Bilateral implantation of a cochlear implant (CI) after a >2 year period of unilateral hearing with a second implant has been shown to result in altered latencies in brainstem responses in children with congenital deafness. In this thesis, a neural source localization method was developed to investigate the effects of unilateral CI use on cortical development after the implantation of a 2nd CI. The electroencephalography (EEG) source localization method is based on the linearly constrained minimum variance (LCMV) vector beamformer and utilizes null constraints to minimize the electrical artifact produced by the CI. The accuracy of the method was assessed and optimized through simulations and comparisons to beamforming with magnetoencephalography (MEG) data. After using cluster analyses to ensure that sources compared across subjects originate from the same neural generators, a study was done to examine the effects of unilateral CI hearing on hemispheric lateralization to monaural responses. It was found that a >2 year period of unilateral hearing results in expanded projections from the 1st implanted ear to the contralateral auditory area that is not reversed by implantation of a 2nd CI. A subsequent study was performed to examine the effects of unilateral CI hearing on the contributions of the 1st and 2nd implanted ears to the binaural response. It was found that in children with > 2 years of unilateral hearing, the binaural response is dominated by the 1st implanted ear. Together, these results suggest that the delay between the 1st and 2nd CI should be minimized in bilateral implantation to avoid dominance of auditory pathways from the 1st implanted ear. This dominance limits developmental competition from the 2nd CI and potentially contributes to poorer performance in speech detection in noise tasks.

Bilateral implantation of a cochlear implant (CI) after a >2 year period of unilateral hearing with a second implant has been shown to result in altered latencies in brainstem responses in children with congenital deafness. In this thesis, a neural source localization method was developed to investigate the effects of unilateral CI use on cortical development after the implantation of a 2nd CI. The electroencephalography (EEG) source localization method is based on the linearly constrained minimum variance (LCMV) vector beamformer and utilizes null constraints to minimize the electrical artifact produced by the CI. The accuracy of the method was assessed and optimized through simulations and comparisons to beamforming with magnetoencephalography (MEG) data. After using cluster analyses to ensure that sources compared across subjects originate from the same neural generators, a study was done to examine the effects of unilateral CI hearing on hemispheric lateralization to monaural responses. It was found that a >2 year period of unilateral hearing results in expanded projections from the 1st implanted ear to the contralateral auditory area that is not reversed by implantation of a 2nd CI. A subsequent study was performed to examine the effects of unilateral CI hearing on the contributions of the 1st and 2nd implanted ears to the binaural response. It was found that in children with > 2 years of unilateral hearing, the binaural response is dominated by the 1st implanted ear. Together, these results suggest that the delay between the 1st and 2nd CI should be minimized in bilateral implantation to avoid dominance of auditory pathways from the 1st implanted ear. This dominance limits developmental competition from the 2nd CI and potentially contributes to poorer performance in speech detection in noise tasks.

Long-term potentiation (LTP) is an activity-dependent increase in the efficacy of synaptic transmission. In concert with long-term depression (LTD), this synaptic plasticity likely underlies some types of learning and memory. It has been suggested that for LTP/LTD to act as effective memory storage mechanisms, homeostatic regulation is required. This need for plasticity regulation is incorporated into the Bienenstock, Cooper and Munro (BCM) theory by a threshold determining LTD/LTP induction, which is altered by the previous history of activity (Bienenstock et al., 1982). The present work aimed to test key predictions of the BCM model. This was done using field and intracellular recordings in area CA1 of hippocampal slices from young, adult male Sprague-Dawley rats. The first prediction tested was that following a strong, high-frequency priming stimulation all synapses on primed cells will show inhibition of subsequent LTP and facilitation of LTD induction (heterosynaptic metaplasticity). This was confirmed using two independent Schaffer collateral pathways to the same CA1 pyramidal cells. Following priming stimulation to one pathway, LTP induction was heterosynaptically inhibited and LTD facilitated. To more fully investigate whether all synapses show metaplastic changes, the priming stimulation was given in a different dendritic compartment, in stratum oriens, prior to LTP induction in stratum radiatum. This experiment supported the conclusion that all synapses show inhibited LTP following priming. A second prediction of the BCM model is that metaplasticity induction is determined by the history of cell firing. To investigate this, cells were hyperpolarized during priming to completely prevent somatic action potentials. Under these conditions inhibitory priming of LTP was still observed, and thus somatic action potentials are not critical for the induction of the effect. The next aim was to determine the mechanism underlying heterosynaptic metaplasticity. One way in which plasticity induction can be altered is through changes in gamma-aminobutyric acid (GABA)-mediated inhibition of pyramidal cells. For this reason, it was tested whether blocking all GABAergic inhibition, for the duration of the experiment, would prevent priming of LTP. However, priming inhibited subsequent LTP and it was concluded that GABAergic changes do not underlie either the induction, or expression, of the metaplastic state. Proposed revisions to the BCM model predict that postsynaptic elevations in intracellular Ca�⁺ determine the induction of metaplasticity. There are many potential sources for postsynaptic Ca�⁺ elevations, including entry through N-methyl-D-asparate receptors (NMDARs) or voltage-dependent calcium channels (VDCCs), or release from intracellular stores. Results of the present work demonstrate that the inhibition of LTP is dependent on the release of Ca�⁺ from intracellular stores during priming; however this release is not triggered by Ca�⁺ entry through NMDARs or VDCCs, or via activation of metabotropic glutamate receptors. Overall, the present results show that, in accordance with the BCM model, a high level of prior activity induces a cell-wide metaplastic state, such that LTD is facilitated and LTP is inhibited. In contrast to predictions of the BCM model, this is not mediated by cell-firing during priming. Instead the release of Ca�⁺ from intracellular stores is critical for induction of the metaplastic state.

Neuroplasticity provides the basis for many of our most fundamental processes including learning, memory and the recovery of function following injury. This thesis is concerned with the neurophysiological and functional correlates of sensorimotor neuroplasticity in the healthy and focal dystonic populations. My initial experiments were conducted to determine the functional correlates of neuroplasticity induced in the primary motor (M1) and primary sensory (S1) cortices during a grip lift task. In healthy subjects these experiments further quantified the role of M1 in the anticipatory control of grip force scaling and demonstrated a role for S1 in triggering subsequent phases of the motor plan. My second series of experiments served to extend these findings by examining the functional correlates of neuroplasticity induced in the supplementary motor area (SMA). This study provided evidence for the role of left SMA in the control of grip force scaling and a role for left and right SMA in the synchronization of grip force and load force during the grip-lift synergy. Afferent input is known to be a powerful driver of cortical reorganisation. In particular, the timing and pattern of afferent input is thought to be crucial to the induction of plastic change. In healthy subjects, I examined the neurophysiological effects of applying “associative” (synchronous) and “non-associative” (asynchronous) patterns of afferent input to the motor points or digits of the hand. I observed an increase in the volume and area of the cortical representation of stimulated muscles when associative stimulation was applied over the motor points of two hand muscles. This pattern of stimulation also caused the centres of gravity of the stimulated muscles to move closer together, mimicking the maladaptive changes seen in focal hand dystonia. Non-associative stimulation and stimulation applied to the digits did not produce such an effect. Task-specific focal dystonia is characterised by excessive representational plasticity resulting in cortical representations which are significantly larger, and demonstrate greater overlap, than those seen in healthy individuals. These changes are thought to be driven, in part, by repetitive movement patterns which promote associative patterns of afferent input over an extended time period. On the basis of this knowledge, I applied non-associative stimulation to the hand muscles of dystonic subjects. Following this intervention, I noted a contraction of representational maps and a separation in the centres of gravity of the stimulated muscles. These neurophysiological changes were accompanied by improvements on a cyclic drawing task. This thesis demonstrates the functional correlates of neuroplasticity in M1, S1 and SMA during object manipulation using a precision grasp. These findings further extend our knowledge on the mechanisms underlying effective grasp control and assist us in the development of future rehabilitation protocols for neurological conditions involving grasp dysfunction. In addition, this thesis is the first to demonstrate an improvement in both neurophysiological and functional measures in focal dystonia following a period of non-associative afferent stimulation. These results open up exciting new avenues for the development of effective treatment protocols in those with focal hand dystonia. / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2010

Neuroplasticity provides the basis for many of our most fundamental processes including learning, memory and the recovery of function following injury. This thesis is concerned with the neurophysiological and functional correlates of sensorimotor neuroplasticity in the healthy and focal dystonic populations. My initial experiments were conducted to determine the functional correlates of neuroplasticity induced in the primary motor (M1) and primary sensory (S1) cortices during a grip lift task. In healthy subjects these experiments further quantified the role of M1 in the anticipatory control of grip force scaling and demonstrated a role for S1 in triggering subsequent phases of the motor plan. My second series of experiments served to extend these findings by examining the functional correlates of neuroplasticity induced in the supplementary motor area (SMA). This study provided evidence for the role of left SMA in the control of grip force scaling and a role for left and right SMA in the synchronization of grip force and load force during the grip-lift synergy. Afferent input is known to be a powerful driver of cortical reorganisation. In particular, the timing and pattern of afferent input is thought to be crucial to the induction of plastic change. In healthy subjects, I examined the neurophysiological effects of applying “associative” (synchronous) and “non-associative” (asynchronous) patterns of afferent input to the motor points or digits of the hand. I observed an increase in the volume and area of the cortical representation of stimulated muscles when associative stimulation was applied over the motor points of two hand muscles. This pattern of stimulation also caused the centres of gravity of the stimulated muscles to move closer together, mimicking the maladaptive changes seen in focal hand dystonia. Non-associative stimulation and stimulation applied to the digits did not produce such an effect. Task-specific focal dystonia is characterised by excessive representational plasticity resulting in cortical representations which are significantly larger, and demonstrate greater overlap, than those seen in healthy individuals. These changes are thought to be driven, in part, by repetitive movement patterns which promote associative patterns of afferent input over an extended time period. On the basis of this knowledge, I applied non-associative stimulation to the hand muscles of dystonic subjects. Following this intervention, I noted a contraction of representational maps and a separation in the centres of gravity of the stimulated muscles. These neurophysiological changes were accompanied by improvements on a cyclic drawing task. This thesis demonstrates the functional correlates of neuroplasticity in M1, S1 and SMA during object manipulation using a precision grasp. These findings further extend our knowledge on the mechanisms underlying effective grasp control and assist us in the development of future rehabilitation protocols for neurological conditions involving grasp dysfunction. In addition, this thesis is the first to demonstrate an improvement in both neurophysiological and functional measures in focal dystonia following a period of non-associative afferent stimulation. These results open up exciting new avenues for the development of effective treatment protocols in those with focal hand dystonia. / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2010

Neuroplasticity provides the basis for many of our most fundamental processes including learning, memory and the recovery of function following injury. This thesis is concerned with the neurophysiological and functional correlates of sensorimotor neuroplasticity in the healthy and focal dystonic populations. My initial experiments were conducted to determine the functional correlates of neuroplasticity induced in the primary motor (M1) and primary sensory (S1) cortices during a grip lift task. In healthy subjects these experiments further quantified the role of M1 in the anticipatory control of grip force scaling and demonstrated a role for S1 in triggering subsequent phases of the motor plan. My second series of experiments served to extend these findings by examining the functional correlates of neuroplasticity induced in the supplementary motor area (SMA). This study provided evidence for the role of left SMA in the control of grip force scaling and a role for left and right SMA in the synchronization of grip force and load force during the grip-lift synergy. Afferent input is known to be a powerful driver of cortical reorganisation. In particular, the timing and pattern of afferent input is thought to be crucial to the induction of plastic change. In healthy subjects, I examined the neurophysiological effects of applying “associative” (synchronous) and “non-associative” (asynchronous) patterns of afferent input to the motor points or digits of the hand. I observed an increase in the volume and area of the cortical representation of stimulated muscles when associative stimulation was applied over the motor points of two hand muscles. This pattern of stimulation also caused the centres of gravity of the stimulated muscles to move closer together, mimicking the maladaptive changes seen in focal hand dystonia. Non-associative stimulation and stimulation applied to the digits did not produce such an effect. Task-specific focal dystonia is characterised by excessive representational plasticity resulting in cortical representations which are significantly larger, and demonstrate greater overlap, than those seen in healthy individuals. These changes are thought to be driven, in part, by repetitive movement patterns which promote associative patterns of afferent input over an extended time period. On the basis of this knowledge, I applied non-associative stimulation to the hand muscles of dystonic subjects. Following this intervention, I noted a contraction of representational maps and a separation in the centres of gravity of the stimulated muscles. These neurophysiological changes were accompanied by improvements on a cyclic drawing task. This thesis demonstrates the functional correlates of neuroplasticity in M1, S1 and SMA during object manipulation using a precision grasp. These findings further extend our knowledge on the mechanisms underlying effective grasp control and assist us in the development of future rehabilitation protocols for neurological conditions involving grasp dysfunction. In addition, this thesis is the first to demonstrate an improvement in both neurophysiological and functional measures in focal dystonia following a period of non-associative afferent stimulation. These results open up exciting new avenues for the development of effective treatment protocols in those with focal hand dystonia. / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2010

Thesis (Ph. D.)--University of Texas at Austin, 2006. / Vita. Includes bibliographical references.

Thesis (Ph. D.)--University of Oregon, 2007. / Typescript. Includes vita and abstract. Includes bibliographical references (leaves 146-163). Also available for download via the World Wide Web; free to University of Oregon users.

Thesis (Ph.D.)--University of Alberta, 2009. / A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Doctor of Philosophy, Centre for Neuroscience. Title from pdf file main screen (viewed on October 31, 2009). Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 102-125).