900 research outputs found

    Investigation of the pathological mechanisms in canine degenerative myelopathy and the potential involvement of extracellular vesicles in disease progression

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    Canine degenerative myelopathy (DM) is a progressive and lethal adult-onset neurodegenerative disease with nonspecific clinical signs that can end in tetraplegia and respiratory dysfunction. It is frequently identified in German shepherd dogs (GSD) but has been described in other breeds. A definitive diagnosis is reached after histopathological examination of the spinal cord where axon degeneration and demyelination are characterised. Mutations in the gene encoding superoxide dismutase 1 (SOD1) are thought to have a pathological role in the disease and genotyping of the Sod1 gene can be used with clinical signs and histology to diagnose DM. The genetics, clinical signs and histology of DM suggests it may be a good naturally occurring large animal model for some forms of the human motor neurone disease, amyotrophic lateral sclerosis (ALS). This study aimed to 1) establish if defective cellular clearance pathways play a role in the aggregation of SOD1 and 2) if these defects contribute to the secretion of SOD1 positive extracellular vesicles (EVs) that 3) can spread mutant protein in a prion-like manner. Finally, 4) was to validate these findings with spinal cord tissue from DM cases using proteomics and biochemistry. In vitro studies using a neuroblastoma derived cell line (SK-N-SH) were conducted to assess the effect of disrupting various cell clearance and toxicity pathways on wildtype (WT) and mutant SOD1 aggregation and EV production. The reducing agent dithiothreitol increased the propensity of WT- and DM-SOD1 to aggregate (p ≤ 0.01) but did not have a statistically significant impact on the production of SOD1 positive EVs from cells. The autophagy inhibitor chloroquine increased the percentage of cells with DM-SOD1 aggregates (p ≤ 0.01), but not WT-SOD1 aggregates. EV secretion was not statistically significantly affected by chloroquine treatment in cells with DM-SOD1, but there was a significant increase in the EV marker flotillin-1 from cells containing WT-SOD1 (p ≤ 0.01). The proteasome inhibitor MG312 significantly increased the number of cells with WT- and DM-SOD1 aggregates (p < 0.0001), but they were higher in DM-SOD1 transfected cells (p ≤ 0.05). Flotillin-1 showed a downward trend from treated cells however this was only statistically supported with EVs from WT-SOD1 containing cells (p ≤ 0.01). WT- and DM-SOD1 showed an upwards trend in the EV fraction, but only reached significance in EVs from the cells containing DM-SOD1 (p ≤ 0.01). Overall, disruption to the main protein processing pathways caused the induction of nontypical clearance pathways and some of these appear to be less effective in the presence of the DM associated Sod1 mutation. Further, mutant SOD1 may have an impact on the stabilisation of the cell membrane as indicated by changes to associated proteins and this could have subsequent effects on protein clearance, particularly at the level of the endosome pathway and EVs. Further studies indicated there is a potential for EVs to spread WT- and DM-SOD1 to other cells in culture which suggests EVs could be recruited in DM for the spread of mutant SOD1 to other cells and may contribute to the progression of DM throughout the thoracic spinal cord and to the cervical and lumbar regions. Biochemical and proteomics analysis of spinal cords from control and DM dogs suggested axon and myelin integrity was disrupted and astrocytes were activated at early stages of DM. Evidence suggested these changes were the consequence of altered cellular metabolism, intracellular structure and protein processing. The Sod1 mutation caused an apparent reduction in SOD1 enzyme activity further suggesting the mutation is a contributor to the pathogenesis and progression of DM. Changes to plasma membrane organisation were also highlighted in the ex vivo study and may indicate perturbations to protein and lipid turnover. Ultimately the findings presented in this thesis contribute to the understanding of DM pathogenesis and will aid the search for DM biomarkers to enable earlier diagnosis, monitor disease progression and identify treatment targets

    Effects of trunk-focused exercise programs and how the training program and the individuals’

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    Trunk-focused exercise programs (TEP) refer to those training programs in which the main target of the exercises resides in the active and/or passive trunk/core structures. Although these programs have shown a positive impact in sport and health contexts throughout recent years, there are several limitations in the literature that hinder the understanding of TEP effect and their relationship to the individual and to the training load characteristics. In this sense, TEP are sometimes compared to exercise control groups and/or other exercise programs that include trunk-focused exercises. Furthermore, although the individual and the training program features are a basic aspect to optimize training programs, experimental TEP studies not always provide this information properly. To address these constraints, the present doctoral thesis includes two systematic reviews and an experimental study. The two systematic reviews aimed at an in-depth analysis of the literature on TEP both, to improve the knowledge about the trunk-focused exercise contribution to increase trunk physical fitness and ameliorate stroke and low back pain symptoms, and to better understand how the individuals and exercise programs characteristics modulate TEP effectiveness. Overall, although the quality of evidence was low, their results showed that TEP were effective to ameliorate stroke and patients’ non-specific chronic low back pain condition, with positive effects in all the outcomes analysed. Furthermore, the analysis of moderator factors revealed that TEP effectiveness in stroke patients seems to be higher when the initial trunk impairment is greater, the patients are older, and the intervention starts earlier. Importantly, the TEP impact on low back pain symptoms (mainly pain reduction) seems higher when a greater improvement in trunk and/or hip range of motion is recorded after the training program and participants have a lower body mass index. These results reinforce the importance of paying close attention to the individuals and to the exercise programs characteristics when designing this type of interventions. On the other hand, the experimental study overcomes some of the problems found in the systematic reviews, especially the lack of experimental works that objectively controlled the training load intensity. This study aimed at the comparison of the effects of a higher intensity and a higher volume core stability exercise (CSE) program on core stability, core endurance and whole-body dynamic balance in young physically active males, using a smartphone-accelerometer to control the CSE intensity. These study results showed the specificity of the effects caused by the CSE programs, with a larger increase in the lumbopelvic postural control during the execution of isometric CSE for the higher intensity CSE program and a larger core endurance increase for the higher volume CSE program. Interestingly, the performance of conventional isometric CSE in lying and quadruped positions during the CSE programs did not have a significant impact on the unstable sitting test, a sudden loading protocol and several whole-body dynamic balance tests. Altogether, the results of the studies included in this doctoral thesis highlight the importance of performing TEP to improve trunk performance, functional capacity,and health status in different populations. Specifically, the two systematic reviews showed how moderator factors related to both, the individual and the training program characteristics can play an important role in modulating TEP effectiveness, which should be considered to maximize and tailor the TEP benefits in stroke and low back pain patients. However, the quality of the evidence for all the outcomes analysed in these systematic reviews was low, and thus, higher quality studies are required to strengthen the evidence on the impact of performing trunk-focused exercises in stroke and low back pain rehabilitation programs. Regarding the experimental study, the training load control performed through the smartphone-accelerometer allowed to describe the specificity of the effects caused by a higher intensity and a higher volume CSE program in young physically active males. Further research is needed to characterize the dose-response relationship of CSE programs in different populations properly.Los programas de ejercicio focalizados en el tronco (PET) son aquellos programas de entrenamiento cuyo foco principal son las estructuras activas y/o pasivas del tronco/core. A pesar de que estos programas han mostrado un efecto positivo tanto en contextos deportivos como de salud a lo largo de los últimos años, se observan varias limitaciones en la literatura que dificultan entender adecuadamente el efecto que tienen estos programas y su relación tanto con las características de los participantes, como con las características de los programas de entrenamiento. En este sentido, los PET son comparados en ocasiones con grupos control y/u otros programas de entrenamiento que incluyen ejercicios focalizados en el tronco. Además, a pesar de que las características de los participantes y de los programas de entrenamiento son aspectos clave para su optimización, los estudios experimentales no siempre aportan esta información. Para abordar estas limitaciones, la presente tesis doctoral incluye dos revisiones sistemáticas y un estudio experimental. Las dos revisiones sistemáticas presentan un análisis detallado de la literatura relacionadas con los PET para, a) mejorar el conocimiento sobre la contribución de los ejercicios focalizados en el tronco sobre el desarrollo de la condición física del tronco y la mejora de los síntomas tanto en personas que han sufrido un ictus, como en pacientes con dolor lumbar, y b) comprender mejor cómo las características de los participantes y de los programas de entrenamiento modulan la efectividad de los PET. En general, a pesar de que la calidad de la evidencia fue baja, los resultados de estas revisiones mostraron la efectividad de los PET para mejorar la condición tanto de las personas que han sufrido un ictus, como de aquellas con dolor lumbar crónico inespecífico, obteniendo efectos positivos sobre todas las variables analizadas. Además, el análisis de los factores moderadores reveló que la efectividad de los PET en personas que han sufrido un ictus parece ser mayor cuando la afectación inicial del tronco es mayor, las personas son mayores o el programa de ejercicio comienza antes. Con respecto a las personas con dolor lumbar, el impacto de los PET sobre la reducción de los síntomas (especialmente la reducción del dolor), parece ser mayor cuando hay un mayor incremento del rango de movimiento del tronco y/o de la cadera y los participantes tienen un menor índice de masa corporal. Estos resultados refuerzan la importancia de prestar atención a las características de los participantes y de los programas de ejercicios cuando se diseñan este tipo de programas. Por otro lado, el estudio experimental que incluye esta tesis doctoral aborda algunos de los problemas observados en las revisiones sistemáticas, especialmente la falta de estudios experimentales que controlen de manera objetiva la carga de entrenamiento de los PET. En este sentido, este estudio tuvo como objetivo comparar los efectos de dos programas de ejercicios de estabilidad del tronco (EET), uno de mayor intensidad y otro de mayor volumen, sobre la estabilidad y resistencia del tronco y el equilibrio dinámico general en hombres jóvenes y físicamente activos, utilizando el acelerómetro integrado en un smartphone para controlar la intensidad de los EET. Los resultados mostraron la especificidad de los efectos de los programas de EET, con mayores mejoras sobre el control lumbo-pélvico durante la ejecución de EET isométricos en el grupo de mayor intensidad y un mayor efecto sobre la resistencia de los músculos tronco en el grupo de mayor volumen. Destacar también que la realización de EET isométricos en posiciones de tumbado y cuadrupedia no tuvo un impacto significativo sobre el test del asiento inestable, sobre un protocolo de perturbaciones súbitas y sobre varios test de equilibrio dinámico general. En resumen, los resultados de los estudios incluidos en esta Tesis Doctoral destacan la importancia de realizar PET para mejorar la condición física del tronco, la capacidad funcional y el estado de salud en diferentes poblaciones. Específicamente, las dos revisiones sistemáticas mostraron cómo factores moderadores relacionados con las características de los participantes y de los programas de entrenamiento pueden jugar un papel importante en la modulación de la efectividad de los PET, lo cual debería tenerse en cuenta para maximizar sus beneficios en personas que han sufrido un ictus y en pacientes con dolor lumbar. Sin embargo, la calidad de la evidencia de los estudios en los parámetros analizados fue baja y, por lo tanto, es necesario que estudios de mayor calidad refuercen y mejoren los resultados obtenidos sobre el impacto de los PET en estas poblaciones. Con respecto al estudio experimental, el control de la carga de entrenamiento a través del acelerómetro integrado en un smartphone permitió describir la especificidad de los efectos de un programa de EET de mayor intensidad y de otro de mayor volumen en hombres jóvenes y físicamente activos. Futuros estudios son necesarios para caracterizar de manera adecuada la relación dosis-respuesta de los programas de EET en diferentes poblaciones

    Fast Sensing and Adaptive Actuation for Robust Legged Locomotion

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    Robust legged locomotion in complex terrain demands fast perturbation detection and reaction. In animals, due to the neural transmission delays, the high-level control loop involving the brain is absent from mitigating the initial disturbance. Instead, the low-level compliant behavior embedded in mechanics and the mid-level controllers in the spinal cord are believed to provide quick response during fast locomotion. Still, it remains unclear how these low- and mid-level components facilitate robust locomotion. This thesis aims to identify and characterize the underlining elements responsible for fast sensing and actuation. To test individual elements and their interplay, several robotic systems were implemented. The implementations include active and passive mechanisms as a combination of elasticities and dampers in multi-segment robot legs, central pattern generators inspired by intraspinal controllers, and a synthetic robotic version of an intraspinal sensor. The first contribution establishes the notion of effective damping. Effective damping is defined as the total energy dissipation during one step, which allows quantifying how much ground perturbation is mitigated. Using this framework, the optimal damper is identified as viscous and tunable. This study paves the way for integrating effective dampers to legged designs for robust locomotion. The second contribution introduces a novel series elastic actuation system. The proposed system tackles the issue of power transmission over multiple joints, while featuring intrinsic series elasticity. The design is tested on a hopper with two more elastic elements, demonstrating energy recuperation and enhanced dynamic performance. The third contribution proposes a novel tunable damper and reveals its influence on legged hopping. A bio-inspired slack tendon mechanism is implemented in parallel with a spring. The tunable damping is rigorously quantified on a central-pattern-generator-driven hopping robot, which reveals the trade-off between locomotion robustness and efficiency. The last contribution explores the intraspinal sensing hypothesis of birds. We speculate that the observed intraspinal structure functions as an accelerometer. This accelerometer could provide fast state feedback directly to the adjacent central pattern generator circuits, contributing to birds’ running robustness. A biophysical simulation framework is established, which provides new perspectives on the sensing mechanics of the system, including the influence of morphologies and material properties. Giving an overview of the hierarchical control architecture, this thesis investigates the fast sensing and actuation mechanisms in several control layers, including the low-level mechanical response and the mid-level intraspinal controllers. The contributions of this work provide new insight into animal loco-motion robustness and lays the foundation for future legged robot design

    A novel behavioural paradigm for characterising anticipatory postural adjustments in mice

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    Daily we use purposeful, voluntary movements to interact with our environment. These movements demand and cause our body to experience a weight redistribution, i.e., anticipatory postural adjustments (APAs), and it’s the appropriate employment of these APAs that allows us to complete said voluntary movements without falling over or losing our equilibrium. The literature suggests that for humans, monkeys, and several quadrupeds, APAs are crucial at initiation and during movement. However, research has been somewhat limited due to the lack of behavioural paradigms that would allow for a better understanding into the neural circuitry involved with APAs. Given the widespread availability of genetic tools and advanced viral techniques in mice I focused my efforts in developing a novel behavioral paradigm for this species. The first chapters detail the reasoning behind the development of this novel behavioural paradigm while also providing a complete description of the different components and their functions. Later chapters use the custom-designed setup to characterise mouse APAs, incorporating various recording approaches designed to quantify APAs and compare them to those described in prior work, highlighting possible interspecifies similarities and differences. Additionally, I briefly discuss the potential neural circuitry of APAs informed by my own data and research that has been done in different animals, providing a comprehensive overview of APAs in mice

    Graphonomics and your Brain on Art, Creativity and Innovation : Proceedings of the 19th International Graphonomics Conference (IGS 2019 – Your Brain on Art)

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    [Italiano]: “Grafonomia e cervello su arte, creatività e innovazione”. Un forum internazionale per discutere sui recenti progressi nell'interazione tra arti creative, neuroscienze, ingegneria, comunicazione, tecnologia, industria, istruzione, design, applicazioni forensi e mediche. I contributi hanno esaminato lo stato dell'arte, identificando sfide e opportunità, e hanno delineato le possibili linee di sviluppo di questo settore di ricerca. I temi affrontati includono: strategie integrate per la comprensione dei sistemi neurali, affettivi e cognitivi in ambienti realistici e complessi; individualità e differenziazione dal punto di vista neurale e comportamentale; neuroaesthetics (uso delle neuroscienze per spiegare e comprendere le esperienze estetiche a livello neurologico); creatività e innovazione; neuro-ingegneria e arte ispirata dal cervello, creatività e uso di dispositivi di mobile brain-body imaging (MoBI) indossabili; terapia basata su arte creativa; apprendimento informale; formazione; applicazioni forensi. / [English]: “Graphonomics and your brain on art, creativity and innovation”. A single track, international forum for discussion on recent advances at the intersection of the creative arts, neuroscience, engineering, media, technology, industry, education, design, forensics, and medicine. The contributions reviewed the state of the art, identified challenges and opportunities and created a roadmap for the field of graphonomics and your brain on art. The topics addressed include: integrative strategies for understanding neural, affective and cognitive systems in realistic, complex environments; neural and behavioral individuality and variation; neuroaesthetics (the use of neuroscience to explain and understand the aesthetic experiences at the neurological level); creativity and innovation; neuroengineering and brain-inspired art, creative concepts and wearable mobile brain-body imaging (MoBI) designs; creative art therapy; informal learning; education; forensics

    LONG-LASTING EFFECTS OF MTBI ON OCULOMOTOR ABILITY AND NEUROMUSCULAR CONTROL

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    Concussions result in short-lived to long-lasting neurological function impairment and disturbances, typically undetectable by standard neuroimaging protocols, which can persist for several months post-trauma. Eye-tracking and virtual reality can be a powerful tool in the assessment of short- and long-term concussed individuals. However, it needs a clear and concise methodology. When acting as an optical flow-induced perturbation of balance metrics and combined with electroencephalographic data, it can differentiate between a non-concussed fatigue state and a concussive state. Furthermore, when employed as a secondary cognitive task, it elicits neural modulations and postural control perturbations that can detect concussion-related impairments up to eight years post-trauma. In this dissertation we sought to (i) develop a virtual reality environment that implements known eye-tracking methodologies and validate its accuracy in differentiating between non-concussed and concussed cohorts, (ii) investigate the presence of neural signatures that could differentiate between a concussive state and a fatigue state, and (iii) determine if long-lasting oculomotor and peripheral muscle control impairments could be reliably detected in a concussed cohort several years post-trauma. Our overarching hypotheses were that (i) eye-tracking metrics observed in a virtual reality environment can differentiate between non- concussed and concussed cohorts, (ii) spectral power of cortical activations are different between non-concussed participants in a fatigued state and concussed participants, and (iii) oculomotor impairments and corticomuscular correlates of balance metrics can be detected in a concussed several months post-trauma. Our findings support the majority of the initial proposed investigation. We detected corticomuscular coherence and postural control differences capable of differentiating between non-concussed and long-term concussed participants, established a link between corticomuscular coherence and postural control adaptations observed in the concussed group, determined some limitations of virtual reality paradigms in concussion assessment

    Proceedings XXIII Congresso SIAMOC 2023

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    Il congresso annuale della Società Italiana di Analisi del Movimento in Clinica (SIAMOC), giunto quest’anno alla sua ventitreesima edizione, approda nuovamente a Roma. Il congresso SIAMOC, come ogni anno, è l’occasione per tutti i professionisti che operano nell’ambito dell’analisi del movimento di incontrarsi, presentare i risultati delle proprie ricerche e rimanere aggiornati sulle più recenti innovazioni riguardanti le procedure e le tecnologie per l’analisi del movimento nella pratica clinica. Il congresso SIAMOC 2023 di Roma si propone l’obiettivo di fornire ulteriore impulso ad una già eccellente attività di ricerca italiana nel settore dell’analisi del movimento e di conferirle ulteriore respiro ed impatto internazionale. Oltre ai qualificanti temi tradizionali che riguardano la ricerca di base e applicata in ambito clinico e sportivo, il congresso SIAMOC 2023 intende approfondire ulteriori tematiche di particolare interesse scientifico e di impatto sulla società. Tra questi temi anche quello dell’inserimento lavorativo di persone affette da disabilità anche grazie alla diffusione esponenziale in ambito clinico-occupazionale delle tecnologie robotiche collaborative e quello della protesica innovativa a supporto delle persone con amputazione. Verrà infine affrontato il tema dei nuovi algoritmi di intelligenza artificiale per l’ottimizzazione della classificazione in tempo reale dei pattern motori nei vari campi di applicazione

    The use of wearable inertial measurement units to assess gait and balance outcomes related to fall risk among older adults

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    Due to the prevalence and associated health, social and economic costs of falls among older adults, this thesis originally aimed to identify a more robust and objective way of assessing fall risk factors with the use of wearable inertial measurement units (IMU). However, due to unforeseen circumstances, the direction of the thesis had to be changed. Therefore, the thesis aimed to investigate whether gait and balance outcomes related to fall risk, when measured with wearable IMUs are sensitive to conditions which may replicate clinical and habitual environments. In Study one, a systematic scoping review was conducted to identify characteristic differences between fallers and non-fallers with the use of IMUs. The lower trunk was the most common anatomical location, whilst walking a predetermined distance indoors was the most common test used with IMUs to distinguish between fallers and non-fallers. In Study two, seventeen older and seventeen younger adults performed multiple walking and standing tasks in a laboratory. Older adults had a lower root mean square of the IMU acceleration signal, harmonic ratio and greater step time asymmetry compared to younger adults. The use of a cognitive dual task caused gait to be slower and less symmetrical among older and younger adults. Trunk displacement to quantify trunk sway during quiet standing was greater among older adults and increased as standing conditions became more difficult. Older adults exhibited distinct differences in gait when walking indoors and outdoors. The results of Study two suggested that IMUs may identify differences between older and younger adults regarding walking speed and time to completion of clinical tests, even when a stopwatch could not. In Study three, twenty older and twenty younger adults had IMUs attached to different anatomical locations during waking hours. There were differences in all gait variables when walking supervised in the laboratory and unsupervised in habitual indoor environments for both older and younger adults. There were also large differences in gait variables when walking indoors and outdoors. These results suggest the need for future studies in continuous, outdoor and unsupervised free-living conditions, with regards to fall risk assessments. This thesis demonstrates that gait and balance outcomes related to fall risk, when measured using wearable IMUs, are sensitive to conditions resembling habitual and clinical environments among both older and younger adults. This could prove valuable for the enhancement of future fall risk research
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