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Skeldon, A. C.

Publications and source records attributed to Skeldon, A. C..

6 recordsLinked to original sources

The two-process model: How simple, complex, unique is it from a mathematical perspective?

The two-process model (2pm) of sleep regulation is a conceptual framework and consists of mathematical equations. It shares similarities with models for cardiac, respiratory and neuronal rhythms and falls within the wider class of coupled oscillator models. The 2pm is related to neuronal mutual inhibition models of sleep-wake regulation. The mathematical structure of the 2pm, in which the sleep-wake cycle is entrained to the circadian pacemaker, explains sleep patterns in the absence of 24-h time cues, in different species and in early childhood. Extending the 2pm with a process describing the response of the circadian pacemaker to light creates a hierarchical entrainment system with feedback which permits quantitative modelling of the effect of self-selected light on sleep and circadian timing. The extended 2pm provides new interpretations of sleep phenotypes and provides quantitative predictions of effects of sleep and light interventions to support sleep and circadian alignment in individuals, including those with neurodegenerative disorders.

neuroscience↗

Using compartmental models to understand excitation-inhibition imbalance in epilepsy

Epileptic seizures are characterized by abnormal synchronous bursting of neurons. This is commonly attributed to an imbalance between excitatory and inhibitory neurotransmission. We introduce compartmental models from epidemiology to study this interaction between excitatory and inhibitory populations of neurons in the context of epilepsy. Neurons could either be bursting or susceptible, and the propagation of action potentials within the brain through the bursting of neurons is considered as an infection spreading through a population. We model the recruitment of neurons into bursting and their subsequent decay to susceptibility to be influenced by the proportion of excitatory and inhibitory neurons bursting, resulting in a two population Susceptible - Infected - Susceptible (SIS) model. This approach provides a tractable framework to inspect the mechanisms behind seizure generation and termination. Considering the excitatory neurotransmission as an epidemic spreading through the neuronal population and the inhibitory neurotransmission as a competing epidemic that stops the spread of excitation, we establish the conditions for a seizure-like state to be stable. Subsequently, we show how an activity-dependent dysfunction of inhibitory mechanisms such as impaired GABAergic inhibition or inhibitory-inhibitory interactions could result in a seizure even when the above conditions are not satisfied.

neuroscience↗

Model integration of circadian and sleep-wake driven contributions to rhythmic gene expression reveals novel regulatory principles

Transcriptome studies aim at gaining insight into the molecular pathways underlying biological processes. Analyses of gene-expression dynamics in research on circadian rhythms and sleep homeostasis describe these two processes independently, using separate models such as sinusoidal oscillations and exponential saturating functions. Rhythmically expressed genes are, however, influenced by both processes. We therefore implemented a driven, damped harmonic oscillator model which can accommodate both types of dynamics by varying the degree of damping. This makes it possible to estimate the contribution of circadian and sleep-wake driven influences on the expression of a gene within the framework of a single model. We applied the model to cortex, liver, and blood data obtained in mice and humans. The model reliably captured a wide range of rhythmic dynamics under various experimental conditions, including the long-term amplitude reduction of cortical clock-gene rhythms observed after sleep deprivation. Cortical gene expression was generally influenced more by sleep-wake driven than circadian factors, while the opposite was observed in liver and blood. Importantly, the model suggested that sleep-wake state can alter gene expression with a delayed, long-lasting response not previously considered. Our model further predicted that, perhaps paradoxically, the gain in sleep time after sleep deprivation, delayed re-establishing baseline expression rhythms of intrinsically oscillatory transcripts indicating that similar to insufficient sleep, also excess sleep can impact rhythmic gene expression. Because of the tissue- and gene-specific responses, sleep deprivation led to a profound intra- and inter-tissue desynchronization which in the cortex lasted well beyond phenotypic sleep-wake recovery. The results demonstrate that analyzing rhythmic gene expression must take the complex interactions between circadian and sleep-wake influences into account. The model is a versatile tool with a low number of free parameters to fit and predict gene expression under a variety of conditions relevant to society.

systems biology↗

Mathematical analysis of light-sensitivity related challenges in assessment of the intrinsic period of the human circadian pacemaker

Accurate assessment of the intrinsic period of the human circadian pacemaker is essential for a quantitative understanding of how our circadian rhythms are synchronised to exposure to natural and man-made light-dark cycles. The gold standard method for assessing intrinsic period in humans is forced desynchrony (FD) which assumes that the confounding effect of light on assessment of intrinsic period is removed by scheduling sleep-wake and associated dim light-dark (LD) cycles to periods outside the range of entrainment of the circadian pacemaker. However, the observation that the mean period of free-running blind people is longer than the mean period of sighted people assessed by FD (24.50 {+/-} 0.17 h versus 24.15 {+/-} 0.20 h, p < 0.001) appears inconsistent with this assertion. Here, we present a mathematical analysis using a simple parametric model of the circadian pacemaker with a sinusoidal velocity response curve (VRC) describing the effect of light on the speed of the oscillator. The analysis shows that the shorter period in FD may be explained by exquisite sensitivity of the human circadian pacemaker to low light intensities and a VRC with a larger advance region than delay region. The main implication of this analysis, which generates new and testable predictions, is that current quantitative models for predicting how light exposure affects entrainment of the human circadian system may not accurately capture the effect of dim light. The mathematical analysis generates new predictions which can be tested in laboratory experiments. These findings have implications for managing healthy entrainment of human circadian clocks in societies with abundant access to light sources with powerful biological effects.

neuroscience↗

Method to determine whether sleep phenotypes are driven by endogenous circadian rhythmicity or environmental light by combining longitudinal data and personalised mathematical models

Sleep timing varies between individuals and can be altered in mental and physical health conditions. Sleep and circadian sleep phenotypes, including circadian rhythm sleep-wake disorders, may be driven by endogenous physiological processes, exogeneous environmental light exposure along with social constraints and behavioural factors. Identifying the relative contributions of these driving factors to different phenotypes is essential for the design of personalised interventions. The timing of the human sleep-wake cycle has been modelled as an interaction of a relaxation oscillator (the sleep homeostat), a stable limit cycle oscillator with a near 24-hour period (the circadian process), man-made light exposure and the natural light-dark cycle generated by the Earths rotation. However, these models have rarely been used to quantitatively describe sleep at the individual level. Here, we present a new Homeostatic-Circadian-Light model (HCL) which is simpler, more transparent and more computationally efficient than other available models and is designed to run using longitudinal sleep and light exposure data from wearable sensors. We carry out a systematic sensitivity analysis for all model parameters and discuss parameter identifiability. We demonstrate that individual sleep phenotypes in each of 34 older participants (65-83y) can be described by feeding individual participant light exposure patterns into the model and fitting two parameters that capture individual average sleep duration and timing. The fitted parameters describe endogenous drivers of sleep phenotypes. We then quantify exogenous drivers using a novel metric which encodes the circadian phase dependence of the response to light. Combining endogenous and exogeneous drivers better explains individual mean mid-sleep (adjusted R-squared 0.64) than either driver on its own (adjusted R-squared 0.08 and 0.17 respectively). Critically, our model and analysis highlights that different people exhibiting the same sleep phenotype may have different driving factors and opens the door to personalised interventions to regularize sleep-wake timing that are readily implementable with current digital health technology. Author summaryDisrupted sleep has long term health consequences and affects our day-to-day ability to function physically, mentally and emotionally. But what determines when and how long we sleep? It is well-known that daily light exposure patterns determine the timing of the body clock. However, creating mathematical models that can take realistic light exposure patterns and predict plausible sleep timing has been challenging. Furthermore, nearly all previous studies have focused on developing models for average behaviour, yet sleep timing and duration are highly individual. In this paper, we present a simple model that combines sleep regulatory and circadian processes. The model can take individual light exposure patterns and, by fitting physiologically plausible parameters, describe individual mean sleep timing and duration. We test our model on data collected from 34 older participants. Our modelling approach suggests that some of the participants slept late because of physiological factors, while for other individuals, late sleep was a consequence of their light environment. This approach of combining a model with longitudinal data could be implemented in digital health technology such that your smart watch could tell you not only how you slept last night, but also how to change your light environment to sleep better tomorrow.

neuroscience↗

Fatigue, Alertness and Risk Prediction for Shift Workers

Executive summaryO_LIThis report describes the principal outcomes of an Impact Acceleration Account project (grant number EP/I000992/1) between the University of Surrey and Transport for London carried out between Oct. 2019 and Mar. 2020. C_LIO_LIThe aim of the project was to compare the Health and Safety Executive (HSE) Fatigue Risk tool with SAFTE and other more recent models of fatigue, where fatigue here primarily means a reduced ability to function effectively and efficiently as a result of inadequate sleep. C_LIO_LIWe have not sought to discuss the useability of the HSE Fatigue Risk tool or SAFTE since this has been discussed comprehensively elsewhere (e.g. [1, 2]). We have instead focussed on the fundamental principles underlying the models. C_LIO_LIAll current biomathematical models have limitations and make asumptions that are not always evident from the accompanying documentation. Since full details of the HSE Fatigue Risk tool and the SAFTE model are not publicly available, Sections 1 and 2 give a mathematical description of the equations that we believe underlie each of these models. C_LIO_LIA comparison of predictions made by our versions of the HSE and SAFTE equations for one particular shift schedule of relevance to the UK and global tunnelling and construction industries is shown in Section 3. In this comparison, we use data collected durings TfLs Crossrail project by Dragados1. Essentially, both models give broadly the same message for the schedule we looked at, but the ability to display fatigue as it develops within a shift is a strength of SAFTE. C_LIO_LIA summary of the strengths and limitations of the use of these kind of scheduling tools is given in the final Section 4. Limitations include: O_LIModels do not describe fatigue during times when people are not in shift (e.g. driving home). However, they could readily be extended to do so. C_LIO_LIModels assume people start well-rested. This is not always a good assumption and can lead to an under-estimate of fatigue. C_LIO_LIMost models are currently based on population averages, but there are large individual different. It would be possible to further develop models to include uncertainty in fatigue predictions associated with individual differences. C_LIO_LIFew mdels include the light environment, which is important both to promote short-term alertness and facilitate circadian alignment. C_LIO_LIModels are not transparent, which makes them hard to independently validate. C_LIO_LIIt is hard to relate the outputs of current models to measureable outcomes in the field. C_LI C_LIO_LIWe also discuss briefly recent developments in mathematical modelling of fatigue and possible future directions. These include O_LIGuidance on scheduling and education on sleep and fatigue should be considered at least as important as current biomathematical models. C_LIO_LIOnly by analysing and integrating high quality individual data on sleep, fatigue, performance, near misses, accidents, actual shift patterns with models can we develop better models and management systems to reduce fatigue and associated risks. Wearables combined with apps present a great opportunity to collect data at scale but need to be used appropriately. C_LIO_LIThe importance of making time for sleep is not always recognised. Education, early diagnosis of sleep disorders such as sleep apnea, and self-monitoring all have a role to play in reducing fatigue-related risk in the work-place. C_LI C_LIO_LISection 3 and Section 4 may be understood without reading the intermediate more mathematical sections. C_LI

neuroscience↗