Towards dynamical network biomarkers in neuromodulation of episodic migraine

Computational methods have complemented experimental and clinical neursciences and led to improvements in our understanding of the nervous systems in health and disease. In parallel, neuromodulation in form of electric and magnetic stimulation is gaining increasing acceptance in chronic and intractable diseases. In this paper, we firstly explore the relevant state of the art in fusion of both developments towards translational computational neuroscience. Then, we propose a strategy to employ the new theoretical concept of dynamical network biomarkers (DNB) in episodic manifestations of chronic disorders. In particular, as a first example, we introduce the use of computational models in migraine and illustrate on the basis of this example the potential of DNB as early-warning signals for neuromodulation in episodic migraine.Comment: 13 pages, 5 figure

Integrated Research Plan to Assess the Combined Effects of Space Radiation, Altered Gravity, and Isolation and Confinement on Crew Health and Performance: Problem Statement

Future crewed exploration missions to Mars could last up to three years and will expose astronauts to unprecedented environmental challenges. Challenges to the nervous system during these missions will include factors of: space radiation that can damage sensitive neurons in the central nervous system (CNS); isolation and confinement can affect cognition and behavior; and altered gravity that will change the astronauts perception of their environment and their spatial orientation, and will affect their coordination, balance, and locomotion. In the past, effects of spaceflight stressors have been characterized individually. However, long-term, simultaneous exposure to multiple stressors will produce a range of interrelated behavioral and biological effects that have the potential to adversely affect operationally relevant crew performance. These complex environmental challenges might interact synergistically and increase the overall risk to the health and performance of the astronaut. Therefore, NASAs Human Research Program (HRP) has directed an integrated approach to characterize and mitigate the risk to the CNS from simultaneous exposure to these multiple spaceflight factors. The proposed research strategy focuses on systematically evaluating the relationships among three existing research risks associated with spaceflight: Risk of Acute (In-flight) and Late Central Nervous System Effects from Radiation (CNS), Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders (BMed), and Risk of Impaired Control of Spacecraft/Associated Systems and Decreased Mobility Due to Vestibular/Sensorimotor Alterations Associated with Spaceflight (SM). NASAs HRP approach is intended to identify the magnitude and types of interactions as they affect behavior, especially as it relates to operationally relevant performance (e.g., performance that depends on reaction time, procedural memory, etc.). In order to appropriately characterize this risk of multiple spaceflight environmental stressors, there is a recognition of the need to leverage research approaches using appropriate animal models and behavioral constructs. Very little has been documented on the combined effects of altered gravity, space radiation, and other psychological and cognitive stressors on the CNS. Preliminary evidence from rodents suggest that a combination of a minimum of exposures to even two of three stressors of: simulated space radiation, simulated microgravity, and simulated isolation and confinement, have produced different and more pronounced biological and performance effects than exposure to these same stressors individually. Structural and functional changes to the CNS of rodents exposed to transdisciplinary combined stressors indicate that important processes related to information processing are likely altered including impairment of exploratory and risk taking behaviors, as well as executive function including learning, memory, and cognitive flexibility all of which may be linked to changes in related operational relevant performance. The fully integrated research plan outlines approaches to evaluate how combined, potentially synergistic, impacts of simultaneous exposures to spaceflight hazards will affect an astronauts CNS and their operationally relevant performance during future exploration missions, including missions to the Moon and Mars. The ultimate goals are to derive risk estimates for the combined, potentially synergistic, effects of the three major spaceflight hazards that will establish acceptable maximum decrement or change in a physiological or behavioral parameters during or after spaceflight, the acceptable limit of exposure to a spaceflight factor, and to evaluate strategies to mitigate any associated decrements in operationally relevant performance

Spontaneous transitions to focal-onset epileptic seizures: A dynamical study

Given the complex temporal evolution of epileptic seizures, understanding their dynamic nature might be beneficial for clinical diagnosis and treatment. Yet, the mechanisms behind, for instance, the onset of seizures are still unknown. According to an existing classification, two basic types of dynamic onset patterns plus a number of more complex onset waveforms can be distinguished. Here, we introduce a basic three-variable model with two time scales to study potential mechanisms of spontaneous seizure onset. We expand the model to demonstrate how coupling of oscillators leads to more complex seizure onset waveforms. Finally, we test the response to pulse perturbation as a potential biomarker of interictal changes. Focal epileptic seizures are characterized by complex spatiotemporal rhythms of electric brain activity. Phenomenologically, there are different types of rhythms, namely, fast-small oscillations, slow-large spiking, and complex waveforms of the voltage. The dynamics of these types are, however, still poorly understood and their clinical characterization is, therefore, mostly descriptive. We use computational modeling of macro-level electrical brain activity to study the spontaneous onset and evolution of major clinical seizure rhythms. Looking at principal models of one and two coupled oscillators with a slow driving population, we show the dynamical characteristics and relationships between basic seizure onset types. In addition, we show that pulse perturbations of background activity can serve as a biomarker for seizure onset

Network resilience

Many systems on our planet are known to shift abruptly and irreversibly from one state to another when they are forced across a "tipping point," such as mass extinctions in ecological networks, cascading failures in infrastructure systems, and social convention changes in human and animal networks. Such a regime shift demonstrates a system's resilience that characterizes the ability of a system to adjust its activity to retain its basic functionality in the face of internal disturbances or external environmental changes. In the past 50 years, attention was almost exclusively given to low dimensional systems and calibration of their resilience functions and indicators of early warning signals without considerations for the interactions between the components. Only in recent years, taking advantages of the network theory and lavish real data sets, network scientists have directed their interest to the real-world complex networked multidimensional systems and their resilience function and early warning indicators. This report is devoted to a comprehensive review of resilience function and regime shift of complex systems in different domains, such as ecology, biology, social systems and infrastructure. We cover the related research about empirical observations, experimental studies, mathematical modeling, and theoretical analysis. We also discuss some ambiguous definitions, such as robustness, resilience, and stability.Comment: Review chapter

Improving outcomes in interstitial lung disease through the application of bioinformatics and systems biology

Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are two distinct respiratory diseases whose features including pathogenesis and progression are not fully understood. However, both clinicians utilise changes in serial pulmonary function measurements to gain an insight into disease severity and control. More accurate prediction of disease progression would be beneficial, particularly for IPF given the variability in its clinical course as an unknown factor at the time of diagnosis. Home-based, real-time monitoring of disease progression by spirometry has provided an opportunity to optimise the delivery of treatment and reduce the length of clinical trials. Therefore, the potential to understand the mechanisms underlying disease progression and generate effective treatment has been improved. In light of this, the motivation for this project is to understand the mathematical features within daily pulmonary function time series generated by IPF patients. Hopefully, statistical models of pulmonary function time series would aid the identification of significant clinical events such as acute exacerbation. The mathematical techniques used to identify potentially important features within pulmonary function time series involved the autocorrelation function, critical transitions and detrended fluctuation analysis (DFA). Temporal properties, such as the serial correlation, abrupt changes in trends and complexity, were assessed using time series from the PROFILE clinical trial and London COPD cohort. Forced vital capacity (FVC) measurements were found to be correlated to the previous day’s reading which may inform the sampling rate of lung function during clinical trials. The presence of short-term memory within FVC time series will influence the management of missing data within clinical trials, particularly methods of imputation. Also, FVC time series’ exhibit long-term memory and adaptability supporting the role of FVC as a surrogate marker for IPF disease progression.Open Acces

Transcriptomic Data Analyses Reveal a Reprogramed Lipid Metabolism in HCV-Derived Hepatocellular Cancer

Reprograming lipid metabolism, one of the major metabolic alterations in cancer, is believed to play an essential role in cancer development, but the exact molecular mechanism remains elusive. Here, we present a computational study of transcriptomic data of HCC with HCV etiology to investigate how lipid metabolism alters during HCC progression. Our analyses reveal that: (1) cancer tissue cells tend to synthesize fatty acids de novo and its phospholipid derivatives; (2) lipid catabolism and fatty acid oxidation are remarkably down-regulated in HCC; (3) the lipid metabolism in HCC is largely independent of lipids in blood circulation; (4) stage-specific co-expression networks for lipid metabolic genes were identified during HCC progression; and (5) the expression levels of several lipid metabolic genes that are differentially expressed or co-expressed specifically at the HCC stage have a strong correlation with cancer survival. Overall, the results provide detailed information about the reprogramed lipid metabolism in HCV-derived HCC. © Copyright © 2020 Liu, Liu, Cui and Xu.This work was supported by grants from the Inner Mongolia Natural Science Foundation of China (2018LH03023) and the Science Foundation for Excellent Youth Scholars of Inner Mongolia University of Science and Technology (2016YQL06)

Topics in perturbation analysis for stochastic hybrid systems

Control and optimization of Stochastic Hybrid Systems (SHS) constitute increasingly active fields of research. However, the size and complexity of SHS frequently render the use of exhaustive verification techniques prohibitive. In this context, Perturbation Analysis techniques, and in particular Infinitesimal Perturbation Analysis (IPA), have proven to be particularly useful for this class of systems. This work focuses on applying IPA to two different problems: Traffic Light Control (TLC) and control of cancer progression, both of which are viewed as dynamic optimization problems in an SHS environment. The first part of this thesis addresses the TLC problem for a single intersection modeled as a SHS. A quasi-dynamic control policy is proposed based on partial state information defined by detecting whether vehicle backlogs are above or below certain controllable threshold values. At first, the threshold parameters are controlled while assuming fixed cycle lengths and online gradient estimates of a cost metric with respect to these controllable parameters are derived using IPA techniques. These estimators are subsequently used to iteratively adjust the threshold values so as to improve overall system performance. This quasi-dynamic analysis of the TLC\ problem is subsequently extended to parameterize the control policy by green and red cycle lengths as well as queue content thresholds. IPA estimators necessary to simultaneously control the light cycles and thresholds are rederived and thereafter incorporated into a standard gradient based scheme in order to further ameliorate system performance. In the second part of this thesis, the problem of controlling cancer progression is formulated within a Stochastic Hybrid Automaton (SHA) framework. Leveraging the fact that cell-biologic changes necessary for cancer development may be schematized as a series of discrete steps, an integrative closed-loop framework is proposed for describing the progressive development of cancer and determining optimal personalized therapies. First, the problem of cancer heterogeneity is addressed through a novel Mixed Integer Linear Programming (MILP) formulation that integrates somatic mutation and gene expression data to infer the temporal sequence of events from cross-sectional data. This formulation is tested using both simulated data and real breast cancer data with matched somatic mutation and gene expression measurements from The Cancer Genome Atlas (TCGA). Second, the use of basic IPA techniques for optimal personalized cancer therapy design is introduced and a methodology applicable to stochastic models of cancer progression is developed. A case study of optimal therapy design for advanced prostate cancer is performed. Given the importance of accurate modeling in conjunction with optimal therapy design, an ensuing analysis is performed in which sensitivity estimates with respect to several model parameters are evaluated and critical parameters are identified. Finally, the tradeoff between system optimality and robustness (or, equivalently, fragility) is explored so as to generate valuable insights on modeling and control of cancer progression

Computational methods toward early detection of neuronal deterioration

In today's world, because of developments in medical sciences, people are living longer, particularly in the advanced countries. This increasing of the lifespan has caused the prevalence of age-related diseases like Alzheimer’s and dementia. Researches show that ion channel disruptions, especially the formation of permeable pores to cations by Aβ plaques, play an important role in the occurrence of these types of diseases. Therefore, early detection of such diseases, particularly using non-invasive tools can aid both patients and those scientists searching for a cure. To achieve the goal toward early detection, the computational analysis of ion channels, ion imbalances in the presence of Aβ pores in neurons and fault detection is done. Any disruption in the membrane of the neuron, like the formation of permeable pores to cations by Aβ plaques, causes ionic imbalance and, as a result, faults occur in the signalling of the neuron.The first part of this research concentrates on ion channels, ion imbalances and their impacts on the signalling behaviour of the neuron. This includes investigating the role of Aβ channels in the development of neurodegenerative diseases. Results revealed that these types of diseases can lead to ionic imbalances in the neuron. Ion imbalances can change the behaviour of neuronal signalling. Therefore, by identifying the pattern of these changes, the disease can be detected in the very early stages. Then the role of coupling and synchronisation effects in such diseases were studied. After that, a novel method to define minimum requirements for synchronicity between two coupled neurons is proposed. Further, a new computational model of Aβ channels is proposed and developed which mimics the behaviour of a neuron in the course of Alzheimer's disease. Finally, both fault computation and disease detection are carried out using a residual generation method, where the residuals from two observers are compared to assess their performance