This research study examined motor control and procedural learning abilities in the oral and manual motor systems of adults who stutter, using people with Parkinson's disease, and age-matched controls as comparison groups. Participants in this study were asked to track a moving target on a computer screen with their jaw and with their dominant hand. Specifically, we compared their tracking accuracy for predictable and unpredictable signals. Procedural learning (defined as increased accuracy over time) was assessed by examining changes in tracking accuracy within a single tracking trial and between consecutive tracking trials of the same predictable condition. There were two main findings in this study related to tracking accuracy and procedural learning in people who stutter (PWS) and age-matched controls (CPWS). First, our analyses revealed that there was no significant difference between PWS and CPWS in the accuracy of tracking of either predictable or unpredictable conditions for either the hand or the jaw, although a trend was observed in which PWS performed more poorly in both for decreased accuracy. Second, both PWS and CPWS showed evidence of procedural learning to the same extent. There were two main findings in this study related to tracking accuracy and procedural learning in people who have Parkinson's disease (PPD) and age-matched controls (CPPD). First, tracking accuracy analyses revealed that PPD performed significantly more poorly than CPPD during jaw tracking of predictable conditions, but they were not significantly different from CPPD in jaw tracking of unpredictable conditions. During hand tracking PPD differed significantly from CPPD in tracking of both predictable and unpredictable conditions for their less accurate performance. Second, there was no significant difference between the two groups in the extent of procedural learning during jaw tracking. However, during hand tracking the PPD group improved less with time than the CPPD, suggesting that the PPD group had reduced procedural learning ability in the manual motor domain. Lastly, age was found to be an important factor determining tracking accuracy in our participants. Younger participants (PWS and CPWS) in the age range of 18-40 years had significantly better accuracy of jaw and hand tracking than the older individuals (PPD and CPPD) in the age range of 57-79 years.

Parkinson’s disease (PD) is a chronic and progressive movement disorder affecting an individual’s ability to move, and can become life threatening when it progresses to the point where an individual has difficulties swallowing, breathing, and chewing. PD is a neurodegenerative disorder caused by the damage of neurons, leading to the loss of nerve function and structure in the brain. Specifically, PD is characterized by the selective loss of the substania nigra, the dopamine (DA)-containing region of the brain. Due to loss of DAergic neurons, it has been suggested that DA serves as an endogenous toxin when there are alterations in the synthesis, metabolism, and regulation of DA. The pathogenesis of PD remains unclear, and many are working on determining what factors cause this neuronal death. Factors hypothesized to be important include: aging, genetics, endogenous toxins, and environmental toxicants. The aim of this work is to explore the role of endogenous neurotoxins, such as toxic dopamine metabolites, oxidative stress (OxS), and reactive oxygen species as contributors to the neurotoxicity relevant to PD, and to examine the potential for regulation of this toxicity by alterations in the antioxidant status of the cell. DA can undergo metabolism by monoamine oxidase (MAO) to 3,4-dihydroxyphenylacetaldehyde (DOPAL), a highly toxic and reactive metabolite; that is hypothesized as a contributor to the neurotoxicity observed in PD. Subsequently, DOPAL can be further metabolized by aldehyde dehydrogenases or reductases to form 3,4- dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylethanol (DOPET), respectively. When evaluating all of these metabolites, DOPAL displays the greatest toxicity both in vitro and in vivo. DOPAL contributes to cell toxicity through a variety of mechanisms; these include: 1) it is able to react with proteins, leading to covalent modification at Lys and Arg residues causing the formation of adducts 2) DOPAL can autooxidize to form quinone species, which are reactive with proteins 3) autooxidation and protein modification by DOPAL results in the generation of reactive oxygen species (ROS) (H₂O₂, O₂•−), which are also toxic. Of note, increasing ROS can impact the OxS levels, creating an imbalance that contributes to cell damage. This insult can include inhibiting the carbonyl metabolizing enzymes, further increasing DOPAL levels. During these interactions, damage occurs to proteins, enzymes, and DNA, causing an inability for the cell to perform properly, consequently leading to cell death. The initial work, described in Chapter 3, was determination of ROS and secondary insults that are produced during DOPAL-mediated neurotoxicity. Methodologies utilizing fluorescence detection were able to identify the production of both hydrogen peroxide (H₂O₂) and superoxide anion radical (O₂•−). The formation of these ROS can result in an imbalance in oxidative status, contributing to augmented OxS in the cell. These ROS were produced both in purified protein assays, as well as, in cell based studies. These assays investigated formation of ROS during protein interaction, but were also tested in the presence of known toxins that have been correlated with PD. The work described in Chapter 4 explores conditions in these neurons that can impact the alteration of OxS through ROS. It was hypothesized that oxygen presence is necessary to catalyze the reaction of DOPAL with proteins. Therefore, work was completed to discover if oxygen deficiency could regulate DOPAL-protein interactions. Identification of protein modification, following oxygen eradication, confirmed that inhibition of DOPAL’s reactivity towards proteins succeeds the loss of oxygen. This led efforts to focus on other mechanisms by which to alter cellular oxidative status to influence DOPAL’s function in these cells. Additional work was completed to discover if radical scavengers similarly control resultant toxicity from DOPAL activity. As previously published, radical scavengers, such as tricine, exhibit a protective effect in regards to modification of proteins. Furthermore, we believe that oxidative status can serve as a target for mediation of DOPAL neurotoxicity. If affecting the capability of producing ROS species can impact OxS in DOPAL-mediated toxicity, it is believed that utilizing agents, such as antioxidants, can serve as a new potential treatment for PD. Chapters 5 (cellular models) and 6 (in vivo model) explore efforts to alter (+/-) antioxidant levels via addition of N-acetylcysteine (NAC), diamide (Dia), and buthionine sulfoxide (BSO). It was found that antioxidants, such as NAC, attenuate the adduction of proteins by DOPAL, alter DA metabolite levels, and inhibit behavioral characteristics of PD in the in vivo model. Conversely, oxidants Dia and BSO increased DOPAL and its subsequent modification of proteins. Finally, Chapter 7 includes a conclusion of the work documented here and addresses future potential directions. This project includes so new findings that need to be further characterized resulting in many future direction that can be explored. One major direction in which this project can be taken would be further validation of NAC to serve as a novel therapy for PD. The future directions will include all aspects of this project including a brief discussion of examining NAC analogs to increase bioavailability leading to a more potent drug model. To date there are limited answers into what is causing this neurodegeneration, and currently, there is no cure for PD. Therefore, my thesis research is making an impact in the field as it, has explored the ways in which a known toxic metabolite is leading to death of these neurons, has identified secondary products that are contributing to the toxicity observed, and has developed a potential new therapy for PD utilizing antioxidants. All of these will help advance research in the field to continue to identify new targets in this cellular pathway leading to a better understanding of the cause of PD.

PhD / When modeling a system as complex as the brain, considerable simplifications are inevitable. The nature of these simplifications depends on the available experimental evidence, and the desired form of model predictions. A focus on the former often inspires models of networks of individual neurons, since properties of single cells are more easily measured than those of entire populations. However, if the goal is to describe the processes responsible for the electroencephalogram (EEG), such models can become unmanageable due to the large numbers of neurons involved. Mean-field models in which assemblies of neurons are represented by their average properties allow activity underlying the EEG to be captured in a tractable manner. The starting point of the results presented here is a recent physiologically-based mean-field model of the corticothalamic system, which includes populations of excitatory and inhibitory cortical neurons, and an excitatory population representing the thalamic relay nuclei, reciprocally connected with the cortex and the inhibitory thalamic reticular nucleus. The average firing rates of these populations depend nonlinearly on their membrane potentials, which are determined by afferent inputs after axonal propagation and dendritic and synaptic delays. It has been found that neuronal activity spreads in an approximately wavelike fashion across the cortex, which is modeled as a two-dimensional surface. On the basis of the literature, the EEG signal is assumed to be roughly proportional to the activity of cortical excitatory neurons, allowing physiological parameters to be extracted by inverse modeling of empirical EEG spectra. One objective of the present work is to characterize the statistical distributions of fitted model parameters in the healthy population. Variability of model parameters within and between individuals is assessed over time scales of minutes to more than a year, and compared with the variability of classical quantitative EEG (qEEG) parameters. These parameters are generally not normally distributed, and transformations toward the normal distribution are often used to facilitate statistical analysis. However, no single optimal transformation exists to render data distributions approximately normal. A uniformly applicable solution that not only yields data following the normal distribution as closely as possible, but also increases test-retest reliability, is described in Chapter 2. Specialized versions of this transformation have been known for some time in the statistical literature, but it has not previously found its way to the empirical sciences. Chapter 3 contains the study of intra-individual and inter-individual variability in model parameters, also providing a comparison of test-retest reliability with that of commonly used EEG spectral measures such as band powers and the frequency of the alpha peak. It is found that the combined model parameters provide a reliable characterization of an individual's EEG spectrum, where some parameters are more informative than others. Classical quantitative EEG measures are found to be somewhat more reproducible than model parameters. However, the latter have the advantage of providing direct connections with the underlying physiology. In addition, model parameters are complementary to classical measures in that they capture more information about spectral structure. Another conclusion from this work was that a few minutes of alert eyes-closed EEG already contain most of the individual variability likely to occur in this state on the scale of years. In Chapter 4, age trends in model parameters are investigated for a large sample of healthy subjects aged 6-86 years. Sex differences in parameter distributions and trends are considered in three age ranges, and related to the relevant literature. We also look at changes in inter-individual variance across age, and find that subjects are in many respects maximally different around adolescence. This study forms the basis for prospective comparisons with age trends in evoked response potentials (ERPs) and alpha peak morphology, besides providing a standard for the assessment of clinical data. It is the first study to report physiologically-based parameters for such a large sample of EEG data. The second main thrust of this work is toward incorporating the thalamocortical system and the basal ganglia in a unified framework. The basal ganglia are a group of gray matter structures reciprocally connected with the thalamus and cortex, both significantly influencing, and influenced by, their activity. Abnormalities in the basal ganglia are associated with various disorders, including schizophrenia, Huntington's disease, and Parkinson's disease. A model of the basal ganglia-thalamocortical system is presented in Chapter 5, and used to investigate changes in average firing rates often measured in parkinsonian patients and animal models of Parkinson's disease. Modeling results support the hypothesis that two pathways through the basal ganglia (the so-called direct and indirect pathways) are differentially affected by the dopamine depletion that is the hallmark of Parkinson's disease. However, alterations in other components of the system are also suggested by matching model predictions to experimental data. The dynamics of the model are explored in detail in Chapter 6. Electrophysiological aspects of Parkinson's disease include frequency reduction of the alpha peak, increased relative power at lower frequencies, and abnormal synchronized fluctuations in firing rates. It is shown that the same parameter variations that reproduce realistic changes in mean firing rates can also account for EEG frequency reduction by increasing the strength of the indirect pathway, which exerts an inhibitory effect on the cortex. Furthermore, even more strongly connected subcircuits in the indirect pathway can sustain limit cycle oscillations around 5 Hz, in accord with oscillations at this frequency often observed in tremulous patients. Additionally, oscillations around 20 Hz that are normally present in corticothalamic circuits can spread to the basal ganglia when both corticothalamic and indirect circuits have large gains. The model also accounts for changes in the responsiveness of the components of the basal ganglia-thalamocortical system, and increased synchronization upon dopamine depletion, which plausibly reflect the loss of specificity of neuronal signaling pathways in the parkinsonian basal ganglia. Thus, a parsimonious explanation is provided for many electrophysiological correlates of Parkinson's disease using a single set of parameter changes with respect to the healthy state. Overall, we conclude that mean-field models of brain electrophysiology possess a versatility that allows them to be usefully applied in a variety of scenarios. Such models allow information about underlying physiology to be extracted from the experimental EEG, complementing traditional measures that may be more statistically robust but do not provide a direct link with physiology. Furthermore, there is ample opportunity for future developments, extending the basic model to encompass different neuronal systems, connections, and mechanisms. The basal ganglia are an important addition, not only leading to unified explanations for many hitherto disparate phenomena, but also contributing to the validation of this form of modeling.

PhD / People with a chronic illness, such as Parkinson’s disease, often live in the community for many years while the illness becomes progressively more debilitating. Little is known about how such people control the impact the disease has upon their various roles in life. This study employed naturalistic qualitative research methods to investigate how people with Parkinson’s disease and their partners continue to actively participate as members of their social community. Using in-depth semi-structured, focused interviews, participants with Parkinson’s disease and their partners were asked to name and describe roles that occupied their daily activity. They were asked about their most significant occupational roles, what they did in these roles, the knowledge or strategies they employed to deal with barriers to occupational role performance, and the personal meaning such roles held. Four basic themes evolved from the data: the impact of the disease on occupational role performance, or ‘doing’, secondary personal limitations to occupational role performance, secondary social limitations to occupational role performance and cumulative barriers to occupational role performance. Loss of control over choice and manner of engagement in occupational roles was a significant element of all four themes. Sense of self and sense of social fit were identified as major elements that informed participants’ perceptions of control. Participants described a range of diverse responses that they used to actively restore personal control of occupational performance in the face of degenerative illness. Learning new coping styles appeared to be underpinned by a personal set of rules or ‘blueprint’, despite professional input. This blueprint was actualised through a problem identification, problem solving and active engagement cycle that was termed a cycle of control. A conceptual model of a cycle of control was proposed as the final stage of the research. The model represented a way of describing how participants acted to restore a sense of personal control once a specific barrier to occupational role performance had been perceived. The findings of this study support the notion that people with chronic illness, such as Parkinson’s disease, are active and knowledgeable participants in health care, and have occupational histories and experiences that they harness when dealing with barriers to performance. Moreover, the findings demonstrate that people with chronic illness work in tandem with significant role partners to constantly maintain the valued partnership in meaningful occupational roles as the disease progresses. A greater understanding of how people with chronic illness and their partners strive to maintain a sense of personal control can enable occupational therapists to work effectively as ancillary partners in care. A greater understanding of the way in which role partners work together to maintain occupational integrity in their lives would be central to assessment and intervention for community programs for people with chronic illness.

<p>The symptoms of Parkinson's disease occur due to degeneration of dopamine neurons in substantia nigra. It has been demonstrated that glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor when it comes to protect and enhance survival of dopamine neurons in animal models of Parkinson's disease. The aim of this study was to evaluate short- and long-term effects of GDNF on survival and nerve fiber outgrowth of dopamine cells and astrocytic migration in mouse fetal ventral mesencephalic (VM) tissue. Primary tissue cultures were made of mouse fetal VM tissue and evaluated at 7 and 21 days in vitro (DIV) in terms of dopaminergic nerve fiber outgrowth and astrocytic migration when developed with GDNF present, partially, or completely absent. The results revealed that VM tissue cultured in the absence of GDNF did not exhibit any significant differences in migration of astrocytes or dopaminergic nerve fiber outgrowth neither after 7 DIV nor after 21 DIV, when compared with tissue cultured with GDNF present. Migration of astrocytes and dopaminergic nerve fiber outgrowth reached longer distances when tissue was left to develop for 21 DIV in comparison with 7 DIV. In order to study the long-term effects of GDNF, mouse fetal dopaminergic tissue was transplanted into the ventricles of adult mice and evaluated after 6 months. No surviving dopamine neurons were present in the absence of GDNF. In contrast dopamine neurons developed with GDNF did survive, indicating that GDNF is an essential neurotrophic factor when it comes to long-term dopamine cell survival. More cases have to be assessed in the future in order to strengthen the findings. Thus, transplanted dopamine neurons will be assessed after 3 and 12 months in order to map out when dopamine neurons deprived of GDNF undergo degeneration.</p>

<p>Pharmacotherapy for Parkinson’s disease (PD) is based on levodopa, the most effective dopaminergic drug. The development of motor complications constitutes the major challenge for new or refined therapies.</p><p>To evaluate the impact of levodopa pharmacokinetics on motor function, an observational study in the patients’ home environment was carried out. A high variability in plasma levodopa levels was found in all patients, irrespective of treatment regimen. The impact of levodopa pharmacokinetics was further studied in a crossover trial comparing sustained-release tablets and continuous daytime intestinal infusion. Infusion produced significantly decreased variability in plasma levels of levodopa, resulting in significantly normalised motor function. A permanent system for long-term levodopa infusion has been developed and 28 patients have been followed for 87 patient-years. Motor response was generally preserved during the long-term observation period, implying that there is no development of tolerance to infusion therapy. Levodopa tablets are normally used in multiples of 50 or 100 mg, thus a rough estimate of individual dosage. A new concept for individualising levodopa/carbidopa doses with microtablets of 5/1.25 mg is under development. An electronic drug-dispensing device for administering the microtablets was tested on patients with PD. All were able to handle the dispenser and most were interested in future use of the concept. Self-assessment of symptoms is accurate in PD, but traditional paper diaries are associated with low compliance. A wireless electronic diary was compared with a corresponding paper diary. The time-stamped and thus completely reliable patient compliance was 88% with the electronic diary.</p><p>To conclude, pharmacokinetics of levodopa is the major determinant for motor fluctuations in PD. Every effort to individualise dosage and to smooth out the fluctuations in levodopa concentrations should be made, e.g. by means of microtablets or enteral infusion. Electronic patient diaries for real-time data capture are suitable for PD studies.</p>

Apathy is a debilitating non-motor symptom in Parkinson’s disease (PD) that is closely associated with cognitive dysfunction, depression, and caregiver burden. The proposed etiology and operational definition of apathy involves a tripartite model that includes cognitive, behavioral, and emotional manifestations. This theoretical model has not been statistically validated. We examined the tripartite structure of apathy in PD, and subsequent associations between apathy factors and demographic, disease, and neuropsychological measures. One hundred forty-one patients with idiopathic PD underwent neurological examination and comprehensive neuropsychological testing including the Apathy Evaluation Scale (AES). Statistical analyses included correlation, means comparison, item analysis, and confirmatory factor analysis using SEM. The AES was found to be a valid and reliable measure of apathy. Although a tripartite model of apathy was not supported, a novel 3-factor structure of apathy (R-Apathy) emerged characterized by Cognitive/Emotional and Behavioral factors. Both education and depression were significantly associated with R-Apathy. When these were controlled, R-Apathy was associated with impairment in select executive function and visuospatial skills. Apathy remains an important dimension in understanding nonmotor changes in PD. As a whole, apathy correlated with specific areas of neuropsychological dysfunction apart from the influence of depression. Manifestations of apathy such as mental disengagement and behavioral withdrawal are key features of the disease presentation. The importance of evaluating apathy as a contributing factor to patients’ neurocognitive status, mood, and psychosocial functioning should not be underestimated. Furthermore, an apathy evaluation should be included as a standard part of a Parkinson’s evaluation.

Background: Idiopathic parkinsonism is a neurodegenerative syndrome of unknown cause and includes Parkinson’s disease (PD) and atypical parkinsonian disorders. The atypical parkinsonian disorders are: Multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). The incidence rates of these diseases in Sweden are largely unknown. The diagnosis of each disease relies mainly on clinical examination although several imaging and laboratory parameters may show changes. A diagnosis based on clinical examination is especially difficult early in the course of each disease; diagnosis is easier later on when disease-charactersistic signs have evolved and become more prominent. However, even in later stages it is not uncommon that patients are misdiagnosed. PD can be divided into subgroups based on the main clinical symptoms, i. e. tremor dominant, postural instability and gait difficulty (PIGD), and indeterminate. The PIGD subtype has worse prognosis including higher risk of dementia. The aims were to study the incidence of idiopathic parkinsonism and the different specific parkinsonian disorders in the Umeåregion and to investigate the patients early in the course of the disease with brainmagnetic resonance tomography (MRI), external anal sphincterelectromyography (EAS-EMG) and oculomotor examination. Can these methods improve the differential diagnostic work-up and/or differentiate between the subtypes of PD? Methods: We examined all patients in our catchment area (142,000 inhabitants) who were referred to us due to a suspected parkinsonian syndrome. Our clinic is the only clinic in the area receiving referrals regarding movement disorders. During the period (January 1, 2004 through April 30,2009) 190 patients fulfilled the inclusion criteria and were included in the study. Healthy volunteers served as controls.  Results: Incidence: We found the highest incidences reported in the literature: PD (22.5/100,000/year), MSA(2.4/100,000/year), and PSP (1.2/100,000/year). No CBD patients were encountered. Brain MRI: Degenerative changes were common both in controls and PD. There were no differences between the PD subtypes. EAS-EMG: Pathological changes in EAS-EMG examination were common in PD, MSA and PSP. It was not possible to separate PD, MSA and PSP by the EAS-EMG examination. Oculomotor examination: Pathological results were common in all diagnosis groups compared to controls. It was not possible to separate PD, MSA and PSP or the PD subtypes with the help of oculomotor examination. Conclusions: The incidences of idiopathic parkinsonism, PD, MSA and PSP were higher than previously reported in the literature. It is not clear weather this is due to a true higher incidence in the Umeå region or a more effective casefinding than in other studies. MRI, EAS-EMG and oculomotor examination could not contribute to the differential diagnostic work-up between PD, MSA and PSP nor differentiate between PD subtypes early in the course of the disease.

Background: The birth of stereotactic functional neurosurgery in 1947 was to a great extent dependent on the development of ventriculography. The last decades have witnessed a renaissance of functional stereotactic neurosurgery in the treatment of patients with movement disorders. Initially, these procedures were largely based on the same imaging technique that had been used since the birth of this technique, and that is still used in some centers. The introduction of new imaging modalities such as Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) provided new potentials, but also new challenges for accurate identification and visualisation of the targets in the basal ganglia and the thalamus with an urge to thoroughly evaluate and optimize the stereotactic targeting technique, as well as evaluate accurately in stereotactic space the location and extent of stereotactic Radiofrequency (RF) lesions and the position of deep brain stimulation (DBS) electrodes. Aims: To study the differences between CT and MRI regarding indirect atlas coordinates in thalamic and pallidal procedures and to evaluate and validate visualisation of the pallidum and the subthalamic nucleus in view of direct targeting irrespective of atlas-derived coordinates. Furthermore, to evaluate the contribution of RF parameters on the size of stereotactic lesions, as well as the impact of size and location on clinical outcome. Method: The coordinates in relation to the landmarks of the 3rd ventricle of the targets in the pallidum and ventrolateral thalamus were compared between CT and MRI in 34 patients. In another 48 patients direct visualization  of the pallidum was evaluated and compared to indirect atlas based targeting. The possibility and versatility of visualizing the Subthalamic Nucleus (STN) on short acquisition MRI were evaluated in a multicentre study, and the use of alternative landmarks in identification of the STN was demonstrated in another study. In 46 patients CT and MRI were compared regarding the volume of the visible RF lesions. The volume was analysed with regard to coagulation parameters, and the location and size of the lesions were further evaluated concerning the clinical outcome. Results:Minor deviations were seen between MRI and  CT coordinates of brain targets. The rostro-caudal direction of these deviations were such that they would be easily accounted for during surgery, why MRI can obviate the need for CT in these procedures. MRI using a proton density sequence provided detailed images of the pallidal structures, which demonstrated considerable inter-individual variations in relation to the landmarks of the 3rd ventricle. By using a direct visualization of the target, each patient will act as his or her own atlas, avoiding the uncertainties of atlas-based targeting. The STN could be visualized on various brands of MRI machines in 8 centers in 6 countries with good discrimination and with a short acquisition time, allowing direct visual targeting. The same scanning technique could be used for postoperative localization of the implanted electrodes. In cases where the lateral and inferior borders of the STN cannot be easily distinguished on MRI the Sukeroku sign and the dent internal-capsule-sign signs might be useful. The volume of a stereotactic RF lesion could be as accurately assessed by CT as by MRI. The lesion´s size was most strongly influenced by the temperature used for coagulation. The lesions´ volumes were however rather scattered and difficult to predict in the individual patient based solely on the coagulation parameters. For thalamotomy, the results on tremor was not related to the lesion´s volume. For pallidotomy, larger and more posterior-ventral lesions had better effect on akinesia while effects on tremor and dyskinesias were not related to size or location of the lesions. Conclusions: The minor deviations of MRI from CT coordinates can be accounted for during surgery, why MRI can obviate the need of CT in these procedures. Direct visualized targeting on MRI of the pallidum is superior to atlas based targeting. The targets in the pallidum and the STN, as well as the location of the electrodes, can be well visualized with short acquisition MRI. When borders of the STN are poorly defined on MRI the Sukeroku sign and the dent internal-capsule-sign signs proved to be useful. The volumes of RF lesions can be accurately assessed by both stereotactic thin slice CT and MRI. The size of these lesions is most strongly influenced by the temperature of coagulation, but difficult to predict in the individual patient based on the coagulation parameters. Within certain limits, there were no clear relationships between lesions´ volume and location and clinical effects of thalamotomies and pallidotomies.

Parkinson’s disease (PD) is a common neurodegenerative disorder that is characterized by the degeneration of dopaminergic (DA) neurons in the substantia nigra and motor deficits. Although the majority of PD cases are sporadic, several genetic defects in rare familial cases have been identified. Animal models of these genetic defects have been created and have provided unique insights into the molecular mechanisms of the pathogenesis of PD. However, the etiology of PD is still not well understood. Here, taking advantage of the unique features offered by zebrafish, I characterized the functions of PINK1 (PTEN-induced kinase 1) gene, which is associated with recessive familial PD, in the development and survival of DA neurons. In zebrafish, antisense morpholino knockdown of pink1 did not cause a large loss of DA neurons in the ventral diencephalon (vDC), but the patterning of these neurons and their projections were perturbed. The pink1 morphants also showed impaired response to touch stimuli and reduced swimming behaviour. Moreover, the pink1 knockdown caused a significant reduction in the number of mitochondria, as well as mitochondrial morphological defects such as smaller size or loss of cristae, thus affecting mitochondrial function. These results suggest that zebrafish pink1 plays conserved important roles in the development of DA neurons and in the mitochondrial morphology and function. To better follow DA neurons after injury or administration of toxins, I generated a transgenic zebrafish line, Tg(dat:EGFP), in which the green fluorescent protein (GFP) is expressed under the control of cis-regulatory elements of dopamine transporter (dat). In Tg(dat:EGFP) fish, all major groups of DA neurons are correctly labeled with GFP, especially the ones in the vDC, which are analogous to the ascending midbrain DA neurons in mammals. In addition, we observed that the DA neurons in the vDC could partially be replaced after severe laser cell ablation. This suggests that zebrafish may have the unique capacity of regenerating DA neurons after injury. Taken together, my studies suggested that zebrafish could be a useful alternative animal model for the study of the molecular mechanisms underlying PD and for the screening of potential therapeutic compounds for PD.