No description available.

Access to and subsequent control of spinal cord function are critical considerations for design of optimal therapeutic strategies for SCI patients. Electrical stimulation of the spinal cord is capable of activating behaviorally-relevant populations of neurons for recovery of function, and is therefore an attractive target for potential devices. A promising method for accessing these spinal circuits is through their axons, which are organized as longitudinal columns of white matter funiculi along the cord exterior. For this thesis, I hypothesized that these funiculi can be selectively recruited via electrodes appropriately placed on the surface of the spinal cord, for functional activation of relevant motor circuitry in a chronically-transected spinal cord. My tandem design goal was to fabricate and implement a conformable multi-electrode array (MEA) that would enable this selective stimulation. To accomplish this design goal, I participated in the design, fabrication, and electromechanical testing of a conformable MEA for surface stimulation of spinal tracts. I then assessed the fundamental capability of this MEA technology to stimulate white matter tracts in a precise, controlled, and functionally-relevant manner. This was accomplished via in vitro experiments that explored the ability of this MEA to locally activate axons via single- and dual-site surface stimulation. The results from these evaluation studies suggest that spinal-cord surface stimulation with this novel MEA technology can provide discrete, minimally-damaging activation of spinal systems via their white matter tracts. To test my hypothesis that surface stimulation can be used to recruit distinct populations in the spinal cord, I performed studies that stimulated lateral funiculi in both chronically-transected and intact in vitro spinal cords. Results from these studies reveal that selective surface stimulation of white matter tracts in the ventrolateral funiculus (VLF) elicit motor outputs not elicited in intact cords. In addition, I was able to demonstrate that the spinal systems activated by this surface stimulation involve synaptic components and are responsive to spatial, temporal, and pharmacologic facilitation. Corresponding labeling of the axonal tracts projecting through the T12 VLF indicate that, after chronic transection, the remaining spinal neurons whose axons travel through the VLF include those with cell bodies in both the intermediate region and dorsal horn. These electrophysiological results show that surface-stimulating technologies used to control motor function after injury should include focal activation of interneuronal systems with axons in the ventrolateral funiculus. As a whole, these studies provide essential starting points for further use of conformable MEAs to effectively activate and control spinal cord function from the surface of the spinal cord.

Doctor of Philosophy / 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.

Thesis (M.S.)--University of Regina, 2004. / Includes bibliographical references (leaves 127-135). Also available online (PDF file) by a subscription to the set or by purchasing the individual file.

Thesis (M. Sc.)--University of Regina, 2004. / Includes bibliographical references (leaves 127-185).

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

Thesis (Ph. D.)--University of Alabama at Birmingham, 2007. / Title from first page of PDF file (viewed Oct. 31, 2007). Includes bibliographical references (p. 75-98).

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 6 uppsatser.

Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2006. / Härtill 4 uppsatser.