初級運動皮質直接負責運動控制。大量關於帕金森式癥(PD)的有效治療手段的研究已經證明，初級運動皮質在病理情況下的功能改變，直接與患者運動障礙相關。本論文的研究重點在於探索初級運動皮質在深部腦刺激治療帕金森氏症的運動障礙的過程中發揮的作用及其與運動學習功能障礙的聯繫。 / 丘腦底核深部腦刺激(STN-DBS) 已被廣泛應用於治療帕金森式症。雖然該項治療手段能顯著地改善患者的運動功能障礙，但其確切的治療機制仍未明確。理論上來說，丘腦底核深部腦刺激能夠直接啟動丘腦底核內部和其周圍很大範圍的神經組織，包括丘腦底核內部本身的神經元胞體，以及與其相連接的輸入輸出核團的神經元軸突。在丘腦底核眾多輸入核團之中，一個重要的神經輸入來自於初級運動皮質(MI)第五層的離皮質神經元(CxFn)，電刺激引起的逆行皮質啟動作用被提出，用於解釋丘腦底核深部腦刺激的治療機制。 / 為了研究逆行皮質啟動效應究竟如何在丘腦底核深部腦刺激的過程之中帶來治療效果，我們採用多通道神經電生理信號記錄系統在自由活動的單側帕金森大鼠的初級運動皮質進行鋒電位元和局部場電位元信號的記錄。實驗結果證明，當對丘腦底核進行高頻電刺激，在運動皮質第五層的離皮質神經元能成功記錄到保持固定延時的逆行鋒電位。由於增加刺激頻率會引起逆行鋒電位被成功記錄到的百分比下降，因此當深部腦刺激的頻率選擇在125Hz時，逆行鋒電位的放電頻率達到最高，而此刺激頻率正好與行為學實驗中帶來最佳治療效果的刺激頻率一致。於此同時，逆行皮質啟動作用還伴隨著初級運動皮質離皮質神經元的自發放電頻率增加、同步性爆發式放電減少等電生理信號特點。場電位分析的結果進一步表明，丘腦底核深部腦刺激減弱了病理情況下出現的beta波頻譜能量增高以及鋒電位-場電位相干性增強。更重要的是，我們發現只有逆行鋒電位被成功誘發，離皮質神經元的發放電機率才能被調節。這點有力地表明由電刺激隨機誘發的逆行鋒電位傳導至初級運動皮質，直接幹預並抑制了離皮質神經元在病理情況下的同步性爆發式放電活動，從而緩解了帕金森氏症的運動障礙。 / 另外，初級運動皮質並不僅僅是一個靜態的運動控制中樞，更為重要的功能在於它參與著與運動學習和運動記憶相關的動態資訊編碼。帕金森氏症患者普遍存在皮質可塑性減弱以及運動技能學習障礙。由於初級運動皮質分層結構的存在，層內神經元之間的突觸連接為神經可塑性提供了很好的結構基礎。因此，我們在初級運動皮質誘發在體長時程增強(LTP)，旨在研究與運動技能學習相關的皮質神經可塑性的動態變化過程，以及探索中腦多巴胺能投射系統對皮質神經可塑性的影響。 / 一方面，我們採用間斷性高頻刺激誘發在體長時程增強，證實六羥多巴損毀後皮質的長時程增強水準顯著下降。另一方面，我們設計前肢抓食的行為學範式用來評價動物在運動技能學習的不同階段皮質可塑性發生的動態變化。實驗結果表明，直接損毀皮質的多巴胺能輸入，模型組大鼠與假實驗組大鼠的行為表現在初期的技能獲取階段並無明顯差異，而只在後期的技能鞏固階段模型組大鼠表現出技能鞏固障礙。更為有趣的是，兩組行為學變化趨勢與各自的在體長時程增強的變化趨勢有很高的一致性。本研究表明多巴胺對初級運動皮質的支配在運動記憶的鞏固過程中起著關鍵作用。在帕金森氏症的病理情況下，多巴胺耗竭將影響皮質的突觸可塑性，從而造成帕金森患者在運動技能的鞏固階段表現出障礙。 / The primary motor cortex (MI) controls movement directly, but is an under-investigated brain region in the pathogenesis and treatment of Parkinsonian motor disability, when compared with the basal ganglia circuitry. In this study, the roles of MI in underlying the therapeutic action of surgical deep brain stimulation and motor learning impairment were investigated. / Deep brain stimulation of the subthalamic nucleus (STN-DBS) is now a recognized therapeutic option for Parkinson’s disease (PD). Although this surgical strategy provides behavioral benefits remarkably, its exact mechanism is still a matter of controversy. In principle, STN-DBS can directly activate a wide range of neuronal elements within the STN and surrounding areas. As the corticofugal neurons (CxFn) in the layer V motor cortex provide a major input to the STN, we hypothesized that the stimulation evoked antidromic cortical activation is involved in the therapeutic mechanism of STN-DBS. In the first series of experiments, we performed simultaneous recordings of multi-unit neuronal activities and local field potentials (LFPs) in MI in freely moving hemi-parkinsonian rats. By identifying stimulation evoked antidromic spike, which occurred at a fixed, short latency, CxFn located in the layer V MI were identified. Increasing stimulation frequency also increased failure rate of activation, resulting in a peak frequency of stochastic antidromic spikes at 125Hz STN-DBS, which was correlated with the optimal therapeutic efficacy observed in behavioral tests. Meanwhile, this antidromic effect was accompanied by the rectification of pathological neuronal activities including increased spontaneous firing rate, reduced burst discharge and synchrony among the CxFn. Field potential analysis revealed that STN-DBS alleviated the dominance of pathological beta band oscillation and spike-field coherence in the MI. More importantly, it was found that the firing probability of CxFn could only be modified following the occurrence of antidromic spikes, suggesting that direct interference of stochastic antidromic spikes with pathological neuronal activities underlies the beneficial effect of STN-DBS. / The MI is not simply a static motor control structure. It also contains a dynamic substrate that participates in motor learning or stores motor memory. In PD patients, loss of cortical plasticity and impaired motor learning is a common feature. As the intrinsic horizontal neuronal connections in MI are a strong candidate of cellular correlate for activity-dependent plasticity, in the second series of experiments, we developed in vivo long-term potentiation (LTP) technique in the MI to investigate the dynamics of cortical plasticity during motor skill learning and the role of the innervation by mesocortical dopamine input. Local depletion of dopamine in the primary motor cortex resulted in reduced performance in the forelimb reaching for food learning task. Although the performance of the PD rats in the initial learning phase was comparable to that of the sham-operated group, as training continued, these animals exhibited deficit in consolidating the motor skill. These deficits closely paralleled the impairment in training-enhanced synaptic connections in layer V neurons, and the in vivo LTP of evoked field excitatory postsynaptic potentials induced by intermittent high frequency stimulation. In addition, progressive recruitment of task-specific neurons was suppressed. Our study therefore revealed that dopamine depletion confined to the MI could lead to impairment in cortical synaptic plasticity which may preferentially affect the consolidation, but not the acquisition, of motor skills. These findings shed light on the cellular mechanisms of motor skill learning and could explain the decreased ability of PD patients in learning new motor skills. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Li, Qian. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 168-190). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts also in Chinese. / CHAPTER 1 --- p.1 / General Introduction --- p.1 / Chapter 1.1 --- Anatomical organization of the basal ganglia --- p.1 / Chapter 1.1.1 --- Overview of the basal ganglia circuit --- p.1 / Chapter 1.1.2 --- Cortico-basal ganglia-cortical circuit --- p.1 / Chapter 1.1.2.1 --- Direct and indirect pathway --- p.2 / Chapter 1.1.2.2 --- Hyperdirect pathway --- p.2 / Chapter 1.1.2.3 --- The midbrain dopamine system --- p.2 / Chapter 1.2 --- Striatum --- p.3 / Chapter 1.2.1 --- Cell types in the striatum. --- p.3 / Chapter 1.2.2 --- The Cortico-striatal system --- p.4 / Chapter 1.3 --- Subthalamic Nucleus --- p.5 / Chapter 1.3.1 --- Neuronal property of the STN. --- p.5 / Chapter 1.3.2 --- Electrophysiological property of the STN --- p.6 / Chapter 1.3.3 --- Cortico-subthalamic system --- p.7 / Chapter 1.3.4 --- Functional significance of the cortico-subthalamic and corticostriatal system. --- p.8 / Chapter 1.4 --- Parkinson’s disease --- p.9 / Chapter 1.4.1 --- Pathogenesis of PD --- p.9 / Chapter 1.4.2 --- Genetic risk factors of PD --- p.10 / Chapter 1.4.3 --- Progressive motor symptoms of PD --- p.11 / Chapter 1.4.4 --- Non-motor symptoms of PD --- p.13 / Chapter 1.4.5 --- Pathological neuronal rhythms in the basal ganglia of PD. --- p.16 / Chapter 1.5 --- Experimental studies of PD. --- p.18 / Chapter 1.5.1 --- Animal modeling of PD. --- p.18 / Chapter 1.5.2 --- Motor deficits evaluation in rodent models of PD --- p.21 / Chapter 1.5.3 --- Non-motor symptoms evaluation in experimental models of PD --- p.24 / Chapter 1.6 --- Deep Brain Stimulation --- p.27 / Chapter 1.6.1 --- DBS in alleviating Parkinsonian motor symptoms --- p.28 / Chapter 1.6.2 --- DBS in alleviating Parkinsonian non-motor symptoms --- p.29 / Chapter 1.6.3 --- Investigation of the STN-DBS mechanism. --- p.31 / Chapter 1.6.3.1 --- Local inhibitory effect within the STN --- p.32 / Chapter 1.6.3.2 --- Excitatory effect at output nuclei --- p.33 / Chapter 1.6.3.3 --- The de-coupling of soma and axons at system level --- p.34 / Chapter 1.6.3.4 --- Effects of DBS on abnormal rate or pattern --- p.35 / Chapter 1.6.3.5 --- Antidromic propagation of DBS effect towards cortex --- p.37 / Chapter 1.7 --- Objective --- p.38 / Chapter 1.8 --- Figures --- p.41 / CHAPTER 2 --- p.47 / General Methods --- p.47 / Chapter 2.1 --- Animals --- p.47 / Chapter 2.2 --- Stereotaxic surgery --- p.47 / Chapter 2.2.1 --- Preoperative preparation --- p.47 / Chapter 2.2.2 --- Anesthesia and craniotomy --- p.48 / Chapter 2.2.3 --- Induction of hemi-Parkinsonian rat model --- p.48 / Chapter 2.2.4 --- Electrode implantation techniques. --- p.49 / Chapter 2.3 --- Behavioral assessment. --- p.50 / Chapter 2.3.1 --- Apomorphine-induced contralateral rotation. --- p.50 / Chapter 2.3.2 --- Open field test --- p.50 / Chapter 2.4 --- STN-DBS protocol --- p.50 / Chapter 2.5 --- Electrophysiological data acquisition --- p.51 / Chapter 2.6 --- Data analysis --- p.52 / Chapter 2.6.1 --- Statistical analysis of behavioral data --- p.52 / Chapter 2.6.2 --- Electrophysiological data --- p.52 / Chapter 2.6.2.1 --- Stimulation artifact removal --- p.52 / Chapter 2.6.2.2 --- Multi-unit spike sorting --- p.53 / Chapter 2.6.2.3 --- Electrophysiological identification of pyramidal neuron and interneuron. --- p.54 / Chapter 2.6.2.4 --- Identification of antidromic cortical activation --- p.54 / Chapter 2.6.2.5 --- Discharge pattern classification --- p.54 / Chapter 2.6.2.6 --- Synchrony level evaluation --- p.55 / Chapter 2.6.2.7 --- Oscillatory rhythm characterization --- p.55 / Chapter 2.6.2.8 --- Coherence Level Measurement --- p.56 / Chapter 2.7 --- Histological verification --- p.56 / Chapter 2.8 --- Figures --- p.58 / CHAPTER 3 --- p.60 / Alleviation of Parkinsonian Motor Symptoms during Deep Brain Stimulation in Hemi-Parkinsonian Rats --- p.60 / Chapter 3.1 --- Introduction --- p.60 / Chapter 3.2 --- Materials & Methods --- p.61 / Chapter 3.2.1 --- Animals --- p.61 / Chapter 3.2.2 --- Chemicals --- p.61 / Chapter 3.2.3 --- Equipment --- p.61 / Chapter 3.3 --- Results --- p.62 / Chapter 3.3.1 --- Time course of the Apomorphine induced rotation behavior --- p.62 / Chapter 3.3.2 --- Dose-dependence of the Apomorphine induced rotation --- p.62 / Chapter 3.3.3 --- Acute behavioral response to STN-DBS. --- p.63 / Chapter 3.3.4 --- The dependence of STN-DBS effect on stimulation paradigm. --- p.64 / Chapter 3.3.5 --- Acute effects of STN-DBS on APO induced rotation. --- p.64 / Chapter 3.3.6 --- Long-term effects of STN-DBS on APO induced rotation --- p.64 / Chapter 3.3.7 --- Histological confirmation of the stimulation electrodes localization --- p.65 / Chapter 3.3.8 --- Loss of DA neurons in the SNc --- p.65 / Chapter 3.3.9 --- Reductions of the DA axon terminals in the striatum --- p.65 / Chapter 3.3.10 --- Chronic STN-DBS failed to rescue nigrostsriatal and striatal DA --- p.66 / Chapter 3.4 --- Discussion --- p.66 / Chapter 3.4.1 --- Neurotoxic mechanism of 6-OHDA --- p.66 / Chapter 3.4.2 --- Time course of dopamine degeneration induced by 6-OHDA --- p.66 / Chapter 3.4.3 --- Failure in observing worsened motor symptoms during low frequency STN-DBS. --- p.67 / Chapter 3.4.4 --- Experimental DBS based on rat model: does it mimic human case? --- p.67 / Chapter 3.4.5 --- Technical issues about STN-DBS --- p.69 / Chapter 3.5 --- Figures --- p.72 / CHAPTER 4 --- p.82 / Direct involvement of the Corticofugal Neurons in Motor Cortex during Therapeutic Deep Brain Stimulation --- p.82 / Chapter 4.1 --- Introduction --- p.82 / Chapter 4.2 --- Materials --- p.83 / Chapter 4.2.1 --- Animals --- p.83 / Chapter 4.2.2 --- Chemicals --- p.83 / Chapter 4.2.3 --- Equipment --- p.83 / Chapter 4.3 --- Results --- p.84 / Chapter 4.3.1 --- Identification of CxFn based on antidromic effect --- p.84 / Chapter 4.3.2 --- Antidromic spikes frequency correlates with therapeutic effect of STN-DBS. --- p.84 / Chapter 4.3.3 --- Pathological changes of neuronal firing rate in MI --- p.85 / Chapter 4.3.4 --- Only high frequency STN-DBS normalizes neuronal firing rate in MI --- p.86 / Chapter 4.3.5 --- Pathological changes of neuronal discharge pattern in MI --- p.88 / Chapter 4.3.6 --- Pathological synchrony of MI neuronal population, especially during burst discharge --- p.89 / Chapter 4.3.7 --- High frequency STN-DBS successfully suppresses synchronized burst discharge in MI --- p.89 / Chapter 4.3.8 --- Pathological β-band oscillatory activity in MI-LFPs induced by 6-OHDA lesion --- p.90 / Chapter 4.3.9 --- High frequency STN-DBS alleviates the β-band oscillation in MI-LFPs --- p.90 / Chapter 4.3.10 --- Synchronized bursting discharge correlates with oscillatory activity --- p.91 / Chapter 4.3.11 --- Pathological increased spike-LFP coherence level induced by 6-OHDA lesion --- p.92 / Chapter 4.3.12 --- High frequency STN-DBS modulated the spike-LFP coherence properties --- p.92 / Chapter 4.3.13 --- Antidromic spikes directly modulate the firing probability of CxFn --- p.93 / Chapter 4.3.14 --- Antidromic spikes modulate the firing probability of INs and non-CxFn nearby. --- p.94 / Chapter 4.3.15 --- The efficiency of antidromic cortical modulation depends on DBS frequency --- p.94 / Chapter 4.3.16 --- Orthodromic vs. antidromic effect: which one is responsible for the beneficial effect of DBS? --- p.95 / Chapter 4.3.17 --- Histology --- p.96 / Chapter 4.4 --- Discussion --- p.96 / Chapter 4.4.1 --- Origin of pathogenic rhythm in basal ganglia circuit --- p.96 / Chapter 4.4.2 --- Suppression of oscillatory synchronization equals to therapeutic effects of DBS? --- p.97 / Chapter 4.4.3 --- Beneficial effect of DBS corresponds to the topographic distribution of cortico-subthalamic projection. --- p.98 / Chapter 4.4.4 --- What is the reason for a stochastic pattern of antidromic activation effect? --- p.99 / Chapter 4.4.5 --- Desynchronization of pathological oscillatory rhythm by antidromic activation --- p.100 / Chapter 4.4.6 --- Antidromic vs. orthodromic: which is the cause of the beneficial effects of DBS? --- p.101 / Chapter 4.4.7 --- Wide propagation of antidromic effect by cortical horizontal circuits --- p.102 / Chapter 4.4.8 --- Significance of antidromic cortical activation in during STN-DBS --- p.102 / Chapter 4.4.9 --- Implication of antidromic activation effect on pathogenesis and treatment of PD --- p.104 / Chapter 4.5 --- Figures --- p.105 / CHAPTER 5 --- p.132 / Impaired Synaptic Plasticity in the Primary Motor Cortex after Dopamine Depletion: Potential Role in Motor Memory Consolidation --- p.132 / Chapter 5.1 --- Introduction --- p.132 / Chapter 5.1.1 --- Characteristics of motor learning --- p.132 / Chapter 5.1.2 --- Motor learning related cortical plasticity. --- p.133 / Chapter 5.1.3 --- Dopaminergic signals in the primary motor cortex --- p.134 / Chapter 5.1.4 --- Impaired cortical plasticity in PD --- p.135 / Chapter 5.1.5 --- Objective --- p.136 / Chapter 5.2 --- Materials --- p.136 / Chapter 5.2.1 --- Animals --- p.136 / Chapter 5.2.2 --- Chemicals --- p.136 / Chapter 5.2.3 --- Equipment --- p.136 / Chapter 5.3 --- Methods --- p.136 / Chapter 5.3.1 --- Functional mapping of the forelimb territory in MI --- p.136 / Chapter 5.3.2 --- Stereotaxic surgery --- p.137 / Chapter 5.3.3 --- Forelimb-reaching Task. --- p.137 / Chapter 5.3.4 --- In-vivo LTP Induction. --- p.138 / Chapter 5.4 --- Results --- p.139 / Chapter 5.4.1 --- Functional mapping of rat forelimb territory. --- p.139 / Chapter 5.4.2 --- Morphologies of evoked field potential response --- p.139 / Chapter 5.4.3 --- LTP of the early, monosynaptic plasticity within horizontal layer V MI --- p.140 / Chapter 5.4.4 --- LTP of the late, polysynaptic plasticity within horizontal layer V MI --- p.140 / Chapter 5.4.5 --- Impaired synaptic plasticity in MI after dopamine depletion --- p.140 / Chapter 5.4.6 --- Learning curve of forelimb-reaching task --- p.140 / Chapter 5.4.7 --- Physiologically enhanced cortical plasticity during motor learning --- p.141 / Chapter 5.4.8 --- Dynamic modulation of cortical neuronal activities during motor skill learning. --- p.142 / Chapter 5.4.9 --- Statistical analysis of ‘task related’ neuron’s modulation pattern. --- p.143 / Chapter 5.4.10 --- Loss of dopamine modulation in the MI --- p.144 / Chapter 5.5 --- Discussion --- p.144 / Chapter 5.5.1 --- Distinguishing between monosynaptic and polysynaptic transmission --- p.144 / Chapter 5.5.2 --- Artificially vs physiologically induced cortical plasticity. --- p.145 / Chapter 5.5.3 --- Cortical synaptic plasticity interprets motor learning dynamics --- p.146 / Chapter 5.5.4 --- Balance between neuronal recruitment and withdrawal in the consolidation stage --- p.147 / Chapter 5.5.5 --- Dopamine’s involvement in mediating the cortical synaptic plasticity. --- p.148 / Chapter 5.6 --- Figures --- p.150 / Conclusion --- p.162 / Abbreviations --- p.165 / References --- p.168

Thesis(M.Tech.: Chiropractic)- Dept. of Chiropractic, Durban Institute of Technology, 2005 xi, 62 leaves / To compare the relative activation and endurance of core stability muscles in 2 different populations i.e. elite athletes and non-athletes, and establish whether these findings correspond to episodes of mechanical lower back pain.

Thesis (MScMedSc)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Parkinson's disease (PD) is a severely debilitating neurodegenerative disorder that results in motor circuit dysregulation and ultimately, causes impairment of movement. This condition is due to the selective degradation of the dopaminergic neurons in the substantia nigra pars compacta in the midbrain, which subsequently results in the pathological symptoms namely bradykinesia, resting tremor, postural instability and rigidity. It was initially hypothesized that individuals who develop PD were exposed to an environmental trigger(s) that caused the onset of the disease, but more recently, a significant genetic component, coupled to environmental factors have been implicated in disease pathogenesis. Currently, there are eight genes (Parkin, PINK1, LRRK2, SNCA, DJ-1, ATP13A2, EIF4G1 and VPS35) that have been directly implicated in PD. Worldwide, the prevalence of neurodegenerative disorders is increasing as populations are living longer. In Europe, Canada and USA, it has been projected that the prevalence of PD may increase by a factor of two between 2010 and 2050; approximately a 92% increase. In Tanzania (the only study done in sub-Saharan Africa) an even larger increase of 184% between 2005 and 2025 is predicted, due to the fact that the speed of populations ageing in developing countries, will exceed that of developed countries. Research into the causes and risk factors underlying neurodegenerative disorders such as PD is therefore urgently needed for policy makers and governments in developing nations to take appropriate action to deal with this impending health care problem. The aim of the present study was to investigate the molecular aetiology of a group of South African PD patients. A total of 262 patients from various ethnic backgrounds were recruited for the study, and 35% had a positive family history of PD with the average age at onset (AAO) being 54.3 years of age (SD = 12.5 years). Mutation screening of the known PD genes (Parkin, PINK1, LRRK2, SNCA and DJ-1) was performed using high resolution melt and Sanger sequencing. Genotyping was done using fluorescently-labelled PCR primers followed by electrophoresis on an ABI 3130xl genetic analyser (for CTG repeats in JPH3) and with a KASP™ Genotyping Assay (for a 16bp indel in DJ-1). In order to identify a novel PD-causing gene, whole exome sequencing (WES) was conducted on three Afrikaner probands with an Illumina Genome Hiseq 2000TM and the sequences were aligned using the NCBI Human Reference Genome 37.2. The BORG (Bio-Ontological Relationship Graph) semantic database, which models the relationship of human and model organism genes to functions, pathways and phenotypes, was used to filter and prioritise genetic variants shared between the three PD exomes. It was determined that the known PD genes do not play a significant role in disease pathogenesis in the South African patients as only 15/262 (5.7%) of the patients harboured mutations: seven in Parkin, one in PINK1, six in LRRK2 and one in SNCA. Only one of the patients harboured a 16bp indel variant at the transcription start site of DJ-1. None of the Black PD patients had pathogenic repeat expansions in JPH3 thereby excluding Huntington disease-like 2 as a cause of the disease phenotype. Genealogical analysis revealed that six of the apparently unrelated Afrikaner PD probands were related to a founder couple that immigrated to South Africa in the 1600s which suggests that there is a possible founder effect for the disease. Bioinformatics analysis of WES data on three of the probands identified 21 variants in 12 genes that were present in all three PD exomes and fulfilled various criteria. Sanger sequencing was used for verification of five variants and of these, two (in CDC27 and NEDD4) were found to be artefacts. The remaining three (in HECDT1, TBCC and RNF40) were excluded based on the lack of cosegregation with disease and the high frequency of the allele in controls. Further work is necessary to verify the presence of the remaining sixteen variants and to characterise each of them for their possible pathogenicity. The discovery of novel PD-causing genes is important as this may shed light on the pathways or processes that are involved. A current hypothesis implicates the lysosome-dependent pathway as a unifying biochemical pathway that can account for the phenotypic spectrum within PD. Notably, although Mendelian forms are thought to account for only about 10- 15% of cases, the study of Mendelian inherited variants is likely to provide insight into the pathophysiology of the more common sporadic form of this condition. Dissecting the key molecular mechanisms underlying PD will provide critical information for improved treatment strategies and drug interventions that will ultimately prevent or halt neuronal cell loss in susceptible individuals. / AFRIKAANSE OPSOMMING: Parkinson se siekte (PS) is 'n erge neurodegeneratiewe bewegings-siekte, wat motorstroombaan disregulasie veroorsaak. Dit lei uiteindelik tot beperkte bewegings vermoëns. Hierdie toestand word veroorsaak weens die selektiewe agteruitgang van die dopaminergeniese neurone in die substantia nigra pars compacta in die midbrein, wat later lei tot die patologiese simptome naamlik: bradykinesia, rustende spiersametrekkings, posturale onstabiliteit en rigiditeit. Daar is aanvanklik vermoed dat individue wat PS ontwikkel, aan 'n omgewingsfaktor(e) blootgestel is wat die aanvang van die siekte veroorsaak het, terwyl meer onlangs is daar 'n aansienlike genetiese komponent tesame met omgewingsfaktore geïdentifiseer, wat betrokke is by die patogenese van die siekte. Tans is daar agt gene (Parkin, PINK1, LRRK2, SNCA, DJ-1, ATP13A2, EIF4G1 en VPS35) wat direk by PS geïmpliseer is. Wêreldwyd is daar ‗n toenemende voorkoms van neurodegeneratiewe siektes aangesien bevolkings langer leef. In Europa, Kanada en die VSA, is daar geprojekteer dat die voorkoms van PS tussen 2010 en 2050 met 'n faktor van twee verhoog kan word. Dit is ongeveer 'n 92%- verhoging. In Tanzanië (die enigste studie wat tot dusver in sub-Sahara Afrika gedoen is) word daar selfs ‗n groter toename, van 184% tussen 2005 en 2025 voorspel. Dit is te danke aan die feit dat die bevolkings- veroudering in ontwikkelende lande die van ontwikkelde lande sal oorskry. Ondersoeke na die oorsake en risiko-faktore onderliggend aan neurodegeneratiewe siektes, byvoorbeeld PS, word dus dringend benodig deur beleidmakers en regerings in ontwikkelende lande, sodat hulle die nodige stappe kan neem om hierdie dreigende gesondheidsorg-probleem op te los. Die doel van die huidige studie was om ondersoek in te stel na die molekulêre etiologie van 'n groep Suid-Afrikaanse PS pasiënte. 'n Totaal van 262 pasiënte van verskillende etniese agtergronde, is gewerf vir die studie. Hiervan het 35% 'n positiewe familiegeskiedenis van PS en die gemiddelde aanvangs ouderdom (AAO) was 54,3 jaar (SD = 12,5 jaar). Mutasie-analise van die bekende PS gene is uitgevoer met behulp van hoë resolusie smelt en Sanger volgordebepaling. Genotipering is gedoen met behulp van fluoresserend geëtiketteerde PKR inleiers met elektroforese, op 'n ABI 3130xl genetiese analiseerder (CTG herhalings in JPH3), en met 'n KASP ™ Genotipering toets (vir 'n 16bp indel in DJ-1). Ten einde, om 'n nuwe PSveroorsakende geen te identifiseer was heel eksoom volgordebepaling (WES) uitgevoer op drie Afrikaner PS positiewe pasiënte met 'n Illumina Genome Hiseq 2000™ en die volgorders is gerangskik met behulp van die NCBI Menslike Verwysings Genoom 37.2. Die BORG (Bio- Ontologiese Verhoudings Grafiek) semantiese databasis, wat gebaseer is op die verhouding van die mens en model organisme gene funksies, paaie en fenotipes, en is gebruik om genetiese variante, wat gedeel word tussen die drie PS exome te filtreer en te prioritiseer. Daar is vasgestel dat die bekende PS gene nie 'n belangrike rol in die patogenese van die siekte in die Suid-Afrikaanse pasiënte speel nie. Dit is aangesien slegs 15/262 (5.7%) van die pasiënte bekende mutasies dra: sewe in Parkin, een in PINK1, ses in LRRK2 en een in SNCA. Slegs een van die pasiënte het 'n 16bp delesie variant in die transkripsie promotor area van DJ-1 gedra. Geen van die Swart PS pasiënte het patogeniese herhalings in JPH3 vertoon nie. Gevolglik is Huntington siekte-agtige 2 uitgesluit as 'n oorsaak van die siekte fenotipe. Genealogiese analise het getoon dat ses van die skynbaar onverwante Afrikaner PS pasiënte verwant is aan 'n stigter paartjie wat in die 1600's na Suid-Afrika geïmigreer het, wat daarop dui dat daar 'n moontlike stigter effek vir die siekte is. Bioinformatiese analise van WES data vir drie van die pasiënte, het 21 variante in 12 gene geïdentifiseer, wat in al drie PS exome teenwoordig was en verskeie kriteria vervul het. Sanger volgordebepaling is gebruik vir die bevestiging van vyf variante en van hierdie, is twee (in CDC27 en NEDD4) bevind om artefakte te wees. Die oorblywende drie (in HECDT1, TBCC en RNF40) is uitgesluit gebaseer op die gebrek aan gesamentlike-segregasie met die siekte en die hoë frekwensie van die allele in die kontrole groep. Verdere werk is nodig om die teenwoordigheid van die oorblywende variante te verifieer en om elkeen van hulle te karakteriseer vir hulle moontlike patogenisiteit. Die ontdekking van die nuwe PS-veroorsakende gene is belangrik aangesien dit lig kan werp op die stelsels of prosesse wat betrokke is. 'n Huidige hipotese impliseer die lisosoom-afhanklike pad as 'n verenigende biochemiese padweg, wat verantwoordelik is vir die fenotipiese spektrum binne PS. Alhoewel Mendeliese vorms vermoedelik verantwoordelik is vir slegs omgeveer 10-15% van die gevalle, is die studie van Mendelse gene geneig om insig te verkry in die patofisiologie van die meer algemene sporadiese vorm van hierdie toestand. Ontleding van die kern molekulêre meganismes onderliggend aan PS sal kritiese inligting vir beter strategieë vir behandeling en geneesmiddel-intervensies voorsien, wat gevolglik neuronale sel verlies in vatbare individue sal voorkom of beëindig. / Medical Research Council / National Research Foundation / Harry Crossley Foundation

Orientador: Vitório Rodrigo / Resumo: Dentre os comprometimentos motores associados à doença de Parkinson (DP), os distúrbios do andar são os mais incapacitantes aos pacientes. Disfunções cognitivas e do córtex cerebral, presentes na DP, influenciam nos comprometimentos do andar. Como o tratamento tradicional para DP (uso regular de medicamentos) apresenta pouco benefício para o controle do andar, faz-se necessário o desenvolvimento de intervenções alternativas. O exercício aeróbio (EA) e a estimulação transcraniana por corrente contínua (ETCC) têm sido apontados como de grande potencial terapêutico na DP, incluindo benefícios para o andar e a cognição. Além disso, especula-se que a combinação das duas técnicas é capaz de potencializar os efeitos positivos. Entretanto novos estudos são necessários para confirmar tal evidência. . Assim, o objetivo do presente estudo foi comparar os efeitos de uma sessão combinada de EA e ETCC anódica do córtex pré-frontal com os de uma sessão de EA na atividade cortical, cognição e no andar usual e no custo da tarefa dupla no andar de pacientes com DP. Era esperado que a combinação da ETCC com EA promovesse benefícios superiores aos apresentados pelo EA isolado. O desenho experimental utilizado foi de estudo crossover randomizado e duplo-cego. Participaram do estudo 20 pacientes com DP. O protocolo de avaliação, que incluiu aspectos cognitivos (questionários e testes computadorizados) e do andar, foi realizado em dois momentos: antes e após uma sessão de intervenção. O andar foi a... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Among the motor impairments associated with Parkinson's disease (PD), gait impairments are incapacitating to patients. Cognitive and cerebral cortex dysfunctions, present in PD, influence gait impairments. As the traditional treatment for PD (regular use of medications) has limited benefit for gait, it is necessary to develop alternative interventions. Aerobic exercise (AE) and transcranial direct current stimulation (tDCS) have been identified with great therapeutic potential in PD, including advantages for gait and cognition. However, the effects of combining such interventions remain poorly understood. The aim of the present study was to compare the effects of a combined session of AE and anodic tDCS of the prefrontal cortex with those of an AE session on cortical activity, cognition, usual gait, and the cost of the dual task on the gait of patients with PD. It was expected that the combination of tDCS and AE would promote greater benefits than those promoted by the isolated AE. Twenty patients with PD participated in this randomized, double-blind and crossover study. The evaluation protocol included cognitive components (questionnaires and computerized tests) and gait. This protocol was performed in two moments: before and after the intervention sessions. Gait was assessed under two conditions: single-task and dual-task. An electronic walkway with pressure sensors (GAITRite®) was used to record spatiotemporal measurements of gait. Prefrontal cortical activity during gait ... (Complete abstract click electronic access below) / Mestre

O objetivo deste trabalho foi caracterizar as alterações de linguagem na doença de Huntington e correlacioná-las com os transtornos motores, cognitivos, psiquiátricos e, também, com o tempo de doença. Foram estudados 26 indivíduos, divididos em grupo leve (11 doentes) e moderado (15 doentes), comparados com dois grupos controle. Foram encontradas alterações em provas de compreensão e expressão da linguagem oral e gráfica para os dois grupos de doentes. Evidências sugerem que não há prejuízo nas representações semânticas, e que as dificuldades de linguagem estão relacionadas com o declínio cognitivo global e, especialmente, com o prejuízo das funções executivas. As alterações de linguagem se correlacionaram com o desempenho em tarefas cognitivas, mas não com as alterações motoras ou psiquiátricas da doença. Também não foi encontrada correlação entre o desempenho de linguagem e o tempo de doença / The objective of this study was to characterize the language alterations in Huntington's disease and how they relate to severity of motor, cognitive, psychiatric disturbances and also with the disease duration. Twenty-six (26) individuals were divided into groups characterized as lightly (11) and moderately ill (15) and compared with two control groups. Alterations in exams of language comprehension and expression were noticed for both groups of sick individuals. The result indicates no evident loss in semantic representation. The language difficulties are related to a global cognitive decline and, principally, to loss of executive functions. The language alterations were significantly correlated to performance in cognitive tasks, but not to the motor or psychiatric alterations of the disease. There was also no correlation observed between the language performance and duration of illness

A dissertation submitted to the Faculty of Engineering and the Built Environment, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Science in Engineering. Johannesburg, 2017 / This study presents the development of a potentially new biomarker for three different movement disorders: Huntington’s Disease (HD), Parkinson’s Disease (PD) and Essential Tremors (ET). A Leap Motion® gaming device was used to record the trajectories of subjects’ forefinger as they trace simple patterns in the air. The patterns used were stepfunction, triangle and circle. The recorded signals were analysed using transform functions and Fourier analysis. Both analysis types yielded features from which differences between the four categories studied: PD, HD, ET and control subjects, were sought and displayed in both graphical and numerical forms. The X-axis and Y-axis of the signals were separately analysed and yielded different results. For the step-function pattern, no distinct differences between the four categories were found from the transfer function analysis whereas the Y-axis of the signal could distinguish between the categories. For the triangle pattern, the X-axis features provided a discrimination between the categories while the Y-axis feature did not. For the circle pattern, neither X-axis nor Y-axis features were able to distinguish between the categories. A Fourier analysis showed a better discrimination ability for both X- and Y- axis. This study is a preliminary one and all results indicate that more subjects of all categories are needed to develop a bio-marker for the diseases studied and that a higher order transfer function analysis is required. However, the methodology outlined in this work, comprising of both the experimental system and the analysis showed a potential to produce a biomarker for movement disorders. / MT2018

Depression and anxiety are common psychiatric disturbances in Parkinson's disease (PD). Past studies have demonstrated a relationship between depression and cognitive decline in PD; however, the unique influence of anxiety has not been well studied. The objective of the present study was to differentiate the unique influences of depression and anxiety on cognitive functioning in PD. Sixty-eight cognitively intact PD patients with mild to moderate motor disease severity completed self-report questionnaires and neuropsychological tests. Two hierarchical regression analyses were conducted with executive functioning performance as the criterion variable, and two additional hierarchical regression analyses were conducted with memory performance as the criterion variable. Depression and anxiety, as measured by the Depression Anxiety and Stress Scales (DASS), served as predictors for all analyses. Each set of analyses examined the amount of added, unique variance accounted for by anxiety when depression was entered as the first predictor, and also examined the amount of added, unique variance accounted for by depression when anxiety was entered as the first predictor. It was found that depression significantly predicted delayed recall memory performance when entered as the first and second predictor. In contrast, anxiety did not significantly predict performance on any of the cognitive measures. Two DASS subscales assess for the physical symptoms of anxiety, and these subscales were not significantly correlated with any cognitive variables. However, the DASS subscales tapping into non-physical aspects of anxiety were significantly associated with several cognitive variables. Patients may have endorsed physical symptoms of anxiety due to the symptoms associated with PD, and not as a result of the genuine presence of anxiety. This could have masked a potential relationship between anxiety and cognitive functioning in PD, and suggests that specific components of anxiety may be associated with cognition in PD. Future adaptation of the DASS may be necessary to differentiate the unique influences of depression and anxiety in PD patients.

This thesis describes three boys diagnosed with dyspraxia and their whanau (families and extended families) as they enter and become part of a community gymnastics group in a city in New Zealand. The study builds on literature that has defined dyspraxia in terms of dysfunction, but generally failed to resolve the disorder. Through the social perspective of health and well-being, participation of children and adults with disabilities has been explored in terms of the person and the environments in which they participate; however, the influence activity itself has on participation has not been thoroughly described. There has been a growing interest in the participation of children with disabilities in recreation and leisure activities and this study provides an in depth cultural perspective of such participation in New Zealand context. This study aims to answer the question "What do children with dyspraxia and their whanau do in a gymnastics group, and what does it mean to them to participate?". The overarching question is "What is the culture of a community gymnastics group in which children with dyspraxia participate?". Ethnographic methodology is employed to ensure that the participants' perspectives, including the beliefs, values and meaning that their participation holds is portrayed, while the associated activities and behaviours are also captured. As the boys with dyspraxia and their whanau entered the gym, they built on their previous experiences to make sense of what they needed to do and what meaning the environment held. I had not planned on the boys being integrated with an established group, but on the first night they spontaneously joined in with a noncompetitive, mixed age, boys group. The parents perceived the Club as professional, while the boys were initially intimidated. Fortunately, the equipment, which made the gym look like a playground, enticed the boys to participate. To shift the boys from their initial perception of the gym being a playground, the coaches used two styles of An Ethnography of Children with Dyspraxia Participating in Gymnastics coaching to support and encourage their participation, while suppressing behaviour that did not fit with the norms of the Club. The boys needed to develop gymnastics skills and fit into the group to become gymnasts. The boys succeeded in fitting into the group by both developing skills and adapting their behaviour, while the type of boys without dyspraxia, the style of coaching afforded, the range of equipment and the activity of gymnastics itself meant that some of their initial difficulties were accommodated and they were seen as group members. The participants developed values and beliefs about what the boys participation in the group meant. Having fun and developing confidence and fitness were highlighted, while the social aspects (making friends and the whanau experiences) were also seen as important. The parents and coaches felt that the boys' experiences in gymnastics had an impact on them that would transfer to the world beyond the gym. This study contributes a qualitative perspective on the participation of children with disabilities in a sports occupation, with a focus on the cultural context of their participation.

Thesis (M.S.)--University of Delaware, 2006. / Principal faculty advisor: Nancy Getchell, Dept. of Health, Nutrition, and Exercise Sciences. Includes bibliographical references.

This thesis describes three boys diagnosed with dyspraxia and their whanau (families and extended families) as they enter and become part of a community gymnastics group in a city in New Zealand. The study builds on literature that has defined dyspraxia in terms of dysfunction, but generally failed to resolve the disorder. Through the social perspective of health and well-being, participation of children and adults with disabilities has been explored in terms of the person and the environments in which they participate; however, the influence activity itself has on participation has not been thoroughly described. There has been a growing interest in the participation of children with disabilities in recreation and leisure activities and this study provides an in depth cultural perspective of such participation in New Zealand context. This study aims to answer the question "What do children with dyspraxia and their whanau do in a gymnastics group, and what does it mean to them to participate?". The overarching question is "What is the culture of a community gymnastics group in which children with dyspraxia participate?". Ethnographic methodology is employed to ensure that the participants' perspectives, including the beliefs, values and meaning that their participation holds is portrayed, while the associated activities and behaviours are also captured. As the boys with dyspraxia and their whanau entered the gym, they built on their previous experiences to make sense of what they needed to do and what meaning the environment held. I had not planned on the boys being integrated with an established group, but on the first night they spontaneously joined in with a noncompetitive, mixed age, boys group. The parents perceived the Club as professional, while the boys were initially intimidated. Fortunately, the equipment, which made the gym look like a playground, enticed the boys to participate. To shift the boys from their initial perception of the gym being a playground, the coaches used two styles of An Ethnography of Children with Dyspraxia Participating in Gymnastics coaching to support and encourage their participation, while suppressing behaviour that did not fit with the norms of the Club. The boys needed to develop gymnastics skills and fit into the group to become gymnasts. The boys succeeded in fitting into the group by both developing skills and adapting their behaviour, while the type of boys without dyspraxia, the style of coaching afforded, the range of equipment and the activity of gymnastics itself meant that some of their initial difficulties were accommodated and they were seen as group members. The participants developed values and beliefs about what the boys participation in the group meant. Having fun and developing confidence and fitness were highlighted, while the social aspects (making friends and the whanau experiences) were also seen as important. The parents and coaches felt that the boys' experiences in gymnastics had an impact on them that would transfer to the world beyond the gym. This study contributes a qualitative perspective on the participation of children with disabilities in a sports occupation, with a focus on the cultural context of their participation.