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The striatum is the major input structure of the basal ganglia, and is composed of two major populations of spiny projection neurons (MSNs), which give rise to the socalled direct and indirect pathways, and several types of interneuron. Dopaminergic inputs to striatum are critical for its proper function. Indeed, loss of dopaminergic neurons in Parkinsonism leads to motor disturbances, grossly disturbs striatal activity, and is associated with the emergence of excessively-synchronized network oscillations at beta frequencies (15-30 Hz) throughout the basal ganglia. How the distinct structural, neurochemical and other properties of striatal neurons are reflected in their firing rates and patterns in vivo is poorly defined, as are their possible cell-type-selective contributions to the aberrant oscillations arising in the Parkinsonian brain. To address these issues, I first used multi-electrode arrays to record the spontaneous firing of ensembles of neurons in dorsal striatum in both anaesthetised dopamine-intact and Parkinsonian (6-hydroxydopamine-lesioned) rats during two well-defined brain states, slow-wave activity (SWA) and spontaneous activation. The chronic loss of dopamine led to an overall increase in the average firing rates of striatal neurons, irrespective of brain state. However, many neurons in the Parkinsonian striatum still exhibited the low firing rates and irregular firing patterns typical of neurons in the dopamine-intact striatum. During SWA in Parkinsonian rats, the firing of striatal neurons was more strongly synchronized at low frequencies, in time with cortical slow (~1 Hz) oscillations. During spontaneous cortical activation in Parkinsonian rats, more striatal neurons engaged in synchronized firing in time with cortical beta oscillations. Under the same experimental conditions, I then recorded the spontaneous firing of individual striatal neurons and juxtacellularly labelled the same neurons to verify their cell types, and locations; indirect pathway and direct pathway MSNs were distinguished by the expression (and lack of expression respectively), of the neuropeptide precursor preproenkephalin (PPE). After chronic dopamine loss, and on average, only indirect pathway (PPE+) MSNs significantly increased their firing rates during both brain states, and engaged in widespread, synchronized firing in the beta-frequency range. This did not hold true for all PPE+ MSNs; the Parkinsonian striatum contained many MSNs that were virtually quiescent, which were just as likely to belong to the indirect pathway as the direct pathway. Direct pathway (PPE-) MSNs increased their firing only during SWA after chronic dopamine loss and rarely engaged in aberrant beta oscillations. Taken together, these data suggest that (1) the firing patterns, as well as the firing rates of many striatal neurons are grossly disturbed by chronic loss of dopamine and (2) that the pathological synchronization of the rhythmic firing of a subpopulation of indirect pathway MSNs could contribute to the propagation of aberrant beta-frequency oscillations to downstream basal ganglia nuclei in Parkinsonism.

Contextual influence on movement was examined for a selection of everyday activities. Non-medicated and medicated Parkinson's disease (PD) patients and control subjects reached for a drinking glass target from both seated and standing postures, and stepped over a surface-level obstacle while walking on a constrained path. Contextual challenge was increased in the seated reach by filling the glass with water, in the standing reach by increasing the depth of the gap between the target and stationary foot position, and in the obstacle negotiation trials by raising the gait path surface above the floor level. In all cases, behaviour among PD patients was uniquely disrupted by contextual challenge. In addition, benefits of conventional medication therapy for PD patients were limited in challenging contexts. The results suggest an adapted movement control mechanism at work in PD patients, with the neural resources used in this adapted response prone for interference during contextual challenges. / xiv, 186 leaves ; 29 cm.

Increasing evidence has shown that abnormal metabolic phenotypes in body fluids reflect the pathogenesis and pathophysiology of Parkinson's disease (PD). However, the relationship between metabolic phenotypes and PD is not fully understood. Mass spectrometry (MS) based metabolomics is a powerful technique, which was frequently used for the sensitive and reproducible detection of hundreds to thousands of metabolites in biofluid samples.. Here we developed and performed MS-based metabolomics studies involving hundreds of human urine samples with data acquired from multiple analytical batches for surveying potential biomarkers of PD. A new software statTarget was developed and introduced. Protocols for liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) were developed, including sample preparation, data acquisition, quality controls, quality assurance and data analysis. Urinary metabolites from a total of 401 clinical urine samples collected from 106 idiopathic PD patients and 104 normal control subjects were profiled by using LC-MS. Quality control (QC) strategy has been performed in MS-based metabolomics for high reproducibility and accuracy of MS data. GC-MS with methyl chloroformate (MCF) derivatization was used for profiling highly polar metabolites in patients with early-, middle- and advanced-stage PD. Our study revealed the significant correlation between clinical phenotypes and urinary metabolite profiles. Comprehensive metabolomics was successfully developed with the goal of identifying urinary metabolite markers that can be used for evaluating the development of PD. A group of 18 metabolites have shown not only a high discriminating ability for the early-stage PD patients but also accurately distinguished the middle- and advanced- stages patients from control subjects. For the evaluation of PD, 18 metabolites showed good potential as metabolite markers with related metabolic pathway variations observed in branched chain amino acid metabolism, glycine derivation, steroid hormone biosynthesis, tryptophan metabolism, and phenylalanine metabolism.. We have further performed targeted analysis of potential biomarkers by using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and GC-MS. The UPLC-MS/MS method was developed and optimized for detecting the concentration variation of metabolites in tryptophan metabolism for alpha-synuclein over-expressed flies (Parkinson's disease model). The altered tryptophan metabolism was proved as one of the common metabolite signatures between PD patients and alpha-synuclein over-expressed fly model of PD, and thus may be used for developing potential markers of the disease and evaluating the efficacy of novel therapeutic agents. An asymmetric labeling strategy and positive chemical ionization gas chromatography-tandem mass spectrometry (PCI-GC-MS-MS) approach was developed for the determination of non-amino organic acids and amino acids, as well as short chain fatty acids. Carboxylic and amino groups could be selectively labelled by propyl and ethyl groups, respectively. The specific neutral losses of C3H8O (60 Da), C3H5O2 (74 Da) and C4H8O2 (88 Da) were useful in the selective identification for qualitative analysis of organic acids and amino acid derivatives. The developed PCI-GC-MS/MS method showed good reproducibility and linear range.. In summary, metabolomics study has its inherent advantage in the characterization of biomarkers for the development of PD and may bring new scientific knowledge as well as impact on the progression of PD and other related neurodegenerative diseases.

Diseases of the central and peripheral nervous systems affect one in five people in North America. Parkinson’s disease (PD) is the second most common neurodegenerative disease, after Alzheimer’s disease, and occurs in approximately 1% of the general North American population. PD is a progressive movement disorder that is characterized by resting tremor, rigidity, bradykinesia (slowness of movement) or akinesia (absence of spontaneous movement), as well as postural instability. Current treatment of PD is symptom-based, and no pharmacological treatment currently exists to slow the progression of bradykinesia and akinesia. In fact, pharmacological therapies produce motor side effects in advanced stages of the disease. Given the difficulty in initiating and controlling movement as PD advances, and the ineffectiveness of medical therapies after prolonged treatment, physical and music therapies can be used to supplement classical therapies. Listening to, and performing, music affects a number of neural regions, including those that mediate motor behaviour, arousal or activation, and emotion. Despite anatomical connections between the auditory and motor systems at the level of the spinal cord, brain stem, midbrain, and cortex, the neural and behavioural mechanisms for sound-induced activation remains unclear. It is known, however, that PD patients recruit external sensory stimuli to improve movement. The aim of the current research was to create an animal model of sound-induced activation and to test the effect of previous motoric experience on the potency of auditory stimuli. To investigate behavioural activation in the normal and haloperidol-treated rat, two tasks were used: 1) orienting responses were analyzed for movement components in saline and haloperidol treated rats v to find out if rats responded in the same to a variety of naturally produced and generated activating sounds, and 2) a grid climbing task allowed for the righting components of naïve and familiar cataleptic rats to be compared. Our findings revealed that familiar auditory cues could release parkinsonian rats from catalepsy. The current research supports the theory that auditory stimulation retains “special access” to motor regions otherwise impaired in PD and likely bypasses basal ganglia circuitry to normalize movement through alternative pathways. / xiv, 142 leaves : ill. (some col.) ; 29 cm

Changes in postural stability following sensory manipulation were investigated among Parkinson's disease patients and healthy older adults. Sixteen Parkinson's disease patients (PD; mean age 68.2 + 2.7 years) and sixteen older adults (control; mean age 67.6 + 2.6 years) performed quiet standing trials that progressed through baseline, sensory manipulation, and reintegration. Postural control following visual deprivation was assessed following alternate removal and reinsertion of visual information. Postural recovery following sensory incongruence was assessed following the termination of visual, somatosensory, and visuosomatosensory incongruence. PD patients' balance was disrupted following visual deprivation, and was initially disrupted when visual information was returned. PD patients' pstural recovery was comparable to control subjects when sensory incongruence ended. These findings indicate that situations of visual deprivation in particular are initially disruptive for PD patients, and imply initial difficulty for sensory reorganization in these patients. Our results provide insight into environmental situations imposing greater fall risk among the parkinsonian population. / xii, 81 leaves ; 29 cm.

Conventional cylinder test measures have limited sensitivity in determining hemiparkinson rat forelimb use asymmetry and approximating substantia nigra (SN) dopaminergic neuron loss. This thesis investigates which cylinder test measures of hemiparkinson rat forelimb use asymmetry best predict methamphetamine-induced rotation and extent of dopaminergic neuron loss. Long-Evans rats were cylinder-tested after unilateral 1-methyl-4-phenylpyridinium (MPP+)-induced SN dopamine depletion. Time and count of numerous forepaw wall contact patterns were documented for MPP+ hemiparkinson rats and sham-operated controls using frame-by-frame video analysis, then regressed against methamphetamine-induced rotation and tyrosine hydroxylase-positive neuron depletion. Severely dopamine-asymmetric rats initiated movements slower and less often with the contralateral-to-lesion forepaw, indicating that the cylinder test may be used to assess Parkinson Disease motor impairments of bradykinesia and akinesia. Several new time and count asymmetry measures may improve cylinder test sensitivity to hemiparkinson-specific forelimb use asymmetries. / xi, 103 leaves : ill. ; 29 cm.

The effects of postural threat on gait initiation and steady state gait among Parkinson’s disease (PD) patients and age-matched adults were examined. Ten healthy adults (CTRL; mean age= 68.8 ± 8.4, range 56-80 years) and ten PD patients (PDOFF / ON ; mean age= 69.7 ± 10.3, range 54-81 years) initiated gait and continued with steady state walking along a walkway of two different height conditions. PD patients were first tested in a non-medicated state followed by testing in a medicated state. The results showed that gait initiation and steady state gait deficits inherent to PD are exacerbated in a postural threatening environment. As well, medication efficacy for overcoming parkinsonian deficits may be context dependent. These findings confirm the dynamic nature of movement deficits characteristic of parkinsonian patients and provide empirical evidence for specific environments that can create movement difficulties for people with PD. / x, 59 leaves : ill. ; 29 cm. --

The reach-to-eat movement, in which a hand is advanced towards a food item, shapes to grasp the food item, and withdrawals to place the food item into the mouth for eating, is a behaviour that is performed daily. The movement is controlled by two sensory systems, vision to guide hand advance and grasping, and somatosensation to guide hand withdrawal and mouth placement. The purpose of the present thesis was to examine how the sensory control of reaching-to-eat develops in infancy and degenerates following neurodegenerative disorder. The tight coupling of vision to hand advance and somatosensation to hand withdrawal has a developmental profile from six months to one year of age. That is, six-month-old infants rely on vision to advance their hand, grasp the target, and withdrawal the target to the mouth. By twelve months of age, infants display the adult pattern of coupling vision to hand advance and grasping. The tight coupling of vision to hand advance degenerates with basal ganglia disease, such that subjects with Parkinson’s disease and Huntington’s disease show an overreliance on vision to guide hand advance for grasping and hand withdrawal for mouth placement. The results of the thesis demonstrate that efficient use of sensory control to guide motor behaviour is an important aspect of development that is disrupted by neurodegenerative disease. / xiv, 286 leaves : ill. ; 29 cm

The sensory control of movements has been shown to be impaired with Parkinson’s disease. I investigated the task, reach-to-eat, in which advancing of the limb towards a target is guided by vision and withdrawal of the grasped target to the mouth is guided by somatosensation (i.e., haptics and proprioception). Parkinson’s diseased subjects display an alteration in the balance of visual and proprioceptive guidance, such that they display increased visual fixation on the target prior to movement onset that persists following the grasp. Music therapy can normalize the balance between visual and proprioceptive guidance on the reach-to-eat task, as visual fixation with the target prior to movement onset is consistent with controls, and disengagement following grasp no longer differs from mild Parkinson’s disease subjects. These results are the first to demonstrate that music can have an ameliorating effect on the sensory impairments seen in the control of forelimb movements in Parkinson’s disease. / xiv, 147 leaves : ill. ; 29 cm. --