京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22745号 / 医博第4663号 / 新制||医||1046(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 林 康紀, 教授 伊佐 正, 教授 村井 俊哉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Parkinson’s disease is a common neurological disease which will progressively damagedopaminergic neurons in the brain. Later stages of the disease will result in death of theneurons. The diagnosis is often made with respect to the motor symptoms, which includetremors, bradykinesia, and rigidity. In addition to motor symptoms, non-motor symptomsappear in many patients, such as cognitive changes and mood disorders. One method used totreat Parkinson’s disease is deep brain stimulation, where electric pulses are emitted to aspecific brain area. A common target is the subthalamic nucleus, which is part of the basalganglia. By using deep brain stimulation, the dose of other medications for Parkinson’sdisease can be lowered. However, the mechanisms of deep brain stimulation are not yetentirely known, and there have been many reports of adverse side-effects caused by thismethod, including depression and other types of mood changes. Even so, information of apossible sex distribution of these side-effects is still limited. Here, a qualitative essay wasmade where 16 articles describing reported side-effects in men and women were compared. Inaddition, unpublished data from optogenetic studies on male and female mice were analysedin order to examine putative sex-differences upon experimental brain stimulation strategies.The results from the optogenetics results did not show any statistically significant sexdifferences.In contrast, by comparing the selected articles in which results of deep brainstimulation treatment in patients were reported, some differences were found. First, it seemsthat women report more depressive-like symptoms than men. Second, while men also reportdepressions, they also report more aggressive behaviour upon the treatment. A preliminaryconclusion of this essay is therefore that certain sex-differences can be observed among theadverse side-effects reported upon deep brain stimulation in Parkinson´s disease. However,since the studied material was limited, more research is required to make firmer conclusions.

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Lesions of the subthalamic nucleus (STN) alleviate the cardinal signs of idiopathic as well as MPTP-induced Parkinson's disease in primates. For this reason, the STN is a target for clinical treatment of Parkinson's disease using deep brain stimulation. Despite its small size, the STN plays a vital role in the cortico-basal ganglia-thalamic network. However, the functional features of the STN have yet to be fully uncovered. The research presented in this thesis examines the functions of the STN by measuring behavioural changes resulting from STN lesions in rats performing executive abilities. In the first experiment, a ‘signal change' reaction time task was developed and the performance of humans and rats was compared. The main findings were that although humans and rats used different strategies in the task, the task did challenge the ability to inhibit unwanted responses. In the second and third experiments, the effects of bilateral lesions of the STN on performance of two variants of the ‘signal change' task were examined. Rats with the STN lesions were able to inhibit responses when under stimulus control, but were less able to inhibit responses that were not under stimulus control. In the final experiment, the effects of lesions of the STN on inhibitory control in a nonmotor, cognitive domain were examined. Rats with STN lesions were not impaired on reversal learning, suggesting intact inhibition of previously rewarded responses. The rats with STN lesions did show impairments in selective attention which resulted in an inability to form an attentional set. Together, these findings challenge the conventional view that the STN simply plays a global inhibitory role. Rather, the contribution of the STN to inhibitory control is more complex and neither the motor nor the cognitive effects of the lesions are easily explained simply as a failure of inhibition.

Introduction: Exploring the brain for optimal locations for deep brain stimulation (DBS) therapy is a challenging task, which can be facilitated by analysis of DBS efficacy in a large number of patients with Parkinson’s disease (PD). The Unified Parkinson's Disease Rating Scale (UPDRS) scores indicate the DBS efficacy of the corresponding stimulation location in a particular patient. The spatial distribution of these clinical scores can be used to construct a functional model which closely models the expected efficacy of stimulation in the region. Designs and Methods: In this study, different interpolation techniques were investigated that can appropriately model the DBS efficacy for Parkinson’s disease patients. These techniques are linear triangulation based interpolation, ‘roving window’ interpolation and ‘Monopolar inverse weighted distance’ (MIDW) interpolation. The MIDW interpolation technique is developed on the basis of electric field geometry of the monopolar DBS stimulation electrodes, based on the DBS model of monopolar cathodic stimulation of brain tissues. Each of these models was evaluated for their predictability, interpolation accuracy, as well as other benefits and limitations. The bootstrapping based optimization method was proposed to minimize the observational and patient variability in the collected database. A simulation study was performed to validate that the statistically optimized interpolated models were capable to produce reliable efficacy contour plots and reduced false effect due to outliers. Some additional visualization and analysis tools including a graphic user interface (GUI) were also developed for better understanding of the scenario. Results: The interpolation performance of the MIDW interpolation, the linear triangulation method and Roving window method was evaluated as interpolation error as 0.0903, 0.1219 and0.3006 respectively. Degree of prediction for the above methods was found to be 0.0822, 0.2986 and 0.0367 respectively. The simulation study demonstrate that the mean improvement in outlier handling and increased reliability after bootstrapping based optimization (performed on Linear triangulation interpolation method) is 6.192% and 12.8775% respectively. The different interpolation techniques used to model monopolar and bipolar stimulation data is found to be useful to study the corresponding efficacy distribution. A user friendly GUI (PDRP_GUI) and other utility tools are developed. Conclusion: Our investigation demonstrated that the MIDW and linear triangulation methods provided better degree of prediction, whereas the MIDW interpolation with appropriate configuration provided better interpolation accuracy. The simulation study suggests that the bootstrapping-based optimization can be used as an efficient tool to reduce outlier effects and increase interpolated reliability of the functional model of DBS efficacy. Additionally, the differential interpolation techniques used for monopolar and bipolar stimulation modeling facilitate study of overall DBS efficacy using the entire dataset.

Introdução: A estimulação cerebral profunda (DBS) tem sido utilizada para controle das alterações motoras nos pacientes com Doença de Parkinson (DP). O núcleo subtalâmico (NST) é o alvo preferencialmente escolhido na cirurgia. Entretanto, a técnica tem sido associada com declínio cognitivo, principalmente na fluência verbal, alterações de humor e de comportamento. Objetivo: Verificar a ocorrência de alterações na cognição, humor e atividades funcionais por meio de avaliação neuropsicológica. Métodos: Vinte e um pacientes submetidos à cirurgia no período de Maio de 2008 a Março de 2013 foram examinados por meio da avaliação neuropsicológica incluindo testes de memória, funções executivas, funções atencionais, linguagem, praxia, escala hospitalar de depressão e ansiedade (HADS) e atividades funcionais (Pfeffer), nas fases pré e pós-operatória. Os dados foram analisados utilizando SPSS versão 17.0 e os resultados foram comparados através do teste pareado t-Student ou chi-quadrado. Foi adotado um nível de significância igual ou menor que 5% (p < 0,05) para todas as análises. Resultados: Não foram encontradas diferenças significativas nas funções cognitivas, no humor e nas atividades funcionais avaliadas. Resultado marginal foi observado na memória episódica imediata verbal (p=0,051). Conclusão: DBS-NST parece não ter impacto negativo nas funções cognitivas e humor. Apesar da amostra ser relativamente pequena, a técnica parece ser segura do ponto de visto cognitivo em pacientes adequadamente selecionados / Introdution: Deep brain stimulation (DBS) has been used for control of motor disorders in patients with Parkinson\'s disease (PD). The subthalamic nucleus (STN) is the main target used in surgery. However, the technique has been associated with cognitive decline, mainly in verbal fluency, mood and behavior. Objective: To investigate the occurrence of changes in cognition, mood, and activities of daily living through neuropsychological assessment. Methods: Twenty one patients operated between May, 2008 and March, 2013 were submitted to pre- and post-operative neuropsychological testing including memory, executive functions, attentional functions, language and praxis assessment, and to hospital anxiety and depression scale (HADS) and activities of daily living (Pfeffer) scale rating as well. Data were analyzed using SPSS version 17.0 and the results were compared using the paired Student t-test or chi-square. A significance level equal or lower than 5% (p < 0.05) was adopted. Results: No significant differences were found in cognitive functions, mood and activities of daily living. Marginal results were observed in immediate verbal episodic memory (p=0.051). Conclusion: DBS - STN did not show a negative impact on cognitive function, mood and daily activities. Despite the relatively small sample, the technique appears to be safe from the cognitive point of view in appropriately selected patients

L’une des caractéristiques électrophysiologiques majeure de la maladie de Parkinson est l’émergence de bouffées de potentiels d’action au niveau du noyau sous-thalamique (NST). Des travaux récents menés in vitro ont soulevé l’hypothèse de l’implication des récepteurs dopaminergiques D5 (RD5) dans la genèse de cette activité pathologique. Nous avons mis en évidence que les RD5, seuls récepteurs D1-like exprimés au niveau du NST, présentent une activité constitutive in vivo, et que celle-ci est bloquée par l’injection locale d’a-flupentixol. Le blocage de cette activité intrinsèque d’une part, améliore le comportement locomoteur d’animaux rendu hémiparkinsonien, et d’autre part réduit la tendance des neurones du NST à décharger en bouffées in vivo et in vitro, signature physiopathologique de la maladie de Parkinson. L’ensemble de ces données souligne le rôle clé des RD5 dans la physiopathologie de la maladie de Parkinson, ce qui ouvre la voie à de nouvelles approches thérapeutiques… Outre cette propriété d’agoniste inverse des RD5, l’a-flupentixol est connu pour ses propriétés antipsychotiques en tant qu’antagoniste des RD2. C’est pourquoi lorsqu’il est injecté de façon systémique il induit des troubles moteurs et une catalepsie caractérisés de syndrome extrapyramidaux, même chez les animaux contrôles. Les mécanismes électrophysiologiques qui sous-tendent cet état cataleptique n’ayant jamais été étudié auparavant, nous avons mis en évidence que l’administration, par voie intra-péritonéale, d’a- flupentixol induit des changements drastiques de l’activité électrique au sein du réseau des ganglions de la base. En effet, nous avons observé une augmentation de la fréquence de décharge des neurones du globus pallidus et une diminution de celle-ci au niveau du NST et de la substance noire pars reticulata, accompagnée d’une désorganisation de l’activité électrique au niveau de ces deux noyaux. Cette étude offre une vue d’ensemble sur les mécanismes électrophysiologiques à l’origine des effets secondaires extrapyramidaux induits par les antipsychotiques, et souligne le caractère fondamental de la désorganisation de l’activité électrique des ganglions de la base dans les troubles moteurs. / Burst-firing in the subthalamic nucleus (STN) is a hallmark of Parkinson’s disease. Previous in vitro studies have raised the hypothesis of the involvement of dopamine D5 receptor (D5R) in the genesis of this pathological activity. Here we have shown that D5R exert a constitutive activity in vivo, which can be blocked by local application of a-flupentixol. Blockade of this intrinsic activity improved locomotor behaviour in an animal model of Parkinson’s disease and alleviate burst-firing of STN neurons both in vitro and in vivo. Taken together, these results highlight the key role play by local D5R in the pathophysiology of Parkinson’s disease and open the way to new pharmacological treatment of the disease… In addition to this property D5R inverse agonist, a-flupentixol is known for its antipsychotic properties as a D2R antagonist. Therefore, when injected systemically, it induced motor disturbances and catalepsy characterized as extrapyramidal motor side-effects. The electrophysiological mechanisms underlying this cataleptic state had never been studied before. Here we have demonstrated that the intra-peritoneal administration of a-flupentixol induced dramatic changes in the electrical activity of the basal ganglia network. Indeed, we observed an increase in firing rate of globus pallidus neurons and a decrease in both STN and substantia nigra pars reticulata, accompanied by a disorganisation of the electrical activity of these two nuclei. This study provides an overview of the electrophysiological mechanisms underlying extrapyramidal motor side-effects induced by antipsychotics, and stresses the fundamental nature of the disorganisation of the electrical activity in the basal ganglia network as a source of movement disorders.

Le rôle respectif des ganglions de la base (GB) et de la région locomotrice dans le contrôle locomoteur et postural n'est pas établi chez l'homme. Au sein de ces circuits, le noyau sous-thalamique (NST) et le noyau pédunculopontin (NPP) semblent impliqués dans le pattern locomoteur et le maintien de l'équilibre. En effet, chez les patients avec maladie de Parkinson (MP), caractérisée par une perte des neurones dopaminergiques et représentant un modèle de dysfonctionnement des GB, des dysfonctionnements de l'activité du NST seraient à l'origine d'un freinage du mouvement, jusqu'au blocage moteur (freezing de la marche-FOG). Dans le NPP, des lésions cholinergiques sont retrouvées chez les patients MP avec des chutes. Dans ce travail de recherche nous avons étudié le rôle du NST et les effets de la modulation de l'activité du NPP sur les étapes de l'initiation de la marche (GI) chez les patients avec MP. Nous avons retrouvé une synchronisation dans la bande de fréquence alpha précédant l'exécution du pas, en cohérence avec le NPP. La stimulation à basse fréquence du NPP améliore le contrôle postural. Ces données suggèrent que le NST est impliqué dans la préparation de la GI, et que le NPP a un rôle dans le contrôle postural chez l'homme. Dans une seconde partie, nous avons examiné le rôle des lésions du circuit cortex-GB-NPP dans la survenue du FOG et des chutes chez des sujets âgés non-parkinsoniens et démontré une lésion sélective de ce circuit chez ces sujets. Finalement, l'ensemble de ces données confortent les hypothèses physiopathologiques à l'origine des troubles de la marche et de l'équilibre chez les patients MP avec lésion/dysfonction du circuit cortex-GB-NPP. / The respective roles of basal ganglia (BG) and the mesencephalic locomotor region (MLR) in the postural control and locomotion are not clearly established in humans. In these circuits, the subthalamic nucleus (STN) and the pedunculopuntine nucleus (PPN), two interconnected structures, appear to be involved in the locomotor pattern control and postural maintenance. Indeed, in patients with Parkinson’s disease (PD), characterized by a progressive loss of dopaminergic neurons and representing a model of dysfunction of the BG, there are dysfunctions of STN activity that could cause braking of movement underlying motor block (freezing of gait-FOG). In the PPN, greater loss of cholinergic neurons is observed in PD patients with falls. In this research, we studied STN activity and the effects of modulating the PPN activity during the stages of gait initiation (GI) in patients with PD. We found a modulation of activity of the STN with synchronization in the alpha frequency band before the postural adjustments and the execution of step, with PPN coherence. Low frequency stimulation of the PPN improved postural control with no significant effect on the locomotion. These data suggest that the STN is involved in the preparation of GI and the PPN has a leading role in postural control in humans. In a second part, we examined the role of the cortex-basal ganglia-PPN circuit in FOG and falls in a non-parkinsonian elderly population and demonstrated a selective lesion of this circuit in these subjects. Taken together, these data support the pathophysiological hypothesis for the origin of abnormal gait and balance in patients with PD, with lesion and/or dysfunction of the cortex-BG-PPN.

Quantification of blood fraction (fblood), blood oxygenation (S<img src="http://onlinelibrary.wiley.com/store/10.1002/jbio.201200055/asset/equation/tex2gif-inf-2.gif?v=1&amp;t=h70man4a&amp;s=4a6d004ec608a2a6ec8e8597f73bdb6be30286e8" />), melanin, lipofuscin and oxidised and reduced Cytochrome aa 3 and c was done from diffuse reflectance spectra captured in cortex, white matter, globus pallidus internus (GPi) and subthalamus during stereotactic implantations of 29 deep brain stimulation (DBS) electrodes with the aim of investigating whether the chromophores can give physiological information about the targets for DBS. Double-sided Mann-Whitney U -tests showed more lipofuscin in GPi compared to white matter and subthalamus (p &lt; 0.05). Compared to the other structures, fbloodwas significantly higher in cortex (p &lt; 0.05) and S<img src="http://onlinelibrary.wiley.com/store/10.1002/jbio.201200055/asset/equation/tex2gif-inf-4.gif?v=1&amp;t=h70man4c&amp;s=855c70105e88a292de25618487573dfc7d30e08a" /> lower in GPi (p &lt; 0.05). Median values and range for fblood were 1.0 [0.2–6.0]% in the cortex, 0.3 [0.1–8.2]% in white matter, 0.2 [0.1–0.8]% in the GPi and 0.2 [0.1–11.7]% in the subthalamus. Corresponding values for S<img src="http://onlinelibrary.wiley.com/store/10.1002/jbio.201200055/asset/equation/tex2gif-inf-6.gif?v=1&amp;t=h70man4e&amp;s=151ec25bee7270bcfc2292e70d6f4aea18348dbc" /> was 20 [0–81]% in the cortex, 29 [0–78]% in white matter, 0 [0–0]% in the GPi and 0 [0–92]% in the subthalamus. In conclusion, the measurements indicate very low oxygenation and blood volume for DBS patients, especially in the GPi. It would be of great interest to investigate whether this is due to the disease, the normal situation or an artefact of doing invasive measurements.