A point process framework for modeling electrical stimulation of the auditory nerve

Model-based studies of auditory nerve responses to electrical stimulation can provide insight into the functioning of cochlear implants. Ideally, these studies can identify limitations in sound processing strategies and lead to improved methods for providing sound information to cochlear implant users. To accomplish this, models must accurately describe auditory nerve spiking while avoiding excessive complexity that would preclude large-scale simulations of populations of auditory nerve fibers and obscure insight into the mechanisms that influence neural encoding of sound information. In this spirit, we develop a point process model of the auditory nerve that provides a compact and accurate description of neural responses to electric stimulation. Inspired by the framework of generalized linear models, the proposed model consists of a cascade of linear and nonlinear stages. We show how each of these stages can be associated with biophysical mechanisms and related to models of neuronal dynamics. Moreover, we derive a semi-analytical procedure that uniquely determines each parameter in the model on the basis of fundamental statistics from recordings of single fiber responses to electric stimulation, including threshold, relative spread, jitter, and chronaxie. The model also accounts for refractory and summation effects that influence the responses of auditory nerve fibers to high pulse rate stimulation. Throughout, we compare model predictions to published physiological data and explain differences in auditory nerve responses to high and low pulse rate stimulation. We close by performing an ideal observer analysis of simulated spike trains in response to sinusoidally amplitude modulated stimuli and find that carrier pulse rate does not affect modulation detection thresholds.Comment: 1 title page, 27 manuscript pages, 14 figures, 1 table, 1 appendi

The role of input noise in transcriptional regulation

Even under constant external conditions, the expression levels of genes fluctuate. Much emphasis has been placed on the components of this noise that are due to randomness in transcription and translation; here we analyze the role of noise associated with the inputs to transcriptional regulation, the random arrival and binding of transcription factors to their target sites along the genome. This noise sets a fundamental physical limit to the reliability of genetic control, and has clear signatures, but we show that these are easily obscured by experimental limitations and even by conventional methods for plotting the variance vs. mean expression level. We argue that simple, global models of noise dominated by transcription and translation are inconsistent with the embedding of gene expression in a network of regulatory interactions. Analysis of recent experiments on transcriptional control in the early Drosophila embryo shows that these results are quantitatively consistent with the predicted signatures of input noise, and we discuss the experiments needed to test the importance of input noise more generally.Comment: 11 pages, 5 figures minor correction

Health-related quality of life among persons with initial mild, moderate, and severe or critical COVID-19 at 1 and 12 months after infection: a prospective cohort study

BACKGROUND: Currently, there is limited evidence about the long-term impact on physical, social and emotional functioning, i.e. health-related quality of life (HRQL) after mild or moderate COVID-19 not requiring hospitalization. We compared HRQL among persons with initial mild, moderate or severe/critical COVID-19 at 1 and 12 months following illness onset with Dutch population norms and investigated the impact of restrictive public health control measures on HRQL. METHODS: RECoVERED, a prospective cohort study in Amsterdam, the Netherlands, enrolled adult participants after confirmed SARS-CoV-2 diagnosis. HRQL was assessed with the Medical Outcomes Study Short Form 36-item health survey (SF-36). SF-36 scores were converted to standard scores based on an age- and sex-matched representative reference sample of the Dutch population. Differences in HRQL over time were compared among persons with initial mild, moderate or severe/critical COVID-19 using mixed linear models adjusted for potential confounders. RESULTS: By December 2021, 349 persons were enrolled of whom 269 completed at least one SF-36 form (77%). One month after illness onset, HRQL was significantly below population norms on all SF-36 domains except general health and bodily pain among persons with mild COVID-19. After 12 months, persons with mild COVID-19 had HRQL within population norms, whereas persons with moderate or severe/critical COVID-19 had HRQL below population norms on more than half of the SF-36 domains. Dutch-origin participants had significantly better HRQL than participants with a migration background. Participants with three or more COVID-19 high-risk comorbidities had worse HRQL than part participants with fewer comorbidities. Participants who completed the SF-36 when restrictive public health control measures applied reported less limitations in social and physical functioning and less impaired mental health than participants who completed the SF-36 when no restrictive measures applied. CONCLUSIONS: Twelve months after illness onset, persons with initial mild COVID-19 had HRQL within population norms, whereas persons with initial moderate or severe/critical COVID-19 still had impaired HRQL. Having a migration background and a higher number of COVID-19 high-risk comorbidities were associated with worse HRQL. Interestingly, HRQL was less impaired during periods when restrictive public health control measures were in place compared to periods without. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12916-022-02615-7

The Necessity of Self-Employment Towards Retirement: Evidence from Labor Market Dynamics and Search Requirements for Unemployment Benefits

Hervorming Sociale Regelgevin

A Threshold Equation for Action Potential Initiation

In central neurons, the threshold for spike initiation can depend on the stimulus and varies between cells and between recording sites in a given cell, but it is unclear what mechanisms underlie this variability. Properties of ionic channels are likely to play a role in threshold modulation. We examined in models the influence of Na channel activation, inactivation, slow voltage-gated channels and synaptic conductances on spike threshold. We propose a threshold equation which quantifies the contribution of all these mechanisms. It provides an instantaneous time-varying value of the threshold, which applies to neurons with fluctuating inputs. We deduce a differential equation for the threshold, similar to the equations of gating variables in the Hodgkin-Huxley formalism, which describes how the spike threshold varies with the membrane potential, depending on channel properties. We find that spike threshold depends logarithmically on Na channel density, and that Na channel inactivation and K channels can dynamically modulate it in an adaptive way: the threshold increases with membrane potential and after every action potential. Our equation was validated with simulations of a previously published multicompartemental model of spike initiation. Finally, we observed that threshold variability in models depends crucially on the shape of the Na activation function near spike initiation (about −55 mV), while its parameters are adjusted near half-activation voltage (about −30 mV), which might explain why many models exhibit little threshold variability, contrary to experimental observations. We conclude that ionic channels can account for large variations in spike threshold

Neurobiological basis and risk factors of persistent fatigue and concentration problems after COVID-19: study protocol for a prospective case-control study (VeCosCO)

INTRODUCTION: The risk factors for persistent fatigue and cognitive complaints after infection with SARS-CoV-2 and the underlying pathophysiology are largely unknown. Both clinical factors and cognitive-behavioural factors have been suggested to play a role in the perpetuation of complaints. A neurobiological aetiology, such as neuroinflammation, could be the underlying pathophysiological mechanism for persisting complaints.To unravel factors associated with persisting complaints, VeCosCO will compare individuals with and without persistent fatigue and cognitive complaints >3 months after infection with SARS-CoV-2. The study consists of two work packages. The first work package aims to (1) investigate the relation between persisting complaints and neuropsychological functioning; (2) determine risk factors and at-risk phenotypes for the development of persistent fatigue and cognitive complaints, including the presence of postexertional malaise and (3) describe consequences of persistent complaints on quality of life, healthcare consumption and physical functioning. The second work package aims to (1) determine the presence of neuroinflammation with [ 18F]DPA-714 whole-body positron emission tomography (PET) scans in patients with persisting complaints and (2) explore the relationship between (neuro)inflammation and brain structure and functioning measured with MRI. METHODS AND ANALYSIS: This is a prospective case-control study in participants with and without persistent fatigue and cognitive complaints, >3 months after laboratory-confirmed SARS-CoV-2 infection. Participants will be mainly included from existing COVID-19 cohorts in the Netherlands covering the full spectrum of COVID-19 acute disease severity. Primary outcomes are neuropsychological functioning, postexertional malaise, neuroinflammation measured using [ 18F]DPA-714 PET, and brain functioning and structure using (f)MRI. ETHICS AND DISSEMINATION: Work package 1 (NL79575.018.21) and 2 (NL77033.029.21) were approved by the medical ethical review board of the Amsterdam University Medical Centers (The Netherlands). Informed consent is required prior to participation in the study. Results of this study will be submitted for publication in peer-reviewed journals and shared with the key population