Essential tremor (ET) is the most common movement disorder worldwide and is characterized by an isolated tremor of the upper limb that worsens over the course of time. Evidence has accumulated to support the theory that the cerebellum is primary involved in the development of ET disease, although the contribution of cerebellar pathology to ET’s aetiology remains poorly understood. Beside motor deficits, numerous studies report the presence of cognitive impairment in ET patients. The cerebellum is crucial for motor as well as cognitive functions as it integrates sensorimotor information to create an internal model of movement using prediction errors. In this study, I tested the performance of 34 ET patients and 34 age-matched healthy controls in a visuomotor adaptation (VMA) task whose proper execution critically depends on the cerebellum. Participants performed the VMA while sitting in front of a computer screen. At the beginning of each trial, eight grey circles in one of eight possible positions arrayed around a central cross appeared on the screen. Next, one of the eight circles was marked as a blue target, and participants had to move from the central cross towards the target using a digital pen moved on a digital tablet. The movement on the tablet was represented as a cursor on the screen. Visual feedback from the moving hand was prevented. Over the course of the experiment, a 30° clockwise visuomotor perturbation of the cursor movement on the screen was introduced abruptly. To this end, subjects implicitly modified the reach direction such that they are able to hit the target again. The extent to which a subject adapts to the visuomotor perturbation can be measured by the angular error between a straight line connecting the center cross and the target, and a line connecting the center cross and the position of the cursor at peak velocity. Reaction times and movement times were analyzed to assess motor performance. In accordance with my hypothesis, I found evidence for impaired visuomotor adaptation in ET that could not be explained by altered general motor performance due to tremor. This deficit was also specific to both early and late adaptation phases. There were no group differences during a baseline phase, in which no visual perturbation was present, as well as at a de-adaptation phase, when the visual perturbation was suddenly removed. This deficit seems to also not relate to clinical features, i.e., disease state (measured by TETRAS/SARA), disease duration, current medication, and patients’ cognitive state (evaluated by MoCA). Thus, these findings support the hypothesis that a functional disturbance of the cerebellum is present in mildly to moderately affected ET patients without marked cerebellar signs and is detectable using a behavioral task that targets cerebellar functionality. What could be further mechanisms that negatively affect visuomotor adaptation in patients with ET and are not associated with basic motor functions? Unlike a pure motor task, the visuomotor adaptation task entails a cognitive component with implicit and/or explicit learning processes. Thus, it could be that cognitive deficits in ET, frequently reported among studies may have driven performance deficits in this task. Note however that I did not find any association between cognitive abilities as measured by MoCA and visuomotor adaptation impairment in the ET cohort. As no extensive neurocognitive testing was performed in our cohort and MoCA was shown to be not very sensitive for cerebellar cognitive symptoms, it is impossible to rule out the effect of cognitive decline in ET on visuomotor adaptation.

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

Indiana University-Purdue University Indianapolis (IUPUI) / Physical and biological phenomena that involve oscillations on multiple time scales attract attention of mathematicians because resulting equations include a small parameter that allows for decomposing a three- or higher-dimensional dynamical system into fast/slow subsystems of lower dimensionality and analyzing them independently using geometric singular perturbation theory and other techniques. However, in most life sciences applications observed dynamics is extremely complex, no small parameter exists and this approach fails. Nevertheless, it is still desirable to gain insight into behavior of these mathematical models using the only viable alternative – ad hoc computational analysis. Current dissertation is devoted to this latter approach. Neural networks in the region of the brain called basal ganglia (BG) are capable of producing rich activity patterns. For example, burst firing, i.e. a train of action potentials followed by a period of quiescence in neurons of the subthalamic nucleus (STN) in BG was shown to be related to involuntary shaking of limbs in Parkinson’s disease called tremor. The origin of tremor remains unknown; however, a few hypotheses of tremor-generation were proposed recently. The first project of this dissertation examines the BG-thalamo-cortical loop hypothesis for tremor generation by building physiologically-relevant mathematical model of tremor-related circuits with negative delayed feedback. The dynamics of the model is explored under variation of connection strength and delay parameters in the feedback loop using computational methods and data analysis techniques. The model is shown to qualitatively reproduce the transition from irregular physiological activity to pathological synchronous dynamics with varying parameters that are affected in Parkinson’s disease. Thus, the proposed model provides an explanation for the basal ganglia-thalamo-cortical loop mechanism of tremor generation. Besides tremor-related bursting activity BG structures in Parkinson’s disease also show increased synchronized activity in the beta-band (10-30Hz) that ultimately causes other parkinsonian symptoms like slowness of movement, rigidity etc. Suppression of excessively synchronous beta-band oscillatory activity is believed to suppress hypokinetic motor symptoms in Parkinson’s disease. Recently, a lot of interest has been devoted to desynchronizing delayed feedback deep brain stimulation (DBS). This type of synchrony control was shown to destabilize synchronized state in networks of simple model oscillators as well as in networks of coupled model neurons. However, the dynamics of the neural activity in Parkinson’s disease exhibits complex intermittent synchronous patterns, far from the idealized synchronized dynamics used to study the delayed feedback stimulation. The second project of this dissertation explores the action of delayed feedback stimulation on partially synchronous oscillatory dynamics, similar to what one observes experimentally in parkinsonian patients. We employ a computational model of the basal ganglia networks which reproduces the fine temporal structure of the synchronous dynamics observed experimentally. Modeling results suggest that delayed feedback DBS in Parkinson’s disease may boost rather than suppresses synchronization and is therefore unlikely to be clinically successful. Single neuron dynamics may also have important physiological meaning. For instance, bistability – coexistence of two stable solutions observed experimentally in many neurons is thought to be involved in some short-term memory tasks. Bistability that occurs at the depolarization block, i.e. a silent depolarized state a neuron enters with excessive excitatory input was proposed to play a role in improving robustness of oscillations in pacemaker-type neurons. The third project of this dissertation studies what parameters control bistability at the depolarization block in the three-dimensional conductance-based neuronal model by comparing the reduced dopaminergic neuron model to the Hodgkin-Huxley model of the squid giant axon. Bifurcation analysis and parameter variations revealed that bistability is mainly characterized by the inactivation of the Na+ current, while the activation characteristics of the Na+ and the delayed rectifier K+ currents do not account for the difference in bistability in the two models.

Notre travail a porté : 1) sur l'étude des modifications d'excitabilité corticale au cours du traitement des poussées de sclérose en plaques (SEP) et de l'évolution naturelle des formes progressives de SEP ; 2) sur la caractérisation du tremblement d'action, fréquemment observé dans le cadre de cette maladie et qui constitue une importante source de handicap. Ceci a conduit à la réalisation de 5 études. La première étude a démontré que l'amélioration rapide des performances motrices observées à la suite du traitement de poussées de SEP par une corticothérapie administrée en flash quotidien sur plusieurs jours, s'accompagnait de modifications significatives d'excitabilité corticale étudiée par stimulation magnétique transcrânienne. Ces modifications portaient sur la balance d'influences GABAergiques et glutamatergiques au sein du cortex moteur. Cette augmentation d'excitabilité survient bien avant toute possibilité de remyélinisation ou de régénérescence axonale et constitue donc une amélioration fonctionnelle induite par le traitement. Dans la deuxième étude, différents paramètres d'excitabilité corticale ont été suivis sur un an chez des patients présentant une forme progressive de SEP, traitée ou non traitée. Cette étude a mis en évidence une diminution de l'inhibition intracorticale et une augmentation du seuil moteur au repos chez les patients non traités, accompagnant une augmentation des scores cliniques de handicap. En revanche, les patients traités restaient stables, aussi bien sur le plan neurophysiologique que clinique. Ces résultats montrent que l'évolution de la SEP progressive est associée à une altération globale et évolutive de l'excitabilité du cortex moteur, portant aussi bien sur les neurones pyramidaux que sur les circuits de contrôle inhibiteur, probablement liée à l'aggravation de la perte neuronale au fil du temps. Nos résultats montrent également que différents types de traitement immunomodulateur peuvent arrêter ce cours évolutif. Dans une troisième étude, nous avons caractérisé l'existence d'un tremblement chez 32 patients atteints de SEP au moyen d'enregistrements électromyographiques et accélérométriques réalisés au membre supérieur. Ces enregistrements n'ont permis de confirmer l'existence d'un véritable tremblement que chez un seul patient. L'étude neurophysiologique concomitante de circuits de contrôle cérébelleux et protubérantiels a permis de montrer que la plupart des aspects cliniques de tremblement dans la SEP ne révélait en fait qu'un pseudo-tremblement lié en grande partie à des dysfonctions cérébelleuses. Nos deux dernières études ont permis de préciser ce résultat, au moyen d'une analyse du signal électromyographique et accélérométrique par décomposition modale empirique associée à une transformée de Hilbert-Huang. Cette méthode d'analyse apparaît valide et performante pour caractériser les tremblements et pseudo-tremblements survenant dans la SEP et les distinguer d'autres types de tremblement, comme le tremblement essentiel. / Our work focused on: 1) the study of cortical excitability changes in the treatment of multiple sclerosis (MS) relapses and the natural history of progressive forms of MS; 2) the characterization of action tremor, which is frequently observed in the course of the disease and is a major source of disability. This has led to the realization of five studies. The first study demonstrated that a rapid improvement in motor performance can be observed following treatment of MS relapses by intravenous corticosteroids administered daily over several days, accompanied by significant changes in cortical excitability parameters studied by transcranial magnetic stimulation techniques. These changes focused on the balance between GABAergic and glutamatergic influences in the motor cortex. An increase in cortical excitability occurs well before any possibility of remyelination or axonal regeneration, demonstrating a functional improvement induced by the treatment. In the second study, different parameters of cortical excitability were followed over one year in patients with progressive MS, treated or untreated. This study showed a decrease of intracortical inhibition and increased motor threshold at rest in untreated patients, accompanying a worsening of clinical disability scores. In contrast, treated patients remained stable, both on clinical and neurophysiological parameters. These results show that the evolution of progressive MS is associated with a global and progressive impairment of motor cortex excitability, concerning both pyramidal neurons on inhibitory control circuits, probably due to the progression of cortical neuronal loss over time. Our results also showed that different types of immunomodulatory therapy can stop this evolutionary course. In a third study, we characterized the existence of action tremor in 32 MS patients using electromyographic and accelerometer recordings in the upper limb. These recordings confirmed the existence of a real tremor in only one patient. Concomitant neurophysiological study of cerebellar and pontine circuits of control showed that most of the clinical aspects of tremor in MS in fact revealed a pseudo-tremor largely due to cerebellar dysfunctions. Our last two studies have clarified this result by means of an analysis of the electromyographic and accelerometer signal using empirical mode decomposition associated with Hilbert-Huang transform. This method of analysis appears valid and effective to characterize tremor or pseudo-tremor occurring in MS patients and to distinguish them from other types of tremor, such as essential tremor.

Ces travaux de thèse portent sur l'étude de nouvelles modalités de guidage de la thérapie transcrânienne par ultrasons focalisés, technique non invasive particulièrement prometteuse pour le traitement de troubles neurologiques tels que le tremblement essentiel ou le tremblement parkinsonien. Une nouvelle technique d'imagerie par résonance magnétique a tout d'abord été utilisée pour imager l'emplacement du faisceau ultrasonore produit par un prototype préclinique : les déplacements induits par les ultrasons dans une cervelle de veau ex vivo ont été imagés sans distorsion à l'aide d'une séquence d'écho de spin accélérée, avec un dépôt d'énergie jusqu'à quatre fois inférieur aux techniques existantes. Nous avons ensuite étudié les effets directs des ultrasons sur l'activité cérébrale par neuromodulation ultrasonore in vivo, de façon similaire à la stimulation magnétique transcrânienne, mais avec les capacités de ciblage millimétriques des ultrasons focalisés. Des expériences ont été tout d'abord menées sur un modèle de rat anesthésié afin d'étudier la pression seuil pouvant induire un effet moteur. Le champ acoustique simulé dans la tête de rat est fortement affectée par des réverbérations, ce qui doit être pris en compte pour l'évaluation in situ des paramètres acoustiques de neurostimulation, en particulier à basse fréquence et pour les petits animaux. Enfin, pour la première fois, nous avons montré que les ultrasons focalisés de faible intensité pouvaient moduler de façon causale le comportement d'un primate non humain éveillé : le temps de latence d'une tâche d'anti-saccade est retardé de façon significative par des ultrasons focalisés dans le champ visuel frontal. / The work presented in this thesis investigates novel modalities to guide Transcranial Magnetic Resonance guided Focused Ultrasound (TcMRgFUS). TcMRgFUS is an emerging and promising non-invasive technique for the treatment of neurological disorders, such as essential tremor or Parkinsonian tremor. A novel Magnetic Resonance Acoustic Radiation Force Imaging (MRARFI) has been used to image the location of the ultrasonic beam produced by a preclinical prototype: an accelerated 2D spin-echo MR ARFI pulse sequence has been introduced to generate undistorted ultrasound-induced displacement maps in ex vivo veal brains with minimum energy deposition. We then investigated direct effects of the ultrasonic beam on brain activity by conducting in vivo ultrasonic neuromodulation, similarly to what is currently achieved with transcranial magnetic stimulation (TMS) but with the millimetric targeting capabilities of the ultrasound. Experiments have been first conducted in an anesthetized rat model to investigate the motor threshold. Numerical simulations have shown that the acoustic pattern in the rat head is affected by reverberations and that special care must be taken when relating acoustic parameters to neurostimulation effects, especially at a low frequency and for small animals. Finally, for the first time, we used low intensity FUS stimulation to causally modulate behavior in an awake nonhuman primate brain. We showed that the latency of an anti-saccade task was delayed significantly in the presence of ultrasonic beam focused in the Frontal Eye Field. Sham experiments did not show any significant change in the latencies.

Ces vingt dernières années, le développement de réseaux haute résolution sismologiques et géodésiques denses a permis la découverte de nouveaux signaux géophysiques parmi lesquels on trouve les trémors non-volcaniques (Non-volcanic tremor, NVT, Obara 2002) et les glissements lents épisodiques (Slow Slip Event, SSE, Dragert et al., 2001). La combinaison de NVT et de SSE est communément observée le long des frontières de plaques, entre la zone sismogénique bloquée à faible profondeur et la zone en fluage ductile à plus grande profondeur (Dragert et al., 2004). Cette association définie des glissements et trémors épisodiques (Episodic Tremor and Slip, ETS), systématiquement associés à des surpressions de fluides et à des conditions proches de la rupture. Dans cette thèse, nous proposons de combiner une étude microstructurale de roches exhumées avec une approche par modélisation numérique afin de reproduire et de mieux comprendre la mécanique des glissements et trémors épisodiques.Nous nous sommes concentrés sur des roches continentales provenant de la Zone de Cisaillement Est du Tende (Corse, France), correspondant à une zone de cisaillement Alpine kilométrique ayant enregistré une déformation dans la zone de subduction (10 kb / 400-450°C, Gueydan et al., 2003). Ces conditions pression-température sont cohérentes avec la localisation des ETS dans les zones de subduction. Les analyses microstructurales et EBSD de ces roches mettent en évidence des localisations de la déformation le long de zones de cisaillement centimétriques contrôlées par une rhéologie dépendante de la taille des grains. La microfracturation de la phase dure (ici du feldspath) et le colmatage de ces microfractures correspondent, respectivement, à de processus de réduction et d’augmentation de la taille des grains.La plupart des récentes modélisations des ETS sont basées sur une loi frictionnelle dite rate-and-state, associant les SSE et les NVT à un cisaillement sur un plan. Contrairement à ces modèles, nous souhaitons modéliser l’ensemble de la roche (et non pas uniquement un plan) avec une rhéologie ductile dépendante de la taille des grains directement guidée par nos observations microstructurales (avec microfracturation et colmatage), Nous faisons l’hypothèse que les SSE peuvent résulter d’une localisation ductile de la déformation et non d’un glissement sur des fractures. Durant la localisation de la déformation, le pompage des fluides peut déclencher une fracturation de la roche par surpression de fluide, ce qui pourrait être la signature des NVT. Le modèle numérique 1D présenté ici nous permettra de valider ces hypothèses. En suivant la loi de Darcy, notre approche nous permet également de prédire les variations de la pression de pore en fonction des variations de la porosité/perméabilité et du pompage des fluides.Les résultats numériques montrent que l’évolution dynamique des microstructures, dépendante des fluides, définie des cycles de localisation ductile de la déformation liés aux augmentations de la pression de fluide. Notre modèle démontre que la disponibilité des fluides et l’efficacité du pompage des fluides contrôlent l’occurrence des ETS. Nous prédisons également les conditions pression-température nécessaires au déclenchement des ETS : 400-500°C et 30-50 km de profondeur en subduction, et ~500°C et 15-30 km de profondeur le long des zones de décrochement. Ces conditions PT sont cohérentes avec les exemples naturels.Aussi simple soit-elle, notre modèle mécanique s’appuyant sur des observations de terrain décrit correctement la relation entre surpressions de fluides, rhéologie dépendant de la taille des grains et le déclenchement des ETS. Des travaux restent à entreprendre comme par exemple la comparaison directe de nos résultats avec des données géophysiques (GPS) ou bien l’introduction d’un nouvelle assemble minéralogique, comme par exemple des roches mafiques pour prendre en compte des minéralogies océaniques. / These last twenty years, the development of dense and highly sensitive seismologic and geodetic networks permits the discovery of new geophysical signals named non-volcanic tremor (Obara 2002) and slow slip events (Dragert et al., 2001). The combination of non-volcanic tremor and transient slow slip is commonly observed at plate interface, between locked/seismogenic zone at low depths and stable/ductile creep zone at larger depths (Dragert et al., 2004). This association defines episodic tremor and slip, systematically highlighted by over-pressurized fluids and near failure shear stress conditions. In this thesis we propose to combine a microstructural analysis of exhumed rocks with a modeling approach in order to accurately reproduce and understand the physics of episodic tremor and slip.We focus on continental rocks from the East Tenda Shear Zone (Corsica, France), a kilometer-wide localized Alpine shear zone that record HP/LT deformation (10kb / 400-450°C, Gueydan et al., 2003). Such pressure-temperature conditions are consistent with the location of episodic tremor and slip in subduction zone. Microstructural and EBSD analyses on these rocks describe a pattern of strain localization in centimeter-scale shear zones guiding by a grain size-sensitive creep. Microfracturing of the strong phase (feldspar here) and the sealing of these microfractures act, respectively, as grain size decrease and grain size increase processes.Most of recent modeling approaches of episodic tremor and slip are based on the rate-and-state variable friction law, describing slow slip event and non-volcanic tremor as slow shear slip on a plane. In contrast with such models, we wish to model the entire rock volume, with a ductile grain size-sensitive rheology guided by our microstructural observations (e.g. microfracturing and sealing as grain size variation processes). We hypothesize that slow slip events may result from ductile strain localization and not transient slip on fractures. Fluid pumping during strain localization may trigger whole rock fracturing at near lithostatic conditions that can be the signature of non-volcanic tremor. The 1D numerical model presented here will allow us to validate these assumptions.We also can predict pore fluid pressure variation as a function of changes in porosity/permeability and strain rate-dependent fluid pumping following the Darcy’s flow law. The fluid-enhanced dynamic evolution of microstructure defines cycles of ductile strain localization related to the increase in pore fluid pressure. We show that slow slip events can be ductile processes related to transient strain localization, while non-volcanic tremor can correspond to fracturing of the whole rock at peak of pore fluid pressure. Our model shows that the availability of fluids and the efficiency of fluid pumping control the occurrence of episodic tremor and slip. We also well predict the temperature and depth ranges of episodic tremor and slip: 400-500°C and 30-50 km in subduction zones and ~500°C and 15-30 km in strike slip settings, consistent with natural examples.As simplistic as it is, our field-guided mechanical model well describe, at first order, the relation between high pore fluid pressure, grain size-sensitive rheology and episodic tremor and slip. Some efforts remain to be done like a real fit of geophysical data (GPS) or the introduction of the new mineralogical assemblage, such as mafic rocks to reproduce oceanic environment.

Essential voice tremor (EVT) is a voice disorder that results from dyscoordination within the laryngeal musculature, which negatively impacts the symmetrical motion of the vocal folds. Several investigators have shown that individuals with EVT experience difficulty speaking and a reduced quality of life (QOL; Cohen, Dupont, & Courey, 2006; Verdonck-de Leeuw & Mahieu, 2004). While traditional voice therapy has been ineffective in lessening the severity of vocal tremor, a current approach (Barkmeier- Kraemer, Lato, & Wiley, 2011) designed to lessen the perception of vocal tremor has resulted in reported patient satisfaction with little actual change in voice quality. The present study focused on achieving positive voice changes by targeting the physiological aspects of voice production that may be altered through inspiratory breathing techniques, i.e., increased lung volume pressure and laryngeal lowering. The hypothesis was that such changes could result in reductions in vocal tremor and lead to perceived improvements in voice quality and concomitant increases in the participant's QOL. An ABAB (treatment reversal) single subject design was used to assess the effectiveness of inspiratory breathing exercises on reducing the severity of tremor in three women diagnosed with EVT. Pre-treatment measures were administered, and participant progress was determined after one week of treatment (post-treatment #1), a week of no treatment, and another week of treatment (post-treatment #2). The following measures were gathered from each participant to document treatment progress and effectiveness:lung pressure volume levels, Voice Handicap Index (VHI) ratings, acoustic analyses of isolated vowels, and perceptual ratings on the Consensus Auditory Perceptual Evaluation of Voice (CAPE-V), as well as untrained listener ratings of vocal steadiness and pleasantness. Physiological, QOL, acoustic, and perceptual data did not triangulate to demonstrate treatment effectiveness. However, individual treatment effects were found in increases in lung pressure volume for participant 1, decreases in CAPE-V scores for participant 3, and decreases in VHI scores for participants 1 and 3. Changes in voice acoustics and untrained listener perceptions were negligible. Thus, the results from this study indicate that inspiratory breathing exercises may show some promise in improving voice and QOL in certain tremor patients and that this technique warrants further research consideration.

Objective: To determine the effects of head position and of different postural control demands on head tremor measures in participants with essential tremor. Methods: Seventeen participants with essential tremor (ET) of the head and 17 control participants took part. Individuals held their heads in varying degrees of rotation, flexion, and extension. Subsequently, individuals sat and stood in different postures, incorporating different foot placements (feet apart and together), surfaces (solid and foam), and vision conditions (eyes open and closed). Neck muscle activity was recorded from three muscles bilaterally (trapezius, sternocleidomastoid, splenius capitis). Three-dimensional head and thorax positions were recorded using an Optotrak system, and head angular velocity with respect to thorax was calculated by differentiating tilt-twist angles. Fourier analysis was used to determine tremor power. Results: ET participants showed sharp peaks at their tremor frequency in spectral plots of kinematic data, whereas CN participants did not. Electromyography data was too noisy for frequency analysis. ET participants displayed increased tremor power in head positions 25° from neutral compared to neutral and positions 50° from neutral. Tremor power increased with increasing difficulty of posture for both participant groups. Removal of vision resulted in decreased tremor power in ET participants; power was significantly decreased in the easier postures, and progressively less so with increasing difficulty of posture. Interestingly, tremor direction was inconsistent in both groups, and two ET participants displayed multiple tremor peaks. Conclusions: The tilt-twist method is a feasible way of measuring head kinematics. Changing stiffness of the neck likely mediates the effect of head position on head tremor power, with the resultant interplay of the central driver and the mechanical resonance driving the amplitude changes. Decreasing stability of posture increases head tremor, likely due to the associated increase in postural sway and stress on the postural control system. Vision appears to exacerbate head tremor through the addition of tremor-related visual noise and an implicit task to stabilize vision; this is possible evidence of a visuomotor deficit. However, stabilizing vision becomes less important with increasing difficulty of posture, resulting in a narrowing gap in tremor power between vision and no vision conditions. / Thesis (Master, Rehabilitation Science) -- Queen's University, 2011-03-31 18:16:59.927

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.

Bakgrund: Essentiell tremor (ET) behandlas bland annat med djup hjärnstimulering (DBS). Många patienter drabbas av stimuleringsinducerad dysartri (SID) till följd av behandlingsmetoden, vilket i sin tur kan påverka talförståeligheten. Oral diadochokinesi (DDK) används av kliniker vid utvärdering av dysartri då det pressar det artikulatoriska systemet. Studier har påvisat samband mellan akustiska egenskaper från DDK och naturligt tal. Ett fåtal studier har undersökt sambandet mellan DDK och talförståelighet men i dagsläget saknas studier inom området som bygger på fler än en kvantifiering av DDK.Syfte: Att undersöka om DDK kan predicera nedsatt talförståelighet till följd av DBS hos patienter med ET. Metod: Inspelade DDK-sekvenser av stavelserna [pa], [ta] och [ka] från 36 patienter med ET samlades in och matchades med skattningar av deras talförståelighet. Inspelningarna märktes upp med hjälp av en tränad mjukvara och kontrollerades sedan manuellt. Ett batteri av 45 akustiska parametrar beräknades på samtliga sekvenser. Statistiska beräkningar genomfördes för att undersöka om erhållna mått kunde predicera talförståelighet.Resultat: För prediktion av talförståelighet påvisades [pa] vara mer värdefull än [ta] och [ka]. Högst uppnådda resultat visade att [pa] kunde förklara 23% av variationen i talförståelighet.Slutsatser: Resultatet visar att DDK kan fungera som en relativt god prediktor av nedsatt talförståelighet till följd av DBS hos patienter med ET. Däremot bör man vara försiktig med att tillskriva DDK ett större förtroende gällande dess samband med talförståelighet, eftersom låga resultat erhölls i vissa beräkningar. Vidare forskning bör validera den använda modellen. / Tal- och rösteffekter av djup hjärnstimulering hos patienter med essentiell tremor, D.nr: 2014-67-32M.