Parkinson’s disease (PD) is characterized by the loss of dopamine in the basal ganglia and leads to paucity of movements, rigidity of the limbs, and rest tremor. Synaptic plasticity was characterized in the substantia nigra pars reticulata (SNr), a basal ganglia output structure, in 18 PD patients undergoing implantation of deep brain stimulating electrodes. Field evoked potentials (fEPs) in SNr were measured with one microelectrode using single pulses from a second microelectrode ~ 1 mm away. High frequency stimulation (HFS – 4 trains of 2s at 100Hz) in the SNr failed to induce a lasting change in test fEPs amplitudes in patients OFF medication. Following L-Dopa, HFS induced a potentiation of the fEPs that lasted more than 150s. Our findings suggest that extrastriatal dopamine modulates activity dependent synaptic plasticity at basal ganglia output neurons. Dopamine medication state clearly impacts fEP amplitude, and the lasting nature of the increase is reminiscent of LTP-like changes, indicating that aberrant synaptic plasticity may play a role in the pathophysiology of PD.

Parkinson’s disease (PD) is accompanied by a significant amount of beta β-band (11Hz-30Hz) neuronal and local field potential (LFP) oscillatory activity in the subthalamic nucleus (STN). The aim of this study was to measure the spatial extent of β coherent activity in the STN and coherence between STN-SNr in PD patients OFF levodopa by systematically varying the vertical distance between two microelectrodes. We found significant β-LFP coherence across the dorsoventral extent of STN. Spatially extended beta LFP was positively correlated with the mUPDRS scores of the PD patients in the OFF state. Additionally, a significant coherence was found between β-LFPs in dorsal STN and dorsal SNr. These data suggest that the whole STN may be entrained within the β band in PD patients OFF meds. The finding of coherence between STN and SNr suggests that β oscillations synchronize both the input and output nuclei of the basal ganglia.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23810号 / 医博第4856号 / 新制||医||1058(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 高橋 淳, 教授 伊佐 正, 教授 渡邉 大 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

The neurodegenerative disorders Alzheimer??s Disease (AD) and Parkinson??s Disease (PD) are characterised by the accumulation of misfolded amyloid beta 1-42 peptide (Aβ1-42) or α-synuclein, respectively. In both cases, there is extensive evidence to support a central role for these aggregation-prone molecules in the progression of disease pathology. However, the precise mechanisms through which Aβ1-42 and α-synuclein contribute to neurodegeneration remain unclear. Organismal, cellular and in vitro models are under development to allow elucidation of these mechanisms. A cellular system for the study of intracellular Aβ1-42 misfolding and localisation was developed, based on expression of an Aβ1-42-GFP fusion protein in the model eukaryote Saccharomyces cerevisiae. This system relies on the known inverse relationship between GFP fluorescence, and the propensity to misfold of an N-terminal fusion domain. To discover cellular processes that may affect the misfolding and localisation of intracellular Aβ1-42, the Aβ1-42-GFP reporter was transformed into the S. cerevisiae genome deletion mutant collection and screened for fluorescence. 94 deletion mutants exhibited increased Aβ1-42-GFP fluorescence, indicative of altered Aβ1-42 misfolding. These mutants were involved in a number of cellular processes with suspected relationships to AD, including the tricarboxylic acid cycle, chromatin remodelling and phospholipid metabolism. Detailed examination of mutants involved in phosphatidylcholine synthesis revealed the potential for phospholipid composition to influence the intracellular aggregation and localisation of Aβ1-42. In addition, an existing S. cerevisiae model of α-synuclein pathobiology was extended to study the effects of compounds that have been hypothesized to be environmental risk factors leading to increased risk of developing PD. Exposure of cells to aluminium, dieldrin and compounds generating reactive oxygen species enhanced the toxicity of α- synuclein expression, supporting suggested roles for these agents in the onset and development of PD. Expression of α-synuclein-GFP in phosphatidylcholine synthesis mutants identified in the Aβ1-42-GFP fluorescence screen resulted in dramatic alteration of α-synuclein localisation, indicating a common involvement of phospholipid metabolism and composition in modulating the behaviours of these two aggregation-prone proteins.

Traditionally, people with Parkinson’s disease (PD) are advised to avoid performing dual-tasks while walking. Rehabilitation programs also emphasise the need to train walking under single-task conditions to improve gait and reduce risk for falls. There are findings that people with PD can walk faster and with longer strides while performing a secondary motor or cognitive task, when cued by a metronome or visual floor stripes. There are also findings that people with PD can walk faster and with longer strides while performing a secondary motor task simply by prioritising their attention to take big steps. Using attention is a convenient strategy favoured by people with PD to manage their gait difficulties. / This thesis examined the immediate and training effects of two attention-priority strategies on dual-cognitive task walking in people with mild to moderate PD. Two groups of participants received 30 minutes of training to prioritise attention to take big steps while performing serial three subtractions (gait-priority strategy) or to divide their attention between taking big steps and the cognitive task (equal-priority strategy). Control groups received no training. Measures of gait hypo-bradykinesia (stride length and gait velocity), stride variability (Coefficient of variation [CV] of stride length and CV of stride time) and cognitive task performance (accurate enumeration rate) were assessed at baseline, during training, immediately after training and 30 minutes after training. Both attention-priority strategies improved stride length and gait velocity during training. The improvement was retained for at least 30 minutes after training. Both strategies have no effect on CVs of stride length, stride time and accurate enumeration rate. / Many daily routines require our ability to overcome single-, dual- and multi-task demands while walking. Rehabilitation strategies should encompass real life demands in order to minimise functional impairments, activity limitations and participation restrictions, as recommended by the World Health Organisation. Putting together the findings of this thesis and the evidence provided by previous studies, it is concluded that traditional recommendations need qualification. Avoiding dual-tasks during walking or gait retraining in people with mild to moderate PD may not be necessary. Gait-priority and equal-priority strategies can be used as compensatory strategies to improve gait during dual-tasks. The two strategies can also be used in training programs for walking rehabilitation.

Thesis (Ed.D.)--Georgia Southern University, 2006. / "A dissertation submitted to the Graduate Faculty of Georgia Southern University in partial fulfillment of the requirements for the degree Doctor of Education." Under the direction of Meta Y. Harris. ETD. Includes bibliographical references (p. 54-61) and appendices.

Thesis (MPhyst. (Faculty of Health Sciences))--University of Pretoria, 2008. / Summary in English and Afrikaans. Includes bibliographical references.

Thesis (Ph. D.)--Auburn University. / Abstract. Vita. Includes bibliographical references.

Thesis (M. S.)--Civil and Environmental Engineering, Georgia Institute of Technology, 2004. / Dr. Michael Hunter, Committee Member ; Dr. Alexander M. Puzrin, Committee Member ; Dr. Nelson Baker, Committee Chair. Includes bibliographical references.

Thesis (Ph. D.)--State University of New York at Binghamton, Department of Psychology, Behavioral Neuroscience, 2008. / Includes bibliographical references.