The Effects of Intracortical Microstimulation Parameters on Neural Responses

RÉSUMÉ Les microstimulations de tissues nerveux du cerveau sont utilisés dans un grand nombre de prothèses sensorielles, de thérapies cliniques et autres activités de recherche se servant de la stimulation électrique. Actuellement, les paramètres de stimulation sont adaptés à chaque application via des tests itératifs. Les méthodes d'optimisation cherchent à améliorer les stimuli développés pour des objectifs spécifiques de stimulation, mais la compréhension fondamentale de la façon dont les paramètres de stimulation influencent les circuits neuronaux qu’ils activent reste largement incomplète. Ce déficit retarde l'optimisation de protocoles existants et rend le développement de nouvelles applications de stimulation difficile. À ce jour, un certain nombre de dispositifs prothétiques validés dès les années 1970 restent en développement, principalement en raison de l'incapacité de ces dispositifs à communiquer efficacement avec le cerveau. Pour utiliser la stimulation électrique afin de transmettre des messages au système nerveux central, une meilleure conception du patron du signal de stimulation est nécessaire. Dans cette thèse, nous étudions l'influence que chaque paramètre du signal (un courant constant, symétrique carré biphasique) exerce sur les réponses qu'il évoquées au travers des microstimulations de la zone intracorticale caudale du membre antérieur dans le cortex moteur chez le rat. Les paramètres de ce signal sont l'amplitude du courant, la fréquence et la durée d'impulsion, l’intervalle d'interphase et la durée du train. Leurs effets ont été évalués par un examen des réponses électromyographiques évoquées dans les muscles des membres antérieurs du rat en réponse à chaque stimulus. Les principaux résultats décrivent comment chaque paramètre de stimulation influence l'amplitude, la latence d’apparition et la durée de la réponse. Une composante jusque-là inexplorée du signal de la réponse (que nous appelons 'activation résiduelle') est aussi analysée pour la première fois. Les théories quant à l'origine et le mécanisme neuronal sous-jacent de ce phénomène sont proposés et les paramètres de stimulation touchant son apparition, la prévalence et la durée sont décrits. La fiabilité des signaux de stimulation pour évoquer des réponses cohérentes est également évaluée par rapport aux variations de paramètres. Une méthodologie pour la conception optimisée des signaux de stimulation est proposée en utilisant un modèle de calcul simple, représentant les relations d'entrée-sortie entre les paramètres de stimulation et les réponses qu'ils évoquent. Ce modèle utilise une approche de réseau neuronal artificiel et peut être utilisé pour prédire les propriétés de la réponse lorsque les paramètres du stimulus sont connus. Compte tenu de la prévalence de la stimulation cérébrale dans les applications cliniques, de recherche et thérapeutiques, les procédures méthodologiques et de modélisation proposées ont des implications importantes dans l'optimisation des paradigmes de stimulation actuels et le développement de protocoles de stimulation pour de nouvelles applications. ----------ABSTRACT Microstimulation of brain tissue plays a key role in a variety of sensory prosthetics, clinical therapies and research applications. At present, stimulus parameters are tailored to each application via iterative testing. Computational optimization methods seek to improve tried and tested waveforms developed for specific purposes, however the fundamental understanding of how stimulation parameters influence the neural circuits they activate remains widely unknown. This deficit hinders both the optimization of existing protocols and the development of new stimulation applications. To date, a number of prosthetic devices validated as early as the 1970’s linger in the development stages largely due to the inability to effectively interface these devices with the brain. In order to use electrical stimulation to convey messages to the central nervous system, a better understanding of stimulus signal design is required. In this thesis, I investigate the influence that each parameter of the constant-current, symmetric, biphasic square waveform exerts on the responses it evokes through intracortical microstimulation of the caudal forelimb area of the rat motor cortex. The parameters under investigation include the current amplitude, pulse frequency, pulse duration, interphase interval and train duration of the stimulus and effects were assessed by examining the electromyographic responses evoked in the rat forelimb muscles in response to each stimulus. The major findings describe how each parameter of the stimulus signal influences the magnitude, onset latency, and duration of the response. A previously unexplored component of the response signal (which we called ‘residual activation’) is analyzed for the first time. Hypotheses as to the origin and underlying neural mechanism of this phenomenon are proposed and the stimulus parameters affecting its occurrence, prevalence and duration are described. The reliability of stimulation signals for evoking consistent responses is also assessed with respect to parameter variations. A methodology for the informed design of stimulation signals is proposed and aided by the development of a simple computational model representing the input-output relationships between stimulation parameters and the responses they evoke. This model uses an artificial neural network approach and can be used to predict the properties of the response when the parameters of the stimulus are known. Given the prevalence of brain stimulation in clinical, research and therapeutic applications the proposed methodological and modeling procedures have important implications in the optimization of current stimulation paradigms and the development of stimulation protocols for new applications

The duration of motor responses evoked with intracortical microstimulation in rats is primarily modulated by stimulus amplitude and train duration

Microstimulation of brain tissue plays a key role in a variety of sensory prosthetics, clinical therapies and research applications, however the effects of stimulation parameters on the responses they evoke remain widely unknown. In particular, the effects of parameters when delivered in the form of a stimulus train as opposed to a single pulse are not well understood despite the prevalence of stimulus train use. We aimed to investigate the contribution of each parameter of a stimulus train to the duration of the motor responses they evoke in forelimb muscles. We used constant-current, biphasic, square wave pulse trains in acute terminal experiments under ketamine anaesthesia. Stimulation parameters were systematically tested in a pair-wise fashion in the caudal forelimb region of the motor cortex in 7 Sprague-Dawley rats while motor evoked potential (MEP) recordings from the forelimb were used to quantify the influence of each parameter in the train. Stimulus amplitude and train duration were shown to be the dominant parameters responsible for increasing the total duration of the MEP, while interphase interval had no effect. Increasing stimulus frequency from 100200 Hz or pulse duration from 0.18-0.34 ms were also effective methods of extending response durations. Response duration was strongly correlated with peak time and amplitude. Our findings suggest that motor cortex intracortical microstimulations are often conducted at a higher frequency rate and longer train duration than necessary to evoke maximal response duration. We demonstrated that the temporal properties of the evoked response can be both predicted by certain response metrics and modulated via alterations to the stimulation signal parameters

China neemt (Volvo) over

De gebeurtenissen sinds de overname van Volvo Cars door het Chinese Geely in 2010 tarten soms de verbeelding, alleszins voor de gemiddelde leek. In dit artikel zal worden aangetoond dat de Chinezen echter een zeer doordachte strategie gebruiken om hun geopolitieke en –economische doelen te verwezenlijken

The stochastic modelling of kleptoparasitism using a Markov process

Kleptoparasitism, the stealing of food items from other animals, is a common behaviour observed across a huge variety of species, and has been subjected to significant modelling effort. Most such modelling has been deterministic, effectively assuming an infinite population, although recently some important stochastic models have been developed. In particular the model of Yates and Broom (Stochastic models of kleptoparasitism. J. Theor. Biol. 248 (2007), 480–489) introduced a stochastic version following the original model of Ruxton and Moody (The ideal free distribution with kleptoparasitism. J. Theor. Biol. 186 (1997), 449–458), and whilst they generated results of interest, they did not solve the model explicitly. In this paper, building on methods used already by van der Meer and Smallegange (A stochastic version of the Beddington-DeAngelis functional response: Modelling interference for a finite number of predators. J. Animal Ecol. 78 (2009) 134–142) we give an exact solution to the distribution of the population over the states for the Yates and Broom model and investigate the effects of some key biological parameters, especially for small populations where stochastic models can be expected to differ most from their deterministic equivalents

Expression analysis of the mouse S100A7/psoriasin gene in skin inflammation and mammary tumorigenesis

BACKGROUND: The human psoriasin (S100A7) gene has been implicated in inflammation and tumor progression. Implementation of a mouse model would facilitate further investigation of its function, however little is known of the murine psoriasin gene. In this study we have cloned the cDNA and characterized the expression of the potential murine ortholog of human S100A7/psoriasin in skin inflammation and mammary tumorigenesis. METHODS: On the basis of chromosomal location, phylogenetic analysis, amino acid sequence similarity, conservation of a putative Jab1-binding motif, and similarities of the patterns of mouse S100A7/psoriasin gene expression (measured by RT-PCR and in-situ hybridization) with those of human S100A7/psoriasin, we propose that mouse S100A7/psoriasin is the murine ortholog of human psoriasin/S100A7. RESULTS: Although mouse S100A7/psoriasin is poorly conserved relative to other S100 family members, its pattern of expression parallels that of the human psoriasin gene. In murine skin S100A7/psoriasin was significantly upregulated in relation to inflammation. In murine mammary gland expression is also upregulated in mammary tumors, where it is localized to areas of squamous differentiation. This mirrors the context of expression in human tumor types where both squamous and glandular differentiation occur, including cervical and lung carcinomas. Additionally, mouse S100A7/psoriasin possesses a putative Jab1 binding motif that mediates many downstream functions of the human S100A7 gene. CONCLUSION: These observations and results support the hypothesis that the mouse S100A7 gene is structurally and functionally similar to human S100A7 and may offer a relevant model system for studying its normal biological function and putative role in tumor progression

Randomized trial of achieving healthy lifestyles in psychiatric rehabilitation: the ACHIEVE trial

<p>Abstract</p> <p>Background</p> <p>Overweight and obesity are highly prevalent among persons with serious mental illness. These conditions likely contribute to premature cardiovascular disease and a 20 to 30 percent shortened life expectancy in this vulnerable population. Persons with serious mental illness need effective, appropriately tailored behavioral interventions to achieve and maintain weight loss. Psychiatric rehabilitation day programs provide logical intervention settings because mental health consumers often attend regularly and exercise can take place on-site. This paper describes the Randomized Trial of Achieving Healthy Lifestyles in Psychiatric Rehabilitation (ACHIEVE). The goal of the study is to determine the effectiveness of a behavioral weight loss intervention among persons with serious mental illness that attend psychiatric rehabilitation programs. Participants randomized to the intervention arm of the study are hypothesized to have greater weight loss than the control group.</p> <p>Methods/Design</p> <p>A targeted 320 men and women with serious mental illness and overweight or obesity (body mass index ≥ 25.0 kg/m²) will be recruited from 10 psychiatric rehabilitation programs across Maryland. The core design is a randomized, two-arm, parallel, multi-site clinical trial to compare the effectiveness of an 18-month behavioral weight loss intervention to usual care. Active intervention participants receive weight management sessions and physical activity classes on-site led by study interventionists. The intervention incorporates cognitive adaptations for persons with serious mental illness attending psychiatric rehabilitation programs. The initial intensive intervention period is six months, followed by a twelve-month maintenance period in which trained rehabilitation program staff assume responsibility for delivering parts of the intervention. Primary outcomes are weight loss at six and 18 months.</p> <p>Discussion</p> <p>Evidence-based approaches to the high burden of obesity and cardiovascular disease risk in person with serious mental illness are urgently needed. The ACHIEVE Trial is tailored to persons with serious mental illness in community settings. This multi-site randomized clinical trial will provide a rigorous evaluation of a practical behavioral intervention designed to accomplish and sustain weight loss in persons with serious mental illness.</p> <p>Trial Registration</p> <p>Clinical Trials.gov NCT00902694</p

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo