System-on-chip design of the cortical-diencephalic centre of the lower urinary tract

This article presents the design of a field programmable gate array (FPGA)-based prototype of a system on chip (SoC) capable of behaving as one of the nerve centres comprising the neuroregulatory system in humans: the cortical-diencephalic nerve centre. The neuroregulatory system is a complex nerve system consisting of a heterogeneous group of nerve centres. These centres are distributed throughout the length of the spinal cord, are autonomous, communicate via interneurons, and govern and regulate the behaviour of multiple organs and systems in the human body. As a result of years of study of the functioning and composition of the neuroregulatory system of the lower urinary tract (LUT), the centres that regulate this system have been isolated. The objective of this study is to understand the individual functioning of each centre in order to create a general model of the neuroregulatory system that is capable of operating at the level of the actual nerve centre. This model represents an advancement of the current black box models that do not allow for isolated or independent treatment of system dysfunction. In this study, we re-visit our research into the viability of the hardware design of one of these centres—the cortical-diencephalic centre. We describe this hardware because functioning of the centre is completely configurable and programmable, which validates the design for other centres that comprise the neuroregulatory system. In this document, we succinctly present the formal model of the centre, propose a hardware design and an FPGA-based prototype, construct a testing and simulation environment to evaluate it and, lastly, analyse and contrast the results using data obtained from real patients, verifying that the functional behaviour fits that observed in humans.This work has been supported by grant University of Alicante projects GRE14-02 and Smart University

An Integration Solution of a Simulator Implemented in Software and a Component Synthesized in Reconfigurable Hardware for a Neuroregulator System

Los trabajos para el desarrollo de un sistema artificial que aporte al mejoramiento de disfunciones del Tracto Urinario Inferior (LUT-Lower Urinary Tract) fundamentados en un marco formal y que emplea sistemas multiagentes para el modelado del sistema neurorregulador y diseños particulares se inscriben en los esfuerzos de aplicar soluciones de hardware como tendencia a desarrollar dispositivos implantables en humanos. Para ello, ha sido necesario diseñar y construir herramientas de software representativas de un modelo teórico-matemático con funcionalidades para simular el comportamiento del tracto urinario inferior y, al mismo tiempo, diseñar prototipos de centros neurorreguladores que se alojen en hardware reconfigurable (FPGA, Field Programmable Gate Array) en una especie de plataforma híbrida para la experimentación sobre diferentes soluciones y arquitecturas candidatas. Esta investigación parte de un modelo teórico-matemático, que conlleva a un simulador en software, al diseño de componentes particulares que implementan funciones de determinados centros neurorreguladores en hardware reconfigurable y que conduce a la necesidad de desarrollar por la vía de la integración una plataforma híbrida software-hardware. En este trabajo se expone una aproximación que diseña e implementa el proceso de integración y que se constituye en una solución imprescindible en este contexto.The work for the development of an artificial system that contributes to the improvement of lower urinary tract dysfunctions (LUT-Lower Urinary Tract) based on a formal framework and that uses multiagent systems for the modeling of the neuroregulatory system and particular designs are part of the efforts to apply hardware solutions as a tendency to develop implantable devices in humans. For this, it has been necessary to design and build software tools representative of a theoretical-mathematical model with functionalities to simulate the behavior of the lower urinary tract and, at the same time, design prototypes of neuroregulatory centers that are housed in reconfigurable hardware (FPGA-Field Programmable Gate Array) in a kind of hybrid platform for experimentation on different solutions and candidate architectures. This research is based on a theoretical-mathematical model, which involves a software simulator, the design of particular components that implement functions of certain neuroregulatory centers in reconfigurable hardware and that leads to the need to develop a hybrid platform through integration. software-hardware. This paper presents an approach that designs and implements the integration process and constitutes an essential solution in this context

System on chip design of the nerve centres of the human neuroregulatory system

Introducción: El sistema neurorregulador humano es un sistema nervioso complejo compuesto por un grupo heterogéneo de centros nerviosos distribuidos a lo largo de la médula espinal. Estos centros actúan de forma autónoma, se comunican mediante interconexiones nerviosas y gobiernan y regulan el comportamiento de órganos en los seres humanos. Por más de 20 años se viene estudiando el sistema neurorregulador del tracto urinario inferior, responsable de los órganos y sistemas que intervienen en el proceso de micción. El objetivo de la investigación ha sido comprender el papel individual de cada centro para crear un modelo general del sistema neurorregulador capaz de operar a nivel de centro nervioso. Métodos: El modelo creado se ha formalizado mediante la teoría de sistemas multiagente de forma que cada agente modele el comportamiento de un centro nervioso. Su granularidad ha abierto la posibilidad de actuar a nivel de centro, lo cual ha sido especialmente interesante en el tratamiento de disfunciones. Resultados y discusión: En este trabajo se enriqueció este modelo teórico con un modelo arquitectural que lo hiciera adecuado para su implementación en hardware. A partir del nuevo modelo, se propuso el diseño system on chip de un procesador específico capaz de desempeñar las funciones de un centro nervioso. En conclusión, la investigación supuso un enfoque original con el objetivo final de crear un chip parametrizable, capaz de desarrollar cualquier función neurorreguladora, que pudiera ser implantable en el cuerpo y con capacidad para trabajar de forma coordinada con el sistema neurorregulador biológico.Introduction: The human neuroregulatory system is a complex nervous system composed of a heterogeneous group of nerve centres distributed along the spinal cord. These centres act autonomously, communicate through neural interconnections, and govern and regulate the behavior of organs in humans. For more than twenty years, the neuroregulatory system of the lower urinary tract has been studied, which controls the organs and systems involved in the urination process. Based on the study of the behavior and composition of the lower urinary tract, we have succeeded in isolating the centres involved in its functioning. The goal has been to understand the individual role played by each centre to create a general model of the neuroregulatory system capable of operating at the level of the nerve centre. Methods: The model has been created and formalized based on Multi-Agent Systems theory: each agent thus models the behaviour of a nerve centre. Its granularity opens up the possibility of acting at the level of the centre, of particular interest to treat dysfunctions. Results and discussion: The present study enriches this theoretical model with an architectural model that makes it suitable to implement in hardware. Based on this new model, we propose a System on Chip (SoC) design of a specific processor capable of performing a nerve centre’s functions. Although this processor can be entirely configured and programmed to adjust to the functioning of the different centres, the present work aimed at facilitating the understanding and validation of the proposal. We thus focused on the cortical-diencephalic centre, responsible for voluntary micturition. As conclusions, the research adopted an original approach with the aim of creating a configurable chip, capable of developing any neuroregulatory function, implantable in the body and being able to function in a coordinated way with the biological neuroregulatory system

Autonomic dysregulation in multiple sclerosis

Multiple sclerosis (MS) is a chronic, progressive central neurological disease characterized by inflammation and demyelination. In patients with MS, dysregulation of the autonomic nervous system may present with various clinical symptoms including sweating abnormalities, urinary dysfunction, orthostatic dysregulation, gastrointestinal symptoms, and sexual dysfunction. These autonomic disturbances reduce the quality of life of affected patients and constitute a clinical challenge to the physician due to variability of clinical presentation and inconsistent data on diagnosis and treatment. Early diagnosis and initiation of individualized interdisciplinary and multimodal strategies is beneficial in the management of autonomic dysfunction in MS. This review summarizes the current literatureon the most prevalent aspects of autonomic dysfunction in MS and provides reference to underlying pathophysiological mechanisms as well as means of diagnosis and treatment. © 2015 by the authors; licensee MDPI, Basel, Switzerland

Central control of visceral pain and urinary tract function

Afferent input from Aδ and C-fibres innervating the urinary bladder are processed differently by the brain, and have different roles in signaling bladder sensation. Aδ fibres that signal bladder filling activate a spino-bulbo-spinal loop, which relays in the midbrain periaqueductal grey (PAG) and pontine micturition centre (PMC). The excitability of this circuitry is regulated by tonic GABAergic inhibitory processes. In humans and socialised animals micturition is normally under volitional control and influenced by a host of psychosocial factors. Higher nervous decision-making in a social context to 'go now' or 'do not go' probably resides in frontal cortical areas, which act as a central control switch for micturition. Exposure to psychosocial stress can have profoundly disruptive influence on the process and lead to maladaptive changes in the bladder. During sleeping the voiding reflex threshold appears to be reset to a higher level to promote urinary continence.Under physiological conditions C-fibre bladder afferents are normally silent but are activated in inflammatory bladder states and by intense distending pressure. Following prolonged stimulation visceral nociceptors sensitise, leading to a lowered threshold and heightened sensitivity. In addition, sensitization may occur within the central pain processing circuitry, which outlasts the original nociceptive insult. Visceral nociception may also be influenced by genetic and environmental influences. A period of chronic stress can produce increased sensitivity to visceral pain that lasts for months. Adverse early life events can produce even longer lasting epigenetic changes, which increase the individual's susceptibility to developing visceral pain states in adulthood

Neurological disorders leading to mechanical dysfunction of the esophagus: an emergent behavior of a neuromechanical dynamical system

An understanding how neurological disorders lead to mechanical dysfunction of the esophagus requires knowledge of the neural circuit of the enteric nervous system. Historically, this has been elusive. Here, we present an empirically guided neural circuit for the esophagus. It has a chain of unidirectionally coupled relaxation oscillators, receiving excitatory signals from stretch receptors along the esophagus. The resulting neuromechanical model reveals complex patterns and behaviors that emerge from interacting components in the system. A wide variety of clinically observed normal and abnormal esophageal responses to distension are successfully predicted. Specifically, repetitive antegrade contractions (RACs) are conclusively shown to emerge from the coupled neuromechanical dynamics in response to sustained volumetric distension. Normal RACs are shown to have a robust balance between excitatory and inhibitory neuronal populations, and the mechanical input through stretch receptors. When this balance is affected, contraction patterns akin to motility disorders are observed. For example, clinically observed repetitive retrograde contractions emerge due to a hyper stretch sensitive wall. Such neuromechanical insights could be crucial to eventually develop targeted pharmacological interventions

Animal Models of Human Disease

© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).The use of animal models of human disease is critical for furthering our understanding of disease mechanisms, for the discovery of novel targets for treatment, and for translational research. This Special Topic entitled “Animal Models of Human Disease” aimed to collect state-of-the-art primary research studies and review articles from international experts and leading groups using animal models to study human diseases. Submissions were welcomed on a wide range of animal models and pathologies, including infectious disease, acute injury, regeneration, cancer, autoimmunity, degenerative and chronic disease. Seven participating MDPI journals supported the Special Topic, namely: Biomedicines, Cells, Current Issues in Molecular Biology, Diagnostics, Genes, the International Journal of Molecular Sciences, and the International Journal of Translational Medicine. In total, 46 papers were published in this Special Topic, with 37 full length original research papers, 2 research communications and 7 reviews. These contributions cover a wide range of clinically relevant, translatable, and comparative animal models, as well as furthering understanding of fundamental sciences, covering topics on physiological processes, on degenerative, inflammatory, infectious, autoimmune, neurological, metabolic, heamatological, hormonal and mitochondrial disorders, developmental processes and diseases, cardiology, cancer, trauma, stress, and ageing.Peer reviewe

Multifaceted superoxide dismutase 1 expression in amyotrophic lateral sclerosis patients: a rare occurrence?

Amyotrophic lateral sclerosis (ALS) is a neuromuscular condition resulting from the progressive degeneration of motor neurons in the cortex, brainstem, and spinal cord. While the typical clinical phenotype of ALS involves both upper and lower motor neurons, human and animal studies over the years have highlighted the potential spread to other motor and non-motor regions, expanding the phenotype of ALS. Although superoxide dismutase 1 (SOD1) mutations represent a minority of ALS cases, the SOD1 gene remains a milestone in ALS research as it represents the first genetic target for personalized therapies. Despite numerous single case reports or case series exhibiting extramotor symptoms in patients with ALS mutations in SOD1 (SOD1-ALS), no studies have comprehensively explored the full spectrum of extramotor neurological manifestations in this subpopulation. In this narrative review, we analyze and discuss the available literature on extrapyramidal and non-motor features during SOD1-ALS. The multifaceted expression of SOD1 could deepen our understanding of the pathogenic mechanisms, pointing towards a multidisciplinary approach for affected patients in light of new therapeutic strategies for SOD1-ALS

The Unmet Needs for Studying Chronic Pelvic/Visceral Pain Using Animal Models

The different definitions of chronic pelvic/visceral pain used by international societies have changed over the years. These differences have a great impact on the way researchers study chronic pelvic/visceral pain. Recently, the role of systemic changes, including the role of the central nervous system, in the perpetuation and chronification of pelvic/visceral pain has gained weight. Consequently, researchers are using animal models that resemble those systemic changes rather than using models that are organ- or tissue-specific. In this review, we discuss the advantages and disadvantages of using bladder-centric and systemic models, enumerating some of the central nervous system changes and pain-related behaviors occurring in each model. We also present some drawbacks when using animal models and pain-related behavior tests and raise questions about possible, yet to be demonstrated, investigator-related bias. We also suggest new approaches to study chronic pelvic/visceral pain by refining existing animal models or using new ones.</jats:p

Potential role of extracellular ATP released by bacteria in bladder infection and contractility

Urgency urinary incontinence (UUI), the result of conditions such as overactive bladder (OAB), could potentially be influenced by both commensal and urinary tract infection-associated bacteria. The sensing of bladder filling involves interplay between various parts of the nervous system eventually resulting in contraction of the detrusor muscle during micturition. Here we model host responses to various urogenital bacteria, firstly by using urothelial bladder cell lines and then with myofibroblast contraction assays. To measure responses, we examined calcium influx, gene expression and alpha smooth muscle actin deposition assays. We found that organisms such as Escherichia coli IA2 and Gardnerella vaginalis ATCC 14018 strongly induced calcium influx and contraction, whereas, Lactobacillus crispatus ATCC 33820 and L. gasseri KC-1 did not induce this response. Additionally, supernatants from lactobacilli impeded influx and contraction induced by the uropathogens. Upon further investigation of factors associated with the purinergic signaling pathways, we found that influx and contraction of cells correlated to the amount of extracellular ATP produced by G. vaginalis ATCC 14018 and E. coli IA2. Certain lactobacilli appear to mitigate this response by utilizing extracellular ATP or producing inhibitory compounds which can act as a receptor agonist or calcium channel blocker. These findings suggest that members of the urinary microbiota may be influencing UUI