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.

Approximately two-thirds of patients will experience pain following spinal cord injury (SCI). This pain can arise as an immediate consequence of SCI, or can develop over time into chronic, neuropathic pain. Individuals are frequently prescribed opioid analgesics, including morphine, for the treatment of pain in both the acute and chronic phases of SCI. Yet, despite the prevalence of opioid use, no studies have examined the addictive potential of opioids, or their secondary effects, following spinal injury. These experiments used a clinically relevant self-administration paradigm to examine both addiction and functional recovery after morphine administration. To assess morphine administration in the acute phase of SCI, animals were placed in operant chambers 24-hours following spinal injury. In the chambers, depression of a reinforced lever resulted in an intravenous infusion of morphine (or vehicle). Animals were placed in the chambers for 7, 12-hour sessions and could administer up to 30 mg of morphine per session. Morphine self-administration was also examined in the chronic phase of injury. Animals were placed into operant chambers for 7, 12-hour sessions beginning 14 or 35 days after injury. The amount of morphine administered, as well as recovery of locomotor function and general health, was compared across subjects with SCI and sham (no injury) controls. In the acute phase of injury, SCI significantly reduced self-administration of morphine, but administration led to decreased recovery of locomotor function and weight loss. In the chronic phase of injury, self-administration did not differ between contused and sham animals. All subjects administered the full amount of morphine available each day. In this phase of injury, morphine administration led to significant weight loss, but did not attenuate recovery of locomotor function. These studies suggest that spinal injury reduced the addictive potential of morphine in the acute, but not the chronic, phase of SCI. However, acute administration of high doses of morphine decreased recovery of locomotor function. Morphine should not be used in this phase of injury for the clinical treatment of pain. In the chronic phase, opioid use must be closely monitored as use may result in addictive behavior.

Altered sexual function is one of the most devastating consequences of spinal cord trauma (SCT). Despite this fact, current knowledge of the neural circuitry regulating sexual response in the spinal cord (SC) in healthy humans is remarkably incomplete. In order to better understand the changes that occur to sexual responses following SCT, we must elucidate the neural transmission of sexual function in healthy humans. Functional magnetic resonance imaging (fMRI) techniques to map neuronal function have been adapted for the SC and can now reveal this neural circuitry. We mapped, with spinal fMRI, neuronal activity in the lower thoracic, lumbar and sacral SC in healthy men (n = 10) and women (n = 9) that occurs in response to intermittent audiovisual stimulation (AVS), intermittent genital self-stimulation (GSS) and the combination of the former and latter, applied continuously and simultaneously until orgasm (AVGSS). MR images revealed predominantly increased signal intensity changes (ΔS+) in the autonomic preganglionic nuclei of the lower thoracic, lumbar and sacral SC in women and mostly decreased signal intensity changes (ΔS-) in comparable regions in men. In functional MR images, ΔS+ are related to increased neuronal input while ΔS- are associated with diminished neuronal input to a particular region. Linear regression analyses uncovered a greater number of inverse correlations between SC ΔS and scores of sexual function in women than in men indicating greater descending modulation of SC circuits regulating sexual responses in women than in men. Taken together, our results demonstrate that spinal fMRI is an effective and sensitive technique that can reveal signal intensity changes in the lower thoracic, lumbar and sacral SC associated with AVS, GSS and AVGSS in healthy men and women. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2009-10-06 21:26:15.011

No description available.

Compared with our knowledge concerning the responses to exercise of able-bodied athletes there is relatively little known about the exercise responses of athletes who have a spinal cord injury (SCI). The purpose of this thesis was to examine the physiological characteristics of endurance trained wheelchair athletes; to assess the importance of various physiological factors to the endurance performance of wheelchair athletes; to describe and examine the physiological and metabolic responses and performances of wheelchair athletes to endurance and brief high intensity exercise; and to assess the influence of level of SCI or wheelchair racing class on these responses to exercise. The mean peak oxygen uptake (V02 pk) achieved by the group of 27 wheelchair athletes during wheelchair treadmill exercise was 2.11 ±0.53 I. min-1. When the athletes were grouped according to the paralympic racing classification system (TK2; TK3; TK4) the V02 pk values were 1.28 ±0.16 l. min-1,2.10 ±0.43 I. min-1 and 2.32 ±0.52 I. min-1 respectively. The mean peak heart rates of these groups were 112 ±4 b. min-1,190 ±9 b. min-i, and 200 ±9 b. min-1 respectively. The relationship between V02 pk and endurance performance (r=-0.69; p<0.01) was not as high as found between % V02 pk utilised at a given submaximal propulsion speed (r=0.89; p<0.01) or a propulsion speed equivalent to a reference blood lactate concentration (BLA) of 4 mmol. l-1 (r=-0.87; p<0.01). During a 10 km treadmill trial the group of athletes maintained a speed equivalent to 78.4 ±13.6% V02 pk. The TK2 racing class appeared to exhibit lower heart rates and respiratory exchange ratio (R) values throughout the test than the other racing classes. During a one hour endurance test at 80% of top speed (TS), an exercise intensity meaningful to the wheelchair athlete, the group were working at 64.6 ±13.5% V02 pk. The responses observed were indicative of steady state exercise. Oxygen uptake and ventilation rate remained stable, there was no cardiovascular drift, there was a decrease in R value, BLA peaked after 15 minutes and then decreased throughout the remainder of the test. Blood glucose (BGL) concentrations remained similar to the value observed at rest throughout the test. In general, it was found that wheelchair athletes were able to maintain a propulsion speed equivalent 75% V02 pk for prolonged periods of time, irrespective of their level of SCI. There were no differences between the physiological and metabolic responses of the two paraplegic racing classes. The tetraplegic group appeared to exhibit lower heart rates, BLA, BGL and R values throughout the duration of the test. The concentrations of plasma free fatty acid, glycerol, ammonia and urea postexercise indicated a tendency towards higher values in the wheelchair racing class with the lowest lesion level athletes (TK4). During a 20 s high intensity exercise fixed work test there was greater metabolic activity in the TK2 racing class than the TK4 racing class. The metabolic responses of the TK3 racing class to this test were, in general, between these two groups. A 30 s arm sprint resulted in a decrease in power output of greater than 50% for each racing class. The mean power outputs (MPO) generated by the TK2, TK3 and TK4 racing classes were 100.2 ±21.7 W, 188.3 ±48.9 W and 247.2 ±40.3 W respectively. The physiological and metabolic responses showed a similar tendency. A 30 s test at 80% MPO showed that the metabolic responses of each racing class were similar. The results of the thesis suggest that the amount of muscle mass available for recruitment during exercise and the degree of disruption to the sympathetic nervous system play an important role in determining the responses to exercise and the racing performance of wheelchair athletes with a SCI.

Previous research has demonstrated that the spinal cord is capable of a simple form of instrumental learning. In this instrumental learning paradigm, rats typically receive a complete spinal transection at the second thoracic vertebra, and are tested 24 hours after surgery. Subjects that receive shock to a hind leg quickly learn to maintain the leg in a flexed position, which reduces net shock exposure (Grau et al., 1998). Prior studies have examined the mechanisms that mediate this learning, but little is known about how or where the consequences of learning are stored (memory). The goal of this dissertation proposal is to examine the neural modification(s) that preserve learned behavioral effects over time. It is clear that the central nervous system plays an essential role in instrumental learning. During the acquisition of instrumental learning, the connections between the peripheral nervous system (PNS) and the central nervous system must remain intact (Crown et al., 2002a). Acquisition is also disrupted by intrathecal application of pharmacological agents (lidocaine) that inhibit spinal reflexes (Crown et al., 2002a). The experiments outlined in this dissertation are motivated by an unexpected observation: while application of lidocaine to the spinal cord prior to training blocks acquisition of the instrumental response, inactivating spinal neurons has no effect on the maintenance of the instrumental response. These data suggest that, after the instrumental response is acquired, a peripheral component is capable of maintaining the instrumental response. Aim 1 examined how inhibiting the spinal cord influenced the maintenance of instrumental learning. Intrathecal lidocaine inhibited a spinal withdrawal reflex and instrumental learning, but did not affect the maintenance of the learned response. Expanding on these results, Aim 2 examined how disconnecting the PNS from the spinal cord would influence the maintenance of instrumental learning. If a PNS to spinal cord connection is needed for the maintenance of instrumental learning, then removing that connection by a sciatic transection should disrupt performance of the instrumental response. Together, the results of Aims 1 & 2 confirm that a peripheral alteration contributions to the maintenance of instrumental behavior. In Aim 3, I developed a procedure that would allow for drug delivery directly to the tibialis anterior muscle. If the neuromuscular junction is capable of influencing a spinal reflex, then blocking the neuromuscular junction with an antagonist (curare) should disrupt the acquisition and maintenance of the instrumental response. Based on the results of Aim 3, Aim 4 investigated how other pharmacological manipulations at the neuromuscular junction can influence the acquisition and maintenance of the instrumental response. Using glutamate receptor antagonists (CNQX and MK-801), I showed that glutamatergic signaling plays an essential role.

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.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Thesis (Ph.D.)--University of Missouri-Columbia, 2006. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on April 27, 2009) Vita. Includes bibliographical references.