Background: Essential tremor (ET) is the most common movement disorder. In cases resistant to pharmacological treatment, functional stereotactic neurosurgery can be an alternative. Lesional surgery has largely been replaced by deep brain stimulation (DBS). The current target of choice is the ventrolateral thalamus (Vim). Vim DBS has generally shown good results, but in some cases it is associated with a suboptimal effect as well as side effects. DBS in the posterior subthalamic area/caudal zona incerta (PSA/cZi) has recently shown promising effects. Recently the role of lesional therapy in selected cases has been discussed. Aim: The aim is to evaluate stereotactic functional procedures in the treatment of ET, with special emphasis on PSA DBS. Further the effects of DBS in the PSA are evaluated. The optimal target is also assessed by evaluating the effect of Vim and PSA DBS in relation to the position of the electrode. An attempt to identify patient-specific factors of prognostic importance for the outcome after DBS will be made. The quality of life (QoL) of patients treated with PSA DBS for ET will be assessed. Finally, the aim is also to analyze retrospectively the long-term outcome of lesional procedures (thalamotomies). Method: The thesis consists of five studies. The optimal electrode location is evaluated in a study analyzing the location of the electrode contact yielding the best effect in Vim DBS and PSA DBS groups. The efficacy of PSA DBS in 21 patients is evaluated in a prospective study. The correlation between outcome, age, tremor grade and gender is established in a prospective study consisting of 68 patients. Finally, the degree of improvement in QoL is determined in 16 patients operated on in the PSA. The very long-term effect of lesional surgery has been investigated in a retrospective study of nine patients who have undergone thalamotomy. Results: In the study of PSA DBS the total score on the Essential Tremor Rating Scale (ETRS) was reduced by 60% compared to the baseline value. Tremor of the arm was improved by 95%. The study evaluating the optimal contact location showed that the best effect was in the PSA in 54% and in the Vim in 12%. The efficacy of DBS was not related to age, gender, or the severity of tremor with regard to the percentage reduction of tremor on stimulation. In patients with a more severe tremor at baseline, a higher degree of residual tremor on stimulation was seen. With regard to QoL, the activities of daily living (ADL) according to the ETRS score were significantly improved, as well as according to the ADL and psychosocial subscores on the Questionnaire for Essential Tremor (QUEST) scale. No significant changes were found on the generic Short Form (SF-36) QoL scale. Thalamotomy had some positive effects, but also a significant amount of side effects that might be attributed to the surgery. Conclusions: The effect of PSA DBS was very satisfying and compares well with the results from Vim DBS. When both Vim and PSA DBS are considered, the optimal target seems to be located in the PSA. PSA DBS shows good results in improving ADL, but the results have been difficult to demonstrate on QoL scales. The efficacy of DBS could not be shown to be associated with gender or age. Nor was it associated with the severity of tremor regarding the percentage of tremor reduction on stimulation. The preoperative severity of tremor was the most important factor regarding outcome following DBS. With regard to thalamotomies, some possible remaining benefit of the surgery could be seen along with some severe side effects.

Accurate Detection of Parkinson`s Disease in Tremor Syndromes Using Olfactory Testing

This study seeks to understand upper limb tremor in subjects with essential tremor (ET). A thorough understanding of tremor distribution will allow for the more effective development of tremor suppression devices, which offer an alternative to current treatments. Previous studies primarily focused on tremor in the hand only. This study seeks to characterize the distribution of tremor throughout the upper limb.We measured tremor in 25 subjects diagnosed with ET using motion capture, which provided displacement information of the limb during multiple postural and kinetic tasks. Inverse kinematics allowed us to analyze the motion capture data in the 7 major degrees of freedom (DOF) of the upper limb. The power spectral density estimate was used to determine: relative tremor magnitude throughout the DOFs, tremor variation between tasks, variation between subjects, and frequency variations between DOFs. Data analysis revealed that tremor increase is roughly proximal to distal. We also show that tremor magnitude in kinetic tasks is significantly higher than in postural tasks. Although we found some variation in tremor distribution between subjects, the roughly proximal to distal increase in tremor severity holds for several subsets of the study population. Finally, we found that tremor frequency doesnt vary significantly (< 1 Hz) between DOFs, in subjects with severe tremor. Our study shows that tremor distribution is quite stereotyped between subjects with ET. Furthermore, we have shown that tremor is greatest in the distal DOFs. This provides a compelling starting point for the development of future tremor suppression devices.

L’objectif général de cette thèse est d’étudier la production quantitative (i.e., nombre de mots) et qualitative (i.e. regroupements et alternances) du verbe d’action dans le vieillissement normal et dans les pathologies du mouvement à travers la tâche de fluence d’action, comparativement aux fluences classiques (i.e., sémantique et littérale). Nous avons montré que la production lors d’une tâche de fluence d’action est altérée chez des adultes âgés (60 ans et plus) comparativement à des adultes jeunes (30 ans et moins) et qu’elle est en lien avec les fonctions exécutives (Expérience 1) et la mémoire de travail (Expérience 3) chez l’adulte âgé. L’effet de l’âge paraît être modifié par le temps de production, les adultes âgés produisant moins de verbes d’action que les adultes jeunes pour un temps de trois minutes (Expérience 1) mais pas pour des temps d’une (Expérience 2) et de deux minutes (Expérience 3). De plus, les adultes âgés prenaient davantage en considération la consigne temporelle lors des tâches de fluence verbale que les adultes jeunes (Expérience 2). Les données d’une tâche d’association verbale (Expérience 4) indiquaient que les associations entre les noms et les verbes sont modifiées par l’âge. Nous avons comparés les performances de patients atteints de pathologiesdu mouvement à celles de participants contrôles lors de la tâche de fluence d’action. Nous avons montré que la production quantitative lors cette tâche est altérée chez des patients atteints de maladie de Parkinson (Expérience 5) et d’atrophie multisystématisée (Expérience 6). Dans le tremblement essentiel (Expérience 7), nous avons montré une atteinte de la fluence d’action alors que le traitement des verbes, lors d’une tâche de décision lexicale, n’était pas altéré. De plus, la chirurgie (stimulation cérébrale profonde) modifiait qualitativement la production dans la tâche de fluence d’action. Nos données montrent un impact du vieillissement normal et des pathologies du mouvement sur la production du verbe d’action, enraison de la nature fortement exécutive de ce processus. / The aim of this thesis is to investigate the production of action verbs through the action fluency task, in comparison to classical fluency tasks (i.e., semantic and letter). In first instance, production has been studied, both quantitatively and qualitatively, in aging. We have shown that action fluency is impacted by healthy aging and is related to executive functions (Experiment 1) and working memory (Experiment 3) in older adults. This effect of age appearsto be affected by production time, with older adults producing fewer action verbs than younger adults in three minutes (Experiment 1) but not in one (Experiment 2) and two minutes (Experiment 3). In addition, older adults took more into account the time instruction during verbal fluency tasks (Experiment 2). The verbal association task’s data (Experiment 4) indicated that associations between nouns and verbs are modified by age. In second instance,the production of action verbs has been studied within movement disorders. We have shown that the production in the action fluency task and the adaptation to time instruction are impacted by Parkinson's disease (Experiment 5). We have also shown that action fluency is altered within an atypical parkinsonism, multiple system atrophy (Experiment 6). In essential tremor (Experiment 7), we have shown an impairment of action fluency while verbs treatment, in a lexical decision task, was not altered. In addition, surgery (deep brain stimulation) qualitatively modified the production of verbs in action fluency. Our data highlight the impact of healthy aging and movement disorders on the production of action verb, due to the highly executive nature of this process.

Le système visuel humain est complexe par son organisation anatomique et par son fonctionnement incomplètement élucidé. Il est fonctionnellement divisé en deux systèmes. Le premier système est destiné à la vision consciente communément appelée voie visuelle principale ou en anglais « image forming visual pathways ». Le second, appelé système secondaire ou accessoire, n’apporte pas d’information visuelle consciente, il est dit « non image forming visual pathway ». Ce dernier apporte à notre cerveau une information sur l’environnement telle que la sensation jour/nuit. Ses fonctions sont sous-tendues par l’afflux d’informations rétiniennes non visuelles sur des structures de l’hypothalamus comme le noyau supra-chiasmatique. Les deux systèmes visuels ont un substratum anatomique complexe faisant intervenir de nombreuses structures anatomiques au sein des différents étages du cerveau cortical et sous-cortical comme les noyaux gris centraux dits « Basal Ganglias » (BG). Le système visuel secondaire intervient aussi comme une structure de contrôle des mouvements oculomoteurs tels que la poursuite ou les saccades nécessaires pour explorer notre environnement. Ainsi les saccades oculomotrices sont sous le contrôle modulateur des BG. De ce fait l’étude des saccades apparait comme un très bon modèle pour explorer le fonctionnement du système extrapyramidal au cours des maladies neuro-dégénératives. Les connaissances actuelles sur ce système de contrôle des saccades proviennent essentiellement des études sur le primate non humain et sur des observations cliniques chez l’homme au cours de pathologies dégénératives ou toxiques des BG. L’observation des structures anatomiques, en particulier du réseau de la substance blanche cérébrale qui supporte les connections axonales, n’est pas accessible à l’imagerie clinique de routine. Pour décrire et étudier ces réseaux de connections, la notion de connectomique a été introduite il y a un dizaine d’années. Dans ce travail, nous nous sommes donné l’objectif de décrire le connectome des saccades oculomotrices sur un plan structurel. Nous avons exploré les structures sous-corticales intervenant dans le contrôle des saccades comme les BG, le colliculus supérieur et le pulvinar. Pour ce faire, nous avons utilisé l’imagerie IRM structurelle en diffuseur de tension (DTI) chez deux groupes de patients présentant une maladie neuro-dégénérative : un groupe souffrant de maladie de Parkinson chez qui une atteinte des BG et une dysfonction des saccades sont reconnues, et un groupe de trembleurs essentiels reconnu pour ne pas présenter de dysfonction des saccades et chez qui les BG sont épargnés. Le résultat de ce travail a permis pour la première fois une description in vivo du connectome des saccades chez l’Homme. Il a de plus montré des différences dans la structure du connectome dans les deux groupes de patients. Une meilleure connaissance de ce connectome pourrait permettre de mieux comprendre certains troubles oculomoteurs et aussi de suivre l’évolution de certaines maladies neurodegeneratives. / Visual system is complex by its anatomy and its function. Neuro-anatomists have been interested in understanding the link between the visual pathways and the brain for centuries. Classical brain fixation and dissection methods were used to describe the visual pathways identifiable macroscopically. Non–image visual pathway, particularly the part involves in saccadic eye movements network in human is still not mastered. Our current knowledge in SCM is based on animal studies, anatomic dissection and brain histopathology examination of specimens from patients with clinical basal ganglia (BG) disorders. Saccadic eye movements (SCM) are under the control of the basal ganglia (BG) and SCM circuitry within the BG represents a good model for studying pathology in the extra-pyramidal system. The diagnosis of Parkinson’s disease (PD), which affects SEM and its distinction from non-dopaminergic, essential tremor (ET) where SEM are not impaired can be challenging and still relies on clinical observations. Diffusion tensor imaging and fiber tractography (DTI-FT), a new MRI technology, can be used to evaluate the presence and integrity of white matter tracts using directional diffusion patterns of water. The purpose of this study is to use DTI-FT to analyse SEM networks within BG and compare the SEM neural pathways or connectome of patients clinically diagnosed with PD and ET. To date, there are no studies, using DTI-FT for the extensive exploration of non-image visual pathways and SCM circuits, notably the deep brain connections. For this goal, we introduced the concept of SCM connectomes, derived from the general concept of connectome. Our study used structural MRI to identify nuclei and fascicles of the SCM connectome in PD and ET patients; imageries were acquired in routine clinical conditions fitted for DBS surgery. We found a reduction of the fiber number in two fascicles of the connectome in PDcompared to ET group.

Gait and balance disorders and the resulting falls are a substantial part of Parkinson's disease (PD) and other movement disorders. Especially in the late stage of PD more than 80 % of the patients fall. History of falls remains the best predictor of falls nonetheless, but it can not be used in falls prevention. Dopaminergic pharmacotherapy improves postural stability and gait in PD only in the early stage and the dopaminergic responsiveness of these symptoms decreases significantly during the disease progression. The impact of this medication on future falls risk remains still unclear. The connection between balance and gait disorders and cognitive impairment in PD is also not fully understood. The current state of knowledge about gait and balance disorders and cognitive impairment in PD is not satisfactory. Therefore the aims of the experimental part of this thesis were prospective monitoring of risk factors and predictors of falls, observation of the impact of dopaminergic medication on future falls risk and verifying the relationship between gait and balance disorders and cognitive impairment in PD. The fourth aim of the thesis was to specify the type and severity of gait and balance disorders in patients with essential tremor (ET). Although ET is one of the most common neurological disorders,...

Background/Aims: The diagnostic value of olfactory testing for the discrimination of tremor-dominant Parkinson’s disease (PD) from other tremor disorders remains enigmatic. We evaluated whether olfactory testing can accurately detect PD in tremor patients. Methods: A retrospective analysis of 299 consecutive subjects referred for the differential diagnosis of a tremor disorder was done. Olfactory testing was performed using ‘Sniffin’ Sticks’, resulting in a composite TDI score of odor threshold (T), discrimination (D), and identification (I). Receiver operating curve (ROC) plots were used to calculate sensitivity/specificity for the detection of PD. Results: Of all subjects, 167 (55.9%) had PD and 85 (28.4%) had essential tremor (ET). The mean TDI score in PD was significantly reduced compared to those in ET and other tremor disorders with no differences between ET and other tremor disorders. ROC analysis revealed strong correlations of TDI scores with PD [area under the curve: 0.85 (95% CI: 0.80–0.89); p < 0.001]. The highest Youden index was observed for a TDI score <25 (Youden index: 0.58). Using this cutoff score and that generated from normative data of healthy controls, the TDI score provided high sensitivity (negative predictive value) and specificity (positive predictive value) of approximately 80% for detecting PD. Conclusion: Olfactory testing is a useful, easily applied and inexpensive diagnostic test which is helpful to detect PD among tremor patients.

Gait and balance disorders and the resulting falls are a substantial part of Parkinson's disease (PD) and other movement disorders. Especially in the late stage of PD more than 80 % of the patients fall. History of falls remains the best predictor of falls nonetheless, but it can not be used in falls prevention. Dopaminergic pharmacotherapy improves postural stability and gait in PD only in the early stage and the dopaminergic responsiveness of these symptoms decreases significantly during the disease progression. The impact of this medication on future falls risk remains still unclear. The connection between balance and gait disorders and cognitive impairment in PD is also not fully understood. The current state of knowledge about gait and balance disorders and cognitive impairment in PD is not satisfactory. Therefore the aims of the experimental part of this thesis were prospective monitoring of risk factors and predictors of falls, observation of the impact of dopaminergic medication on future falls risk and verifying the relationship between gait and balance disorders and cognitive impairment in PD. The fourth aim of the thesis was to specify the type and severity of gait and balance disorders in patients with essential tremor (ET). Although ET is one of the most common neurological disorders,...

Estudos recentes têm sugerido que as imagens de tensor de difusão podem ser úteis para diagnosticar doença de Parkinson (DP). Nosso objetivo foi estimar a exatidão diagnóstica da anisotropia fracionada da substância negra (FA-SN) para o diagnóstico de DP, em uma amostra mais próxima do cenário clínico, incluindo pacientes com tremor essencial (TE) e voluntários sadios (VS). Para uma compreensão mais profunda de nossos achados, também realizamos uma revisão sistemática da literatura e meta-análise para estimar a mudança média da FA-SN induzida pela DP e a precisão diagnóstica dessa medida. Nossa amostra consistiu de 135 pacientes: 72 pacientes com DP, 21 com TE e 42 VS. Dois exames em RM 3T foram realizados em diferentes locais. Em nossa amostra, não encontramos diferenças significativas entre os grupos e a FA-SN não foi útil para o diagnóstico. O maior componente da variabilidade foi a interação sítio-sujeito. Os resultados desta amostra foram fundidos em uma meta-análise que incluiu 1549 indivíduos compostos de 896 pacientes com DP e 653 VS. Utilizaram-se os modelos bivariados e inversos de variância inversa para resumir as medidas de acurácia diagnóstica e as diferenças de médias, respectivamente. A meta-análise estimou uma pequena diminuição nos valores médios da FA-SN na DP (0,03 menor nos pacientes com DP (IC: 0,01 - 0,06)). Apesar disso, sua capacidade discriminatória para o diagnóstico da DP foi baixa. A sensibilidade e a especificidade combinadas foram, respectivamente, 70% (IC: 65 - 74) e 63% (IC: 57 - 69). Houve alta heterogeneidade entre os resultados dos estudos (I2 = 92%). O estudo de caso-controle e a meta-análise das medidas de anisotropia fracionada na substância negra de pacientes com doença de Parkinson e voluntários sadios demonstram que o seu uso como biomarcador de DP não é confiável / Recent studies have suggested that diffusion tensor images can be useful to diagnose Parkinson\'s disease (PD). Our goal was to estimate the diagnostic accuracy of substantia nigra fractional anisotropy (SN-FA) for PD diagnosis in a sample closer to the clinical setting, including patients with essential tremor (ET) and healthy controls (HC). To a deeper understanding of our findings, we also performed a systematic literature review and meta-analysis to estimate mean change of SN-FA induced by PD, and diagnostic accuracy of this measurement. Our sample consisted of 135 subjects: 72 PD and 21 ET patients and 42 HC. Two 3T MRI scans were performed in different sites. In our sample, we did not find significant mean difference between groups and SN-FA was useless for diagnosis. The largest component of explained variability of SN-FA was site-subject interaction. MRI results of this sample were merged in a meta-analysis that included 1549 subjects composed of 896 PD patients and 653 HC. The normal bivariate and the inverse-variance random-effect models were used to summarize diagnostic accuracy measures and mean differences respectively. Meta-analysis estimated a small decrease in mean SN-FA values in PD (0.03 lower in PD patients (CI: 0.01 - 0.06)). Despite this fact, its discriminatory capability to diagnose PD was low. The pooled sensitivity and specificity was respectively 70% (CI: 65 - 74) and 63% (CI: 57 - 69). There was high heterogeneity between studies results (I2 = 92 %). This case-control study and meta-analysis of substantia nigra fractional anisotropy measurements in Parkinson\'s disease and healthy volunteers demonstrate that their use as a PD biomarker is not reliable

Positron emission tomography (PET) is a functional imaging method that allows studying physiological, biochemical or pharmacological processes in vivo. PET is being used in both research and clinical practice. In the brain, it has been used to investigate metabolism, receptor binding, and alterations in regional blood flow. This thesis involves both preclinical and clinical dual-tracer PET imaging studies of different neurological disorders. In this way, different radiotracers were used along the projects. The first project focused on the implementation and in vivo validation of the simultaneous dual-tracer PET imaging technique on the rat brain and its applications in the study of cerebral ischemia. In particular, in this project two biological processes were studied at the same time: cerebral blood flow and cerebral glucose metabolism. The second project consisted in a clinical correlation study of the GABAergic and serotonin systems in a population with Essential Tremor (ET), the most commonly movement disorders. / La tomografia per emissió de positrons (PET) és un mètode d'imatge funcional que permet l'estudi in vivo de processos fisiològics, bioquímics i farmacològics. La PET s'utilitza tant en la pràctica clínica com en la recerca. Al cervell, s'ha utilitzat per investigar el metabolisme, la neurotransmissió, i les alteracions en el flux sanguini regional. Aquesta tesi implica estudis preclínics i clínics de la tècnica PET en diversos trastorns neurològics. D'aquesta manera, es van utilitzar diferents radiotraçadors al llarg dels projectes. El primer projecte es va centrar en la implementació i validació in vivo de la tècnica PET del doble-marcador simultani en el cervell de rata i les seves aplicacions en l'estudi de la isquèmia cerebral. En particular, en aquest projecte es van estudiar en el mateix moment dos processos biològics: el flux sanguini cerebral i el metabolisme cerebral de la glucosa. El segon projecte va consistir en un estudi clínic de correlació dels sistemes GABAèrgic i serotoninèrgic en una població amb tremolor essencial (TE), el trastorn del moviment més comú