism for the control of autonomic dysreflexia via a minimally invasive treatment modality.