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Striatal oscillatory activity associated with movement, reward, and decision-making is observed in several interacting frequency bands. Rodent striatal local field potential recordings show dopamine- and reward-dependent transitions between a 'spontaneous' state involving beta (15-30 Hz) and low gamma (40-60 Hz) and a 'dopaminergic' state involving theta (4-8 Hz) and high gamma (60-100 Hz) activity. The mechanisms underlying these rhythmic dynamics and their functional consequences are not well understood. In this thesis, I construct a biophysical model of striatal microcircuits that comprehensively describes the generation and interaction of these rhythms as well as their modulation by dopamine and rhythmic inputs, and test its predictions using human electroencephalography (EEG) data. Chapter 1 describes the striatal model and its dopaminergic modulation. Building on previous work suggesting striatal projection neuron (SPN) networks can generate beta oscillations, I construct a model network of striatal fast-spiking interneurons (FSIs) capable of generating delta/theta (2-6 Hz) and gamma rhythms. This FSI network produces low gamma oscillations under low (simulated) dopaminergic tone, and high gamma activity nested within a delta/theta oscillation under high dopaminergic tone. In a combined model under high dopaminergic tone SPN network beta oscillations are interrupted by delta/theta-periodic bursts of gamma-frequency FSI inhibition. This high dopamine-induced periodic inhibition may enable switching between beta-rhythmic SPN cell assemblies representing motor programs, suggesting that dopamine facilitates movement in part by allowing for rapid, periodic changes in motor program execution. Chapter 2 describes the model's response to square-wave periodic cortical inputs. Comparing models with and without FSIs reveals that the FSI network: (i) prevents the SPN network's generation of phase-locked beta oscillations in response to beta's harmonic frequencies, ensuring fidelity of transmission of cortical beta rhythms; and (ii) limits or entrains SPN activity in response to certain gamma frequency inputs. Chapter 3 describes an analysis of phase-amplitude coupling at cortical electrodes in human EEG data during a reward task. The alternating rhythms predicted by the model appear in response to positive feedback. While the origins of these rhythms remain unclear, if they represent striatal signals, they provide a direct link between human behavior and striatal cellular function.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22001号 / 医博第4515号 / 新制||医||1038(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 井上 治久, 教授 林 康紀, 教授 高橋 淳 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13324号 / 論医博第2192号 / 新制||医||1043(附属図書館) / (主査)教授 井上 治久, 教授 高橋 淳, 教授 福原 俊一 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23089号 / 医博第4716号 / 新制||医||1050(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 高橋 淳, 教授 浅野 雅秀, 教授 伊佐 正 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23095号 / 医博第4722号 / 新制||医||1050(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 伊佐 正, 教授 井上 治久, 教授 渡邉 大 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Although tremor is the most common movement disorder, there exist few effective tremor-suppressing devices, in part because the characteristics of tremor throughout the upper limb are unknown. To clarify, optimally suppressing tremor requires a knowledge of the mechanical origin, propagation, and distribution of tremor throughout the upper limb. Here we present the first systematic investigation of how tremor propagates between the shoulder, elbow, forearm, and wrist. We simulated tremor propagation using a linear, time-invariant, lumped-parameter musculoskeletal model relating joint torques and the resulting joint displacements. The model focused on the seven main degrees of freedom (DOF) from the shoulder to the wrist and included coupled joint inertia, damping, and stiffness. We deliberately implemented a simple model to focus first on the most basic effects. Simulating tremorogenic joint torque as a sinusoidal input, we used the model to establish fundamental principles describing how input parameters (torque location and frequency) and joint impedance (inertia, damping, and stiffness) affect tremor propagation. We expect that the methods and principles presented here will serve as the groundwork for future refining studies to understand the origin, propagation, and distribution of tremor throughout the upper limb in order to enable the future development of optimal tremor-suppressing devices.

La maladie de Parkinson est une maladie neurodégénérative progressive qui affecte le système nerveux central et se caractérise par des symptômes moteurs et non moteurs. Ces derniers comprennent des troubles du sommeil, des perturbations neuropsychiatriques et comportementales. En particulier, environ 50 % des patients atteints de la maladie de Parkinson (MP) souffrent de troubles du comportement du sommeil paradoxal (TDS), une parasomnie caractérisée par des comportements moteurs liés à des rêves. Les patients atteints de la MP souffrant de RBD ont tendance à présenter des symptômes moteurs et non moteurs plus graves que les patients ne souffrant pas de RBD, ce qui suggère que le RBD est un marqueur d'un processus neurodégénératif plus répandu. Parmi les symptômes non moteurs, les troubles neuropsychiatriques sont fréquents dans la DP et comprennent la dépression, les symptômes d'anxiété, l'apathie et les troubles du contrôle des impulsions (DCI), une complication déclenchée par la thérapie de remplacement de la dopamine (TRP). Pourtant, aucune étude n'a évalué si les patients atteints de MP et de troubles respiratoires chroniques présentent une fréquence accrue de symptômes neuropsychiatriques, en particulier des troubles du contrôle des impulsions et de l'apathie. Objectifs : évaluer si la DBR est associée aux maladies inflammatoires chroniques et/ou à l'apathie dans la maladie de Parkinson et caractériser le profil neuropsychiatrique des patients atteints de DBR. Matériel et méthodes : n=216 patients PD non déments consécutifs consultant une clinique universitaire de troubles du mouvement à Turin et Clermont-Ferrand (130 M, âge moyen : 66,9±10,8 ans) ont rempli des questionnaires pour le RBD et les CIM. En outre, 40 patients atteints de MP ayant reçu un diagnostic clinique de maladie inflammatoire chronique et 40 patients atteints de MP sans maladie inflammatoire chronique, appariés par sexe et âge, ont subi une vidéopolysomnographie (v-PSG) afin de déterminer la fréquence de la DBR. L'apathie a été évaluée chez 36 patients ayant subi une v-PSG (n=18 patients atteints de MP avec DCI, n=18 patients atteints de la MP), et sa relation avec la dépression, avec un large éventail de fonctions neuropsychologiques ainsi qu'avec des symptômes moteurs et non moteurs a été évaluée. Résultats : la DBR probable a été associée à un risque de 2,6 de développer des symptômes de CIM dans l'ensemble (p=0,001) et à un risque de 4,9 pour le jeu pathologique (p= 0,049). La RBD confirmée par le VPSG a été trouvée chez 34/40 (85%) des patients atteints de PD-ICD contre 21/40 (53%) des patients atteints de PD-noICD (p=0,003). L'association était significative après ajustement de la durée de la maladie, de l'âge d'apparition, de la gravité et de la dose de traitement (p=0,01) et l'état de la CIM est associé à un rapport impair de 5,44 pour avoir une DBR. L'apathie était plus élevée chez les patients atteints de DBR que chez les patients atteints de la MP sans DBR. Après 11 ajustements en fonction de l'âge, de la durée de la DP, des doses de DRT, des mesures cognitives et de la dépression, nous avons constaté que les PD-RBD présentent un manque d'initiative (p=0,03) ainsi qu'une tendance à la réduction des intérêts et à la recherche de nouveauté. L'ampleur de l'effet était importante (>0,8) ou presque (>0,75) pour ces variables. De plus, l'apathie était significativement corrélée à la mesure du sommeil paradoxal sans atonie. Conclusions : Nous avons montré pour la première fois que le RBD est associé à des DCI dans le DP. De plus, les patients RBD sans DAI sont plus apathiques que les patients sans RBD. Un traitement dysfonctionnel de la récompense dans le DP-RBD, résultant peut-être d'une altération plus grave de la voie méso-cortico-limbique, peut contribuer à la fois à une apathie accrue et à une fréquence accrue des DAI lorsqu'ils sont traités avec des doses plus élevées de DRT. / Parkinson’s disease is a progressive neurodegenerative disorder affecting the central nervous system characterized by motor and non-motor symptoms. The latter include sleep disorders as well as neuropsychiatric and behavioral disturbances. In particular, about 50% of patients with Parkinson's disease (PD) suffer from REM sleep behavior disorder (RBD), a parasomnia characterized by dream-enactment motor behaviors. PD patients with RBD tends to have more severe both motor and non-motor symptoms than PD without RBD, suggesting that RBD is a marker of a more widespread neurodegenerative process. Among non-motor symptoms, neuropsychiatric disorders are frequent in PD and include depression, anxiety symptoms, apathy and impulse control disorders (ICD), a complication triggered by dopamine replacement therapy (DRT). Yet, no study has assessed whether PD- RBD patients have an increased frequency of neuropsychiatric symptoms, particularly ICD and apathy. Objectives: to assess whether RBD is associated to ICDs and/or apathy in Parkinson’s Disease and to characterize the neuropsychiatric profile of PD patients with RBD. Material and methods: n=216 consecutive non-demented PD patients consulting a university movement disorders clinics in Turin and Clermont-Ferrand (130 M, mean age:66.9±10.8yrs.) filled out questionnaires for RBD and ICDs. Furthermore, 40 consecutive PD patients with a clinical diagnosis of ICD and 40 sex-and age-matched PD patients without ICD underwent to video-polysomnography (v-PSG) in order to determine the frequency of RBD. Apathy was assessed in 36 v-PSG recorded PD patients (n=18 PD with RBD, n=18 age- and sex-matched PD without RBD), and its relationship with depression, with a broad array of neuropsychological functions as well as with motor and non-motor symptoms was evaluated. Results: probable RBD was associated to a risk of 2.6 to develop ICD symptoms as a whole (p=0.001) and a risk of 4.9 for pathological gambling (p= 0.049). VPSG-confirmed RBD was found in 34/40 (85%) PD-ICD patients versus 21/40 (53%) PD-noICD (p=0.003). The association was significant after adjusting for PD duration, age of onset, severity and treatment dose (p=0.01) and the condition of ICD is associated to an odd ratio of 5.44 to have RBD. Apathy was higher in patients with RBD compared to PD without RBD. After 11 adjusting for age, PD duration, DRT doses, cognitive measures and depression, we found that PD-RBD have a lack of Initiative (p=0.03) together with a trend for reduced interests and novelty seeking. The effect size was large (>0.8) or almost large (>0.75) for these variables. Furthermore, apathy significantly correlated with measure of REM sleep without atonia. Conclusions: We showed for the first time that RBD is associated to ICDs in PD. Furthermore, RBD patients without ICD are more apathetic compared to patients without RBD. Dysfunctional reward processing in PD-RBD, possibly resulting from a more severe impairment of the meso-cortico-limbic pathway, may contribute to both increased apathy, and increased frequency of ICDs when treated with higher doses of DRT.

In recent years, several studies have discovered traces of Alzheimer's (AD) biomarkers in a large portion of patients with Parkinson's disease (PD), which have been associated with subsequent dementia (PDD). However, the manifestation of AD biomarkers in PD is not fully understood. At present, few studies have investigated how common AD biomarkers are in newly diagnosed and unmedicated patients with PD. This cross-sectional cohort study investigated whether AD biomarkers were present in unmedicated and newly diagnosed patients with PD and patients with PD and overlapping clinical symptoms (cognitive impairment, depression, olfactory dysfunction). Cerebrospinal fluid (CSF) levels of AD biomarkers Amyloid-β-42 (Aβ42), phosphorylated-tau (p-tau), and total-tau (t-tau) were assessed in 343 patients with the mean age of 68,69 (SD=9,60), including 31 healthy controls with the mean age of 68,90 (SD=5,64). The participants were recruited from The New Parkinson Patient in Umea (NYPUM & PARKNY). The results showed a significant difference in CSF AD biomarkers between patients with PD and healthy controls, but not in patients with PD and overlapping clinical symptoms. The results point to the presence of AD pathology in early PD; however, the presence of AD pathology could not be further strengthened by the clinical overlapping symptoms. More prospective studies on newly diagnosed patients with PD need to be carried out to investigate the prognostic values of the presence of AD pathology found in PD.

Introduction: Idiopathic Parkinson’s Disease is a multisystem neurodegenerative disease that is characterized by asymmetric impairment in regions of the midbrain, forebrain, and brainstem. Of the known neurodegenerative diseases, Parkinson’s is the second most commonly diagnosed worldwide with a global prevalence expected to reach 9 million individuals by 2030. As fall rates range between 35-68% annually, falling during walking is amongst the primary concerns for this demographic. Interestingly, despite the close association between loss of arm swing (due to Parkinson’s Disease) and future falls, evidence to-date has not examined the effect different arm swing conditions have on walking stability during unperturbed and perturbed (cognitive and mechanical) conditions. Dynamic stability research in this demographic is further limited in that evidence examining differences between the least and most affected leg is sparse. Research Objectives: To examine the differences between natural arm swing (unrestricted) and when arm swing was physical restricted (restricted) in people with Parkinson’s Disease. The effect of arm swing was assessed when people with Parkinson’s Disease walked in steady-state, dual-task, destabilizing terrains as well as in response to slips. Additionally, this thesis examined differences between the least and most affected sides, during the aforementioned conditions, that stem from the asymmetric progression in Parkinson’s Disease. Methods: Twenty individuals with Parkinson’s Disease were recruited for this research. Individuals walked on a CAREN-Extended System with unrestricted (natural) and restricted (absent) arm swing. Arm conditions were combined with steady-state walking, walking while performing a secondary dual-task, walking on minor destabilizing environments (hilly, rocky and mediolateral translational), and in response to slips for the heel-strikes of the perturbed (slipped) leg and recovery (contralateral) leg. The minor destabilizing terrains were assessed separately to steady-state walking for the arm swing condition resulting in three types of analyses (arms-rocky, arms-rolling hills, and arms-mediolateral). Data were processed in Vicon, Visual 3D, and OpenSim before being exported to Matlab to calculate dynamic stability (Margin of Stability, Harmonic Ratios and Coefficient of Variation), average spatiotemporal parameters, as well as trunk linear and angular velocities. Statistical analyses were conducted in SPSS with a significance level set a priori at (p<0.05). Results: During unperturbed walking with the restricted arm swing condition, compared to unrestricted, average trunk angular velocity increased in the transverse plane while instantaneous linear velocity at heel-strike decreased in the sagittal plane. Further, on the least affected leg, the Margin of Stability increased, average step length decreased, and coefficient of variation for step length increased. Contrastingly, step time coefficient of variation increased in the most affected leg. In the presence of the dual-task, average angular velocity in the frontal plane increased, average step time decreased (most affected leg), and step width coefficient of variation increased (bilaterally). Compared to unrestricted arm swing, restricted arm swing reduced average step length (arm-rolling hills) and time (arm-rocky), and increased COV step time (arm-rolling hills). The arm-rolling hills analysis revealed that the most affected leg had a shorter step length than the least affected. The destabilizing surface effects revealed that during the arm-rolling hills and arm-rocky analyses step time decreased, step width increased, and the COV for step time, length and width increased. No main effects occurred for the arm-mediolateral analysis. Additionally, when comparing the arm swing conditions in response to a slip, the restricted arm swing condition, compared to unrestricted, caused a faster step time during the slipped step. Compared to the most affected leg, the least affected had a wider step width during the slipped step. During the recovery step, the least affected leg had a larger anteroposterior Margin of Stability and longer step time than the most affected. Conclusion: The findings revealed that when people with Parkinson’s Disease walk without arm swing, trunk rotational velocity increases which internally perturbs gait. This destabilization elicited unique responses from dynamic stability metrics that were specific to the terrain encountered. Since Parkinson’s Disease primarily affects movement timing, the results suggest that loss of arm swing is particularly perturbing to foot placement timing while changes in spatial foot placement reflect compensation to maintain an existing level of global dynamic stability and symmetry. Additionally, the evidence indicates that the independent behavior of the least and most affected leg respond uniquely to loss of arm swing. However, as people with Parkinson’s Disease adjust the least affected leg’s foot placement to mirror the contralateral leg, functional interlimb differences may only be revealed when individuals encounter perturbations.