HPVsim: An agent-based model of HPV transmission and cervical disease.

In 2020, the WHO launched its first global strategy to accelerate the elimination of cervical cancer, outlining an ambitious set of targets for countries to achieve over the next decade. At the same time, new tools, technologies, and strategies are in the pipeline that may improve screening performance, expand the reach of prophylactic vaccines, and prevent the acquisition, persistence and progression of oncogenic HPV. Detailed mechanistic modelling can help identify the combinations of current and future strategies to combat cervical cancer. Open-source modelling tools are needed to shift the capacity for such evaluations in-country. Here, we introduce the Human papillomavirus simulator (HPVsim), a new open-source software package for creating flexible agent-based models parameterised with country-specific vital dynamics, structured sexual networks, and co-transmitting HPV genotypes. HPVsim includes a novel methodology for modelling cervical disease progression, designed to be readily adaptable to new forms of screening. The software itself is implemented in Python, has built-in tools for simulating commonly-used interventions, includes a comprehensive set of tests and documentation, and runs quickly (seconds to minutes) on a laptop. Performance is greatly enhanced by HPVsim's multiscale modelling functionality. HPVsim is open source under the MIT License and available via both the Python Package Index (via pip install) and GitHub (hpvsim.org).

Admission screening testing of patients and staff N95 masks are cost-effective in reducing COVID-19 hospital acquired infections.

BACKGROUND: COVID-19 outbreaks in acute care settings can have severe consequences for patients due to their underlying vulnerabilities, and can be costly due to additional patient bed days and the need to replace isolating staff. This study assessed the cost-effectiveness of clinical staff N95 masks and admission screening testing of patients to reduce COVID-19 hospital-acquired infections. METHODS: An agent-based model was calibrated to data on 178 outbreaks in acute care settings in Victoria, Australia between October 2021 and July 2023. Outbreaks were simulated under different combinations of staff masking (surgical, N95) and patient admission screening testing (none, RAT, PCR). For each scenario, average diagnoses, COVID-19 deaths, quality-adjusted life years (QALYs) from discharged patients, and costs (masks, testing, patient COVID-19 bed days, staff replacement costs while isolating) from acute COVID-19 were estimated over a 12-month period. FINDINGS: Compared to no admission screening testing and staff surgical masks, all scenarios were cost saving with health gains. Staff N95s + RAT admission screening of patients was the cheapest, saving A$78.4M [95%UI 44.4M-135.3M] and preventing 1,543 [1,070-2,146] deaths state-wide per annum. Both interventions were individually beneficial: staff N95s in isolation saved A$54.7M and 854 deaths state-wide per annum, while RAT admission screening of patients in isolation saved A$57.6M and 1,176 deaths state-wide per annum. INTERPRETATION: In acute care settings, staff N95 mask use and admission screening testing of patients can reduce hospital-acquired COVID-19 infections, COVID-19 deaths, and are cost-saving because of reduced patient bed days and staff replacement needs.

Inferring the natural history of HPV from global cancer registries: insights from a multi-country calibration.

Human papillomavirus (HPV) is the cause of almost all cases of cervical cancer, a disease that kills some 340,000 women per year. The timeline from initial infection with HPV to the onset of invasive cervical cancer spans decades, and observational studies of this process are limited to settings in which treatment of precancerous lesions was withheld or inadequate. Such studies have been critical for understanding the natural history of HPV. Modeling can shed additional insight on the natural history of HPV, especially across geographical settings with varying prevalence of factors known to affect the host-side immune response to HPV, such as HIV and tobacco use. In this study, we create models for the 30 most populous countries in Sub-Saharan Africa, each with country-specific demographic, and behavioral inputs. We found that it was not possible to fit the data if we assumed that the natural history parameters were exactly identical for all countries, even after accounting for demographic and behavioral differences, but that we could achieve a good fit with the addition of a single immunocompetence parameter for each country. Our results indicate that variation in host immune responses may play a role in explaining the differences in the burden of cervical cancer between countries, which in turn implies a greater need for more geographically diverse data collection to understand the natural history of HPV.

COVID-19 outbreaks in residential aged care facilities: an agent-based modeling study.

Introduction: A disproportionate number of COVID-19 deaths occur in Residential Aged Care Facilities (RACFs), where better evidence is needed to target COVID-19 interventions to prevent mortality. This study used an agent-based model to assess the role of community prevalence, vaccination strategies, and non-pharmaceutical interventions (NPIs) on COVID-19 outcomes in RACFs in Victoria, Australia. Methods: The model simulated outbreaks in RACFs over time, and was calibrated to distributions for outbreak size, outbreak duration, and case fatality rate in Victorian RACFs over 2022. The number of incursions to RACFs per day were estimated to fit total deaths and diagnoses over time and community prevalence.Total infections, diagnoses, and deaths in RACFs were estimated over July 2023-June 2024 under scenarios of different: community epidemic wave assumptions (magnitude and frequency); RACF vaccination strategies (6-monthly, 12-monthly, no further vaccines); additional non-pharmaceutical interventions (10, 25, 50% efficacy); and reduction in incursions (30% or 60%). Results: Total RACF outcomes were proportional to cumulative community infections and incursion rates, suggesting potential for strategic visitation/staff policies or community-based interventions to reduce deaths. Recency of vaccination when epidemic waves occurred was critical; compared with 6-monthly boosters, 12-monthly boosters had approximately 1.2 times more deaths and no further boosters had approximately 1.6 times more deaths over July 2023-June 2024. Additional NPIs, even with only 10-25% efficacy, could lead to a 13-31% reduction in deaths in RACFs. Conclusion: Future community epidemic wave patterns are unknown but will be major drivers of outcomes in RACFs. Maintaining high coverage of recent vaccination, minimizing incursions, and increasing NPIs can have a major impact on cumulative infections and deaths.

Keeping kids in school: modelling school-based testing and quarantine strategies during the COVID-19 pandemic in Australia.

Background: In 2021, the Australian Government Department of Health commissioned a consortium of modelling groups to generate evidence assisting the transition from a goal of no community COVID-19 transmission to 'living with COVID-19', with adverse health and social consequences limited by vaccination and other measures. Due to the extended school closures over 2020-21, maximizing face-to-face teaching was a major objective during this transition. The consortium was tasked with informing school surveillance and contact management strategies to minimize infections and support this goal. Methods: Outcomes considered were infections and days of face-to-face teaching lost in the 45 days following an outbreak within an otherwise COVID-naïve school setting. A stochastic agent-based model of COVID-19 transmission was used to evaluate a 'test-to-stay' strategy using daily rapid antigen tests (RATs) for close contacts of a case for 7 days compared with home quarantine; and an asymptomatic surveillance strategy involving twice-weekly screening of all students and/or teachers using RATs. Findings: Test-to-stay had similar effectiveness for reducing school infections as extended home quarantine, without the associated days of face-to-face teaching lost. Asymptomatic screening was beneficial in reducing both infections and days of face-to-face teaching lost and was most beneficial when community prevalence was high. Interpretation: Use of RATs in school settings for surveillance and contact management can help to maximize face-to-face teaching and minimize outbreaks. This evidence supported the implementation of surveillance testing in schools in several Australian jurisdictions from January 2022.

COVID-19 epidemic modelling for policy decision support in Victoria, Australia 2020-2021.

BACKGROUND: Policy responses to COVID-19 in Victoria, Australia over 2020-2021 have been supported by evidence generated through mathematical modelling. This study describes the design, key findings, and process for policy translation of a series of modelling studies conducted for the Victorian Department of Health COVID-19 response team during this period. METHODS: An agent-based model, Covasim, was used to simulate the impact of policy interventions on COVID-19 outbreaks and epidemic waves. The model was continually adapted to enable scenario analysis of settings or policies being considered at the time (e.g. elimination of community transmission versus disease control). Model scenarios were co-designed with government, to fill evidence gaps prior to key decisions. RESULTS: Understanding outbreak risk following incursions was critical to eliminating community COVID-19 transmission. Analyses showed risk depended on whether the first detected case was the index case, a primary contact of the index case, or a 'mystery case'. There were benefits of early lockdown on first case detection and gradual easing of restrictions to minimise resurgence risk from undetected cases. As vaccination coverage increased and the focus shifted to controlling rather than eliminating community transmission, understanding health system demand was critical. Analyses showed that vaccines alone could not protect health systems and need to be complemented with other public health measures. CONCLUSIONS: Model evidence offered the greatest value when decisions needed to be made pre-emptively, or for questions that could not be answered with empiric data and data analysis alone. Co-designing scenarios with policy-makers ensured relevance and increased policy translation.

Preservation of thalamocortical circuitry is essential for good recovery after cardiac arrest.

Continuous electroencephalographam (EEG) monitoring contributes to prediction of neurological outcome in comatose cardiac arrest survivors. While the phenomenology of EEG abnormalities in postanoxic encephalopathy is well known, the pathophysiology, especially the presumed role of selective synaptic failure, is less understood. To further this understanding, we estimate biophysical model parameters from the EEG power spectra from individual patients with a good or poor recovery from a postanoxic encephalopathy. This biophysical model includes intracortical, intrathalamic, and corticothalamic synaptic strengths, as well as synaptic time constants and axonal conduction delays. We used continuous EEG measurements from hundred comatose patients recorded during the first 48 h postcardiac arrest, 50 with a poor neurological outcome [cerebral performance category ( CPC = 5 ) ] and 50 with a good neurological outcome ( CPC = 1 ). We only included patients that developed (dis-)continuous EEG activity within 48 h postcardiac arrest. For patients with a good outcome, we observed an initial relative excitation in the corticothalamic loop and corticothalamic propagation that subsequently evolved towards values observed in healthy controls. For patients with a poor outcome, we observed an initial increase in the cortical excitation-inhibition ratio, increased relative inhibition in the corticothalamic loop, delayed corticothalamic propagation of neuronal activity, and severely prolonged synaptic time constants that did not return to physiological values. We conclude that the abnormal EEG evolution in patients with a poor neurological recovery after cardiac arrest may result from persistent and selective synaptic failure that includes corticothalamic circuitry and also delayed corticothalamic propagation.

The changing health impact of vaccines in the COVID-19 pandemic: A modeling study.

Much of the world's population had already been infected with COVID-19 by the time the Omicron variant emerged at the end of 2021, but the scale of the Omicron wave was larger than any that had come before or has happened since, and it left a global imprinting of immunity that changed the COVID-19 landscape. In this study, we simulate a South African population and demonstrate how population-level vaccine effectiveness and efficiency changed over the course of the first 2 years of the pandemic. We then introduce three hypothetical variants and evaluate the impact of vaccines with different properties. We find that variant-chasing vaccines have a narrow window of dominating pre-existing vaccines but that a variant-chasing vaccine strategy may have global utility, depending on the rate of spread from setting to setting. Next-generation vaccines might be able to overcome uncertainty in pace and degree of viral evolution.

Modelling herd immunity requirements in Queensland: impact of vaccination effectiveness, hesitancy and variants of SARS-CoV-2.

Long-term control of SARS-CoV-2 outbreaks depends on the widespread coverage of effective vaccines. In Australia, two-dose vaccination coverage of above 90% of the adult population was achieved. However, between August 2020 and August 2021, hesitancy fluctuated dramatically. This raised the question of whether settings with low naturally derived immunity, such as Queensland where less than [Formula: see text] of the population is known to have been infected in 2020, could have achieved herd immunity against 2021's variants of concern. To address this question, we used the agent-based model Covasim. We simulated outbreak scenarios (with the Alpha, Delta and Omicron variants) and assumed ongoing interventions (testing, tracing, isolation and quarantine). We modelled vaccination using two approaches with different levels of realism. Hesitancy was modelled using Australian survey data. We found that with a vaccine effectiveness against infection of 80%, it was possible to control outbreaks of Alpha, but not Delta or Omicron. With 90% effectiveness, Delta outbreaks may have been preventable, but not Omicron outbreaks. We also estimated that a decrease in hesitancy from 20% to 14% reduced the number of infections, hospitalizations and deaths by over 30%. Overall, we demonstrate that while herd immunity may not be attainable, modest reductions in hesitancy and increases in vaccine uptake may greatly improve health outcomes. This article is part of the theme issue 'Technical challenges of modelling real-life epidemics and examples of overcoming these'.

Risk of sustained SARS-CoV-2 transmission in Queensland, Australia.

We used an agent-based model Covasim to assess the risk of sustained community transmission of SARSCoV-2/COVID-19 in Queensland (Australia) in the presence of high-transmission variants of the virus. The model was calibrated using the demographics, policies, and interventions implemented in the state. Then, using the calibrated model, we simulated possible epidemic trajectories that could eventuate due to leakage of infected cases with high-transmission variants, during a period without recorded cases of locally acquired infections, known in Australian settings as "zero community transmission". We also examined how the threat of new variants reduces given a range of vaccination levels. Specifically, the model calibration covered the first-wave period from early March 2020 to May 2020. Predicted epidemic trajectories were simulated from early February 2021 to late March 2021. Our simulations showed that one infected agent with the ancestral (A.2.2) variant has a 14% chance of crossing a threshold of sustained community transmission (SCT) (i.e., > 5 infections per day, more than 3 days in a row), assuming no change in the prevailing preventative and counteracting policies. However, one agent carrying the alpha (B.1.1.7) variant has a 43% chance of crossing the same threshold; a threefold increase with respect to the ancestral strain; while, one agent carrying the delta (B.1.617.2) variant has a 60% chance of the same threshold, a fourfold increase with respect to the ancestral strain. The delta variant is 50% more likely to trigger SCT than the alpha variant. Doubling the average number of daily tests from ∼ 6,000 to 12,000 results in a decrease of this SCT probability from 43 to 33% for the alpha variant. However, if the delta variant is circulating we would need an average of 100,000 daily tests to achieve a similar decrease in SCT risk. Further, achieving a full-vaccination coverage of 70% of the adult population, with a vaccine with 70% effectiveness against infection, would decrease the probability of SCT from a single seed of alpha from 43 to 20%, on par with the ancestral strain in a naive population. In contrast, for the same vaccine coverage and same effectiveness, the probability of SCT from a single seed of delta would decrease from 62 to 48%, a risk slightly above the alpha variant in a naive population. Our results demonstrate that the introduction of even a small number of people infected with high-transmission variants dramatically increases the probability of sustained community transmission in Queensland. Until very high vaccine coverage is achieved, a swift implementation of policies and interventions, together with high quarantine adherence rates, will be required to minimise the probability of sustained community transmission.

Preventing a cluster from becoming a new wave in settings with zero community COVID-19 cases.

BACKGROUND: In settings with zero community transmission, any new SARS-CoV-2 outbreaks are likely to be the result of random incursions. The level of restrictions in place at the time of the incursion is likely to considerably affect possible outbreak trajectories, but the probability that a large outbreak eventuates is not known. METHODS: We used an agent-based model to investigate the relationship between ongoing restrictions and behavioural factors, and the probability of an incursion causing an outbreak and the resulting growth rate. We applied our model to the state of Victoria, Australia, which has reached zero community transmission as of November 2020. RESULTS: We found that a future incursion has a 45% probability of causing an outbreak (defined as a 7-day average of > 5 new cases per day within 60 days) if no restrictions were in place, decreasing to 23% with a mandatory masks policy, density restrictions on venues such as restaurants, and if employees worked from home where possible. A drop in community symptomatic testing rates was associated with up to a 10-percentage point increase in outbreak probability, highlighting the importance of maintaining high testing rates as part of a suppression strategy. CONCLUSIONS: Because the chance of an incursion occurring is closely related to border controls, outbreak risk management strategies require an integrated approaching spanning border controls, ongoing restrictions, and plans for response. Each individual restriction or control strategy reduces the risk of an outbreak. They can be traded off against each other, but if too many are removed there is a danger of accumulating an unsafe level of risk. The outbreak probabilities estimated in this study are of particular relevance in assessing the downstream risks associated with increased international travel.

Covasim: An agent-based model of COVID-19 dynamics and interventions.

The COVID-19 pandemic has created an urgent need for models that can project epidemic trends, explore intervention scenarios, and estimate resource needs. Here we describe the methodology of Covasim (COVID-19 Agent-based Simulator), an open-source model developed to help address these questions. Covasim includes country-specific demographic information on age structure and population size; realistic transmission networks in different social layers, including households, schools, workplaces, long-term care facilities, and communities; age-specific disease outcomes; and intrahost viral dynamics, including viral-load-based transmissibility. Covasim also supports an extensive set of interventions, including non-pharmaceutical interventions, such as physical distancing and protective equipment; pharmaceutical interventions, including vaccination; and testing interventions, such as symptomatic and asymptomatic testing, isolation, contact tracing, and quarantine. These interventions can incorporate the effects of delays, loss-to-follow-up, micro-targeting, and other factors. Implemented in pure Python, Covasim has been designed with equal emphasis on performance, ease of use, and flexibility: realistic and highly customized scenarios can be run on a standard laptop in under a minute. In collaboration with local health agencies and policymakers, Covasim has already been applied to examine epidemic dynamics and inform policy decisions in more than a dozen countries in Africa, Asia-Pacific, Europe, and North America.

Controlling COVID-19 via test-trace-quarantine.

Initial COVID-19 containment in the United States focused on limiting mobility, including school and workplace closures. However, these interventions have had enormous societal and economic costs. Here, we demonstrate the feasibility of an alternative control strategy, test-trace-quarantine: routine testing of primarily symptomatic individuals, tracing and testing their known contacts, and placing their contacts in quarantine. We perform this analysis using Covasim, an open-source agent-based model, which has been calibrated to detailed demographic, mobility, and epidemiological data for the Seattle region from January through June 2020. With current levels of mask use and schools remaining closed, we find that high but achievable levels of testing and tracing are sufficient to maintain epidemic control even under a return to full workplace and community mobility and with low vaccine coverage. The easing of mobility restrictions in June 2020 and subsequent scale-up of testing and tracing programs through September provided real-world validation of our predictions. Although we show that test-trace-quarantine can control the epidemic in both theory and practice, its success is contingent on high testing and tracing rates, high quarantine compliance, relatively short testing and tracing delays, and moderate to high mask use. Thus, in order for test-trace-quarantine to control transmission with a return to high mobility, strong performance in all aspects of the program is required.

Role of masks, testing and contact tracing in preventing COVID-19 resurgences: a case study from New South Wales, Australia.

OBJECTIVES: The early stages of the COVID-19 pandemic illustrated that SARS-CoV-2, the virus that causes the disease, has the potential to spread exponentially. Therefore, as long as a substantial proportion of the population remains susceptible to infection, the potential for new epidemic waves persists even in settings with low numbers of active COVID-19 infections, unless sufficient countermeasures are in place. We aim to quantify vulnerability to resurgences in COVID-19 transmission under variations in the levels of testing, tracing and mask usage. SETTING: The Australian state of New South Wales (NSW), a setting with prolonged low transmission, high mobility, non-universal mask usage and a well-functioning test-and-trace system. PARTICIPANTS: None (simulation study). RESULTS: We find that the relative impact of masks is greatest when testing and tracing rates are lower and vice versa. Scenarios with very high testing rates (90% of people with symptoms, plus 90% of people with a known history of contact with a confirmed case) were estimated to lead to a robustly controlled epidemic. However, across comparable levels of mask uptake and contact tracing, the number of infections over this period was projected to be 2-3 times higher if the testing rate was 80% instead of 90%, 8-12 times higher if the testing rate was 65% or 30-50 times higher with a 50% testing rate. In reality, NSW diagnosed 254 locally acquired cases over this period, an outcome that had a moderate probability in the model (10%-18%) assuming low mask uptake (0%-25%), even in the presence of extremely high testing (90%) and near-perfect community contact tracing (75%-100%), and a considerably higher probability if testing or tracing were at lower levels. CONCLUSIONS: Our work suggests that testing, tracing and masks can all be effective means of controlling transmission. A multifaceted strategy that combines all three, alongside continued hygiene and distancing protocols, is likely to be the most robust means of controlling transmission of SARS-CoV-2.

Estimating and mitigating the risk of COVID-19 epidemic rebound associated with reopening of international borders in Vietnam: a modelling study.

BACKGROUND: Vietnam has emerged as one of the world's leading success stories in responding to COVID-19. After a prolonged period of little to no transmission, there was an outbreak of unknown source in July, 2020, in the Da Nang region, but the outbreak was quickly suppressed. We aimed to use epidemiological, behavioural, demographic, and policy data from the COVID-19 outbreak in Da Nang to calibrate an agent-based model of COVID-19 transmission for Vietnam, and to estimate the risk of future outbreaks associated with reopening of international borders in the country. METHODS: For this modelling study, we used comprehensive data from June 15 to Oct 15, 2020, on testing, COVID-19 cases, and quarantine breaches within an agent-based model of SARS-CoV-2 transmission to model a COVID-19 outbreak in Da Nang in July, 2020. We applied this model to quantify the risk of future outbreaks in Vietnam in the 3 months after the reopening of international borders, under different behavioural scenarios, policy responses (ie, closure of workplaces and schools), and ongoing testing. FINDINGS: We estimated that the outbreak in Da Nang between July and August, 2020, resulted in substantial community transmission, and that higher levels of symptomatic testing could have mitigated this transmission. We estimated that the outbreak peaked on Aug 2, 2020, with an estimated 1060 active infections (95% projection interval 890-1280). If the population of Vietnam remains highly compliant with mask-wearing policies, our projections indicate that the epidemic would remain under control even if a small but steady flow of imported infections escaped quarantine into the community. However, if complacency increases and testing rates are relatively low (10% of symptomatic individuals are tested), the epidemic could rebound again, resulting in an estimated 2100 infections (95% projected interval 1050-3610) in 3 months. These outcomes could be mitigated if the behaviour of the general population responds dynamically to increases in locally acquired cases that exceed specific thresholds, but only if testing of symptomatic individuals is also increased. INTERPRETATION: The successful response to COVID-19 in Vietnam could be improved even further with higher levels of symptomatic testing. If the previous approaches are used in response to new COVID-19 outbreaks, epidemic control is possible even in the presence of low levels of imported cases. FUNDING: Ministry of Science and Technology (Vietnam). TRANSLATION: For the Vietnamese translation of the abstract see Supplementary Materials section.

Metastable brain waves.

Traveling patterns of neuronal activity-brain waves-have been observed across a breadth of neuronal recordings, states of awareness, and species, but their emergence in the human brain lacks a firm understanding. Here we analyze the complex nonlinear dynamics that emerge from modeling large-scale spontaneous neural activity on a whole-brain network derived from human tractography. We find a rich array of three-dimensional wave patterns, including traveling waves, spiral waves, sources, and sinks. These patterns are metastable, such that multiple spatiotemporal wave patterns are visited in sequence. Transitions between states correspond to reconfigurations of underlying phase flows, characterized by nonlinear instabilities. These metastable dynamics accord with empirical data from multiple imaging modalities, including electrical waves in cortical tissue, sequential spatiotemporal patterns in resting-state MEG data, and large-scale waves in human electrocorticography. By moving the study of functional networks from a spatially static to an inherently dynamic (wave-like) frame, our work unifies apparently diverse phenomena across functional neuroimaging modalities and makes specific predictions for further experimentation.

NFTsim: Theory and Simulation of Multiscale Neural Field Dynamics.

A user ready, portable, documented software package, NFTsim, is presented to facilitate numerical simulations of a wide range of brain systems using continuum neural field modeling. NFTsim enables users to simulate key aspects of brain activity at multiple scales. At the microscopic scale, it incorporates characteristics of local interactions between cells, neurotransmitter effects, synaptodendritic delays and feedbacks. At the mesoscopic scale, it incorporates information about medium to large scale axonal ranges of fibers, which are essential to model dissipative wave transmission and to produce synchronous oscillations and associated cross-correlation patterns as observed in local field potential recordings of active tissue. At the scale of the whole brain, NFTsim allows for the inclusion of long range pathways, such as thalamocortical projections, when generating macroscopic activity fields. The multiscale nature of the neural activity produced by NFTsim has the potential to enable the modeling of resulting quantities measurable via various neuroimaging techniques. In this work, we give a comprehensive description of the design and implementation of the software. Due to its modularity and flexibility, NFTsim enables the systematic study of an unlimited number of neural systems with multiple neural populations under a unified framework and allows for direct comparison with analytic and experimental predictions. The code is written in C++ and bundled with Matlab routines for a rapid quantitative analysis and visualization of the outputs. The output of NFTsim is stored in plain text file enabling users to select from a broad range of tools for offline analysis. This software enables a wide and convenient use of powerful physiologically-based neural field approaches to brain modeling. NFTsim is distributed under the Apache 2.0 license.

A unified model of melatonin, 6-sulfatoxymelatonin, and sleep dynamics.

A biophysical model of the key aspects of melatonin synthesis and excretion has been developed, which is able to predict experimental dynamics of melatonin in plasma and saliva, and of its urinary metabolite 6-sulfatoxymelatonin (aMT6s). This new model is coupled to an established model of arousal dynamics, which predicts sleep and circadian dynamics based on light exposure and times of wakefulness. The combined model thus predicts melatonin levels over the sleep-wake/dark-light cycle and enables prediction of melatonin-based circadian phase markers, such as dim light melatonin onset (DLMO) and aMT6s acrophase under conditions of normal sleep and circadian misalignment. The model is calibrated and tested against group average data from 10 published experimental studies and is found to reproduce quantitatively the key dynamics of melatonin and aMT6s, including the timing of release and amplitude, as well as response to controlled lighting and shift work.

A biophysical model of dynamic balancing of excitation and inhibition in fast oscillatory large-scale networks.

Over long timescales, neuronal dynamics can be robust to quite large perturbations, such as changes in white matter connectivity and grey matter structure through processes including learning, aging, development and certain disease processes. One possible explanation is that robust dynamics are facilitated by homeostatic mechanisms that can dynamically rebalance brain networks. In this study, we simulate a cortical brain network using the Wilson-Cowan neural mass model with conduction delays and noise, and use inhibitory synaptic plasticity (ISP) to dynamically achieve a spatially local balance between excitation and inhibition. Using MEG data from 55 subjects we find that ISP enables us to simultaneously achieve high correlation with multiple measures of functional connectivity, including amplitude envelope correlation and phase locking. Further, we find that ISP successfully achieves local E/I balance, and can consistently predict the functional connectivity computed from real MEG data, for a much wider range of model parameters than is possible with a model without ISP.

Exploring sleepiness and entrainment on permanent shift schedules in a physiologically based model.

The effects of permanent shift work on entrainment and sleepiness are examined using a mathematical model that combines a model of sleep-wake switch in the brain with a model of the human circadian pacemaker entrained by light and nonphotic inputs. The model is applied to 8-hour permanent shift schedules to understand the basic mechanisms underlying changes of entrainment and sleepiness. Average sleepiness is shown to increase during the first days on the night and evening schedules, that is, shift start times between 0000 to 0700 h and 1500 to 2200 h, respectively. After the initial increase, sleepiness decreases and stabilizes via circadian re-entrainment to the cues provided by the shifts. The increase in sleepiness until entrainment is achieved is strongly correlated with the phase difference between a circadian oscillator entrained to the ambient light and one entrained to the shift schedule. The higher this phase difference, the larger the initial increase in sleepiness. When entrainment is achieved, sleepiness stabilizes and is the same for different shift onsets within the night or evening schedules. The simulations reveal the presence of a critical shift onset around 2300 h that separates schedules, leading to phase advance (night shifts) and phase delay (evening shifts) of the circadian pacemaker. Shifts starting around this time take longest to entrain and are expected to be the worst for long-term sleepiness and well-being of the workers. Surprisingly, we have found that the circadian pacemaker entrains faster to night schedules than to evening ones. This is explained by the longer photoperiod on night schedules compared to evening. In practice, this phenomenon is difficult to see due to days off on which workers switch to free sleep-wake activity. With weekends, the model predicts that entrainment is never achieved on evening and night schedules unless the workers follow the same sleep routine during weekends as during work days. Overall, the model supports experimental observations, providing new insights into the mechanisms and allowing the examination of conditions that are not accessible experimentally.