Gait variability: methods, modeling and meaning

The study of gait variability, the stride-to-stride fluctuations in walking, offers a complementary way of quantifying locomotion and its changes with aging and disease as well as a means of monitoring the effects of therapeutic interventions and rehabilitation. Previous work has suggested that measures of gait variability may be more closely related to falls, a serious consequence of many gait disorders, than are measures based on the mean values of other walking parameters. The Current JNER series presents nine reports on the results of recent investigations into gait variability. One novel method for collecting unconstrained, ambulatory data is reviewed, and a primer on analysis methods is presented along with a heuristic approach to summarizing variability measures. In addition, the first studies of gait variability in animal models of neurodegenerative disease are described, as is a mathematical model of human walking that characterizes certain complex (multifractal) features of the motor control's pattern generator. Another investigation demonstrates that, whereas both healthy older controls and patients with a higher-level gait disorder walk more slowly in reduced lighting, only the latter's stride variability increases. Studies of the effects of dual tasks suggest that the regulation of the stride-to-stride fluctuations in stride width and stride time may be influenced by attention loading and may require cognitive input. Finally, a report of gait variability in over 500 subjects, probably the largest study of this kind, suggests how step width variability may relate to fall risk. Together, these studies provide new insights into the factors that regulate the stride-to-stride fluctuations in walking and pave the way for expanded research into the control of gait and the practical application of measures of gait variability in the clinical setting

Etude expérimentale des dynamiques temporelles du comportement normal et pathologique chez le rat et la souris

155 p.Modern neuroscience highlights the need for designing sophisticated behavioral readout of internal cognitive states. From a thorough analysis of classical behavioral test, my results supports the hypothesis that sensory ypersensitivity might be the cause of other behavioural deficits, and confirm the potassium channel BKCa as a potentially relevant molecular target for the development of drug medication against Fragile X Syndrome/Autism Spectrum Disorders. I have also used an innovative device, based on pressure sensors that can non-invasively detect the slightest animal movement with unprecedented sensitivity and time resolution, during spontaneous behaviour. Analysing this signal with sophisticated computational tools, I could demonstrate the outstanding potential of this methodology for behavioural phenotyping in general, and more specifically for the investigation of pain, fear or locomotion in normal mice and models of neurodevelopmental and neurodegenerative disorders

КОНЦЕПТУАЛЬНІ ПІДХОДИ ДО АЛГОРИТМІЗАЦІЇ ПРОЦЕСІВ МОНІТОРИНГУ ПОКАЗНИКІВ СТАНУ ОРГАНІЗМУ

Background. The approaches to the formation of personalized knowledge about the state and health of a person in the tasks of mobile medicine are considered. The range of conceptual and methodological approaches for assessing various parameters of the physical condition of the body and physical fitness of a person is analyzed. Conclusions. It is proposed to use the parameters of the attractors of the cardiovascular system of the body on the basis of using the methods of the phase spaces of the patient's states. We also recommend new approaches to identify the parameters of the state vector of the human body in the multidimensional phase space of states for assessing and modeling the dynamics of the human cardiovascular system. The approaches are associated not only with the absolute value of various indicators, but also with the rate of change of the studied parameters, their accelerations under load, as well as with the indicators of synergy.Рассмотрены подходы к формированию персонализированных знаний о состоянии и здоровье человека в задачах мобильной медицины. Проанализирован спектр концептуальных и методических подходов для оценки различных параметров физического состояния организма и физической подготовленности человека. Предложено на основании использования методов фазовых пространств состояний пациента применять параметры аттракторов показателей сердечно-сосудистой системы организма. Рекомендуются также новые подходы к идентификации параметров вектора состояния организма человека в многомерном фазовом пространстве Для оценки и моделирования динамики сердечно-сосудистой системы человека. ПоДходы связаны не только с абсолютной величиной различных показателей, но и со скоростью изменений изучаемых параметров, их ускорениями при нагрузке, а также с показателями синергизма.Розглянуто підходи до формування персоналізованих знань про стан і здоров'я людини в задачах мобільної медицини. Проаналізовано спектр концептуальних і методичних підходів для оцінки різних параметрів фізичного стану організму і фізичної підготовленості людини. Запропоновано на підставі використання методів фазових просторів станів пацієнта застосовувати параметри атракторів показників серцево-судинної системи організму. Рекомендуються також нові підходи до ідентифікації параметрів вектора стану організму людини в багатовимірному фазовому просторі для оцінки та моделювання динаміки серцево-судинної системи людини. Підходи пов'язані не тільки з абсолютною величиною різних показників, а й зі швидкістю змін досліджуваних параметрів, їх прискоренням при навантаженні, а також з показниками синергізму

Pacemaking Neurons in the study of Parkinson’s Disease

Parkinson’s disease is the second most common neurodegenerative disorder with a signiVcant social cost. The disease that develops over years results in signiVcant movement related problems for the aUected. The pathogenesis however is partially understood. Computational approaches are signiVcant in the analysis of events that are multi-factorial. Parkinson’s Disease results from a system failure that leads to severe degeneration in the substantia nigra , a locus in the mid-brain. Traditional approaches tend to focus on isolated sub-components of the pathogenic pathways. However, such an approach may be inadequate to describe the pathogenesis. Substantia nigra neurons function on an expensive energy budget, due to a high level of arborisation and pacemaking activity. Spontaneous oscillations of these neurons are an important feature of motor control. Pacemaking involves the L-type calcium channel, and could impose long-term accumulation of calcium within its organelles. Modelling of this activity is an important part of developing an understanding of the pathogenic process. We develop a mathematical paradigm to describe this activity with a single compartment approach. To develop the mathematical framework we initially identify the components that contribute to the process and investigate an appropriate mathematical representation for the respective components. In the next part, we bring together such representation to develop a model that can reproduce measured data. Global optimisation strategies are adopted to tune important parameters. The model explicitly describes the dynamics of the transmembrane potential with changes in the levels of important cations. The model is veriVed for two major observations in literature regarding its response in the presence of channel blockers. The model is analysed for parameter bifurcation and stability of oscillations. Finally a framework is proposed to extend the model to include aspects of calcium homeostasis

Microglial adipobiology: a new concept for understanding the adipose tissue-brain crosstalk in health and disease

This article proposes the concept of “microglial adipobiology” as a new theoretical framework for the crosstalk between the adipose tissue and the central nervous system in health and disease. It reviews an important mechanistic link, explaining the neuropsychiatric complications of obesity, including the role of adipose-secreted signaling proteins (adipokines) and adipose-derived stem cells in influencing microglial function and neuroinflammation. An increasing body of evidence suggests that neuroinflammation mediated by microglia, macrophage-like cells in the brain, plays a contributory role in the pathogenesis of various neurodegenerative diseases. The specific positive and negative effects of the major types of dietary fats are also discussed in the case of obesogenic and ketogenic diets. Furthermore, it explores the effects of microglial cells on adipose tissue via modulating the central control of energy homeostasis in the hypothalamus and proposes the concept of “transgenerational adipobiology” as a framework explaining the neurological and metabolic complications of the offspring of obese mothers. Finally, potential directions for future therapeutic interventions are considered

XXII International Conference on Mechanics in Medicine and Biology - Abstracts Book

This book contain the abstracts presented the XXII ICMMB, held in Bologna in September 2022. The abstracts are divided following the sessions scheduled during the conference

Molecular mechanisms involved in the protective effects of tibolone in astrocytic cells treated with palmitic acid

La obesidad se asocia con un aumento de la neuroinflamación crónica e incrementa el riesgo de neurodegeneración. Esto empeora durante el proceso de envejecimiento normal cuando se reducen los niveles de hormonas gonadales endógenas. La tibolona es un esteroide sintético utilizado para la terapia hormonal durante la posmenopausia y tiene efectos estrogénicos, progestogénicos y androgénicos. En estudios clínicos y preclínicos, se ha observado que la tibolona tiene acciones antioxidantes, antiinflamatorias y antidepresivas. Sin embargo, se desconoce su acción sobre células astrocitarias expuestas al ácido palmítico, un ácido graso utilizado para modelar la obesidad in vitro. Esta tesis demuestra que la tibolona previene la muerte celular y protege las células T98G contra el daño mitocondrial y los cambios morfológicos inducidos por el ácido palmítico. El efecto de la tibolona sobre las mitocondrias fue mediado por el receptor de estrógeno β. El análisis de la expresión génica mostró que la tibolona tiene un efecto antiinflamatorio debido a sus acciones para reducir la expresión de los genes IL6, IL1B y miR155-3p. Interesantemente, la tibolona atenuó el aumento de la expresión de los genes involucrados en los mecanismos epigenéticos como la metilación del ADN (DNMT3B) y el complejo telomérico (TERT, TERC) inducidos por el ácido palmítico. Finalmente, se observó que la inhibición de la telomerasa (TERT) redujo la expresión de IL6 en células tratadas con ácido palmítico e interfirió con el efecto protector de la tibolona sobre la muerte celular. Este estudio mostró por primera vez los principales mecanismos moleculares implicados en los efectos de la tibolona en un modelo de obesidad in vitro. Esta tesis contribuye a un nuevo conocimiento sobre la biología molecular y celular de la proteína telomerasa, ya que es el primer trabajo que evalúa el papel del TERT en las acciones de tibolona y ácido palmítico. Estos resultados demuestran que la tibolona tiene efectos beneficiosos sobre las células astrocíticas a nivel celular y molecular, y sugieren que la tibolona podría ser un esteroide neuroactivo con acciones terapéuticas sobre diferentes enfermedades. Sin embargo, estudios futuros en modelos in vivo son necesarios para evaluar la posible aplicación clínica de tibolona en el tratamiento de enfermedades que afectan el sistema nervioso central.Fundación CeiBa, Programa Rodolfo Llinás (Beca de Doctorado)COLCIENCIAS, proyecto # 824-2017L´Oreal-UNESCO, ICETEX, COLCIENCIAS (For Women in Science program)Obesity is associated with increased chronic neuroinflammation and with an augmented risk for neurodegeneration. This is worsened during the normal aging process when the levels of endogenous gonadal hormones are reduced. Tibolone is a synthetic steroid used for hormone therapy during postmenopausal period and it has estrogenic, progestogenic and androgenic effects. In clinical and preclinical studies, it has been observed that tibolone has antioxidant, anti-inflammatory and anti-depressive actions. However, its actions on astrocyte cells exposed to palmitic acid, a saturated fatty acid used to model obesity in vitro, are unknown. This PhD thesis demonstrates that tibolone prevents cell death and protects T98G cells against mitochondrial damage and morphological changes induced by palmitic acid. Tibolone effect on mitochondria was mediated by estrogen receptor β. The gene expression analysis showed that tibolone has an anti-inflammatory effect because of its actions on reducing the expression of IL6, IL1B and miR155-3p genes. Interestingly, tibolone attenuated the increased expression of genes involved in epigenetic mechanisms, such as DNA methylation (DNMT3B) and telomere-regulating genes (TERT, TERC) induced by palmitic acid. Finally, it was observed that telomerase (TERT) inhibition reduced the IL6 expression in cells treated with palmitic acid and it interfered with the protective effect of tibolone on cell death. This study showed for the first time the main molecular mechanisms involved in tibolone effects in an obesity model in vitro. This thesis contributes with new knowledge about the molecular and cellular biology of the telomerase protein since it is the first work evaluating the role of TERT in tibolone and palmitic acid actions. These results demonstrate that tibolone has beneficial effects on astrocytic cells at the cellular and molecular level and suggest that tibolone might be a neuroactive steroid with therapeutic actions upon different diseases. However, future studies on in vivo models are necessary to evaluate the possible clinical application of tibolone in the treatment of diseases affecting the central nervous system.Doctor en Ciencias BiológicasDoctorad

Three Pillars of Automated Home-Cage Phenotyping of Mice: Novel Findings, Refinement, and Reproducibility Based on Literature and Experience

Animal models of neurodegenerative and neuropsychiatric disorders require extensive behavioral phenotyping. Currently, this presents several caveats and the most important are: (i) rodents are nocturnal animals, but mostly tested during the light period; (ii) the conventional behavioral experiments take into consideration only a snapshot of a rich behavioral repertoire; and (iii) environmental factors, as well as experimenter influence, are often underestimated. Consequently, serious concerns have been expressed regarding the reproducibility of research findings on the one hand, and appropriate welfare of the animals (based on the principle of 3Rs—reduce, refine and replace) on the other hand. To address these problems and improve behavioral phenotyping in general, several solutions have been proposed and developed. Undisturbed, 24/7 home-cage monitoring (HCM) is gaining increased attention and popularity as demonstrating the potential to substitute or complement the conventional phenotyping methods by providing valuable data for identifying the behavioral patterns that may have been missed otherwise. In this review, we will briefly describe the different technologies used for HCM systems. Thereafter, based on our experience, we will focus on two systems, IntelliCage (NewBehavior AG and TSE-systems) and Digital Ventilated Cage (DVC®, Tecniplast)—how they have been developed and applied during recent years. Additionally, we will touch upon the importance of the environmental/experimenter artifacts and propose alternative suggestions for performing phenotyping experiments based on the published evidence. We will discuss how the integration of telemetry systems for deriving certain physiological parameters can help to complement the description of the animal model to offer better translation to human studies. Ultimately, we will discuss how such HCM data can be statistically interpreted and analyzed.Peer reviewe