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

Sulforaphane Decreases Ezh2 Expression in PC3 Prostate Cancer Cells

Prostate cancer is one of the most prevalent types of cancer in the U.S. and is among the leading causes of death in men of all races. One predictor of advanced prostate cancer and aggressive tumor behavior is the overexpression of the histone methyl transferase EZH2. EZH2 functions in the nucleus by catalyzing the tri-methylation of histone H3 lysine 27 (H3K27) and mediates the silencing of target genes involved in essential cellular processes such as cell cycle regulation and cell identity. While EZH2 is also found in the cytoplasm of advanced cancer cells, its function here is not yet well understood. In the context of prostate cancer, dysregulated EZH2 represses the transcription of the tumor suppressor genes promoting tumor cell proliferation. Inhibition of EZH2 has been found to block prostate cancer cell growth, making EZH2 and valuable target for cancer therapy. Epidemiological data suggests that eating cruciferous vegetables such as broccoli and cauliflower lowers risk of prostate cancer. It has been hypothesized that sulforaphane—a bioactive compound found in cruciferous vegetables—decreases prostate cancer cell proliferation. However, the mechanism by which sulforaphane exerts its effect is still under investigation. In other cancer cell types, treatment with sulforaphane has been found to decrease EZH2 levels in cells. The purpose of this study is to determine the effect of SFN on EZH2 expression in prostate cancer cells and identify potential mechanisms for the control of EZH2. To answer these questions we looked at PC3 prostate cancer cells—a cancer line derived from human advanced malignant androgen-independent prostate tumor. PC3 cells were treated with 15mM sulforaphane or left untreated. Our study found that sulforaphane treatment caused a decrease in EZH2 expression compared to untreated cells. In contrast, sulforaphane treatment had no effect on H3K27me3 levels. It was also determined that the decrease in EZH2 expression was due to a decrease in cytoplasmic EZH2 leaving nuclear EZH2 largely unaffected

Sulforaphane Decreases Ezh2 Expression in PC3 Prostate Cancer Cells

Prostate cancer is one of the most prevalent types of cancer in the U.S. and is among the leading causes of death in men of all races. One predictor of advanced prostate cancer and aggressive tumor behavior is the overexpression of the histone methyl transferase EZH2. EZH2 functions in the nucleus by catalyzing the tri-methylation of histone H3 lysine 27 (H3K27) and mediates the silencing of target genes involved in essential cellular processes such as cell cycle regulation and cell identity. While EZH2 is also found in the cytoplasm of advanced cancer cells, its function here is not yet well understood. In the context of prostate cancer, dysregulated EZH2 represses the transcription of the tumor suppressor genes promoting tumor cell proliferation. Inhibition of EZH2 has been found to block prostate cancer cell growth, making EZH2 and valuable target for cancer therapy. Epidemiological data suggests that eating cruciferous vegetables such as broccoli and cauliflower lowers risk of prostate cancer. It has been hypothesized that sulforaphane—a bioactive compound found in cruciferous vegetables—decreases prostate cancer cell proliferation. However, the mechanism by which sulforaphane exerts its effect is still under investigation. In other cancer cell types, treatment with sulforaphane has been found to decrease EZH2 levels in cells. The purpose of this study is to determine the effect of SFN on EZH2 expression in prostate cancer cells and identify potential mechanisms for the control of EZH2. To answer these questions we looked at PC3 prostate cancer cells—a cancer line derived from human advanced malignant androgen-independent prostate tumor. PC3 cells were treated with 15mM sulforaphane or left untreated. Our study found that sulforaphane treatment caused a decrease in EZH2 expression compared to untreated cells. In contrast, sulforaphane treatment had no effect on H3K27me3 levels. It was also determined that the decrease in EZH2 expression was due to a decrease in cytoplasmic EZH2 leaving nuclear EZH2 largely unaffected

Editorial

Editorial for the April 2023 issue

Design and methods of the Longitudinal Eating Disorders Assessment Project research consortium for veterans

Introduction Military service members must maintain a certain body mass index and body fat percentage. Due to weight-loss pressures, some service members may resort to unhealthy behaviors that place them at risk for the development of an eating disorder (ED). Objectives To understand the scope and impact of EDs in military service members and veterans, we formed the Longitudinal Eating Disorders Assessment Project (LEAP) Consortium. LEAP aims to develop novel screening, assessment, classification, and treatment tools for veterans and military members with a focus on EDs and internalizing psychopathology. Methods We recruited two independent nationally representative samples of post-9/11 veterans who were separated from service within the past year. Study 1 was a four-wave longitudinal survey and Study 2 was a mixed-methods study that included surveys, structured-clinical interviews, and qualitative interviews. Results Recruitment samples were representative of the full population of recently separated veterans. Sample weights were created to adjust for sources of non-response bias to the baseline survey. Attrition was low relative to past studies of this population, with only (younger) age predicting attrition at 1-week follow-up. Conclusions We expect that the LEAP Consortium data will contribute to improved information about EDs in veterans, a serious and understudied problem

Annulment of Oil Licences in Nigeria’s Upstream Petroleum Sector: A Legal Critique of the Costs and Benefits

Owing to various reasons, tenable and untenable, successive governments in Nigeria have annulled licenses duly granted to identifiable upstream petroleum operators. With due sense of circumspect, when irregularities manifest in the process and the grant of substantive licences, such does not vest in the government an unfettered right to annul the licence. There are evidences of such occurrence in spite of established procedures regulating annulments, commonly referred to as revocation or cancellation. This paper is a critique of the annulment of oil licenses and the associated contractualregulatory dimensions. The validity of the Federal Government’s actions also comes to the fore, particularly in the light of renewed drive to attract investments into the upstream sector. Thus, as some benefits are accruable to the players, it is also important to appraise the consequential costs attributable to undue annulment of oil licenses. The paper adopts a descriptive analytical method of available facts, expounds requisite statutory provisions and utilizes judicial precedents to highlight the context of the study. It is imperative that the Federal Government adheres to established procedures on oil license annulment, as a contrary posture will amount to several negative outcomes

IL7 genetic variation and toxicity to immune checkpoint blockade in patients with melanoma

Treatment with immune checkpoint blockade (ICB) frequently triggers immune-related adverse events (irAEs), causing considerable morbidity. In 214 patients receiving ICB for melanoma, we observed increased severe irAE risk in minor allele carriers of rs16906115, intronic to IL7. We found that rs16906115 forms a B cell-specific expression quantitative trait locus (eQTL) to IL7 in patients. Patients carrying the risk allele demonstrate increased pre-treatment B cell IL7 expression, which independently associates with irAE risk, divergent immunoglobulin expression and more B cell receptor mutations. Consistent with the role of IL-7 in T cell development, risk allele carriers have distinct ICB-induced CD8+ T cell subset responses, skewing of T cell clonality and greater proportional repertoire occupancy by large clones. Finally, analysis of TCGA data suggests that risk allele carriers independently have improved melanoma survival. These observations highlight key roles for B cells and IL-7 in both ICB response and toxicity and clinical outcomes in melanoma

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

The Utilization of Data Analysis Techniques in Predicting Student Performance in Massive Open Online Courses (MOOCs)

The growth of the Internet has enabled the popularity of open online learning platforms to increase over the years. This has led to the inception of Massive Open Online Courses (MOOCs) that enrol, millions of people, from all over the world. Such courses operate under the concept of open learning, where content does not have to be delivered via standard mechanisms that institutions employ, such as physically attending lectures. Instead learning occurs online via recorded lecture material and online tasks. This shift has allowed more people to gain access to education, regardless of their learning background. However, despite these advancements in delivering education, completion rates for MOOCs are low. In order to investigate this issue, the paper explores the impact that technology has on open learning and identifies how data about student performance can be captured to predict trend so that at risk students can be identified before they drop-out. In achieving this, subjects surrounding student engagement and performance in MOOCs and data analysis techniques are explored to investigate how technology can be used to address this issue. The paper is then concluded with our approach of predicting behaviour and a case study of the eRegister system, which has been developed to capture and analyse data. Keywords: Open Learning; Prediction; Data Mining; Educational Systems; Massive Open Online Course; Data Analysi