A wearable biofeedback device to improve motor symptoms in Parkinson’s disease

Dissertação de mestrado em Engenharia BiomédicaThis dissertation presents the work done during the fifth year of the course Integrated Master’s in Biomedical Engineering, in Medical Electronics. This work was carried out in the Biomedical & Bioinspired Robotic Devices Lab (BiRD Lab) at the MicroElectroMechanics Center (CMEMS) established at the University of Minho. For validation purposes and data acquisition, it was developed a collaboration with the Clinical Academic Center (2CA), located at Braga Hospital. The knowledge acquired in the development of this master thesis is linked to the motor rehabilitation and assistance of abnormal gait caused by a neurological disease. Indeed, this dissertation has two main goals: (1) validate a wearable biofeedback system (WBS) used for Parkinson's disease patients (PD); and (2) develop a digital biomarker of PD based on kinematic-driven data acquired with the WBS. The first goal aims to study the effects of vibrotactile biofeedback to play an augmentative role to help PD patients mitigate gait-associated impairments, while the second goal seeks to bring a step advance in the use of front-end algorithms to develop a biomarker of PD based on inertial data acquired with wearable devices. Indeed, a WBS is intended to provide motor rehabilitation & assistance, but also to be used as a clinical decision support tool for the classification of the motor disability level. This system provides vibrotactile feedback to PD patients, so that they can integrate it into their normal physiological gait system, allowing them to overcome their gait difficulties related to the level/degree of the disease. The system is based on a user- centered design, considering the end-user driven, multitasking and less cognitive effort concepts. This manuscript presents all steps taken along this dissertation regarding: the literature review and respective critical analysis; implemented tech-based procedures; validation outcomes complemented with results discussion; and main conclusions and future challenges.Esta dissertação apresenta o trabalho realizado durante o quinto ano do curso Mestrado Integrado em Engenharia Biomédica, em Eletrónica Médica. Este trabalho foi realizado no Biomedical & Bioinspired Robotic Devices Lab (BiRD Lab) no MicroElectroMechanics Center (CMEMS) estabelecido na Universidade do Minho. Para efeitos de validação e aquisição de dados, foi desenvolvida uma colaboração com Clinical Academic Center (2CA), localizado no Hospital de Braga. Os conhecimentos adquiridos no desenvolvimento desta tese de mestrado estão ligados à reabilitação motora e assistência de marcha anormal causada por uma doença neurológica. De facto, esta dissertação tem dois objetivos principais: (1) validar um sistema de biofeedback vestível (WBS) utilizado por doentes com doença de Parkinson (DP); e (2) desenvolver um biomarcador digital de PD baseado em dados cinemáticos adquiridos com o WBS. O primeiro objetivo visa o estudo dos efeitos do biofeedback vibrotáctil para desempenhar um papel de reforço para ajudar os pacientes com PD a mitigar as deficiências associadas à marcha, enquanto o segundo objetivo procura trazer um avanço na utilização de algoritmos front-end para biomarcar PD baseado em dados inerciais adquiridos com o dispositivos vestível. De facto, a partir de um WBS pretende-se fornecer reabilitação motora e assistência, mas também utilizá-lo como ferramenta de apoio à decisão clínica para a classificação do nível de deficiência motora. Este sistema fornece feedback vibrotáctil aos pacientes com PD, para que possam integrá-lo no seu sistema de marcha fisiológica normal, permitindo-lhes ultrapassar as suas dificuldades de marcha relacionadas com o nível/grau da doença. O sistema baseia-se numa conceção centrada no utilizador, considerando o utilizador final, multitarefas e conceitos de esforço menos cognitivo. Portanto, este manuscrito apresenta todos os passos dados ao longo desta dissertação relativamente a: revisão da literatura e respetiva análise crítica; procedimentos de base tecnológica implementados; resultados de validação complementados com discussão de resultados; e principais conclusões e desafios futuros

Cerebellar resting-state functional connectivity in Parkinson's disease and multiple system atrophy: Characterization of abnormalities and potential for differential diagnosis at the single-patient level

Background: Recent studies using resting-state functional connectivity and machine-learning to distinguish patients with neurodegenerative diseases from other groups of subjects show promising results. This approach has not been tested to discriminate between Parkinson's disease (PD) and multiple system atrophy (MSA) patients. Objectives: Our first aim is to characterize possible abnormalities in resting-state functional connectivity between the cerebellum and a set of intrinsic-connectivity brain networks and between the cerebellum and different regions of the striatum in PD and MSA. The second objective of this study is to assess the potential of cerebellar connectivity measures to distinguish between PD and MSA patients at the single-patient level. Methods: Fifty-nine healthy controls, 62 PD patients, and 30 MSA patients underwent resting-state functional MRI with a 3T scanner. Independent component analysis and dual regression were used to define seven restingstate networks of interest. To assess striatal connectivity, a seed-to-voxel approach was used after dividing the striatum into six regions bilaterally. Measures of cerebellar-brain network and cerebellar-striatal connectivity were then used as features in a support vector machine to discriminate between PD and MSA patients. Results: MSA patients displayed reduced cerebellar connectivity with different brain networks and with the striatum compared with PD patients and with controls. The classification procedure achieved an overall accuracy of 77.17% with 83.33% of the MSA subjects and 74.19% of the PD patients correctly classified. Conclusion: Our findings suggest that measures of cerebellar functional connectivity have the potential to distinguish between PD and MSA patients

INFLUENCE OF PLANNING RESOURCES ON GAIT CONTROL IN PARKINSON’S DISEASE

Movement disturbances in individuals with Parkinson’s disease (PD) have been associated with difficulties to plan complex actions. Performance of simple and complex actions overloads resources for individuals with Parkinson’s disease (PD). However, it is unclear if central resources required to plan gait adjustments while walking exacerbate gait disturbances of patients with PD. More specifically, it is unclear how gait impairments, sensory processing, and the dopaminergic system influence the load on processing resources (e.g. cognitive load) during the planning of step modifications. In order to investigate the relative influence of these factors on cognitive load and its impact on gait control, three experiments were conducted that utilized a naturalistic gait task, which challenged planning resources during obstacle avoidance. While the tasks were being performed, dual task interference on gait, and dual task performance were assessed in order to estimate participants’ cognitive load during these tasks. Gait control during obstacle approach and crossing were also evaluated to observe dual task interference on steps known to demand greater planning. In experiment 1 (chapter 2), the influence of gait impairments on planning resources was investigated. The results of this study demonstrated that the planning of gait adaptations in participants with freezing of gait (PD-FOG) resulted in a greater increase in cognitive load, relative to participants with more preserved gait PD-nonFOG (same disease severity without severe gait impairments). The influence of sensory processing on movement planning was investigated in experiment 2 (chapter 3). The results of this study revealed that removal of visual feedback of self-motion affected gait control when the planning of gait adjustments was necessary for successful crossing. In addition, PD patients prioritized walking over the secondary task when visual feedback was reduced, in order to compensate for impaired proprioceptive processing. Lastly, experiment 3 investigated the influence of the dopaminergic system on gait adjustments. The results of this study revealed that dopaminergic replacement partially decreased the effect of cognitive load on gait and drastically improved gait velocity as participants approached obstacles. This study also demonstrates that the cognitive load and the dopaminergic impairments in PD, did not force patients to rely more than healthy participants, on visual information from obstacle as to correct step adjustments. In sum, the current thesis suggests that increases in cognitive load during the planning of gait adaptations causes gait impairments, in individuals with PD. These increases in cognitive load appear to be associated with impaired sensorimotor processing during gait. Dopaminergic activity modulated sensorimotor processing during movement planning and partially the cognitive load caused by movement planning. Finally, the results of these studies suggest that the complexity to plan gait adjustments, while walking, overtax processing resources of individuals with PD causing some observable gait impairments

Gait Retraining in Parkinson’s Disease: A Cognitive Cueing Approach

Parkinson’s disease (PD) is characterized by resting tremor, bradykinesia, rigidity, and postural instability. These cardinal symptoms commonly affect gait performance and therefore researchers have been investigating techniques to manage and treat gait impairment in individuals with PD. This thesis explores a progressive approach to gait rehabilitation using a novel intervention that combines traditional gait cueing techniques with motor learning approaches to facilitate self-cued gait improvement. Five participants with PD-related gait impairment completed the home-based gait training intervention. This intervention included video footage of each individual participant walking with and without verbal instructional cues, audio coaching, and practice periods. Participants were given the video to practice at home for two-weeks. Kinematic parameters of gait were assessed pre-intervention, at two weeks post-intervention, and at two months post-intervention. Results indicate that individuals with PD are capable of learning verbal-cueing strategies and utilizing these to generate long-term gait improvements through self-cueing

Doctor of Philosophy

dissertationIntegration of sensory inputs by the central nervous system (CNS) is necessary for adequate postural stability, but diminishes with age and is further impaired in Parkinson disease (PD). As a result, the CNS cannot appropriately weight sensory stimuli to facilitate postural responses to sudden changes in sensory input. Training the sensorimotor system to ignore or rapidly adapt to aberrant postural cues may improve postural control in PD. We evaluated the influence of acute and repeated exposure to galvanic vestibular stimulation (GVS) on postural responses during static and dynamic tasks to determine whether training improved these responses. We hypothesized that individuals with PD would demonstrate impaired postural recovery responses to acute GVS relative to healthy controls and that individuals with PD and healthy elders would demonstrate diminished adaptive responses to repeated GVS compared to young adults. Twelve individuals with PD (PD group), 15 healthy young adults (HY group), and 11 healthy elders (HE group) participated. Timing of GVS was randomly applied during each task. Fifteen acquisition and nine retention trials with GVS were compared to assess learning. The PD group took longer to stabilize their center of pressure (COP) in quiet stance following GVS acutely compared to controls. The PD and HE groups had lower sample entropy (SaEn) compared to the HY. Neither the PD nor HE groups demonstrated changes in SaEn or meaningful improvements in postural control during acquisition or retention. SaEn in the HY group acutely decreased and then increased at retention which coincided with a meaningful improvement in postural control. The PD group had impaired motor planning, postural preparation, and postural stability during a rise to toes task following acute GVS, but these constructs returned to baseline at later acquisition and retention time points. Controls suppressed GVS acutely Postural coordination decreased acutely in the PD group during tether release. This persisted and an adaptive trend in BOS transition was noted with repeated GVS exposure in this group. No changes were observed in the control groups. Taken together, these results demonstrated that acute GVS differentially affects postural control in individuals with PD. Our results support the hypothesis that reweighting of sensory stimuli is impaired in PD. We also show that individuals with PD are able to suppress attention to a vestibular illusion and demonstrate adaptive responses to a postural threat

Gait and cognition: mapping the global and discrete relationships in ageing and neurodegenerative disease

Recent research highlights the association of gait and cognition in older adults but a stronger understanding is needed to discern coincident pathophysiology, patterns of change, examine underlying mechanisms and aid diagnosis. This structured review mapped associations and predictors of gait and cognition in older adults with and without cognitive impairment, and Parkinson's disease. Fifty papers out of an initial yield of 22,128 were reviewed and a model of gait guided analysis and interpretation. Associations were dominated by the pace domain of gait; the most frequently studied domain. In older adults pace was identified as a predictor for cognitive decline. Where comprehensive measurement of gait was conducted, more specific pathological patterns of association were evident highlighting the importance of this approach. This review confirmed a robust association between gait and cognition and argues for a selective, comprehensive measurement approach. Results suggest gait may be a surrogate marker of cognitive impairment and cognitive decline. Understanding the specific nature of this relationship is essential for refinement of diagnostics and development of novel therapies

How does the treadmill affect gait in Parkinson’s disease?

[Abstract] Parkinson’s disease (PD) is clinically characterized by symptoms of akinesia, rigidity, and resting tremor, which are related to a dopaminergic deficiency of the nigrostriatal pathway. Disorders of gait are common symptoms of PD that affect the quality of life in these patients. One of the main focuses of physical rehabilitation in PD is to improve the gait deficits in the patients. In the last decade, a small number of studies have investigated the use of the treadmill for the rehabilitation of gait in PD patients. Although, the results of these studies are promising, the mechanisms underlying the therapeutic effect of the treadmill in PD are still largely unknown. This paper reviews 10 years of investigation of treadmill training in PD, focusing on the possible mechanisms involved in the therapeutic effect of the treadmill. Understanding these mechanisms may improve the prescription and design of physical therapy programs for PD patients.Ministerio de Ciencia e Innovación; PSI2008-03175Xunta de Galicia; 2009/00

The efficacy of exercise interventions for people with Parkinson´s disease : a systematic review and meta-analysis

Tese de mestrado, Neurociências, Universidade de Lisboa, Faculdade de Medicina, 2019Background Parkinson Disease (PD) is the second most common neurodegenerative disorder characterized bymotor and non-motor symptoms that frequently affect patients’ physical activity. Recent studies showed that PD patients spend 75% of all awake time in sedentary behaviors and are 30% less physically active than age-matched comparison subjects. Exercise may improve PD symptomatic control, and perhaps even modify diseases progression. Even though several studies have been published, in the last years, a robust evidence of exercise efficacy in PD is still missing. This study intends to investigate the efficacy of exercise, described as a structured and planned physical activity, associated with an energy expenditure, with the aim of improving physiological and motor function, as a therapeutic intervention in PD. Based on this, assumptions for PD clinical practice and research are made. Methods It was performed a systematic review of published randomized clinical trials assessing exercise interventions in Parkinson Disease. Studies were identified using MEDLINE, PubMed,PEDro andCochraneLibrary(from its inception to February2017). A mixed methods approach was undertaken using narrative and random effects meta-analysis methods. The methodological characteristics and quality of reporting were assessed using Cochrane Risk of Bias tool. Results Fifty-two studies were included. The most frequently used type of exercise was aerobic exercise (32.6% of the included studies). It is also important to highlight that 34.6% of the included studies assessed the effect of the exercise on motor impairment/disability. Exercise appears to be efficacious improving UPDRS III score, falls frequency and gait measured through the 6-minutes walking test. However, due to the reduced number of studies, conclusions cannot be drawn about the relevance of the improvement. Exercise has not shown to contribute to a significant improvement in the quality of life and balance of Parkinson's disease patients. Conclusions Data, from the included studies, suggests that exercise has a potential positive effect in falls frequency, PD patients’ motor impairment and gait parameters. However, the number of studies was small and to better conclude about exercise efficacy on PD additional studies with larger samples, using the recommended outcomes tools for PD and a placebo or sham-intervention comparator should be performed. The role of exercise as disease modifying intervention, the best type of exercise, intensity and frequency of exercise for each disease stage and therapeutic purpose are still unanswered questions.Contextualização A doença de Parkinson é a segunda doença neurodegenerativa mais comum. Um conjunto de sintomas motores e não motores conduzem a uma progressiva dependência nas atividades da vida diária e consequente perda de qualidade de vida para estes doentes. Os primeiros sintomas e a sua progressão não são lineares, existindo uma grande variabilidade no decurso da doença. Habitualmente, no início, a doença de Parkinson é unilateral e o tratamento farmacológico permite o controlo sintomático. Contudo após dois a cinco anos, a maioria dos pacientes desenvolve complicações motoras associadas à Levodopa. Estudos recentes mostraram que os doentes com Parkinson gastam 75% do seu tempo em atividades sedentárias e que, em comparação com adultos da mesma idade, são 30% menos ativos, diferença que se acentua com a progressão da doença. O exercício tem sido cada vez mais recomendado como intervenção coadjuvante às intervenções farmacológica e cirúrgica. Por isso, torna-se cada vez mais relevante investigar que efeitos tem o exercício e como atua nos sintomas e nos mecanismos neurofisiológicos da doença de Parkinson. Estudos prévios em animais realçaram o seu potencial benefício na neuroplasticidade, uma vez que, com o exercício ocorre um aumento da síntese e libertação de dopamina e um aumento dos seus níveis no estriado. Esta revisão sistemática da literatura é especialmente relevante para investigar a eficácia do exercício na DP e para definir diretrizes para novos ensaios clínicos e para o seu uso enquanto potencial ferramenta terapêutica, quer como coadjuvante, quer como potencial modificador da progressão da doença. Objetivos Este estudo visa investigar a eficácia do exercício cujo objetivo é a melhoria da função fisiológica e motora como intervenção terapêutica na DP, descrito como uma atividade física estruturada e planeada, associada a um gasto energético, e cujo objetivo é a melhoria da função fisiológica e motora. Com base nos resultados, procuraremos delinear recomendações para a prática clínica e investigação na área da DP. Métodos Foi realizada uma pesquisa eletrónica de ensaios clínicos que investigassem o efeito do exercício na doença de Parkinson nas seguintes bases de dados: MEDLINE, PubMed, PEDro and Cochrane Library, desde o início do estudo até Fevereiro de 2017. Na seleção de artigos foram considerados os seguintes critérios de inclusão: 1) estudos clínicos randomizados e controlados 2) a população incluída nos estudos ser composta por doentes deParkinsonem qualquer estádiodadoença3) estudos queavaliem eficácia terapêutica do exercício, entendido como uma atividade física planeada e estruturada, à qual está associado um gasto de energia e cujo objetivo é a melhoria da função fisiológica e motora 4) estudos com uma das seguintes intervenções como grupo de controlo: não intervenção, cuidados habituais, placebo, sham-intervention ou outro tipo de exercício 5) incluir pelo menos um dos seguintes outcomes: marcha, qualidade de vida, incapacidade, capacidade aeróbia, amplitudes articulares, força muscular ou cognitivo. Foi construída uma grelha de recolha de dados dos artigos selecionados, na qual cinco domínios foram tidos em conta: informação geral (título, nome e país do autor de correspondência, língua de publicação, ano e jornal de publicação, tipo de intervenção, aprovação ética e consentimento informado), métodos (critérios de elegibilidade, tipo de desenho doestudo, método derandomização, presençadeocultação daaleatorização, tipo de ocultação e duração do follow-up, número total de doentes e de doentes por grupo), intervenção (tipo, duração e timming da intervenção), análise dos dados (tipo de análise, métodos estatísticos utilizados, objetivos, desistências, cálculo do tamanho da amostra, outcomes pré-definidos, instrumentos de avaliação e comparabilidade dos grupos) e resultados. A qualidade metodológica dos estudos foi avaliada com recurso à ferramenta da Cochrane para avaliar o risco de viés – Cochrane tool Cochrane Risk of bias. Todos os estudos foram classificados de acordo com o risco de viés. Foi realizada uma análise estatística descritiva dos resultados. A meta-análise foi conduzida recorrendo ao RevMan 5.3.5 software. Para que se pudesse avaliar a eficácia, apenas os estudos que tinham como intervenção no grupo de controlo o não exercício, foram incluídos nameta-análise. Os estudos foram analisados de acordo com os outcomes e incluídos na meta-análise se o outcome e a respetiva ferramenta de avaliação fossem usados em pelo menos outros dois estudos. Foi conduzida uma análise por subgrupos tendo por base o tipo de exercício (exercício aeróbio vs multimodal), para o único outcome que tinham dados suficientes para comparar dois tipos de exercícios diferentes e outra com base na progressão da intensidade ao longo do estudo (intensidade mantida versus aumento progressivo da intensidade ao longo do estudo). Resultados A pesquisa eletrónica identificou 368 citações, das quais 159 potencialmente elegíveis. A aplicação dos critérios de inclusão resultou na exclusão de 107 estudos. As principais razões de exclusão foram: não serem ensaios clínicos randomizados (n=32), não avaliarem a eficácia do exercício (n=48), o grupo de controlo ser constituído por participantes sem doença de Parkinson (n=18), tipo de outcomes (n=2), estudos duplicados (n=6) e a língua de publicação (n=1). A intervenção mais frequentemente utilizada nos estudos incluídos foi o exercício aeróbio (32.6% dos estudos) e os doentes foram, na sua grande maioria avaliados sob o efeito da medicação. O outcome primário mais utilizado foi o comprometimento motor/incapacidade e os outcomes secundários mais avaliados foram a marcha e a qualidade de vida. Na meta-analise avaliámos o efeito do exercício nos seguintes outcomes: comprometimento motor/incapacidade, equilíbrio, parâmetros de marcha, frequência de quedas e qualidade de vida. O exercício poderá ter benefícios no comprometimento motor (UPDRS, parte III), na diminuição da frequência de quedas e na marcha avaliada através do teste dos 6 minutos de marcha, no entanto, em nenhuma das análises a melhoria foi significativa. Na análise de subgrupos, foram comparados o exercício multimodal com o aeróbio, sendo mais benéfico o exercício multimodal para a melhoria na UPDRS parte III, no entanto, mais uma vez os resultados não foram estatisticamente significativos. Na análise de subgrupos, na qual comparámos estudos com intensidade mantida com estudos com aumento progressivo da intensidade, não se registaram diferenças significativas, embora o aumento progressivo da intensidade tenha melhorias superiores na UPDRS parte III. A maioria dos estudos não reporta efeitos adversos da intervenção, apresenta baixo risco de víeis e só têm ocultação do avaliador. Conclusões A revisão sistemática sugere que o exercício poderá ter um impacto positivo nos sintomas motores da doença de Parkinson, com especial impacto no comprometimento motor/incapacidade, avaliado pelo UPDRS parte III, na frequência de quedas e nalguns parâmetros da marcha. No entanto, as melhorias encontradas não são estatisticamente significativas. Nos estudos incluídos, nesta revisão sistemática da literatura, não foram encontrados benefícios significativos do exercício para a qualidade de vida ou para a melhoria do equilíbrio na DP. Este estudo observou que, na maioria dos estudos incluídos, a intensidade e frequência do exercício seguem as indicações definidas pelas ACSM relativas à prescrição do exercício para o adulto idoso. O número reduzido de estudos, o tamanho reduzido da amostra, a diversidade de outcomes entre os estudos limitam as conclusões sobre os benefícios do exercício em doentes de Parkinson, que podem ser retiradas com esta revisão sistemática. Estudos futuros são necessários para perceber os efeitos do exercício noutros parâmetros de saúde e para avaliar a correlação entre o exercício e os benefícios alcançados porque só assim será possível que os profissionais de saúde escolham o programa mais eficaz para os doentes de Parkinson. Outro aspeto importante passa pela avaliação da eficácia em estádios mais avançados da patologia, assim como o estudo do impacto do recurso ao exercício em fases precoces da doente e do seu potencial papel como modificador da progressão da doença