A neurophysiological assessment of the bladder guarding response in spinal cord injury.

Neuroregeneration and repair of the spinal cord following traumatic injury (SCI) provide the ultimate goal in the treatment of this patient group and in the challenge to end the permanence of paralysis. To assess the effectiveness of these techniques as they are developed it is important to have sensitive functional assessment tools capable of detecting the repair of damaged pathways. Routine assessment of SCI subjects currently relies on subjective clinical measurement using the ASIA classification and Impairment Score, which is not always consistently rated and excludes autonomic function. In eight chapters this thesis describes work executed to fill this niche by, optimising and standardizing a somatovisceral neurophysiological tool that combines the evoked potential of the sacral somatic pudendo-anal reflex response (PAR) (as a surrogate marker of the pudendo-urethral reflex) with bladder function as a measure of the integrity of the guarding response (GR) for assessing residual supra-sacral bladder and sphincter function in SCI subjects. Presented is the confirmation of the predominant absence of the GR in complete SCI and its preservation, variability and inverse correlation with the degree of impairment in iSCI. Normally suppressed during voiding, the GR is enhanced in SCI, due to aberrant sacral reflexes leading to overactivity of the bladder and dyssynergia of the sphincters. For the first time shown is the residual control of the sphincter in SCI by facilitation of the PAR that gives the best systematic correlation with ASIA grading. And the localised cortical stimulation with TMS facilitates the PAR and may provide an additional means to test the precise integrity and timing of residual cerebro-spinal pathways facilitating the guarding response and pelvic floor muscles. The relationship of this somatovisceral measure with the ASIA/IMSOP scale has been confirmed and finally discussed is how the GR, through neurophysiological testing of somatovisceral reflexes could potentially present an assessment tool for those with SCI

Pathophysiology of Spinal Cord Injury (SCI)

Spinal cord injury (SCI) leads to paralysis, sensory, and autonomic nervous system dysfunctions. However, the pathophysiology of SCI is complex, and not limited to the nervous system. Indeed, several other organs and tissue are also affected by the injury, directly or not, acutely or chronically, which induces numerous health complications. Although a lot of research has been performed to repair motor and sensory functions, SCI-induced health issues are less studied, although they represent a major concern among patients. There is a gap of knowledge in pre-clinical models studying these SCI-induced health complications that limits translational applications in humans. This reprint describes several aspects of the pathophysiology of spinal cord injuries. This includes, but is not limited to, the impact of SCI on cardiovascular and respiratory functions, bladder and bowel function, autonomic dysreflexia, liver pathology, metabolic syndrome, bones and muscles loss, and cognitive functions

The rat spinal cord following traumatic injury: An anatomical and behavioural study examining NADPH-d and fos

The general aim of this current work was to examine spinal cord injury (SCI), and in particular to examine the pathology of injury as it relates to changes in sensory transmission. Due to the limited possibilities for experimentation in humans, a range of animal models of SCI have been developed and are reviewed here. The weight drop SCI model is the most similar to the clinical presentation of SCI in humans and has been widely used in the rat. It was selected for the series of experiments reported in this thesis. Many of the functional deficits produced by SCI result from a cascade of biochemical events set into motion by the injury. Included amongst these is the activation of the enzyme nitric oxide synthase which produces the gaseous neuromodulator, nitric oxide (NO). NO is amongst the most widely distributed and widely utilised molecule in virtually all living organisms, and it is an important signalling molecule in the nervous system. One of the major functions performed by NO appears to relate to sensory transmission, and thus alterations in sensory transmission observed as a result of SCI may involve alterations to NO synthesis. One of the principal aims of this thesis was to examine the effect of SCI on the NO producing cells of the spinal cord and to consider what any changes in NO synthesis may suggest in regards to sensation. NO producing cells were examined using NADPH diaphorase (NADPH-d) histochemistry. As the symptoms of SCI such as motor loss and changes in sensory processing are functional changes, it was also useful to examine changes in neuronal function as a result of SCI. Widespread neuronal function was examined via immunohistochemical detection of the gene product of the immediate early gene, c-fos. It is not known how extensive the biochemical changes resulting from SCI may be, thus another of the aims of the present thesis was to examine the effects of SCI on NO synthesis not only at the level of injury, but also distant to the injury. Findings of the present thesis indicated that traumatic SCI resulted in a decrease in the number of NADPH-d positive cells from the superficial dorsal horn (SDH) of the spinal cord, while the number of these cells are increased in the ventral horn. These changes were restricted to spinal segments adjacent to the injury. Fos expression was also altered by injury and was found to decrease. The most profound changes were found to occur in lamina III, although the other laminae also demonstrated similar changes. Changes in fos expression however were notably more widespread than those for NADPH-d and were not restricted to the level of the injury, occurring at all levels of the spinal cord examined. It was interpreted that alterations in NO synthesis appear to be modulated by the local injury-induced environment while fos expression may be altered by widespread changes to the global level of activity within the central nervous system. Having observed that the number of NADPH-d positive cells of the SDH is reduced following injury, it was of interest to determine whether these cells were in fact killed, or whether they were still present but with reduced NADPH-d activity. Cell counts suggested that the NADPH-d positive cells, which were likely to represent a population of inhibitory interneurons, were not killed following injury, but rather are disrupted such that their normal biochemistry is altered. Since these cells were likely to be inhibitory and were located in laminae involved in sensory transmission, the question arose how disruption of these cells may relate to the neuropathic pain observed to develop following SCI. Thus both NADPH-d and fos expression were again examined, but this time in conjunction with the sensory function of the rats. Sensory thresholds to pain-like behaviour were determined prior to and after injury using Von Frey filaments. Rats that demonstrated a decrease in sensory threshold of at least two Von Frey filament gradations (>70%) were classed as allodynic, while those with a less than a 70% decrease in threshold were classed as non-allodynic. A subpopulation of each of the groups of rats (uninjured, non-allodynic and allodynic) underwent a somatic stimulation paradigm. It was found that stimulation resulted in an increase in the number of NO producing cells but only in the allodynic group of animals. Since this group of animals by definition would perceive this stimulation as noxious, it is likely that the noxious nature of the stimulation resulted in the increased number of NO producing cells observed. This effect occurred only in segments adjacent to the injury. When fos expression was examined in the uninjured animals it was noted that somatic stimulation resulted in a decrease in fos expression, almost exclusively in lamina III. Following injury, there was no change in fos expression in lamina III observed. Instead the only change observed was an increase in fos expression in the deep dorsal horn (DDH, lamina IV and V). This occurred most profoundly in the allodynic group. These results suggested that SCI may lead to misprocessing of sensory signals such that non-noxious somatic stimuli are processed in the DDH rather than lamina III following SCI. It is proposed here that this change in laminae processing may be responsible for the perception of pain towards a non-noxious stimulus, and that the reported injury-induced loss of NO producing inhibitory interneurons in the SDH may be responsible for this alteration in sensory processing following SCI. Sensation is also processed by a number of supraspinal structures and a number of these have been implicated in the development of neuropathic pain states. The effects of SCI on neuronal activity as well as NO synthesis were examined in the periaqueductal grey region of the mid brain (PAG). SCI was shown to result in reduced neuronal activity in the PAG. This reduction in activity did not follow the somatotopy of the lateral column of the PAG (lPAG). It was suggested the reduced activity may not be solely caused by reduced spinal input as a result of SCI. Reduced neuronal activity in the PAG may indicate reduced PAG function, which includes descending modulation of spinal sensory transmission. Injury was not found to alter NADPH-d expression in the PAG. The effect of traumatic lumbar SCI on the parietal (sensorimotor) cortex of the rat was also examined, as loss of inputs following SCI have been shown to result in a profound reorganisation of the cortex. Results indicated that SCI results in a virtual cessation of neuronal activity in areas 1 and 2 of the parietal cortex, likely as a result of lost afferent drive. Theories of cortical plasticity suggest that while the primary inputs via the lumbar spinal cord may be lost following SCI, other less dominants input will remain and become more dominant. It has been proposed previously that cortical reorganisation involves a rapid reorganisation of the entire sensory system. It was interpreted that a similar process may explain the system-wide reduction in neuronal activity observed in the present series of studies

Controls of tachykinin release in the mammalian spinal cord

The purpose of this series of investigations was to elucidate the endogenous control mechanisms active at primary afferent terminals of nociceptive origin in the dorsal laminae of the spinal cord grey matter. Such studies may enable the researcher to make certain conclusions about endogenous mechanisms of pain control in vivo. Furthermore, these studies may help to identify novel areas for the development of analgesic drugs or protocols of therapeutic value in both human and veterinary pain management.Experiments were centred on one particular family of neuropeptides, the tachykinin peptides, and their release in response to peripheral noxious stimulation as determined by the antibody microprobe technique. A review of the anatomy and physiology of tachykinins in the spinal cord is presented at the start of this thesis. The antibody microprobe technique itself is also fully described.Various means of modulating tachykinin release pharmacologically were tested and are presented in this thesis. The results presented here relate to studies on 1) morphine, 2) noradrenaline and the imidazoline derivative drug, medetomidine, 3) neuropeptide Y. A short review on the pharmacological actions of each of these drugs is included. All the results presented are derived from experiments on barbiturate anaesthetised, spinalised cats

Deep Brain Stimulation (DBS) Applications

The issue is dedicated to applications of Deep Brain Stimulation and, in this issue, we would like to highlight the new developments that are taking place in the field. These include the application of new technology to existing indications, as well as ‘new’ indications. We would also like to highlight the most recent clinical evidence from international multicentre trials. The issue will include articles relating to movement disorders, pain, psychiatric indications, as well as emerging indications that are not yet accompanied by clinical evidence. We look forward to your expert contribution to this exciting issue