Deafness in early development can alter how the brain responds to sound, compromising the restoration of hearing with cochlear implants. We asked how the naïve brain responds to initial cochlear implant stimulation in children who are deaf. Results indicated large variability in initial responses. Deafness associated with GJB-2 mutations led to more uniformity in cortical responses than other etiologies. Responses associated with GJB-2 mutations were characterized by a response peak with large contributions from temporal and frontal regions of the brain. This response may reflect an early stage of auditory development. By contrast, another response type, typical of normal hearing children, received less contribution from frontal regions. Through consistent cochlear implant use, frontal regions of the brain may not be as strongly recruited. Effects of deafness in early development are heterogeneous, which may reflect differences in etiology of deafness and different stages of auditory development.

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

Orientadora: Gisele Zoccal Mingoti / Banca: Joaquim Mansano Garcia / Banca: Flávio Vieira Meirelles / Resumo: Butirolactona I (Bl-I) pode ser utilizada em sistemas PIV de embriões para bloquear a meiose durante o transporte de oócitos obtidos de OPU. O objetivo deste estudo foi verificar a concentração de BL-I eficaz durante o transporte de oócito bovinos. Oócitos (n=4581) foram pré-maturados em criotubos contendo meio com 10 ou 100μM de Bl-I, acrescido ou não de HEPES (20mM), no período de 5 horas em estufa portátil Minitub e transferidos para incubadora com atmosfera e temperatura controlada, permanecendo por mais 19 horas. Em seguida foram maturados a 38,5ºC em atmosfera de 5% de CO2 durante 20 horas, fecundados e os zigotos cultivados. Foram avaliadas a maturação nuclear e a maturação citoplasmática após pré-MIV e MIV (24h.-controles e 20h.-tratados). A fertilização foi avaliada após 18 h. da inseminação. Os embriões foram analisados quanto ao seu desenvolvimento e qualidade. Os dados foram avaliados por ANOVA (p<o,o5). A maioria dos oócitos tratados permaneceu em GV e após MIV houve a reversão do bloqueio, mas a eficiência foi menor com 10 μM de Bl-I. A maturação citoplasmática foi beneficiada de acordo a distribuição das mitocôndrias, no entanto, quanto à distribuição dos grânulos corticais apenas o bloqueio realizado com 100 μM Bl-I permitiu uma maturação. A taxa de fecundação foi prejudicada pelo tempo de transporte, mesmo nos oócitos tratados. A ocorrência de polispermia foi correlacionada à porcentagem de oócitos com grânulos corticais imaturos. O desenvolvimento embrionário sofreu um atraso pela utilização de 100μM de Bl-I, porém boa porcentagem de blastocistos de qualidade foi atingida. Assim, o bloqueio com 100μM de Bl-I possui efeitos benéficos na PIV de embriões de oócitos transportados por longo tempo. / Abstract: Butirolactone-I (Bl-I), can be used in systems for in vitro production (IVP) of embryos to block meiosis during the transport of oocytes from OPU. The objective of this study is to assess the concentration of BL-I more efficient during the transport of bovine oocytes. Oocytes (n = 4581) were prematured in criotubes containing medium with 10 or 100 μM of Bl-I with or without HEPES (20mM) in a portable incubator at 38,5°C without CO2 equilibration in the first 5 h, being later transferred to a incubator at 38.5°C and 5% CO2 in humidified air during the 19 hours remaining. Following were matured, fertilized and the zygotes cultured at 38.5°C and 5% CO2. Were evaluated the nuclear maturation and the cytoplasmic maturation after pre-IVM and after IVM (24h. controls and 20 h. treatments). Fertilization was assessed 18 hours after insemination. The embryos development and quality were analyzed. The data were evaluated by ANOVA (P< 0, 05). Most remained in GV oocytes treated and after IVM was the reversal of the blockage, but the efficiency was lower with 10 μM of Bl-I. The cytoplasmic maturation during the time of meiosis blockage was benefited from the distribution agreement and potential of mitochondria, however, about the distribution of cortical granules only blocking conducted with 100μM Bl-I had a complete maturation. The rate of fertilization was damage by the time of transport, and the meiosis blockage with Bl-I did not improve the percentage of fertilized oocytes. The occurrence of polispermia was correlated with the percentage of oocytes with immature cortical granules. The embryo developmentb was delayed by the use of 100μM of Bl-I, but a good percentage of blastocysts of good quality reached. So, the use of 100μM of Bl-I has beneficial effects on the IPV of embryos from oocytes transported at a long time. / Mestre

Made available in DSpace on 2013-08-07T19:03:49Z (GMT). No. of bitstreams: 1 000422598-Texto+Completo-0.pdf: 1351554 bytes, checksum: 22248aa2eb43d9dad9079ea2b7472de1 (MD5) Previous issue date: 2010 / Introduction: focal cortical dysplasia is one of the most frequent malformations of cortical development and is closely related intractable epilepsy in children and adults. They are characterized by histological, imaging and electrophysiological characteristics. So far have been described 5 types of magnetic resonance imaging of patients with focal cortical dysplasia. Objectives: To study the relationship between cortical dysplastic lesions and epileptiform electroencephalogram surface and Electrocorticography. Describe the histological patterns, imaging and electrophysiological and surgical results found. Try to correlate electrophysiological patterns and outcome after surgery. Methods: Will be evaluated histology, electroencephalogram, electrocorticography and the MRI of 63 patients operated in the service of epilepsy surgery at the Hospital São Lucas da Pontificia Universidade Católica do Rio Grande do Sul surgical results (regarding the seizure control) were assessed by review of medical records, verifying the status of the rate of success in controlling seizures in consultation with latest revision. These data were confirmed and detailed with a telephone call, where specific questions were performed according to structured form.Results: We observed that 55. 5% of patients were seizure-free at 1 year after surgery. The last visit 47% of patients remained seizure-free. The variables that correlated with favorable prognosis were complete resection of discharges during the surgery and to be free of attacks in the first year after surgery. The only variable that correlated with seizure-free interval was complete resection of the discharges. A magnetic resonance imaging correlated significantly with histopathology findings. Finally, due to the peculiar behavior of epileptic seizures in patients with focal cortical dysplasia, was described a new scale of surgical outcomes for this disease. Conclusion: The surgical outcome of the seizure according to data presented correlates statistically significantly with complete resection of epileptogenic discharges suggestive of dysplasia and with a favorable outcome at one year after surgery. / Introdução: Displasia cortical focal é uma das formas mais freqüentes de malformações do desenvolvimento cortical, estando intimamente relacionada com epilepsia de difícil controle em crianças e adultos. Caracterizam-se por alterações histológicas, imaginológicas e eletrofisiológicas peculiares. Até o momento foram descritos 5 tipos de achados na ressonância magnética de pacientes com displasia cortical focal. Objetivos: Estudar as relações entre lesões displásicas corticais e descargas epileptiformes ao eletroencefalograma de superfície e à Eletrocorticografia. Descrever os padrões histológicos, imaginológicos e eletrofisiológicos, bem como os resultados cirúrgicos encontrados. Tentar correlacionar padrões eletrofisiológicos e desfecho pós-cirúrgico. Métodos: Serão avaliados a histologia, o eletroencefalograma, a eletrocorticografia e a ressonância magnética de 63 pacientes operados no serviço de cirurgia da epilepsia do Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul. Os resultados cirúrgicos (quanto ao controle de crises) foram avaliados através de revisão de prontuários, verificando-se o status quanto à taxa de sucesso no controle de crises na consulta de revisão mais recente. Estes dados foram confirmados e detalhados através de ligação telefônica, onde foram efetuadas perguntas específicas de acordo com ficha estruturada.Resultados: Foi observado que 55,5% dos pacientes estavam livres de crise em um ano após a cirurgia. Na última visita 47% dos pacientes permaneceram sem crises. As variáveis que se correlacionaram com prognóstico favorável foram ressecção completa das descargas durante a cirurgia, estar livre de crises no primeiro ano do pós-operatório. A única variável que se correlacionou com o intervalo livre de crises foi ressecção completa das descargas. A ressonância magnética de crânio se correlacionou de forma significativa com os achados histopatológicos. Por fim, devido ao comportamento peculiar das crises epilépticas nos pacientes com displasia cortical focal, foi descrito uma nova escala de resultados cirúrgicos para esta patologia. Conclusão: O resultado cirúrgico das crises segundo os dados apresentados se correlaciona de forma estatisticamente significativa com ressecção completa das descargas epileptogênicas sugestivas de displasia e com um resultado favorável em um ano após a cirurgia.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-08-25T20:54:16Z No. of bitstreams: 1 MalekChouchane_TESE.pdf: 3043835 bytes, checksum: b90ef34a2d4072ef5abda48d216aebb4 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2016-08-26T21:40:31Z (GMT) No. of bitstreams: 1 MalekChouchane_TESE.pdf: 3043835 bytes, checksum: b90ef34a2d4072ef5abda48d216aebb4 (MD5) / Made available in DSpace on 2016-08-26T21:40:31Z (GMT). No. of bitstreams: 1 MalekChouchane_TESE.pdf: 3043835 bytes, checksum: b90ef34a2d4072ef5abda48d216aebb4 (MD5) Previous issue date: 2016-02-29 / Recently, the field of cellular reprogramming has been revolutionized by works showing the potential to directly lineage-reprogram somatic cells into neurons upon overexpression of specific transcription factors. This technique offers a promising strategy to study the molecular mechanisms of neuronal specification, identify potential therapeutic targets for neurological diseases and eventually repair the central nervous system damaged by neurological conditions. Notably, studies with cortical astroglia revealed the high potential of these cells to reprogram into neurons using a single neuronal transcription factor. However, it remains unknown whether astroglia isolated from different regions of the central nervous system have the same neurogenic potential and generate induced neurons (iN) with similar phenotypes. Similarly, little is known about the fate that iNs could adopt after transplantation in the brain of host animals. In this study we compare the potential to reprogram astroglial cells isolated from the postnatal cerebral cortex and cerebellum into iNs both in vitro and in vivo using the proneural transcription factors Neurogenin-2 (Neurog2) and Achaete scute homolog-1 (Ascl1). Our results indicate cerebellar astroglia can be reprogrammed into induced neurons (iNs) with similar efficiencies to cerebral cortex astroglia. Notably however, while iNs in vitro adopt fates reminiscent of cortical or cerebellar neurons depending on the astroglial population used for reprogramming, in situ, after transplantation in the postnatal and adult mouse brain, iNs adopt fates compatible with the region of integration. Thus, our data suggest that the origin of the astroglial population used for lineage-reprogramming affects the fate of iNs in vitro, but this imprinting can be overridden by environmental cues after grafting.

The purpose of this study was to examine the effects of cortical spreading depression on neuronal activity in the rat motor (M1) cortex. It is known that cortical spreading depression causes widespread neuronal and glial activity in the cortex, but the degree to which it exerts its effects is unclear. Cortical spreading depression was induced in eight Sprague-Dawley male rats. After two hours, animals were euthanized and immunohistochemistry was performed on the brain to stain for the presence of c-Fos, an immediate early gene that is a well-known marker of neuronal activity. Sections were counterstained for Nissl substance to reveal two populations of cells: Nissl-stained neurons that were c-Fos positive, activated cells and Nissl-stained neurons that were c-Fos negative, non-activated cells. Three sections for each animal were examined and 20-30% of the total M1 cortex was analyzed. Cells were counted using systematic random sampling for each of the six cortical layers. Our results show that the cortical spreading depression did not produce an activation of all neurons. When layers were individually examined, there was a main effect of layer on neuronal activation. This confirmed previous findings that cortical spreading depression had the strongest effect on superficial layers of the cortex

Transcranial direct current stimulation (TDCS) allows for the noninvasive modulation of cortical activity. In this study, the effects of cathodal and anodal TDCS treatment on baseline activity in the motor cortex of rats were investigated via translaminar electroencephalogram (EEG) recording and power spectral density analysis. Treatment with low intensity anodal TDCS for five minutes was found to increase delta and theta frequency cortical activity during and for up to five minutes following treatment. This study also assessed the interaction of TDCS with the phenomenon of cortical spreading depression (CoSD), which has been implicated in numerous disease states, including migraine and stroke. TDCS treatment was given concurrently with induction of CoSD via administration of potassium chloride to the surface of the dura. The presence of the spreading depression event, a characteristic low frequency wave observed to travel outwards from the point of CoSD induction and downwards through the cortex, was used as a proxy measure for the occurrence of CoSD. It was observed that animals treated with cathodal TDCS exhibited fewer spreading depression events relative to those treated with anodal TDCS or those receiving sham treatment. In this study, animals were segregated into groups that exhibited stimulus artifact during TDCS treatment and those that did not. Stimulus artifact was defined as a characteristic alpha and/or beta frequency activity spike lasting throughout and not longer than the period of stimulation. Those animals receiving TDCS without exhibiting stimulus artifact were considered for the purposes of this study to not have received proper TDCS treatment, and acted as a sham treatment group. Because salient differences emerged between the stimulus artifact positive and stimulus artifact negative groups, this study suggests that the presence of stimulus artifact could be used as a proxy measure for successful TDCS dosage.

Complex regional pain syndrome (CRPS) is a chronic neuropathic pain disorder characterized by both central and peripheral symptoms that can be debilitating in children. CRPS treatment typically consists of intensive physical, occupational, and psychological therapy with evidence supporting the efficacy of this approach. Among these outcomes, some patients report significant improvements in pain while others report no change. Identifying baseline predictors of treatment resistance would refine our treatment approach and provide additional targets for intervention. The current study examined baseline brain structure via cortical thickness and gray matter volume (GMV) in 29 pediatric CRPS patients enrolled in an intensive pain rehabilitation program. All participants underwent MRI using a high-resolution T1-weighted sequence. Patients were categorized as pain treatment “responders” (n=19) or “non-responders” (n=10) based on change in reported pain levels from admission to follow up. Compared to treatment responders, non-responders demonstrated significantly less GMV in the bilateral nucleus accumbens p<0.05 and right: putamen p<0.01, pallidum p<0.05, and amygdala p<0.05. Furthermore, treatment non-responders exhibited significant cortical thickening in the left anterior insular cortex and medial frontal gyrus, and cortical thinning in the bilateral precentral gyrus and superior frontal gyrus; right: middle frontal gyrus, fusiform gyrus, inferior temporal gyrus, middle temporal gyrus, and anterior prefrontal cortex; and left: parahippocampal gyrus. Though we did see significant thinning of the primary motor cortex in treatment non-responders compared to responders, the majority of our findings were localized to regions associated with reward, motivation, learning, and emotion. We, therefore, postulate that treatment non-responders, when compared to responders, likely have an intrinsically reduced reward responsiveness, diminished motivation, and impaired learning, overall contributing to their negative treatment outcomes and chronification of pain. In conclusion, these baseline differences overall suggest these regional morphometric alterations may potentially serve as predictors of treatment response in pediatric CRPS. Furthermore, these areas may also indicate possible targets for future treatment.