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no / There are a wide variety of ways to objectively detect neurological signs, but these either require special hard-ware (such as wearable technology) or patient behaviour change (such as engagement with smartphone tasks) [2]. Neither constraint applies to the technology of computer vision, which is the processing of single or multiple camera images by computer to automatically derive useful information. The only equipment involved is ubiquitous: camera and computer.We report a computer vision-enhanced video sequence from a 68-year-old man, diagnosed with idiopathic Parkinson’s disease 2 years previously.

Activities of daily living (ADL) such as writing, eating, and object manipulation are challenging for patients suffering from pathological tremors. Pathological tremors are involuntary, rhythmic, and oscillatory movements that manifest in limbs, the head, and other body parts. Among the existing treatments, mechanical loading through wearable rehabilitation devices is popular for being non-invasive and innocuous to the human body. In particular, a few exoskeletons are developed to actively mitigate pathological tremors in the forearm. While these forearm exoskeletons can effectively suppress tremors, they still require significant improvements in ergonomics to be implemented for ADL applications. The ergonomics of the exoskeleton can be improved via design and motion control pertaining to human biomechanics, which leads to better efficiency, comfort, and safety for the user. The wrist is a complicated biomechanical joint with two coupled degrees of freedom (DOF) pivotal to human manipulation capabilities. Existing exoskeletons either do not provide tremor suppression in all wrist DOFs, or can be restrictive to the natural wrist movement. This motivates us to explore a better exoskeleton solution for wrist tremor suppression. We propose TAWE - a wearable exoskeleton that provides alleviation of pathological tremors in all wrist DOFs. The design adopts a 6-DOF rigid linkage mechanism to ensure unconstrained natural wrist movements, and wearability features without extreme tight-binding or precise positioning for convenient ADL applications. When TAWE is equipped by the user, a closed-kinematic chain is formed between the exoskeleton and the forearm. We analyze the coupled multibody dynamics of the human-exoskeleton system, which reveals a few robotic control problems - (i) The first problem is the identification of the unknown wrist kinematics within the closed kinematic chain. We realize the real-time wrist kinematic identification (WKI) based on a novel ellipsoidal joint model that describes the coupled wrist kinematics, and a sparsity-promoting Extended Kalman Filter for the efficient real-time regression; (ii) The second problem is the exoskeleton motion control for tremor suppression. We design a robust adaptive controller (IO-RAC) based on model reference adaptive control and inverse optimal robust control theories, which can identify the unknown model inertia and load, and provide stable tracking control under disturbance; (iii) The third problem is the estimation of voluntary movement from tremorous motion data for the motion planning of exoskeleton. We develop a lightweight and data-driven voluntary movement estimator (SVR-VME) based on least square support vector regression, which can estimate voluntary movements with real-time signal adaptability and significantly reduced time delay. Simulations and experiments are carried out to test the individual performance of robotic control algorithms proposed in this study, and their combined real-time performance when integrated into the full exoskeleton control system. We also manufacture the prototype of TAWE, which helps us validate the proposed solutions in tremor alleviation exoskeletons. Overall, the design of TAWE meets the expectations in its compliance with natural wrist movement and simple wearability. The exoskeleton control system can execute stably in real-time, identify unknown system kinematics and dynamics, estimate voluntary movements, and suppress tremors in the wrist. The results also indicate a few limitations in the current approaches, which require further investigations and improvements. Finally, the proposed exoskeleton control solutions are developed based on generic formulations, which can be applied to not only TAWE, but also other rehabilitation exoskeletons. / Doctor of Philosophy / Activities of daily living (ADL) such as writing, eating, and object manipulation are challenging for patients suffering from pathological tremors, which affect millions of people worldwide. Tremors are involuntary, rhythmic, and oscillatory movements. In recent years, rehabilitation exoskeletons are developed as non-invasive solutions to pathological tremor alleviation. The wrist is pivotal to human manipulation capabilities. Existing exoskeletons either do not provide tremor suppression in all wrist movements, or can be restrictive to natural wrist movements. To explore a better solution with improved performance and ergonomics, we propose TAWE - a wearable exoskeleton that provides tremor alleviation in full wrist motions. TAWE adopts a high-degree-of-freedom mechanism to ensure unconstrained natural wrist movements, and wearability features for convenient ADL applications. The coupled dynamics between the forearm and TAWE leads to a few robotic control problems. We propose novel real-time robotic control solutions in the identification of unknown wrist kinematics, robust adaptive exoskeleton control for tremor suppression, and voluntary movement estimation for motion planning. Later, simulations and experiments validate the TAWE prototype and its exoskeleton control framework for tremor alleviation, and reveal limitations in the current approaches that require further investigations and improvements. Finally, the proposed exoskeleton control solutions are developed based on generic formulations, which can be applied to not only TAWE, but also other rehabilitation exoskeletons.

Neonatal abstinence syndrome (NAS) is a condition caused by in-utero exposure to opioids, and its occurrence is increasing nationwide. NAS patients are newborns who can experience withdrawal symptoms including tremors, poor feeding, and respiratory distress. Presently, the Finnegan Scoring System, a subjective rating scale, is commonly used to judge the patient's condition and determine appropriate treatment methods. This project sought to develop a sensor system that is capable of objectively assessing symptoms of withdrawal, including tremors and high pitched cry. The system developed is composed of five wireless accelerometers, for attachment to a subject's limbs and chest, and an external microphone. The sensor system is targeted toward quantifying limb movements of the subject and recording audio information that includes samples of the subject's cry. The sensor system was used as part of a research study, and data was collected from recruited participants. A total of 29 out of 30 desired participants were enrolled and studied as part of the data collection process. Gathered data was analyzed using MATLAB, with motion data being searched for tremor activity in NAS participants, and cry samples searched for unique characteristics. Results generated indicate that detection of tremors was successful, and that the average fundamental frequency of cry differs between the NAS and non-NAS participants. Future considerations for this project include expanding to measure more symptoms, and system refinement to minimize the number of sensors. / Master of Science / Neonatal abstinence syndrome (NAS) is a condition affecting newborns, caused by exposure to opioids before birth, and its occurrence is increasing nationwide. NAS patients are newborns who can experience withdrawal symptoms including tremors, poor feeding, and respiratory distress. Presently, the Finnegan Scoring System, a manual scoring method, is commonly used to judge the patient’s condition and determine appropriate treatment methods. This project sought to develop a sensor system that is capable of measuring symptoms of withdrawal, specifically tremors and high pitched cry. The system developed is composed of five wireless accelerometers, for attachment to a subject’s limbs and chest, and an external microphone. The sensor system is targeted toward quantifying limb movements of the subject and recording audio information that includes samples of the subject’s cry. The sensor system was used as part of a research study, and data was collected from recruited participants. A total of 29 out of 30 desired participants were enrolled and studied as part of the data collection process. Gathered data was analyzed using MATLAB, with motion data being searched for tremor activity in NAS participants, and cry samples searched for unique characteristics. Results generated indicate that detection of tremors was successful, and that the average cry for NAS participants was higher pitched than those of non-NAS participants. Future considerations for this project include expanding to measure more symptoms, and minimizing the number of sensors used. If successful, such a system could be used to assist medical personnel and continuously monitor NAS newborns.

Background: The posterior subthalamic area (PSA) is essentially composed of the caudal Zona incerta and the prelemniscal radiation. Subthalamotomy in the PSA was renowned for its effectiveness in alleviating movement disorders and particularly tremor. The modern literature on DBS of this area is limited, but promising results have been presented for Parkinson’s disease (PD), essential tremor (ET) and other movement disorders.   Aim: To evaluate the safety of PSA DBS with emphasis on the panorama of side effects, the distribution of stimulation-induced side effects and the effects of PSA DBS on verbal fluency. To evaluate the therapeutic effect of PSA DBS on less common forms of tremor, tremor-dominant PD, and concerning the long-term results in ET. Method: 40 patients were evaluated regarding side effects of the procedure. 28 patients with ET were analyzed for stimulation-induced side effects in a standardized manner. The locations of the contacts that caused stimulation-induced side effects were plotted on atlas slides. A 3-D model of the area was created based on these slides. Verbal fluency was analyzed in 17 patients with ET before surgery, after 3 days and finally after 1 year. Five patients with less common forms of tremor and 18 with ET were evaluated according to the ETRS at baseline and one year or 3-5 years after surgery, respectively. 14 patients with mainly unilateral tremor-dominant PD were evaluated a mean of 18 months after surgery according to the motor part of UPDRS. Results: PSA DBS was associated with few serious side-effects, but a transient and mild postoperative dysphasia was found in 22.5% of the patients. There was a slight transient decline in the performance on verbal fluency tests immediately after surgery. Visualization of the contacts causing stimulation-induced side effects showed that identical responses can be elicited from various points in the PSA and its vicinity. The effect on the less common forms of tremor was excellent except for neuropathic tremor where the effect was moderate. A pronounced and sustained microlesional effect was seen for some of the patients. After a mean of 4 years with unilateral PSA DBS the total ETRS score was improved by 52.4%, tremor by 91.8% and hand function by 78.0% in the patients with ET. There was no increase in the stimulation strength over time. In PD, the scores improved 47.7% for contralateral UPDRS III. Contralateral tremor, rigidity, and bradykinesia improved by 82.2%, 34.3%, and 26.7%, respectively. Conclusions: PSA DBS generally seem to be a safe procedure, but it may be associated with transient declines of verbal fluency. There was no clear somatotopic pattern with regard to stimulation-induced side effects in the PSA. PSA DBS can alleviate tremor regardless of the etiology. The long-term effects in ET were favorable when compared to our previous results of Vim DBS. The effect on Parkinsonian tremor was satisfying, however, the reductions of rigidity and bradykinesia were less compared to previous studies of PSA DBS for PD.

This dissertation is a comprehensive summary of four papers on the development and application of new strategies for locating tremor and relocating events in earthquake catalogs. In the first paper, two new strategies for relocating events in a catalog are introduced. The seismicity pattern of an earthquake catalog is often used to delineate seismically active faults. However, the delineation is often hindered by the diffuseness of earthquake locations in the catalog. To reduce the diffuseness and simplify the seismicity pattern, a relocation and a collapsing method are developed and applied. The relocation method uses the catalog event density as an a priori constraint for relocations in a Bayesian inversion. The catalog event density is expressed in terms of the combined probability distribution of all events in the catalog. The collapsing method uses the same catalog density as an attractor for focusing the seismicity in an iterative scheme. These two strategies are applied to an aftershock sequence after a pair of earthquakes which occurred in southwest Iceland, 2008. The seismicity pattern is simplified by application of the methods and the faults of the mainshocks are delineated by the reworked catalog. In the second paper, the spatial distribution of seismicity of the Hengill region, southwest Iceland is analyzed. The relocation and collapsing methods developed in the first paper and a non-linear relocation strategy using empirical traveltime tables are used to process a catalog collected by the Icelandic Meteorological Office. The reworked catalog reproduces details of the spatial distribution of seismicity that independently emerges from relative relocations of a small subset of the catalog events. The processed catalog is then used to estimate the depth to the brittle-ductile transition. The estimates show that in general the northern part of the area, dominated by volcanic processes, has a shallower depth than the southern part, where tectonic deformation predominates. In the third and the fourth papers, two back-projection methods using inter-station cross correlations are proposed for locating tremor sources. For the first method, double correlations, defined as the cross correlations of correlations from two station pairs sharing a common reference station, are back projected. For the second method, the products of correlation envelopes from a group of stations sharing a common reference station are back projected. Back projecting these combinations of correlations, instead of single correlations, suppresses random noise and reduces the strong geometrical signature caused by the station configuration. These two methods are tested with volcanic tremor at Katla volcano, Iceland. The inferred source locations agree with surface observations related to volcanic events which occurred during the tremor period.

A Síndrome do X frágil (SXF) é a forma mais comum de deficiência intelectual herdada. É causada por uma mutação no gene FMR1; (Fragile X Mental Retardation 1;), que resulta na deficiência da proteína FMRP (Fragile X Mental Retardation Protein;). O gene FMR1;, localizado no braço longo do cromossomo X, em Xq27.3, possui uma repetição de trinucleotídeos (CGG)n em sua região 5\' não traduzida (região reguladora). Na população geral, o tamanho dessa repetição varia entre 5 a 44 trincas de bases. Uma expansão superior a 200 trinucleotídeos leva à hipermetilação e consequente silenciamento da transcrição do gene. Quando isso ocorre, tem-se uma mutação completa, a causa da SXF. Se a repetição expandida tem de 55 a 200 trincas de bases, chamada de pré-mutação, não ocorre hipermetilação e a proteína FMRP é produzida; portanto, a pré-mutação não está associada à SXF, porém está relacionada a outros quadros clínicos, particularmente à síndrome de tremor/ataxia associada ao X frágil (FXTAS; Fragile-X associated Tremor Ataxia Syndrome;) e à insuficiência ovariana primária associada ao X frágil (FXPOI; Fragile-X associated Primary Ovarian Insufficiency;). O objetivo deste trabalho foi investigar duas famílias cujos casos-índice foram encaminhados para o Centro de Pesquisa sobre o Genoma Humano e Células-Tronco para investigar ataxia espinocerebelar e nos quais a avaliação clínica e a história familial sugeriram a possibilidade de FXTAS; em ambos os pacientes, pré-mutação do gene FMR1; foi detectada. Na Família 1, foi feito o diagnóstico de SXF em um neto da propósita e foi identificada a mutação completa em várias filhas e netas, todas com dificuldade de aprendizado. Na Família 2 não foram identificadas mutações completas e em um dos netos do propósito detectou-se mosaicismo de alelo intermediário e pré-mutação. Assim, diante da variada apresentação fenotípica, a possibilidade de condição associada ao gene FMR1; deve ser considerada frente aos fenótipos de deficiência intelectual, dificuldade de aprendizado, falência ovariana prematura e síndrome de tremor-ataxia. O diagnóstico de FXTAS em famílias em que não há registro de SXF não é frequente, provavelmente diante do desconhecimento dessa possibilidade, mas tem importância fundamental para o aconselhamento genético, particularmente quanto à ocorrência de deficiência intelectual / RIBEIRO, M. D. O. From top to bottom: genetic counseling in families ascertained through fragile X-associated tremor/ataxia syndrome (FXTAS) 2017. 64 f. Dissertação (Mestrado em Aconselhamento Genético e Genômica Humana) - Instituto de Biociências, Universidade de São Paulo, São Paulo, 2017. Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. It is caused by a mutation in the Fragile X Mental Retardation 1 (FMR1;) gene located on the long arm of the X chromosome at Xq27.3 that results in FMRP (Fragile X Mental Retardation Protein) deficiency. The FMR1; gene has a trinucleotide repeat (CGG)n at the 5\' untranslated region (regulatory region); in the general population, this repeat varies in size from 5 to 44 CGG triplets. An expanded repeat of more than 200 trinucleotides leads to hypermethylation and consequent silencing of the gene transcription - the full mutation that causes FXS. The repeat containing 55 to 200 triplets characterizes a premutation; there is no hypermethylation, the gene is transcribed, and the FMRP is produced; then premutations are not associated with FXS, but are related to other clinical conditions: Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) and Fragile X-associated Primary Ovarian Insufficiency (FXPOI). The objective of this study was to investigate two families whose index cases were referred to the Centro de Pesquisa sobre o Genoma Humano e Células-Tronco to investigate spinocerebellar ataxia, whose clinical evaluation and family history suggested the possibility of FXTAS. Both probands were found to carry FMR1; premutations. In Family 1, the diagnosis of FXS was established in a grandson of the proband, and the full mutation was also identified in several of her daughters and granddaughters, all presenting with learning difficulties. In Family 2, no full mutations were detected; a proband\'s grandson had size mosaicism for FMR1; ; alleles, carrying an intermediate allele and a premutation. Although uncommon, possibly due to lack of knowledge about the syndrome, the diagnosis of FXTAS in families without FXS is important for genetic counseling, particularly regarding the occurrence of intellectual disability

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,...

A Síndrome do X frágil (SXF) é a forma mais comum de deficiência intelectual herdada. É causada por uma mutação no gene FMR1; (Fragile X Mental Retardation 1;), que resulta na deficiência da proteína FMRP (Fragile X Mental Retardation Protein;). O gene FMR1;, localizado no braço longo do cromossomo X, em Xq27.3, possui uma repetição de trinucleotídeos (CGG)n em sua região 5\' não traduzida (região reguladora). Na população geral, o tamanho dessa repetição varia entre 5 a 44 trincas de bases. Uma expansão superior a 200 trinucleotídeos leva à hipermetilação e consequente silenciamento da transcrição do gene. Quando isso ocorre, tem-se uma mutação completa, a causa da SXF. Se a repetição expandida tem de 55 a 200 trincas de bases, chamada de pré-mutação, não ocorre hipermetilação e a proteína FMRP é produzida; portanto, a pré-mutação não está associada à SXF, porém está relacionada a outros quadros clínicos, particularmente à síndrome de tremor/ataxia associada ao X frágil (FXTAS; Fragile-X associated Tremor Ataxia Syndrome;) e à insuficiência ovariana primária associada ao X frágil (FXPOI; Fragile-X associated Primary Ovarian Insufficiency;). O objetivo deste trabalho foi investigar duas famílias cujos casos-índice foram encaminhados para o Centro de Pesquisa sobre o Genoma Humano e Células-Tronco para investigar ataxia espinocerebelar e nos quais a avaliação clínica e a história familial sugeriram a possibilidade de FXTAS; em ambos os pacientes, pré-mutação do gene FMR1; foi detectada. Na Família 1, foi feito o diagnóstico de SXF em um neto da propósita e foi identificada a mutação completa em várias filhas e netas, todas com dificuldade de aprendizado. Na Família 2 não foram identificadas mutações completas e em um dos netos do propósito detectou-se mosaicismo de alelo intermediário e pré-mutação. Assim, diante da variada apresentação fenotípica, a possibilidade de condição associada ao gene FMR1; deve ser considerada frente aos fenótipos de deficiência intelectual, dificuldade de aprendizado, falência ovariana prematura e síndrome de tremor-ataxia. O diagnóstico de FXTAS em famílias em que não há registro de SXF não é frequente, provavelmente diante do desconhecimento dessa possibilidade, mas tem importância fundamental para o aconselhamento genético, particularmente quanto à ocorrência de deficiência intelectual / RIBEIRO, M. D. O. From top to bottom: genetic counseling in families ascertained through fragile X-associated tremor/ataxia syndrome (FXTAS) 2017. 64 f. Dissertação (Mestrado em Aconselhamento Genético e Genômica Humana) - Instituto de Biociências, Universidade de São Paulo, São Paulo, 2017. Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. It is caused by a mutation in the Fragile X Mental Retardation 1 (FMR1;) gene located on the long arm of the X chromosome at Xq27.3 that results in FMRP (Fragile X Mental Retardation Protein) deficiency. The FMR1; gene has a trinucleotide repeat (CGG)n at the 5\' untranslated region (regulatory region); in the general population, this repeat varies in size from 5 to 44 CGG triplets. An expanded repeat of more than 200 trinucleotides leads to hypermethylation and consequent silencing of the gene transcription - the full mutation that causes FXS. The repeat containing 55 to 200 triplets characterizes a premutation; there is no hypermethylation, the gene is transcribed, and the FMRP is produced; then premutations are not associated with FXS, but are related to other clinical conditions: Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) and Fragile X-associated Primary Ovarian Insufficiency (FXPOI). The objective of this study was to investigate two families whose index cases were referred to the Centro de Pesquisa sobre o Genoma Humano e Células-Tronco to investigate spinocerebellar ataxia, whose clinical evaluation and family history suggested the possibility of FXTAS. Both probands were found to carry FMR1; premutations. In Family 1, the diagnosis of FXS was established in a grandson of the proband, and the full mutation was also identified in several of her daughters and granddaughters, all presenting with learning difficulties. In Family 2, no full mutations were detected; a proband\'s grandson had size mosaicism for FMR1; ; alleles, carrying an intermediate allele and a premutation. Although uncommon, possibly due to lack of knowledge about the syndrome, the diagnosis of FXTAS in families without FXS is important for genetic counseling, particularly regarding the occurrence of intellectual disability

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,...